PRODRUGS OF PHOSPHOROUS-CONTAINING PHARMACEUTICALS

Abstract: Pharmaceutical compounds with the formula: Drug-P(=O)-O-Linker(-R2')k-R2 where Drug-P(=O)-O- is the residue of a drug comprising a phosphonate, phosphinate or phosphoryl function, such as alendronate or foscarnet, R2 and R2' (if present) are independently the acyl residue of an aliphatic amino acid; Linker is an at least difunctional moiety comprising a first function ester-bonded to the phosphonate, phosphinate or phosphoryl function spaced from a second function ester-bonded to R2; and k is 1 or zero; have enhanced bioavailability or other pharmacokinetic performance relative to the parent drug.

Description: PRODRUGS OF PHOSPHOROUS-CONTAINING PHARMACEUTICALS Technical Field This invention relates to the field of phosphorous-containing pharmaceuticals, including phosphonates, phosphinates and phosphates and in particular to prodrugs of such pharmaceuticals. The invention provides novel pharmaceutical compounds and compositions, methods for their preparation and pharmaceutical methods employing them. Background Art Many phosphorous-containing pharmaceuticals have not reached their full clinical potential due to difficulties in administering them, particularly via the oral route. Bis- phosphonate bone resorption agents such as alendronate, for example, have oral bioavailabilities of just a few percent and adsorption is diminished by food fruit juice coffee, dairy products etc. This poor bioavailability is exacerbated by the caustic nature of the drug which leads to irritation of the gastric walls, resulting in an administration regime calling for a fasted stomach and the patient standing for half an hour after ingestion to ensure transport of the drug past the gastric region. A significant amount of work has been done to attempt to solve the administration difficulties by optimising the formulation of phosphorous-containing drugs. Merck for example describe various formulations of the bis-phosphonate alendronate, such as a pH buffered formulation in WO98 14196, an effervescent formulation in WO97 44017, the monohydrate and disodium in WO96 39410, the anhydrate in WO96 39149, a liquid formulation with complexing agent in WO95 33755 and calcium salts in EP 449 405. To our knowledge, however, none of these conventional formulation approaches has produced a clinically succesful administration form. Merck and others have also explored prodrugs of bis-phosphonate bone resorption agents in an attempt to improve the clinical utility of these drugs. For example, Leiras OY's US 5,376,649 describes esters of halogenated bis-phosphonates of the clodronate type, wherein the prodrug moiety comprises an alkyl, alkenyl, alkynyl, aryl, aralkyl and silyl. No improvements in bioavailability are reported. Leo's US 2 4,732,998, US 4,870,063 and WO86 00902 describe prodrugs of certain non- hydroxylated bis-phosphonates. In particular the pivaloyloxymethyl and acetoxymethyl tetraesters are prepared (although no improvements in bioavailability are reported) and certain other esters postulated, such as the C 3 -C 6 alkanoyloxymethyl, C 4 -C 7 l-(alkanoyloxy)ethyl, C 5 -C 3 1 -methyl- 1- (alkanoyloxy)ethyl, C 4 -C 7 1 -(alkoxycarbonyloxy)ethyl, C 3 -C 6 alkoxycarbonyloxymethyl, C 4 -C 7 l-alkoxycarbonyloxy)ethyl, C 5 -C 8 1 -methyl- 1- (alkoxycarbonyloxy)ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, (2- oxo-l,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl, (5-phenyl- 2-oxo-l,3-dioxolen-4-yl)methyl, dialkylaminoalkyl, acetonyl and methoxymethyl. Merck's US 5,227,506 describes acyloxymethyl esters of a number of bis- phosphonates, notable alendronate, wherein the acyl component is C,-C 12 alkanoyl. As with the Leo patents above the preferred prodrug is pivaloylxoymethyl, although no bioavailability data is provided. Other phosphorous-containing drugs where attempts to improve bioavailability shortcomings have employed prodrugs include the antiviral agent foscarnet (phosphonoformate). Astra's WO98 16537 and WO9825938 describe monosaccharide and cyclic esters of foscarnet. Boehringer's WO9722368, Hostetler's US 5,696,277 and WO94/13682, UC's WO96 15132 (inter alia) describe lipid or glycerol esters of foscarnet. Iyer et al, Tett. Letters 30 No 51, 7141-7144 (1989) describe acyloxyalkyl esters, wherein the acyl component is C r C 4 alkanoyl. Glazier's WO91/19721 describes acyloxybenzyloxy esters. Walker et al, Int J Pharmaceutics 104 (1994)157-167 describes foscamet-tyrosine conjugates wherein the hydroxy group on the amino acid side chain is esterified to the phosphonate. These compounds are not however orally administered prodrugs, but rather are designed to penetrate the blood brain barrier following iv administration. A still further group of pharmaceuticals where prodrugs have been proposed to attempt to overcome bioavailability shortcomings are the phosphonate nucleoside analogues, such as those disclosed in Gilead's WO98 04569 and an extensive series of patents in the name Rega Stichting/Institute of Organic Chemistry & Biochemistry 3 of the Academy of Sciences of the Czech Republic including EP 481214. However, to our knowledge, the only such phosphonates to show clinical practicality are the now marketed bis-POM and bis-POC adefovir (bis-pivoxil and bis- isopropyloxycarbonyloxymethyl esters, respectively). WO 95/01363 also shows a form of phosphonate nucleoside analogue. Monophosphate esters of monophosphorylated nucleoside analogues are desclosed in EP 763049 (glyceryl diethers), WO 95 32984 (lipid esters), US 5484911 (ether lipids)WO 98 51692 (substituted benzyl esters) WO 96 33201 (alkylthioacyl esters) Glazier's WO 91/19721 (above) and US 5 627 165 and Texas Uni's WO 90/08155 purport to provide prodrugs of diverse phosphorous-containing pharmaceuticals. Bodor's WO 92/00988 employs a phosphonate prodrug of non-phosphorous pharmaceuticals to target compounds to the brain. Brief Description of the Invention A first aspect of the invention provides pharmaceutical compound with the formula: Drug-P(=O)-O-Linker (-R 2 ') k -R 2 where Drug-P(=O)-O- is the residue of a drug comprising a phosphonate, phosphinate or phosphoryl function, R 2 and R 2 ' (if present) are independently the acyl residue of an aliphatic amino acid; Linker is an at least difunctional moiety comprising a first function ester-bonded to the phosphonate, phosphinate or phosphoryl function spaced from a second function ester-bonded to R 2 ; and k is 1 or zero. The enzymatic and/or chemical cleavage of the compounds of the present invention occurs in such a manner that the parent drug is released and the moiety or moieties split off remain non-toxic or are metabolized so that non-toxic or acceptable amounts of metabolic products are produced.The present compounds thus modify the in vivo availability of the parent compound compared to what would be the case if the parent compound was to be administered itself. For instance the prodrugs of the invention may give higher bioavailabities, varied bioavailability kinetics or bioavailabilities with a decreased interpersonal spread. Representative phosphorous-containing drugs amenable to the prodrugs of the present invention include phosfestrol, (E)-(α,β-diethyl-4,4'- stilbenylen)bis(dihydrogenphosphate), nucleoside analogue phosphonates, nucleotide analogue mono-, di or triphosphates, phosphonoformic acid, phosphonoacetic acid, bis phosphonate bone metabolism agents, fosinoprilate, β-phosphonocarboxylic acid farnesyl protein transferase inhbitors, α-phosphonosulfonate squalene synthase inhibitors, phosphonomethylamine neutral endopeptidase (24.11) inhibitors. Favoured -linker (-R 2 ') k -R 2 structures include those of the formulae: R 4L R o ■ 4 R 2 - O - Qql- ()qr-T 0 - R 4L R ■ 4R or R '4R O R, — O - Qql — Ring — ()qr-T ■ o - R 4 lib where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, hydroxymethyl, C,. 3 alkyl, C 3 -C 6 cycloalkyl, C,- C 3 alkyl-C,-C 6 cycloalkyl, phenyl or benzyl, R 4R and R 4R ' are independently H, C i alkyl or phenyl, ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- 5 R 4 is H or C^alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle. Additional -linker (-R 2 ') k -R 2 structures and intermediates for their application, such as those of the formula: R2 — O-i O -oJJ-o^ R2'— O - where R 2 and R 2 ' are as described above are disclosed and claimed in our co-pending application PCT/SE99/00194, the contents of which are hereby incorporated by reference. Further linker-R 2 structures include: R 2^O ^ \ such as alanyloxymethyl-, valyloxymethyl-, leucyloxymethyl- t-leucyloxymethyl- or isoleucyloxymethyl, especially valyloxymethyl-. Where the Drug comprises a phosphonate or phosphoryl function, or a plurality of such functions, the compound of the invention may comprise a plurality of -linker (-R 2 ') k -R 2 structures, preferably identical to each other for ease of synthesis. Preferred values for R 4R and R 4R ' are hydrogen for ease of synthesis, although compounds wherein one of R 4R and R 4R ' is hydrogen and the other methyl have the advantage of releasing the innocuous biproduct ethanol upon degradation. Representative values for R 4L and R 4L ' include methyl, hydrogen; hydroxymethyl, methyl; or ethyl, ethyl, respectively. A particularly preferred value is methyl, methyl. Favoured values for ql and qr, respectively, include 1,0; 2,0; 6 3,0; or 4,0; particularly 1,0 when the -linker (-R 2 ') k -R 2 structure has the formula Ila. Alternative convenient values for ql and qr, respectively, include 1,1; 2,1; 3,1; 4,1; or 2,2. Where the -linker (-R 2 ') k -R 2 structure has the formula lib, that is includes a -ring- moiety an alternative convenient configuration has ql and qr both 0. The -ring- moiety in the above depicted -linker (-R 2 ') k -R 2 structure may comprise furyl, thienyl, pyranyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like or bicyclic rings especially of the above fused to a phenyl ring such as indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothienyl etc. The carbo or heterocyclic ring may be bonded via a carbon or via a hetero atom, for instance a nitrogen atom, such as N-piperidyl, N-morpholinyl etc. The -ring- moiety is conveniently phenyl, furyl, pyridyl, cyclobutyl, cyclopentyl or cyclohexyl. The -ring- moiety can be optionally substituted with one to three substituents such as halo, amino, mercapto, oxo, nitro, NHCι-C 6 alkyl, N(C,-C 6 alkyl) 2 , C,-C 6 alkyl, C r C 6 alkenyl, C r C 6 alkynyl, C,-C 6 alkanoyl, C,-C 6 alkoxy, thio - alkyl, thioC r C 6 alkoxy, hydroxy, hydroxy - alkyl, haloC,-C 6 alkyl, aminoC r C 6 alkyl, C,-C 6 alkyl, cyano, carboxyl, carbalkoxy, carboxamide, carbamoyl, sulfonylamide, benzyloxy, 7 morpholyl-C,-C 6 alkyloxy, a monocyclic carbo- or heterocycle, as defined above, a carbo- or heterocyclic group spaced by alkyl, such as C,. 3 alkylaryl, etc. A favoured optional substituent comprises an additional group R 2 -( ) ql -. The aliphatic amino acid R 2 is derived from D- or L- glycine, alanine, valine, leucine, tert-leucine and isoleucine. Preferably the or each R 2 is derived from L-valine to ensure nature identical breakdown products. The currently preferred value for T is a bond. Representative phosphorous-containing drugs include phosfestrol, (E)-(α,β-diethyl- 4,4'-stilbenylen)bis(dihydrogenphosphate) and cytostatic metabolites such as phosphorylated nucleoside anlaogues such as FLG, cytarabin or gemcitabin. Representative drugs comprising a phosphonate function include antiviral nucleoside or nucleotide analogues such as PMEA, HPMPC, PMPA and the like or phosphates such as the monophosphates, diphosphate or triphospates of those nucleoside analogues which require phosphorylation for activity, such as gemcitabine, ACV, AZT, ddl, ddC, PCV, GCV, H2G, BVDU, FMAU, 3TC, FTC etc. Certain mixed amino acid/fatty acid acyloxyalkylphosphonates are proposed in our copending application PCT SE97 001903 and it should be thus appreciated that the prodrugs of the present invention are fatty acyl-free and/or apply the novel linkers defined herein in the phosphonate nucleotide field. Taking the phosphonate antivirals adefovir and cidovir as examples, prodrugs of the invention can be applied as shown in Formula PF2: R 4L R Base O 4R O I I R — O - ()ql ()qr-T- O O - P . .0. R R Rf3 '4L Rf4 or R Base O '4R O R 2 — O — ()ql -ring- ()qr-T- O o-p. o. R MARR 1 R 3 Rf4 where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,_ 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C,- ^lkyl-C^CgCycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C,. 3 alkyl or phenyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C, .3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; base is a natural or unnatural nucleotide base, especially guanine, adenine or cytosine, Rβ is H or a further structure of the formula Ila or lib and Rf4 is H or CH 2 OH. Currently favoured values in formula PF2 include: R 3R and R 3R ' are preferably H and/or R 3L and R 3L ' are preferably ethyl or especially methyl. T is preferably -O- or more preferably a bond. Preferably qr is 1 or more preferably 0 and ql is 0 or more preferably 1. Thus a preferred group of phosphonate antivirals within the scope of the invention include: 9 9-[2-phosphonomethoxy)ethyl]adenine, mono(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono(2-(L-valyloxy)-3-methyl-(S)-(+)- butyryloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono(2-(-L-valyloxy)-2-phenyl-DL- acetyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono((l,3-di-valyloxy)propyl-2- oxycarbonyloxy methyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono(2-L-valyloxy)-DL- propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono-(5-(L-valyloxy)-2,2- dimethylvaleryloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono [4-( L-valyloxy)-butanoyloxymethyl] ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono-(4-(L-valyloxy) benzoyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono-(3-(3,4-di-(L-valyloxy) phenyl) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono-(2 -methyl- 1 -(L-valyloxy)-2- propoxycarbonyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine, mono-(4-N- valyloxy)cyclohexanoyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine, mono-(l-valyloxy-2-methylpropane-2- aminocarbonyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine, mono-(l-(2-L-valyloxyethyl)-6-oxo-l,6- dihydro-pyridine-3-carbonyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine, mono-((l,3-di-(valyloxy)propyl-2- oxycarbonyloxy methyl) ester 10 9-[2-phosphonomethoxy)ethyl]adenine, mono-(2-hydroxymethyl-2- methylpropionyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine, mono-(2-(L-valyloxymethyl)-2-ethyl butyroyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine, mono-(3-(L-valyloxy)-2-methyl- propionyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine, mono-(3-(L-valyloxy)-2-methyl, 2- hydroxymethylpropionyloxymethyl) ester the corresponding bis esters and pharmaceutically acceptable salts thereof. A further preferred group comprises the corresponding derivatives of PMPA and HPMPC. A particularly preferred group comprises. 9-[2-phosphonomethoxy)ethyl]adenine di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester 9-[2-phosphonomethoxy)ethyl]adenine di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester and especially 9-[2-phosphonomethoxy)ethyl]adenine di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester and 9-[2-phosphonomethoxy)ethyl]adenine mono-(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester; and the corresponding derivatives of PMPA and HPMPC. A further convenient group comprises 11 9-[2-phosphonomethoxy)ethyl]adenine mono -(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine mono -(2-methyl-2-(L-leucyloxymethyl) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine mono -(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine mono -(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, 9-[2-phosphonomethoxy)ethyl]adenine mono (2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, the corresponding bis esters and the corresponding derivatives of PMPA and HPMPC. A further group of useful compounds comprises: 9-[2-phosphonomethoxy)ethyl]adenine mono-L-valyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine di-L-valyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine mono-L-leucyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine di-L-leucyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine mono-L-isoleucyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine di-L-isoleucyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine mono-L-t-leucyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine di-L-t-leucyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine mono-L-alanyloxymethyl ester, 9-[2-phosphonomethoxy)ethyl]adenine di-L-alanyloxymethyl ester, and the corresponding derivatives of HPMPC and PMPA. This aspect of the invention further provides a method for the treatment or prophylaxis of virus infections comprising the oral administration of an effective amount of a compound of the invention to a mammal (including humans) in need thereof. Viral infections include herpesvirus infections such as HSV-1, HSV-2, VZV, CMV, HHV6, HHV8 and retroviruses such as HIV-1 and HIV-2. The invention further provides the use of the compounds defined above in medicine and the use of 12 these compounds in the preparation of a medicament for the prophylaxis or treatment of viral infections. A further group of phosphorous containing antivirals amenable to the invention include foscarnet (phosphono formate) and PAA (phosphonoacetate). Taking foscarnet as an example: O O HO-P 11 — u II— OH I o H it will be apparent that aside from conventional pharmaceutically acceptable esters applied to the carboxy function, one or two -linker(-R 2 ') k -R 2 structures, preferably those of formula Ila or lib can be applied to the phosphonate function to define compounds such as : o o R 2\ O O ' ^^O-P— — OH I o H Thus a preferred group of compounds comprises foscarnet derivatives of the formula PF1 : R '4L R 4R O O O R 2 -O Qql- ()qr-T JL O O - P- O — Rf2 ό R • 4L R '4R Rf1 or R O • 4R O O R 9 — O — Qql — Ring — ()qr-T O -O - P I -U- O — Rf2 O R 4R' I Rf1 13 where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,. 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C,- 3 alkyl-C,C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, Cj. 3 alkyl or phenyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C,. 3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; and Rfl is H, a further ester of formula Ila or lib and Rf2 is H, a further linker(-R 2 ') k - R 2 ester or a conventional pharmaceutically acceptable ester, including acyloxyalkyl esters. Currently favoured values in Formula PF1 include: R 4R and R 4R ' are preferably H and/or R 4L and R 4L ' are preferably ethyl or especially methyl. T is preferably -O- or more preferably a bond. Preferably qr is 1 or more preferably 0 and ql is 0 or preferably 1. If Rfl is a further ester it is convenient if it is identical to the other linker(R 2 ') k -R 2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters or alternatively a similar structure to the linker(-R 2 ') k -R 2 moiety as envisaged in our copending PCT/SE99/00194. A favoured group of compounds within formula PF1 include: phosphonoformic acid, mono(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, phosphonoformic acid, mono(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, phosphonoformic acid, mono(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester, phosphonoformic acid, mono(2-(-L-valyloxy)-2-phenyl-DL-acetyloxyrnethyl) ester, phosphonoformic acid, mono((l,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester, phosphonoformic acid, mono(2-L-valyloxy)-DL-propionyloxymethyl) ester, 14 phosphonoformic acid, mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester, phosphonoformic acid, mono-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester, phosphonoformic acid, mono [4-( L-valyloxy)-butanoyloxymethyl] ester, phosphonoformic acid, mono-(4-(L-valyloxy) benzoyloxymethyl) ester, phosphonoformic acid, mono-(3-(3,4-di-(L-valyloxy) phenyl) propionyloxymethyl) ester, phosphonoformic acid, mono- (2 -methyl- l-(L-valy loxy)-2- propoxycarbonyloxymethyl) ester, phosphonoformic acid, mono-(4-N-valyloxy)cyclohexanoyloxymethyl) ester phosphonoformic acid, mono-(l-valyloxy-2-methylpropane-2- aminocarbonyloxymethyl) ester phosphonoformic acid, mono-( 1 -(2-L-valyloxyethyl)-6-oxo- 1 ,6-dihydro-pyridine-3- carbonyloxymethyl) ester phosphonoformic acid, mono-((l,3-di-(valyloxy)propyl-2-oxycarbonyloxy methyl) ester phosphonoformic acid, mono-(2-hydroxymethyl-2-methylpropionyloxymethyl) ester phosphonoformic acid, mono-(2-(L-valyloxymethyl)-2-ethyl butyroyloxymethyl) ester phosphonoformic acid, mono-(3-(L-valyloxy)-2-methyl-propionyloxymethyl) ester phosphonoformic acid, mono-(3-(L-valyloxy)-2-methyl, 2-hydroxymethyl- propionyloxymethyl) ester the corresponding bis esters, the corresponding compounds additionally bearing a conventional carboxyl ester, and pharmaceutically acceptable salts thereof. An especially favoured group comprises: phosponoformic acid di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester phosponoformic acid mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester phosponoformic acid di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, phosponoformic acid mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, phosponoformic acid di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, phosponoformic acid mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester and especially 15 phosponoformic acid di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester phosponoformic acid mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester; and pharmaceutically acceptable salts and conventional pharmaceutical carboxy- esters thereof. A further useful group of compounds comprises: phosponoformic acid mono-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, phosponoformic acid mono-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, phosponoformic acid mono-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, phosponoformic acid mono-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, phosponoformic acid mono-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, and the corresponding bis esters, conventional pharmaceutically acceptable carboxy esters and pharmaceutically acceptable salts thereof. A further group of useful compounds comprises: phosponoformic acid mono-L-valyloxymethyl ester, phosponoformic acid di-L-valyloxymethyl ester, phosponoformic acid mono-L-leucyloxymethyl ester, phosponoformic acid di-L-leucyloxymethyl ester, phosponoformic acid mono-L-isoleucyloxymethyl ester, phosponoformic acid di-L-isoleucyloxymethyl ester, phosponoformic acid mono-L-t-leucyloxymethyl ester, phosponoformic acid di-L-t-leucyloxymethyl ester, phosponoformic acid mono-L-alanyloxymethyl ester, phosponoformic acid di-L-alanyloxymethyl ester, conventional pharmaceutically acceptable carboxy esters and pharmaceutically acceptable salts thereof. 16 This aspect of the invention further provides a method for the treatment or prophylaxis of virus infections comprising the oral administration of an effective amount of a compound of the invention to a mammal (including humans) in need thereof. Viral infections include herpesvirus infections such as HSV-1, HSV-2, VZV, CMV, HHV6, HHV8 and retroviruses such as HIV-1 and HIV-2. The invention further provides the use of the compounds defined above in medicine and the use of these compounds in the preparation of a medicament for the prophylaxis or treatment of viral infections. A further class of phosphonates which are amenable to the invention and which share a structural similarity with phosphonoformic acid are the β-phosphonocarboxylic acid farnesyl protein transferase inhibitors, especially those of the of the formula PF4: R R Rf2 4L '4R O O— O O I I H R o- Qql" ()qr -T o- O- P O Rf3 R '4L R 4R O Rf1 or R O O— Rf2 O '4R O " H R 2 - O - Qql — Ring — ()qr -T O -O- P. . S R O Rf3 • 4R I O Rf1 where RF1 is H or a further structure of formula Ila or lib Rf2 is H or a conventional pharmaceutically acceptable ester, Rf3 is a polyunsaturated, branched C 6 . 22 alkyl, R 2 is the acyl residue of an aliphatic amino acid, 17 R 4L and R 4L ' are independently H, C,. 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C,- 3 alkyl-C 1 C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, Cj. 3 alkyl or phenyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C,. 3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle. Currently favoured values in Formula PF4 include: R 4R and R 4R ' are preferably H and/or R 4L and R 4L ' are preferably ethyl or especially methyl. T is preferably -O- or more preferably a bond. Preferably qr is 1 or more preferably 0 and ql is 0 or preferably 1. If Rfl is a further ester it is convenient if it is identical to other linker- R 2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters or alternatively a similar structure to the linker-R 2 moiety as envisaged in our copending PCT/SE99/00194. A convenient polyunsaturated alkyl RO has the formula: where the asterisk shows the point of attachment. Other structurally similar phosponates include α-phosphonosulphonates such as squalene synthase inhibitors of the formula PF5: 18 O ° " .0— Rf2 R '4. L R '4R O O I I R 2 — O- Qql- ()qr -T O O- P Rf3 R '.4L R O '4R I Rf1 or Λ O R °. * o -0 — Rf2 O ■ 4R 0 ^ R 2 - O - ()ql- Ring ()qr -T _IL O °- P " Rf3 O R 4R' I Rfl where RF1 is H or a further structure of formula Ila or lib Rf2 is H or a conventional pharmaceutically acceptable ester a further structure of formula Ila or lib Rf3 is a polyunsaturated, branched C 6 . 22 alkyl, R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,. 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C 3 alkyl-C, C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C,. 3 alkyl or phenyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C, .3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle. Currently favoured values in Formula PF5 include: R 4R and R 4R ' are preferably H and/or R 4L and R 4L ' are preferably ethyl or especially methyl. T is preferably -O- or more preferably a bond. Preferably qr is 1 or more preferably 0 and ql is 0 or preferably 1. If Rfl is a further ester it is convenient if it is identical to other linker- R 2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters, or alternatively a similar structure to the linker-R 2 moiety. A convenient polyunsaturated alkyl Rf3 has the formula: 19 where the asterisk denotes the point of attachment. The aspects of the invention immediately above further provide respective methods for the treatment or prophylaxis of neoplasma or cholesterol disorders comprising the oral administration of an effective amount of a compound of the invention to a mammal (including humans) in need thereof. The invention further provides the use of the compounds defined above in medicine and the use of these compounds in the preparation of a medicament for the prophylaxis or treatment of neoplasma or cholesterol disorders. A particularly preferred group of phosphorous containing drugs are the bisphosphonates active in bone and calcium metabolism. Favoured bis-phosphonates drugs have the formula: Y O HO-V- -P-OH HO OH X where X is H, halo, hydroxy; and Y is a) C, .10 alkyl, optionally substituted with heterocycle, - j R b , where R a and R b are independently hydrogen, C,. 6 alkyl or join together to form a 5 to 7 membered ring, optionally containing a further hetero atom, OH, halo, -S(C,_ 6 alkyl), phenyl, -C,_ 7 cycloalkyl, (optionally substituted with -NR a R b or OH); b) C 3 . 7 cycloalkyl, optionally substituted with -NR^R b , OH, halo, -S(C,_ 6 alkyl), phenyl, morpholino or pyridyl; 20 c) halo; d) piperidinyl; e) pyrrolidinyl; f) -S(C,_ 6 alkyl), optionally substitued with -NR a R b , OH, halo or phenyl; g) -S-phenyl, optionally substituted with halo, nitro, C,. 6 alkyl, C,_ 6 alkoxy, trifluormethyl, -CONRaR b or -COOH. Preferred bis-phosphonates include alendronate (X is hydroxy, Y is NH 2 CH 2 CH 2 CH 2 -), clodronate (X is chloro, Y is chloro), etidronate (X is hydroxy, Y is CH 3 -), pamidronate (X is hydroxy, Y is NH,CH 2 CH 2 -), ibandronate (X is hydroxy, Y is N (CH 2 CH 2 CH 2 CH 2 CH3)(CH 3 )CH 2 CH 2 -), tiludronate (X is H, Y is 4-chlorophenylthio-), risedronate (X is hydroxy, Y is 3-pyridinylmethylene-) and zoledronate (X is hydroxy, Y is (2-(lH-imidazol-l-yl)methylene-) Preferred compounds within this bis-phosphonate aspect of the invention thus include those of the formula Al : YY O O Ra1— O - P P- O — Ra2 O O XX \ Ra3 Ra4 A-1 wherein YY and XX have the following values: NH 2 (CH 2 ) 3 - OH (alendronate) NH 2 (CH 2 ) 2 - OH (pamidronate) cycloheptylamino- H (cimadronate) chloro- chloro (clodronate) pyrrolidin- 1 -ylCH 2 CH 2 - OH (EB 1053) CH 3 - OH (etidronate) 21 methylpentylaminoCH 2 CH 2 - OH (ibandronate) dimethylaminoCH 2 CH 2 - OH (olpadronate) pyridin-3-ylCH 2 - OH (risedronate) (4-chlorophenyl)-thio- H (tiludronate) imidazo-( 1 ,2-a)pyridin-3-ylCH 2 - OH (YH 529) lH-imidazol-lylCH 2 - OH (zoledronate) wherein amino groups on YY can be optionally substituted with conventional pharmaceutically acceptable amide groups such as -C(=O)C,. 6 alkyl or an aminoacyl or peptidyl derivative, as described in WO 96/31227; and wherein at least one of Ral-Ra4 is a structure of the formula R '4L o R 4R R„— O - ()ql- Qqr-T ■ o - R L R • 4R or R o 4R R, — O — Qql Ring Qqr-T JL ■ O - R 4R where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,_ 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C r 3 alkyl-C,C 6 cycloalkyl, phenyl or benzyl, R 4R and R 4R ' are independently H or C,_ 3 alkyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C,. 3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; 22 and the remainder of Ral -4 are hydrogen or conventional pharmaceutically acceptable esters. Preferably Ral and Ra2 comprise the same structure of formula Ila or lib and Ra3 and Ra4 are H. A free amine group on YY could also be protected with the same linker (R 2 ') k -R 2 structure, as envisaged in our copending application no PCT/SE99/00194. In formula A-l, R 4R and R 4R ' are preferably H and/or R 4L and R 4L ' are preferably ethyl or especially methyl. T is preferably -O- or more preferably a bond. Preferably qr is 1 or more preferably 0 and ql is 0 or more preferably 1. Representative compounds within formula A-l thus include; (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di (2-(L-valyloxy)-3-methyl-(S)-(+)- butyryloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di (2-(-L-valyloxy)-2-phenyl-DL- acetyloxymethyl) ester, (4-amino-l-hydroxybutylidine)-bisphosphonate, di ((l,3-di-valyloxy)propyl-2- oxycarbonyloxy methyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di (2-L- valyloxy)-DL- propionyloxymethyl) ester, (4-amino-l-hydroxybutylidine)-bisphosphonate, di-(5-(L-valyloxy)-2,2- dimethyl valeryloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di-((2-(L-valyloxy)- ethoxycarbonyloxy) methyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, bis [4-(L-valyloxy)- butanoyloxymethyl] ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di-(4-(L-valyloxy) benzoyloxymethyl) ester, (4-amino-l-hydroxybutylidine)-bisphosphonate, di-(3 -(3, 4-di-(L-valyloxy) phenyl) propionyloxymethyl) ester, 23 (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di- (2 -methyl- 1 -(L-valyloxy)-2- propoxycarbonyloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di-(4- valyloxy)cyclohexanoyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di- [N-(2-L-valyloxy- 1 , 1 -dimethyl- ethyl) aminocarbonyloxymethyl] ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di- ( 1 -(2-L-valyloxyethyl)-6-oxo- l,6-dihydro-pyridine-3-carbonyloxymethyl) (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di-(( 1 ,3-di-(valyloxy)propyl-2- oxycarbonyloxy methyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di-(2-hydroxymethyl-2- methylpropionyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di-(2-(L-valyloxymethyl)-2-ethyl butyroyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di (3-(L-valyloxy)-2-methyl- propionyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, di (3-(L-valyloxy)-2-methyl,2- hydroxymethyl-propionyloxymethyl) ester 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-bw phosphonate, di(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-bw phosphonate, di(2-methyl-2-(L- valyloxy) propionyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bw phosphonate, di (2-(L-valyloxy)-3- methyl-(S)-(+)-butyryloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bw phosphonate, di (2-(-L-valyloxy)-2- phenyl-DL-acetyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bw phosphonate, di ((1,3-di- valyloxy)propyl-2-oxycarbonyloxy methyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bw phosphonate, di (2-L-valyloxy)-DL- propionyloxymethyl) ester, 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-bw phosphonate, di-(5-(L-valyloxy)- 2,2-dimethylvaleryloxymethyl) ester, 24 l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z ' ,s phosphonate, di-((2-(L-valyloxy)- ethoxycarbonyloxy) methyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-Z?w phosphonate, bis [4-(L-valyloxy)- butanoyloxymethyl] ester, 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-bώ phosphonate, di-(4-(L-valyloxy) benzoyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z ' s phosphonate, di-(3-(3,4-di-(L- valyloxy) phenyl) propionyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-όώ phosphonate, di- (2-methyl-l-(L- valyloxy)-2-propoxycarbonyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z ' s phosphonate, di-(4- valyloxy)cyclohexanoyloxymethyl) ester 1 -hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bz ' s phosphonate, di-[N-(2-L-valyloxy- 1 , 1 -dimethyl-ethyl) aminocarbonyloxymethyl]ester l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-tø phosphonate, di- (l-(2-L- valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3-carbonyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3w phosphonate, di-((l,3-di- (valyloxy)propyl-2-oxycarbonyloxy methyl) ester 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-δώ phosphonate, di-(2-hydroxymethyl- 2-methylpropionyloxymethyl) ester 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene- ώ phosphonate, di-(2-(L- valyloxymethyl)-2-ethyl butyroyloxymethyl) ester l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3w phosphonate, di-(3-(L-valyloxy)-2- methyl-propionyloxymethyl) ester 1 -hydroxy-2-(l H-imidazolyl- 1 -yl)ethylidene-3z ' 5 phosphonate, di-(3-(L-valyloxy)-2- methyl,2-hydroxymethyl-propionyloxymethyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene bw-phosphonate di(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, 1 -hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, di(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene tø-phosphonate, di (2-(L-valyloxy)-3-methyl- (S)-(+)-butyryloxymethyl) ester, 25 l-hydroxy-2-(pyrid-3-yl)ethylidene όz ' s-phosphonate, di (2-(-L-valyloxy)-2-phenyl- DL-acetyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bw-phosphonate, di ((l,3-di-valyloxy)propyl-2- oxycarbonyloxy methyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene tø-phosphonate, di (2-L-valyloxy)-DL- propionyloxymethyl) ester, 1 -hydroxy-2-(pyrid-3-yl)ethylidene tø-phosphonate, di-(5-(L-valyloxy)-2,2- dimethylvaleryloxymethyl) ester, 1 -hydroxy-2-(pyrid-3 -yl)ethylidene bώ-phosphonate, di-((2-(L-valyloxy)- ethoxycarbonyloxy) methyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, bis [4-(L-valyloxy)- butanoyloxymethyl] ester, 1 -hydroxy-2-(pyrid-3-yl)ethylidene όz ' s-phosphonate, di-(4-(L-valyloxy) benzoyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, di-(3-(3,4-di-(L-valyloxy) phenyl) propionyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, di- (2-methyl-l-(L-valyloxy)-2- propoxycarbonyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene έώ-phosphonate, di-(4- valyloxy)cyclohexanoyloxymethyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene όz ' s-phosphonate, di-[N-(2-L-valyloxy- 1,1- dimethyl-ethyl) aminocarbonyloxymethyl] ester l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, di- (l-(2-L-valyloxyethyl)-6- oxo- 1 ,6-dihydro-pyridine-3-carbonyloxymethyl) ester l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, di-((l,3-di-(valyloxy)propyl-2- oxycarbonyloxy methyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene bώ-phosphonate, di-(2-hydroxymethyl-2- methylpropionyloxymethyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, di-(2-(L-valyloxymethyl)-2- ethyl butyroyloxymethyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, di-(3-(L-valyloxy)-2-methyl- propionyloxymethyl) ester 26 l-hydroxy-2-(pyrid-3-yl)ethylidene bw-phosphonate, di-(3-(L-valyloxy)-2-methyl, 2- hydroxymethylpropionyloxymethyl) ester and pharmaceutically acceptable salts thereof. A further group of representative compounds include: (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, (4-amino-l -hydroxybutylidine)-bisphosphonate, mono(2-(L-valyloxy)-3-methyl-(S)- (+)-butyryloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono(2-(-L-valyloxy)-2-phenyl- DL-acetyloxymethyl) ester, (4-amino-l-hydroxybutylidine)-bisphosphonate, mono((l,3-di-valyloxy)propyl-2- oxycarbonyloxy methyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono(2-L-valyloxy)-DL- propionyloxymethyl) ester, (4-amino-l-hydroxybutylidine)-bisphosphonate, mono-(5-(L-valyloxy)-2,2- dimethylvaleryloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-((2-(L-valyloxy)- ethoxycarbonyloxy) methyl) ester, (4-amino-l-hydroxybutylidine)-bisphosphonate, mono [4-( L-valyloxy)- butanoyloxymethyl] ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-(4-(L-valyloxy) benzoyloxymethyl) ester, (4-amino-l-hydroxybutylidine)-bisphosphonate, mono-(3-(3,4-di-(L-valyloxy) phenyl) propionyloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono- (2 -methyl- 1 -(L-valyloxy)-2- propoxycarbonyloxymethyl) ester, (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-(4- valyloxy)cyclohexanoyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono- [N-(2-L-valyloxy- 1,1- dimethyl-ethyl) aminocarbonyloxymethyl] ester 27 (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-( 1 -(2-L-valyloxyethyl)-6- oxo- 1 ,6-dihydro-pyridine-3-carbonyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-(( 1 ,3-di-(valyloxy)propyl-2- oxycarbonyloxy methyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-(2-hydroxymethyl-2- methylpropionyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-(2-(L-valyloxymethyl)-2- ethyl butyroyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-(3 -(L-valyloxy)-2-methyl- propionyloxymethyl) ester (4-amino- 1 -hydroxybutylidine)-bisphosphonate, mono-(3-(L-valyloxy)-2-methyl,2- hydroxymethylpropionyloxymethyl) ester l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3w phosphonate, mono(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, 1 -hydroxy-2-(l H-imidazolyl- 1 -yl)ethylidene-όz ' 5 phosphonate, mono(2-methyl-2-(L- valyloxy) propionyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bz ' 5 phosphonate, mono (2-(L- valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z " 5 phosphonate, mono (2-(-L- valyloxy)-2-phenyl-DL-acetyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bw phosphonate, mono ((1,3-di- valyloxy)propyl-2-oxycarbonyloxy methyl) ester, l-hydroxy-2-(lH-imidazolyl-l-yl)ethylidene-bώ phosphonate, mono (2-L-valyloxy)- DL-propionyloxymethyl) ester, 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-/3z ' ,s' phosphonate, mono-(5-(L- valyloxy)-2,2-dimethylvaleryloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z ' 5 phosphonate, mono- ((2-(L- valyloxy)-ethoxycarbonyloxy) methyl) ester, l-hydroxy-2-(l H-imidazolyl- l-y ethylidene-bz ' .s' phosphonate, mono [4-(L- valyloxy)-butanoyloxymethyl] ester, 1 -hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bz " 5 phosphonate, mono-(4-(L-valyloxy) benzoyloxymethyl) ester, 28 l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bzs phosphonate, mono-(3-(3,4-dι-(L- valyloxy) phenyl) propionyloxymethyl) ester, l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z5 phosphonate, mono- (2 -methyl- 1- (L-valyloxy)-2-propoxycarbonylmethyl) ester, 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene- z5 phosphonate, mono-(4-N- valyloxy)cyclohexanoyloxymethyl) ester, 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-bz5 phosphonate, mono- [N-(2-L- valyloxy- 1,1 -dimethyl-ethyl) aminocarbonyloxymethyl] ester, 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-£zs phosphonate, mono-( 1 -(2-L- valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3-carbonyloxymethyl) ester l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bz^ phosphonate, mono-(( 1,3 -di- (valyloxy)propyl-2-oxycarbonyloxy methyl) ester l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z5 phosphonate, mono-(2- hydroxymethyl-2-methylpropionyloxymethyl) ester 1 -hydroxy-2-( 1 H-imidazolyl- 1 -yl)ethylidene-&zs phosphonate, mono-(2-(L- valyloxymethyl)-2-ethyl butyroyloxymethyl) ester l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-3z5 phosphonate, mono-(3-(L- valyloxy)-2-methyl-propionyloxymethyl) ester l-hydroxy-2-(l H-imidazolyl- l-yl)ethylidene-bz5 phosphonate, mono-(3-(L- valyloxy)-2-methyl,2-hydroxymethyl-propιonyloxymethyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene bzs-phosphonate mono(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, 1 -hydroxy-2-(pyrid-3-yl)ethylidene bzs-phosphonate, mono(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bis -phosphonate, mono (2-(L-valyloxy)-3- methyl-(S)-(+)-butyryloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bzs-phosphonate, mono (2-(-L-valyloxy)-2- phenyl-DL-acetyloxymethyl) ester, 1 -hydroxy-2-(pyrid-3-yl)ethylidene bzs-phosphonate, mono((l ,3-di-valyloxy)propyl- 2-oxycarbonyloxy methyl) ester, 1 -hydroxy-2-(pyrid-3-yl)ethylidene 3zs-phosphonate, mono(2-L-valyloxy)-DL- propionyloxymethyl) ester, 29 1 -hydroxy-2-(pyrid-3 -yl)ethylidene όz ' s-phosphonate, mono-(5 -(L-valyloxy)-2,2- dimethylvaleryloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene όz ' s-phosphonate, mono-((2-(L-valyloxy)- ethoxycarbonyloxy) methyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, mono [4-( L-valyloxy)- butanoyloxymethyl] ester, 1 -hydroxy-2-(pyrid-3-yl)ethylidene bώ-phosphonate, mono-(4-(L-valyloxy) benzoyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bzs-phosphonate, mono-(3-(3,4-di-(L-valyloxy) phenyl) propionyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bώ-phosphonate, mono- (2-methyl-l-(L- valyloxy)-2-propoxycarbonyloxymethyl) ester, l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, mono-(4 - valyloxy)cyclohexanoyloxymethyl) ester l-hydroxy-2-(pyrid-3-yl)ethylidene bw-phosphonate, mono- [N-(2-L-valyloxy- 1,1- dimethyl-ethyl) aminocarbonyloxymethyl] ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene tø-phosphonate, mono-(l -(2-L-valyloxyethyl)- 6-oxo-l,6-dihydro-pyridine-3-carbonyloxymethyl) ester l-hydroxy-2-(pyrid-3-yl)ethylidene 3z5 -phosphonate, mono-((l,3-di- (valyloxy)propyl-2-oxycarbonyloxy methyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene όz ' s-phosphonate, mono-(2-hydroxymethyl-2- methylpropionyloxymethyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, mono-(2-(L-valyloxymethyl)- 2-ethyl butyroyloxymethyl) ester l-hydroxy-2-(pyrid-3-yl)ethylidene bz ' s-phosphonate, mono-(3-(L-valyloxy)-2- methyl-propionyloxymethyl) ester 1 -hydroxy-2-(pyrid-3-yl)ethylidene te-phosphonate, mono-(3-(L-valyloxy)-2- methyl, 2-hydroxymethyl-propionyloxymethyl) ester and pharmaceutically acceptable salts thereof. A favoured group of compounds within formula A-l include: alendronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, 30 alendronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, alendronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, alendronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, alendronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, alendronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, alendronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, risedronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, risedronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, risedronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, risedronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, zoledronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, zoledronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, zoledronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, zoledronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, pamidronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, pamidronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, pamidronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, pamidronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, cimadronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, cimadronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, cimadronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, 31 cimadronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, clodronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, clodronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, clodronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, clodronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, [l-hydroxy-3-(l-pyrrolidinyl)-propylidine]-3z.s'-phosphonate mono-(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-3-(l-pyrrolidinyl)-propylidine]-3z ' 5-phosphonate di-(2-methyl-2-(D- valyloxymethyl) propionyloxymethyl) ester, [ 1 -hydroxy-3-(l -pyrrolidinyl)-propylidine]-bz.s'-phosphonate mono-(2-methyl-2-(D- valyloxymethyl) propionyloxymethyl) ester, [1 -hydroxy-3-( 1 -pyrrolidiny^-propylidinej-bώ-phosphonate di-(2-methyl-2-(L- valyloxy) propionyloxymethyl) ester, [1 -hydroxy-3-(l -pyrrolidinyl)-propylidine]-bz5 , -phosphonate mono-(2-methyl-2-(L- valyloxy) propionyloxymethyl) ester, [l-hydroxy-3-(l-pyrrolidinyl)-propylidine]-bz.?-phosphonate di-(2-methyl-2-(D- valyloxy) propionyloxymethyl) ester, [ 1 -hydroxy-3-( 1 -pyrrolidinyl)-propylidine]-3z.s-phosphonate mono-(2-methyl-2-(D- valyloxy) propionyloxymethyl) ester, etidronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, etidronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, etidronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, etidronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, olpadronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, olpadronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, 32 olpadronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, olpadronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, olpadronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, ibandronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, ibandronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, ibandronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, ibandronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-όz ' 5-phosphonate mono-(2- methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-bz ' -v-phosphonate di-(2-methyl-2- (D-valyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-έz ' 5-phosphonate mono-(2- methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-έz5-phosphonate di-(2-methyl-2- (L-valyloxy) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-έ»z ' 5-phosphonate mono-(2- methyl-2-(L-valyloxy) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-3z5-phosphonate di-(2-methyl-2- (D-valyloxy) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-/ z ' 5-phosphonate mono-(2- methyl-2-(D-valyloxy) propionyloxymethyl) ester, tiludronate mono-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, tiludronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, tiludronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, tiludronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, tiludronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, tiludronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, tiludronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, 33 and pharmaceutically acceptable salts thereof. A particularly favoured group of compounds of the invention comprises: alendronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, [1 -hydroxy-3 -( 1 -pyrrolidinyl)-propylidine]-3w-phosphonate di-(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, tiludronate di-(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, [ 1 -hydroxy-2imidazo-( 1 ,2-a)pyridin-3-ylethylidine]-3z ' 5-phosphonate di-(2-methyl-2- (L- valyloxymethyl) propionyloxymethyl) ester, and pharmaceutically acceptable salts thereof, especially the alendronate, zoledronate and risedronate derivatives. A further useful group of compounds within formula A-l include: alendronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, alendronate di-(2-methyl-2-(L-leucyloxymethyl) propionyloxymethyl) ester, alendronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, alendronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, alendronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, 34 zoledronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-3-(l-pyrrolidinyl)-propylidine]-/3z5-phosphonate di-(2-methyl-2-(L- isoleucyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-3-(l-pyrrolidinyl)-propylidine]-bώ-phosphonate di-(2-methyl-2-(L- leucyoxymethyl) propionyloxymethyl) ester, [ 1 -hydroxy-3-( 1 -pyrrolidinyl)-propylidine]-bz5-phosphonate di-(2-methyl-2-(L-t- leucyloxymethyl) propionyloxymethyl) ester, [ 1 -hydroxy-3-( 1 -pyrrolidinyl)-propylidine]-/ z5-phosphonate di-(2-methyl-2-(L- alanyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-3-(l-pyrrolidinyl)-propylidine]-3z5-phosphonate di-(2-methyl-2-(L- glycyloxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, 35 etidronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-leucyoxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-t-leucyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-alanyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-glycyloxymethyl) propionyloxymethyl) ester, [1 -hydroxy-2imidazo-(l ,2-a)pyridin-3-ylethylidine]-bώ-phosphonate di-(2-methyl-2- (L-isoleucyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-3z5-phosphonate di-(2-methyl-2- (L-leucyoxymethyl) propionyloxymethyl) ester, [1 -hydroxy-2imidazo-(l ,2-a)pyridin-3-ylethylidine]-3z5-phosphonate di-(2-methyl-2- (L-t-leucyloxymethyl) propionyloxymethyl) ester, [1 -hydroxy-2imidazo-(l ,2-a)pyridin-3-ylethylidine]-3z5-phosphonate di-(2-methyl-2- (L-alanyloxymethyl) propionyloxymethyl) ester, [l-hydroxy-2imidazo-(l,2-a)pyridin-3-ylethylidine]-bzΛ'-phosphonate di-(2-methyl-2- (L-glycyloxymethyl) propionyloxymethyl) ester, and pharmaceutically acceptable salts thereof, especially the alendronate, zoledronate and risedronate derivatives. A further group of representative compounds comprises alendronate mono-L-valyloxymethyl ester, alendronate di-L-valyloxymethyl ester, alendronate mono-L-leucyloxymethyl ester, alendronate di-L-leucyloxymethyl ester, alendronate mono-L-isoleucyloxymethyl ester, alendronate di-L-isoleucyloxymethyl ester, 36 alendronate mono-L-t-leucyloxymethyl ester, alendronate di-L-t-leucyloxymethyl ester, alendronate mono-L-alanyloxymethyl ester, alendronate di-L-alanyloxymethyl ester, risedronate mono-L-valyloxymethyl ester, risedronate di-L-valyloxymethyl ester, risedronate mono-L-leucyloxymethyl ester, risedronate di-L-leucyloxymethyl ester, risedronate mono-L-isoleucyloxymethyl ester, risedronate di-L-isoleucyloxymethyl ester, risedronate mono-L-t-leucyloxymethyl ester, risedronate di-L-t-leucyloxymethyl ester, risedronate mono-L-alanyloxymethyl ester, risedronate di-L-alanyloxymethyl ester, zoledronate mono-L-valyloxymethyl ester, zoledronate di-L-valyloxymethyl ester, zoledronate mono-L-leucyloxymethyl ester, zoledronate di-L-leucyloxymethyl ester, zoledronate mono-L-isoleucyloxymethyl ester, zoledronate di-L-isoleucyloxymethyl ester, zoledronate mono-L-t-leucyloxymethyl ester, zoledronate di-L-t-leucyloxymethyl ester, zoledronate mono-L-alanyloxymethyl ester, zoledronate di-L-alanyloxymethyl ester, and pharmaceutically acceptable salts thereof. This aspect of the invention further provides a method for the treatment or prophylaxis of bone and calcium disorders comprising the oral administration of an effective amount of a compound of the invention to a mammal (including humans) in need thereof. Bone and calcium disorders include osteoporosis, Paget's disease, hypercalcaemia of malignancy, tooth loss, bone loss in immunotherapy and rheumatoid arthritis, decreasing fracture, post orthopedic prosthesis and inhibiting ossification. The invention further provides the use of the compounds defined above 37 in medicine and the use of these compounds in the preparation of a medicament for the prophylaxis or treatment of bone and calcium disorders. A still further preferred group of prodrugs of the invention are those based on fosinoprilate having the formula PF3: O H OH R 2 — O — or R 2 — O — Qql -ring- ()qr-T — r O O where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C,- 3 alkyl-CιC 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H or C j _ 3 alkyl ql is 0-3, qr is 0-3, T is a bond, -NR 3 - or -O- R 3 is H or C,. 3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; and pharmaceutically acceptable salts thereof. 38 In formula PF3, R 4R and R 4R ' are preferably H and/or R 4L and R 4L ' are preferably ethyl or especially methyl. T is preferably -O- or more preferably a bond. Preferably qr is 1 or more preferably 0 and ql is 0 or preferably 1. Representative compounds within formula PF3 thus include (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (2-methyl-2- (L-valyloxymethyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (2-methyl-2- (L-valyloxy) propionyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (2-(L- valyloxy)-3 -methyl-(S)-(+)-butyryloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (2-(-L- valyloxy)-2-phenyl-DL-acetyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, ((1,3-di- valyloxy)propyl-2-oxycarbonyloxy methyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (2-L- valyloxy)-DL-propionyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl j-L-proline, (5-(L- valyloxy)-2,2-dimethylvaleryloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, ((2-(L- valyloxy)-ethoxycarbonyloxy) methyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, [4-( L- valyloxy)-butanoyloxymethyl] ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (4-(L- valyloxy) benzoyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (3-(3,4-di-(L- valyloxy) phenyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl ]-L-proline, (2 -methyl- 1- (L-valyloxy)-2-propoxycarbonyloxymethyl) ester, (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phόsphinyl]acetyl ]-L-proline,(4-N- valyloxy)cyclohexanoyloxymethyl) ester 39 (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, [N-(2-L- valyloxy- 1,1 -dimethyl-ethyl) aminocarbonyloxymethyl] ester (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,(l-(2-L- valyloxyethyl)-6-oxo- 1 ,6-dihydro-pyridine-3 -carbonyloxymethyl) ester (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline, ((1 ,3-di- (valyloxy)propyl-2-oxycarbonyloxy methyl) ester (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline(2- hydroxymethyl-2-methylpropionyloxymethyl) ester (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline(2-(L- valyloxymethyl)-2-ethyl butyroyloxymethyl) ester (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (3-(L- valyloxy)-2-methyl-propionyloxymethyl) ester 4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (3-(L- valyloxy)-2-methyl,2-hydroxymethyl-propionyloxymethyl) ester and pharmaceutically acceptable salts thereof. A favoured group of compounds within formula PF3 comprises: (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L- valyloxymethyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (D-valyloxymethyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L- valyloxy) propionyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline mono-(2- methyl-2-(D-valyloxy) propionyloxymethyl) ester, and especially; (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L-valyloxymethyl) propionyloxymethyl) ester: and pharmaceutically acceptable salts thereof A further group of convenient compounds comprises 40 (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L-isoleucyloxymethyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L-leucyoxymethyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L-t-leucyloxymethyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L-alanyloxymethyl) propionyloxymethyl) ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline (2-methyl-2- (L-glycyloxymethyl) propionyloxymethyl) ester, and pharmaceutically acceptable salts thereof. A further group of useful compounds comprises: (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline L- valyloxymethyl ester, (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline L- leucyloxymethyl ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline L- isoleucyloxymethyl ester, (4S)-4-cyclohexyl-l-[[(R)(4-phenylbutyl)ρhosphinyl]acetyl]-L-proline L-t- leucyloxymethyl ester, (4S)-4-cyclohexyl- 1 -[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline L- alanyloxymethyl ester, and pharmaceutically acceptable salts thereof. This aspect of the invention further provides a method for the treatment or prophylaxis of hypertension comprising the oral administration of an effective amount of a compound defined above to a mammal (including humans) in need thereof. The invention further provides the use of these compounds in medicine and their use in the preparation of a medicament for the treatment or prophylaxis of hypertension 41 A further phosphonate compound amenable to the prodrugs of the invention are the neutral endopeptidase inhibitors such as CGS-24592 (Novartis), preferably those of the formula PF6: R4L R4R Rf2 O O II NH O R2— O— Qql- ()qr -T O -O-P ' I O O R4L' R4R' O Rf1 or Rf2 R4R O O I II NH o R2— O— Qql Ring ()qr -T O- -O-P ' R4R" O O o Rf1 where RF1 is H or a further structure of formula Ila or lib Rf2 is H or a conventional pharmaceutically acceptable ester, R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,. 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C 3 alkyl-C,C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H or C,. 3 alkyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C^alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; and pharmaceutically acceptable salts thereof. 42 Currently favoured values in Formula PF6 include: R 4R and R 4R ' are preferably H and/or R 4L and R 4L ' are preferably ethyl or especially methyl. T is preferably -O- or more preferably a bond. Preferably qr is 1 or more preferably 0 and ql is 0 or preferably 1. If Rfl is a further ester it is convenient if it is identical to other linker- R 2 moiety. Conventional pharmaceutically acceptable esters for Rf2 include the methyl, ethyl and isopropyl esters. Compounds of the invention are typically prepared by esterifying the mother compound in which exposed functions such as the 4-amino group of alendronate or the carboxy group of foscarnet are protected with conventional amine and carboxy etc protecting groups respectively, with a structure of the formula Ila or lib, the preparation of which are described in the abovementioned PCT/SE99/00194: R 4L R 4R O * R 2 - 0 - Qql- ()qr-T O - halo R 4L R 4R or R O 4R k R ? — O — ()ql — Ring — ()qr-T O - halo R '4R lib' *R 2 is the acyl residue of an aliphatic amino acid, N-protected with a conventional N- protecting group such as CBz, Fmoc or Boc R 4L and R 4L ' are independently H, C 3 alkyl, hydroxymethyl, C 3 - 6 cycloalkyl, C 3 alkyl-C,C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H or C 3 alkyl ql is 0-3, qr is 0-3, T is a bond, -NR 3 - or -O- 43 R 3 is H or C,. 3 alkyl; "ring" is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; and halo is bromo, chloro and especially iodo. Alternatively, iodomethyl N-protected aminoacid esters are employed for linker-R 2 structures of the formula: R 2^O^\ Hydroxymethyl bearing linkers such as those within formula Ila are prepared by methoxybenzylation of the free carboxy group of a bis hydroxy compound such as glycerol or bis 2,2 hydroxymethyl propionic acid, CBz monoprotection of one of the hydroxy groups, esterification with the N-protected R 2 group, debenzylation, reaction with chloroiodomethyl and iodination as shown below prior to esterificaiton to a phosphorous-containing pharmaceutical. The mother compounds, that is the phosphorous containing drug, are all well known and readily accessible to those in the art. In drugs comprising multiple phosphoryl/phosphonate/phosphinate functions, it is generally advantageous that an hydroxy group on each phosphorous moiety is esterified with a linker (-R 2 ') k -R 2 structure such as those of formula Ila or lib etc. Regioselective protecting groups which bridge the phosphate groups of bis phosphonates and thus assist mono and diacylation include Si compounds such as dichlorotetraisopropyldisosiloxane or cresols. Methodology for the derivatisation of phosphorous-containing compounds with acyloxyalkyl groups and which can be used analogously for the coupling of the -linker (-R 2 ') k -R 2 structure is described in US patent 5 227 506, WO 94/13682, WO 94/13324, WO 98/04569, Starret et al J Med Chem 37 1857-1864 (1994) and Iyer et al Tetrahedron Lett 30 7141-7144 (1989). A number of approaches are also illustrated in the examples below. The N-protecting group on group R 2 is removed by conventional methodology. The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino 44 group against undesirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" (John Wiley & Sons, New York, 1981), which is hereby incorporated by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3 ,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1 -methylethoxycarbonyl, α,α-dimethyl-3 ,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Favoured N-protecting groups include formyl, acetyl, allyl, F-moc, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz). Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2- methoxyethoxymethyl and the like, silyl ethers such as trimethylsilyl (TMS), t- butyldimethylsilyl (TBDMS) tribenzylsilyl, triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like, substituted ethyl ethers such as 1-ethoxymethyl, 1- methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, dipehenylmethyl, triphenylmethyl and the like, aralkyl groups such as trityl, and pixyl (9-hydroxy-9- phenylxanthene derivatives, especially the chloride). Ester hydroxy protecting groups 45 include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonate hydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyl and the like. The compounds of the invention can form salts which form an additional aspect of the invention. Appropriate pharmaceutically acceptable salts of the compounds of the invention include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids. The compounds of the invention may in some cases be isolated as the hydrate. While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation. Such a formulation will comprise the above defined active agent together with one or more acceptable carriers/excipients and optionally other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. The formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the formulation is an orally administered formulation. The formulations may conveniently be presented in 46 unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of the invention or its pharmaceutically acceptable salt in conjunction or association with a pharmaceutically acceptable carrier or vehicle. If the manufacture of pharmaceutical formulations involves intimate mixing of pharmaceutical excipients and the active ingredient in salt form, then it is often preferred to use excipients which are non-basic in nature, i.e. either acidic or neutral. Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc. With regard to compositions for oral administration (e.g. tablets and capsules), the term suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate 47 stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent. Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier. Detailed Description of the Invention Various aspects of the invention will now be illustrated by way of example only with reference to the following non-limiting synthesis and biological examples: Preparation of intermediates Example P-I-l N-BOC-L-isoleucine iodomethyl ester 48 O A 0 A N , O. H O a) N-BOC-L-isoleucine chloromethyl ester To a solution of N-BOC-L-isoleucine (23.1 g, 0.1 mol) in dioxane (500 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (65.6 mL, 0.1 mol). After stirring for 15 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (500 mL) and then chloroiodomethane (72.8 mL, 1 mol) was added and the solution was stirred for 6h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane / ethyl acetate (1 :1 v/v, 400 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and then filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1-2% MeOH in CH 2 C1 2 ), to give 20.8 g of N- BOC-L-isoleucine chloromethyl ester. b) N-BOC-L-isoleucine iodomethyl ester. To a solution of N-BOC-L-isoleucine chloromethyl ester (19.6 g, 70 mmol) in acetonitrile (300 mL), was added sodium iodide (31.5 g, 210 mmol). The solution was stirred for 4 h at 60 °C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH 2 C1 2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na;,SO 4 ) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 2% MeOH in CH 2 C1 2 ), to give 22.6 g of N-BOC-L-isoleucine iodomethyl ester. 'H-NMR (CDC1 3 ): 6.04 (d, 1H), 5.82 (d, 1H), 4.97 (d, 1H), 4.25 (dd, 1H), 1.98-1.80 (m, 1H), 1.43 (s, 9H), 1.50-1.05 (m, 2H), 0.97-0.88 (m, 6H). Example PI-2 49 2.2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid iodomethyl ester λ . a) 2,2-dimethyl-3-( N-Boc-L-valyloxy)propionic acid. N-Boc-L-valine (10.8g, 50 mmole), 4-dimethylaminopyridine (610 mg, 5 mmole) and DCC (6.18 g, 30 mmole) were dissolved in methylene chloride (100 ml). After stirring for 2 hour the mixture was filtered. To the filtrate were added 2,2-dimethyl-3- hydroxy-propionic acid (3.54g, 30 mmole) and pyridine (10 ml). After 18 hr, the reaction mixture was filtered, and the filtrate was poured into sodium hydrogen carbonate aqueous solution, the organic phase was then washed with citric acid aqueous solution and water succesively. After evaporation the product was isolated with silica gel column chromatography to yield 4.4g. b) 2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid chloromethyl ester. 2,2-Dimethyl-3-(N-Boc-L-valyloxy)propionic acid (3.9 g, 12.3 mmole) was dissolved in dioxane (60 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40 %, 7.78 ml, 12 mmole). The solution was dried in vacuo, and it was coevaporated with toluene for several times. The residue was dissolved in methylene chloride and then chloroiodomethane (18.9 ml, 260 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography to yield 3.7 g. c) 2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid iodomethyl ester. 2,2-Dimethyl-3-( N-Boc-L-valyloxy)propionic acid chloromethyl ester ( 3.6 g, 10 mmole ) was dissolved in acetonitrile (50 ml). Sodium iodide (2.1 g, 14 mmole) was added to the solution. After reaction at 70° C for 2 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave 4.34g of the titled product.. Η-NMR (CDC1 3 ): 5.92 (dd, 2H) 5.10 (d, 1H) 4.24 (m, 1H) 4.15 (dd, 2H) 2.01 (m, 1H) 1.44 (s, 9H) 1.25 (d, 6H) 0.91 (m, 6H ) 50 Example P-I-3 3.3- bis (N-CBz-L-valyloxymethylVpropionic acid iodomethyl ester a) 3,3-Bis (N-CBz-L-valyloxymethyl)-ρropionic acid chloromethyl ester. 3,3- bis (N-CBz-L-valyloxymethyl)-propionic acid (3 g, 5 mmole) prepared according to PCT/SE99/00194) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40 %, 3.11 ml, 4.8 mmole). The solution was dried in vacuo, and it was coevaporated with toluene several times. The residue was dissolved in methylene chloride (15 ml) and then chloroiodomethane (7.3 ml, 100 mmole) was added to the solution. The reaction solution was refluxed for 18 hr and then evaporated and the product was isolated with silica gel column chromatography. 900 mg. b) 3,3-bis-(N-CBz-L-valyloxymethyl)propionic acid iodomethyl ester . 3,3-Bis (N-CBz-L-valyloxymethyl)-propionic acid chloromethyl ester (900 mg, 1.38 mmole) was dissolved in acetonitrile (5 ml). Sodium iodide (289 mg, 1.93 mmole) was added to the solution. After reaction at 70° C for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (5 ml) and refiltered. The solution was dried and gave the titled product. 800 mg. 'H-NMR (CDC1 3 ): 7.35 (m, 10 H) 5.88 (dd, 2H) 5.25 (d, 2H) 4.29 (m, 2H) 4.18 (m, 4H) 2.56 (m, 1H) 2.42 (d, 2H) 2.16 (m, 2H) 0.93 (m 12 H) Example P-I-4 2-(N-CBz-L-valyloxy)ethoxycarbonyloxymethyl iodide 51 2-(N-CBz-L-valyloxy)ethoxycarbonyloxymethyl chloride (1.16 g, 3 mmole) was dissolved in acetonitrile (10 ml). Sodium iodide (630 g, 4.2 mmole) was added to the solution. After reaction at 65° C for 2.5 hr, the reaction mixture was cooled down to room temperature and filtered and the residue was dissolved in methylene chloride (5 ml) and refiltered. The solution was dried and gave the titled product. 1.2 g. 'H-NMR (CDClj): 7.35 (m, 5H) 5.93 (dd, 2H) 5.26 (d, 1H) 5.11 (s, 2H) 4.39 (m, 5H) 2.18 (m, lH) 0.94 (m, 6 H). Example P-I-5 1.3-bis(TSr-tert-butoxycarbonyl-L-valyloxy " )-2-propyl iodomethyl carbonate) O N-Boc-Valyl — O- J^ O O "I N-Boc-Valyl — a) l-O-(N-tert-butoxycarbonyl-L-valyl)glycerol. N-tert-Butoxycarbonyl-L-valine (32.53 g, 0.150 mol), NN'-dicyclohexyl- carbodiimide (37.85 g, 0.183 mol, and 4-dimethylaminopyridine (1.83 g, 0.015 mol) were added to glycerol (138.12 g., 1.5 mol) in 500 mL dry DMF and the mixture was stirred at rt under N 2 for 3 days. The reaction mixture was filtered, concentrated under vacuum, and then partitioned between 300 mL EtOAc and 150 mL H 2 O. The aqueous phase was reextracted with 150 mL EtOAc. The organic phases were combined and washed successively with 100 mL each of saturated aqueous NaHCO 3 , saturated NH 4 C1, and brine. Drying over anhydrous Na 2 SO4, and concentration under vacuum gave a viscous light yellow oil as crude product. Flash column chromatography on silica gel with 4/1 EtOAc - petroleum ether (BP 40-60 °C) gave 18.27 g (42%) of product (alternative nomenclature: 3-(N-tert- 52 butoxycarbonyl-L-valyloxy)-l,2-propanediol). Reactions done overnight gave similar yields. b) 1 ,3-di-0-(7V-tert-butoxycarbonyl-L-valyl)glycerol. l-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (17.95 g. 61.6 mmol), Boc-L-valine (6.69 g, 30.8 mmol), DMAP (0.38 g, 3.1 mmol), and DCC (7.10 g, 34.4 mmol) in 240 mL CH 2 C1 2 and 60 mL DMF were stirred at rt under N 2 for 18 h. The reaction mixture was filtered, concentrated under vacuum, and redissolved in 200 mL EtOAc. The organic solution was washed with 50 mL saturated NH 4 C1. The aqueous phase was reextracted with 50 mL EtOAc. The organic phases were combined, washed successively with 50 mL saturated NaHCO 3 and 50 mL brine, dried over Na^O^ and concentrated under vacuum. Flash column chromatography of the crude material on silica gel (eluent 2/1 petroleum ether - EtOAc, and then EtOAc) gave 7.41 g (49%) of the title compound (alternative nomenclature: l,3-bis(N-tert-butoxycarbonyl-L- valyloxy)-2-propanol). c) 2-O-chloromethoxycarbonyl- 1 ,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol Chloromethyl chloroformate (2.70 mL, 30 mmol) was added to a solution of 1,3-di- 0-(V-tert-butoxycarbonyl-L-valyl)glycerol (7.27 g, 14.8 mmol) and pyridine (7.2 mL, 89 mmol) in 60 mL dry CH 2 C1 2 , in an ice bath, under N 2 . After stirring for 1 h 45 min, the reaction mixture was diluted with 100 mL CH 2 C1 2 and washed with 40 mL water. The aqueous phase was reextracted with 20 mL H 2 O. The organic phases were combined, washed with 40 mL saturated NaHCO 3 , followed by 2 x 50 mL brine, dried over Na j SO^ and concentrated under vacuum. Flash column chromatography on silica gel with 2/1 hexane- EtOAc gave 8.03 g (93%) of the title compound (alternative nomenclature: l,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2- propyl chloromethyl carbonate). d) 2-O-iodomethoxycarbonyl- 1 ,3-di-0-(V-tert-butoxycarbonyl-L- valyl)glycerol. A solution of 2-0-chloromethoxycarbonyl-l,3-di-O-(N-tert-butoxycarbonyl-L- valyl)propane-l,2,3-triol (7.86 g, 13.5 mmol) and Nal (8.09 g, 54.0 mmol) in 135 mL dry acetonitirile was refluxed at 80 °C for 4 h under N 2 . The reaction mixture was 53 concentrated under vacuum, and then partitioned between 150 mL diethyl ether and 50 mL H 2 O. The aqueous layer was reextracted with 2 x 25 mL ether. The combined organic phases were washed successively with 25 mL aqueous Na^O;, and 50 mL brine, dried over Na^O^ and concentrated. Flash column chromatography (silica gel, 2/1 hexane-ethyl acetate gave 8.38 g (92%) title product (alternative name: 2- iodomethoxycarbonyloxy- l,3-bis-(N-tert-butoxycarbonyl-L- valyloxy )propane or 1,3- bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl iodomethyl carbonate) as a white solid. Η NMR (250 MHz, CDC1 3 ) δ 0.81 (d, 6H), 0.88 (m, 6H), 1.36 (s, 18H), 2.06 (m, 2H), 4.11-4.46 (m, 6H), 5.0 (br d, 2H), 5.12 (m, 1H), 5.88 (s, 2H). Example P-l-6 3-benzyloxycarbonylpropionic acid iodomethyl ester a) Succinic acid monobenzyl ester . Succinic anhydride (30 g, 300 mmole) was dissolved in methylene chloride (300 ml). To the solution were added benzyl alcohol (10.2 ml, 100 mmole), 4- dimethylaminopyridine (1.22 g, 10 mmole) and pyridine (48 ml). After 3 hours the reaction mixture was poured in to citric acid aqueous solution. The organic phase was concentrated to small volume and sodium hydrogen carbonate and water were added. Then mixture was stirred for 30 min. The aqueous phase was collected, and to it was added citric acid aqueous solution. The product precipitated out, was collected and dried. 15.3 g. b) 3-benzyloxycarbonylpropionic acid chloromethyl ester. Succinic acid monobenzyl ester (4.16 g, 20 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40 %, 11.6 ml, 18 mmole). The solution was dried in vacuo and coevaporated with toluene several times. The residue was dissolved in methylene chloride (60 ml) and then chloroiodomethane (14.5 ml, 200 mmole) was added to the solution. The reaction solution was stirred for 18 hr and then evaporated and the product was isolated with silica gel column chromatography. 3.64 g 54 Η-NMR (CDClj): 7.35 (m, 5H), 5.67 (s, 2H), 5.13 (s, 2H), 2.72 (s, 4H). c) 3-Benzyloxycarbonylpropionic acid iodomethyl ester. 3-Benzyloxycarbonylpropionic acid chloromethyl ester (2 g, 1.38 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.6 g, 10.9 mmole) was added to the solution. After reaction at 70° C for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave intermediate 3-benzyloxycarbonylpropionic acid iodomethyl ester in quantitative yield. This intermediate is bonded to an accessible function of a drug, such as a ring hydroxy or carboxy function using conventional alkylation/acylation conditions as described generally herein. Following deprotection of the terminal carboxy, a di/trifunctional linker bearing R 2 , such as 1,3-bis- O-(L-valyl)glycerol or iodomethyloxy-L-valyl is acylated/alkylated thereon or R 2 amide bonded thereon by conventional techniques as described herein, such as with DCC coupling agent. A-I-l Iodomethyl 2 -methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl ' ) propionate a) 4-Methoxybenzyl 2-(hydroxymethyl)-2-methyl propionate. 2-(Hydroxymethyl)-2-methyl propionic acid was esterified by alkylation with 4- methoxybenzyl chloride by conventional means, namely treatment with aqueous NaOH, followed by evaporation and dissolution in an organic solvent such as DMF to which the 4-methoxybenzyl chloride is added and the reaction warmed and agitated, such as stirring at 60 C for one hour. The reaction mixture is cooled, concentrated by rotavapor and the resulting concentrated suspension partitioned between water and dichloromethane. The organic phase is evaporated and the residue subjected to silica gel column chromatography, for example with 0, 2, 4% EtOH in dichloromethane to yield the title compound (7.10 g). R f (2%MeOH CHCl 3 ) 0.40. b) 4-Methoxybenzyl 2-(N- benzyloxycarbonyl-L-valyloxymethyι)-2- methyl propionate. 55 4-Methoxybenzyl 2-(hydroxymethyl)-2-methyl propionate (2.50 g, 10.5 mmol), N- benzyloxy carbonyl-L-valine (2.51 g, 10 mmole), 4-dimethylaminopyridine (183 mg) and 1 -hydroxybenzotriazole (1.35g, 10 mmole) were mixed and dissolved in N,N- dimethylformamide (90 ml). Then dicyclohexyl-carbodiimide (2.47 g 12 mmol) was added. After stirring for 3 days at room temperature the suspension was filtered and the filtrate evaporated in vacuo. The residue was partitioned between 0.1M citric acid and dichloromethane. The organic phase was then extracted with aqueous saturated NaHCO 3 and evaporated in vacuo. The residue was silica gel column chromatographed (0, 1, 2, 3% ethanol in dichloromethane). The appropriate fractions were pooled and evaporated in vacuo to give the title compound (2.72 g). R f (2%MeOH/CHCl 3 ) 0.75. d) 2-(N- benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionic acid. To a solution of 4-methoxybenzyl 2-(N- benzyloxycarbonyl -L-valyloxymethyl)-2- methyl propionate (2.72 g, 5.76 mmole), was added trifluoroacetic acid (11.5 ml) and the emerging dark red solution was stirred for 30 min at room temperature. The solution was evaporated to dryness with dioxane and toluene. The residue was silica gel column chromatographed (2, 3, 4% ethanol in dichloromethane). The appropriate fractions were pooled and evaporated in vacuo to give the title compound (1.86 g). R f (2%MeOH/CHCl 3 ) 0.30. 'H- MR (CDC1 3 ): 7.32 (s, 5H), 5.32 (d, 1H), 5.10 (s, 2H), 4.32 (d,d, 1H), 4.21 (d,d, 2H), 2.13 (m, 1H), 1.26 (s, 3H), 1.25 (s, 3H), 0.95 (d, 3H), 0.86 (d, 3H). c) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionate. 2-(N- benzyloxycarbonyl -L-valyloxymethyl)-2 -methyl propionic acid was esterified by conventional techniques, namely dissolution in an organic solvent such as dioxane and dropwise addition of aqueous tetrabutylammonium hydroxide, followed by evaporation. The residue is dissolved in dichloromethane and then chloroiodomethane and the mixture stirrred for 6 hours at room temperature, followed by partition, shaking the filtrate with aqueous sodium thiosulphate. 0.1M, filtration and evaporation. The title compound (1.40 g) was obtained after silica gel 56 column chromatography (0, 1, 2, 3% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.80. c) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionate. Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionate was converted to iodide by conventional techniques, namely addition to Nal in acetonitrile, stirring and heating, for instance to 75 C for four hours. The resulting suspension is filtered and the filtrate evaporated, dissolved in organic solvent such as toluene and shaken with aqueous sodium thiosulphate (0.1M) and evaporation to give the title compound (1.25 g) practically pure. R f (2%MeOH/CHCl 3 ) 0.80. 'H-NMR (CDC1 3 ): 7.35 (s, 5H), 5.90 (d,d, 2H), 5.24 (d, 1H), 5.10 (s, 2H), 4.31 (d,d, 1H), 4.14 (d,d, 2H), 2.16 (m, 1H), 1.22 (s, 6H), 0.96 (d, 3H), 0.87 (d, 3H). Example A-I-2 Iodomethyl 2-fN-benzyloxycarbonyl-L-valyloxyVDL-propionate. O O O. Λ CBzNH ° a) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-DL-propionate. 2-(N-benzyloxycarbonyl-L-valyloxy) propionic acid (1 g) was esterified by the method described in Example A-I-I, step d. The title compound (0.76 g) was obtained after silica gel column chromatography (0, 1 % ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.75. b) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-DL-propionate. Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionate was converted to iodide by the method described in Example A-I- 1 , step e to give the title compound (0.95 g) practically pure. R f (2%MeOH/CHCl 3 ) 0.75. 57 'H-NMR (CDCI 3 ): 7.33 (s, 5H), 5.98 (d, 1H), 5.86 (d, 1H), 5.26 (d, 1H), 5.10 (s, 2H), 5.07 (q, 1H), 4.38 (d,d, 1H), 2.30 (m, 1H), 1.49 (d, 3H), 1.03 (d, 3H), 0.95 (d, 3H). Example A-I-3 Iodomethyl ( 1.3-di-(N-benzyloxycarbonylVL-valyloxy 2-propyl carbonate. O N-CBz-Valyl— J^ O "I N-CBz-Valyl— a) Chloromethyl (1 ,3-di-(N-benzyloxycarbonyl)-L-valyloxy)-2-propyl carbonate. To a solution of 1 ,3-di-((N-benzyloxycarbonyl)-L-valyloxy)propan-2-ol (1.34 g, 2.4 mmole) in dichloromethane (10 ml) was added dry pyridine (1.15 ml, 14.4 mmol) and chloromethyl chloro formate (0.43 ml, 4.8 mmole) at 0°C. The reaction was then stirred for 30 min and then poured into aqueous 50% saturated sodium chloride / 0.1M citric acid solution and extracted with dichloromethane. The organic phase was evaporated and the residue silica gel column chromatographed (0, 1, 1.5% ethanol in dichloromethane). The appropriate fractions were pooled and evaporated in vacuo to give the title compound (1.26g). R f (2%MeOH/ CHC1 3 ) 0.85. b) Preparation of iodomethyl (l,3-di-(N-benzyloxycarbonyl)-L-valyloxy)- 2-propyl carbonate. Chloromethyl (l,3-di-(N-benzyloxycarbonyl)valyloxy)-2-propyl carbonate was converted to iodide by the method described in Example A-I-l, step e) to give the title compound (1.37 g) practically pure. R f (2%MeOH/CHCl 3 ) 0.85. 'H-NMR (CDC1 3 ): 7.34 (s, 10H), 5.93 (d, 1H), 5.89 (d, 1H), 5.21 (m, 3H), 5.11 (s, 4H), 4.50-4.17 (m, 6H), 2.12 (m, 2H), 0.97 (d, 6H), 0.88 (d, 6H). Example A-I-4 Iodomethyl 2-( -benzyloxycarbonyl-L-valyloxy1isobutyrate. 58 O O, CBzNH- O ' O a) 4-Methoxybenzyl 2-hydroxyisobutyrate. 2-hydroxy isobutyric acid (1.56 g) was esterified by alkylation with 4- methoxybenzyl chloride by the method described in Example A-I-l, step a). The title compound (2.65 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.45. b) 4-Methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate. 4-methoxybenzyl 2-hydroxyisobutyrate was acylated with N-benzyloxycarbonyl-L- valine by the method described in Example A-I-l, step b). The title compound (3.21 g) was obtained after silica gel column chromatography (0, 1, 1.5% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.70. c) 2-(N-benzyloxycarbonyl-L- valyloxy) isobutyric acid. 4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate was de-esterified by the method described in Example A-I-l step c. The title compound (2.01 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.30. Η-NMR (CDC1 3 ): 7.32 (s, 5H), 5.33 (d, 1H), 5.10 (s, 2H), 4.31 (d,d, 1H), 2.22 (m, 1H), 1.57 (s, 6H), 0.98 (d, 3H), 0.89 (d, 3H). d) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate. 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyric acid was esterified by the method described in Example A-I-l , step d. The title compound (1.90 g) was obtained after silica gel column chromatography (0, 1, 1.5% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.80. e) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate. 59 Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate was converted to iodide by the method described in Example A-I-l, step e to give the title compound (2.32 g) practically pure. R f (2%MeOH/CHCl 3 ) 0.80. 'H-NMR (CDC1 3 ): 7.33 (s, 5H), 5.89 (s, 2H), 5.22 (d, 1H), 5.11 (s, 2H), 4.29 (d,d, 1H), 2.21 (m, 1H), 1.55 (s, 3H), 1.53 (s, 3H), 1.00 (d, 3H), 0.93 (d, 3H). EXAMPLE A-I-5 Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxyV3-methyl-(SV( ' +Vbutyrate. O O, CBzNH' O O a) 4-Methoxybenzyl 2-hydroxy-3-methyl-(S)-(+)-butyrate. 2-hydroxy-3-methyl-(S)-(+)-butyric acid (1.77 g) was esterified by alkylation with 4- methoxybenzyl chloride by the method described in Example A-I-l, step a. The title compound (3.10 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.50. b) 4-Methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3 -methyl-(S)- (+)-butyrate. 4-Methoxybenzyl 2-hydroxy-3-methyl-(S)-(+)-butyrate was acylated with N- benzyloxycarbonyl-L-valine by the method described in Example A-I-l, step b. The title compound (5.74 g) was obtained after silica gel column chromatography (0, 1, 1.5% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.70. c) 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyric acid. 4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate was de-esterified by the method described in Example A-I-l, step c. The title compound (3.41 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). R f (2%MeOH CHCl 3 ) 0.45. 60 'H-NMR (CDCI 3 ): 7.36 (s, 5H), 5.38 (d, 1H), 5.11 (s, 4H), 4.90 (d, 1H), 4.41 (d,d, 1H), 2.28 (m, 2H), 1.04-0.89 (m, 12H). d) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3 -methyl-(S)-(+)- butyrate. 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyric acid was esterified by the method described in Example A-I-l, step d. The title compound (2.96 g) was obtained after silica gel column chromatography (0, 1 , 2% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.85. e) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)- butyrate. Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate was converted to iodide by the method described in Example A-I-l , step e to give the title compound (3.64 g) practically pure. R f (2%MeOH/CHCl 3 ) 0.85. 'H-NMR (CDC1 3 ): 7.36 (s, 5H), 6.00 (d, 1H), 5.83 (d, 1H), 5.28 (d, 1H), 5.11 (s, 4H), 4.83 (d, 1H), 4.41 (d,d, 1H), 2.29 (m, 2H), 1.05-0.90 (m, 12H). EXAMPLE A-I-6 Iodomethyl 2-fN-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate. O O, CBzNH" o O a) 4-Methoxybenzyl 2-hydroxy-2-phenyl-DL-acetate. DL-mandelic acid (2.28 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-l , step a. The title compound (3.69 g) was obtained after silica gel column chromatography (0, 1, 1.5% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.55. 61 b) 4-Methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL- acetate. 4-Methoxybenzyl 2-hydroxy-2-phenyl-DL-acetate was acylated with N- benzyloxycarbonyl-L- valine by the method described in Example A-I-l, step b. The title compound (6.50 g) was obtained after silica gel column chromatography (0, 1, 1.5% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.75. c) 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetic acid. 4-Methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate was de-esterified by the method described in Example A-I-l , step c. The title compound (4.75 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.40. 'H-NMR (CDC1 3 ): 7.36 (m, 10H), 5.91 (d, 1H), 5.27 (m, 1H), 5.04 (s, 2H), 4.57-4.40 (2xd,d, 1H), 2.30 (m, 1H), 1.01-0.82 (m, 6H). d) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL- acetate. 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetic acid was esterified by the method described in Example A-I-l, step d. The title compound (1.69 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.80. e) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate. Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate was converted to iodide by the method described in Example A-I-l, step e to give the title compound (1.89 g) practically pure. R f (2%MeOH/CHCl 3 ) 0.80. Η-NMR (CDC1 3 ): 7.36 (m, 10H), 5.94-5.82 (m, 3H), 5.28 (m, 1H), 5.10 (s, 2H), 4.46 (m, 1H), 2.21 (m, 1H), 1.08-0.85 (m, 6H). Example A-I- 7 62 Iodomethyl 4-fN-benzyloxycarbonyl-L-valyloxy) benzoate. CBzNH O a) 4-Methoxybenzyl 4-hydroxybenzoate. 4-Hydroxybenzoic acid (1.38 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-l, step a. The title compound (2.06 g) was obtained after silica gel column chromatography (0, 1, 2, 3% ethanol in dichloromethane). R f (2%MeOH CHCl 3 ) 0.40. b) 4-Methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate. 4-Methoxybenzyl 4-hydroxybenzoate was acylated with N-benzyloxycarbonyl-L- valine by the method described in Example A-I-l, step b. The title compound (2.71 g) was obtained after silica gel column chromatography (0, 1% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.70. c) 4-(N-benzyloxycarbonyl-L-valyloxy) benzoic acid. 4-Methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate was de-esterified by the method described in Example A-I-l, step c. The title compound (1.86 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.20. 'H-NMR (CDC1 3 ): 8.15 (d, 2H), 7.34 (m, 5H), 7.22 (d, 2H), 5.38 (d, 1H), 5.17 (s, 2H), 4.58 (d,d, 1H), 2.34 (m, 1H), 1.12 (s, 3H), 0.96 (d, 3H). d) Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate. 4-(N-benzyloxycarbonyl-L-valyloxy) benzoic acid was esterified by the method described in Example A-I-l, step d. The title compound (0.95 g) was obtained after silica gel column chromatography (0, 1% ethanol in dichloromethane). R f (2%MeOH/CHCl 3 ) 0.80. 63 e) Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate. Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate was converted to iodide by the method described in Example A-I-l, step e to give the title compound (1.16 g) practically pure. R f (2%MeOH/CHCl 3 ) 0.80. 'H-NMR (CDC1 3 ): 8.11 (d, 2H), 7.35 (m, 5H), 7.21 (d, 2H), 6.15 (s, 2H), 5.32 (d, IH), 5.14 (s, 2H), 4.55 (d,d, IH), 2.34 (m, IH), 1.10 (s, 3H), 1.03 (d, 3H). Example A- 1-8 Iodomethyl 5-(N-CBz-L-valyloxy)-2.2-dimethylvalerate O .Cbz-Val a) 4-Methoxybenzyl 2,2-dimethyl-4-pentenoate To a solution of 2,2-dimethyl-4-pentenoic acid (11.5 g, 90 mmol) in DMF (250 mL) at room temperature, was added potassium tert-butoxide (11.1 g, 99 mmol). The reaction mixture was stirred at 60 °C for lh. 4-Methoxybenzyl chloride (16.9 g, 108 mmol) was added and the reaction mixture was stirred at 60 °C for 4h. The DMF was evaporated under vacuum, the residue was dissolved in ether (500 mL) and washed with water (3 x 200 mL). The organic phase was dried with Na 2 SO 4 and evaporated to give 21.4 g of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate. b) 4-Methoxybenzyl 5-hydroxy-2,2-dimethylvalerate. A mixture of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate (9.50 g, 38 mmol) and 9- BBN (115 mL, 57 mmol, 0.5 M in THF) was stirred at 60 °C for 60 min, whereupon the reaction mixture was cooled to -5 °C. H 2 O (35 mL) was added, the reaction mixture was stirred for 5 min at -5 °C, an aqueous solution of NaOH (35 mL, 3M) was added and the reaction mixture was stirred for a further 10 min at -5 °C. An aqueous solution of H 2 O 2 (35 mL, 30%) was added dropwise and the temperature of the reaction mixture was allowed to assume room temperature, whereupon the reaction mixture was stirred for 30 min at room temperature. After evaporation, water (200 mL) was added and the resulting mixture was extracted with CH 2 C1 2 (5 x 200 mL). The combined organic layers were dried (Na-^SOJ and concentrated under 64 reduced pressure. The crude product was column chromatographed (silica gel, 1→8% MeOH in CH 2 C1 2 ), to give 6.32 g of 4-methoxybenzyl 5-hydroxy-2,2- dimethylvalerate. c) 4-Methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate. To a mixture of DCC (9.41 g, 46 mmol), DMAP (0.586 g, 4.8 mmol) and N-CBz-L- valine (12.1 g, 48 mmol) in CH 2 C1 2 (200 mL) at 0 °C, was added dropwise a solution of 4-methoxybenzyl 5-hydroxy-2,2-dimethyl-valerate (6.40 g, 24 mmol) in CH 2 C1 2 (50 mL). After lh at 0 °C, the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 1→4% MeOH in CH 2 C1 2 ), to give 8.61 g 4-methoxybenzyl 5-(N-CBz-L- valyloxy)-2,2-dimethylvalerate. d) 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid. To a solution of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (8.24 g, 16.5 mmol) in CH 2 C1 2 (100 mL) at room temperature, was added trifluoroacetic acid (5 mL). After lh at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3- 5% MeOH in CH 2 C1 2 ), to give 6.00 g of 5-(N-CBz-L-valyloxy)-2,2- dimethylvaleric acid. 'H-NMR (CDC1 3 ): 10.94 (br s, IH), 7.35 (s, 5H), 5.45 (d, IH), 5.11 (s, 2H), 4.30 (dd, IH), 4.21-4.00 (m, 2H), 2.28-2.07 (m, IH), 1.68-1.51 (m, 4H), 1.21 (s, 6H), 0.97 (d, 3H), 0.89 (d, 3H). e) Chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate. To a solution of 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid (5.88 g, 15.5 mmol) in dioxane (100 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (10.1 g). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue 65 was dissolved in dichloromethane (100 mL) and then chloroiodomethane (11.3 mL, 155 mmol) was added and the solution was stirred for 6h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane / ethyl acetate (1:1 v/v, 200 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1-4% MeOH in CH 2 C1 2 ), to give 3.95 g of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate. f) Iodomethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate. To a solution of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (3.85 g, 9 mmol) in acetonitrile (50 mL), was added sodium iodide (5.40 g, 36 mmol). The solution was stirred for 4 h at 60 °C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH 2 C1 2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na j SO and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH 2 C1 2 ), to give 4.26 g of iodomethyl 5- (N-CBz-L-valyloxy)-2,2-dimethylvalerate 'H-NMR (CDC1 3 ): 7.34 (s, 5H), 5.90 (s, 2H), 5.32 (d, IH), 5.10 (s, 2H), 4.29 (dd, IH), 4.18-4.02 (m, 2H), 2.26-2.08 (m, IH), 1.65-1.50 (m, 4H), 1.17 (s, 6H), 0.97 (d, 3H), 0.89 (d, 3H). Example A- 1-9 2-(N-CBz-L-valyloxyVethyl iodomethyl carbonate O A \ O-(N-Cbz)-Val I O O ^ a) 2-(N-CBz-L-valyloxy)-ethanol To a mixture of DCC (11.4 g, 55 mmol), DMAP (0.611 g, 5 mmol) and ethyleneglycol (55.8 mL, 1 mol) in CH 2 C1 2 (300 mL) at 0 °C, was added dropwise a solution of N-CBz-L-valine (12.6 g, 50 mmol) in CH 2 C1 2 (100 mL). After lh at 0 °C, the temperature of the reaction mixture was allowed to assume room temperature and 66 then the mixture was stirred for 5h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 5— »10% MeOH in CH 2 C1 2 ), to give 12.0 g 2-(N-CBz-L-valyloxy)-ethanol. b) 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate. To a mixture of 2-(N-CBz-L-valyloxy)-ethanol (12.0 g, 40.6 mmol) and pyridine (19.7 mL, 0.24 mmol) in CH 2 C1 2 (300 mL) at 0 °C, was added dropwise chloromethyl chloroformate (10.5 g, 81.2 mmol). After 30 min at 0 °C, the reaction mixture was washed with H 2 O (200 mL). The H 2 O phase was washed with CH 2 C1 2 (100 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was column chromatographed (silica gel, 0.5→1% MeOH in CH 2 C1 2 ), to give 8.26 g 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate. c) 2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate. To a solution of 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate (3.88 g, 10 mmol) in acetonitrile (50 mL), was added sodium iodide (7.50 g, 50 mmol). The solution was stirred for 4 h at 60 °C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH 2 C1 2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na j SO and concentrated under reduced pressure, to give 4.51 g 2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate. 'H-NMR (CDC1 3 ): 7.34 (s, 5H), 5.93 (s, 2H), 5.26 (d, IH), 5.11 (s, 2H), 4.48-4.26 (m, 5H) 2.28-2.10 (m, IH), 0.97 (d, 3H), 0.90 (d, 3H). Example A-I- 10 2.2-dimethyl-3-( N-CBz-D-valyloxyVpropionic acid iodomethyl ester X O HN o- 67 a) 2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid. To a solution of 2,2-dimethyl propionic acid 4-methoxybenzyl ester (4.7 g, 20 mmole) and N-CBz-D-valine (5.5 g, 22 mmole) in dichloromethane (100 ml) were added 4-dimethyaminopyridine (305 mg, 2.5 mmole) and DCC (5.15 g, 25 mmole). After 18 hr, the solution was washed successively with sodium bicarbonate aqueous solution, citric acid solution and water. The organic phase was dried and the residue was dissolved in dichloromethane (100 ml). To the solution was added trifluoroacetic acid (10 ml). After 3 hr, it was evaporated and the product was isolated with silica gel column chromatography. 4.5 g. 'H-NMR (CDC1 3 ): 7.36 (m, 5 H) 5.11 (s, 2H) 4.30 (m, IH) 4.18 (dd, 2H) 2.17 (m, IH), 1.23 (d, 6 H) 0.93 (m, 6H). b) 2,2-dimethyl-3- ( N-CBz-D- Valyloxy )-propionic acid chloromethyl ester. (2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid (4.5 g, 12.8 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40 %, 8.3 ml, 12.8 mmole). The solution was dried in vacuo, and it was coevaporated with toluene several times. The residue was dissolved in methylene chloride and then chloroiodomethane (18 ml, 260 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography. 3.5 g. c) 2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid iodomethyl ester. 2,2-Dimethyl-3-(N-CBz-D-valyloxy)-propionic acid chloromethyl ester (2.4 g, 6 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.26 g, 8.4 mmole) was added to the solution. After reaction at 70° C for 2 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave the titled product. 2.68g. Η-NMR (CDC1 3 ): 7.36 (m, 5 H) 5.90 (dd, 2H) 5.26 (d, IH) 5.11 (s, 2H) 4.31 (m, IH) 4.15 (dd, 2H) 2.18 (m, IH) 1.22 (d, 6H) 0.92 (m, 6H). 68 Example A-l -11 4-(N-CBz-L-valyloxy) butyric acid iodomethyl ester a) 4-(N-CBz-L-valyloxy) butyric acid t-butyl ester. N-CBz-L-valine (16.25 g, 65 mmole) was dissolved in DMF (40 ml). To the solution was added potassium t-butoxide (7.24 g, 65 mmole). After 10 min, 4-bromobutyric acid t-butyl ester (12 g, 53 mmole) was added. The reaction mixture was kept at 65° C for 2.5 hr and then poured into sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was dried and the product was isolated with silica gel column chromatography. 20.1 g. b) 4-(N-CBz-L-valyloxy)butyric acid chloromethyl ester. 4-( N-CBz-L-valyloxy) butyric acid t-butyl ester (20 g, 50.8 mmole) was treated with trifluoroacetic acid (30 ml) at 0° C for 3 h and then evaporated. The residue was coevaporated with toluene several time. The intermediate acid (2.56 g, 7.6 mmole) was dissolved in dioxane (10 ml) and to the solution was added tetrabutylammonium hydroxide (40 %, 4.66 ml, 7.2 mmole). The solution was dried and dissolved in dichloromethane (20 ml) and then chloroiodomethane (10 ml, 144 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography. Yield 2.1 g. c) 4-(N-CBz-L-valyloxy)butyric acid iodomethyl ester. 4-(N-CBz-L- valyloxy) butyric acid chloromethyl ester (1.54 g, 4 mmole) was dissolved in acetonitrile (15 ml). Sodium iodide (840 mg, 5.6 mmole) was added to the solution. After reaction at 55° C for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave the titled product. Yield 1.9 g. 69 Η-NMR (CDCI 3 ): 7.36 (m, 5H) 5.90 (dd, 2 H) 5.25 (d, IH) 5.11 (s, 2H) 4.29 (dd, IH 4.18 (t, 2H) 2.43 (t, 2H) 2.20 (m, IH) 2.00 (m, 2H) 0.93 (dd, 6 H). Example A-I- 12 Iodomethyl 3-fN-benzyloxycarbonyl-L-valyloxyVbenzoate O CBzNH O ^ a) 4-Methoxybenzyl 3-hydroxybenzoate. To a solution of 3-hydroxybenzoic acid (6.9g, 50 mmole) in DMF (100 ml) was added potassium-tert.-butoxide (6.17 g, 55 mmole) and the mixture was stirred at room temperature for one hour. 4-Methoxybenzyl chloride (9.4g, 60 mmole) was added and the mixture was stirred for 16 hours at 60°C. The mixture was evaporated under reduced pressure and ethyl acetate (250 ml) were added. The organic phase was washed five times with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 10.5g = 81 % b) 4-Methoxybenzyl 3-(N-benzyloxycarbonyl-L-valyloxy) benzoate. To a cooled solution of 4-methoxybenzyl 3-hydroxybenzoate (7.7g, 29.8 mmole), 4- dimethylaminopyridine (0.73g, 6 mmole) and N-benzyloxycarbonyl-L-valine (8.3g, 33 mmole) in 100 ml dichloromethane was added dicyclohexyl-carbodiimide (7.22g, 35 mmole) and the mixture was stirred for 2 days at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated and ethyl acetate (250 ml) was added. The organic phase was washed twice with 5% acetic acid; 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 13.9g = 94% c) 3 -(N-benzyloxycarbonyl-L- valyloxy) benzoic acid. 70 To a solution of 4-methoxybenzyl-3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (13.7g, 27.8 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred for 2 hours at room temperature. The solution was evaporated under reduced pressure and the product crystallized from toluene. Yield: 10.1g = 87%. 'H-NMR (DMSO d-6) 1.01 (m, 6H) 2.21 (m, IH) 4.17 (d, d, IH) 5.08 (s, 2H) 7.28-7.96 (m, 10H) d) Chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate. To a solution of 3-(N-benzyloxycarbonyl-valyloxy)benzoic acid (7.42g, 20 mmole) in 1,4-dioxane (100 ml) was added a 40% solution of tetrabutylammonium hydroxide (12.97g, 20 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (50 ml) and chloroiodomethane (35.3g, 200 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Ethyl acetate (100 ml) was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure: The product was isolated by silica gel column chromatography. Yield: 3.8g = 45%. e) Iodomethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate. To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (2.0g, 4.76 mmole) in dry acetone (30 ml) was added sodium iodide (3.15g, 21 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.3g = 94%. 'H-NMR (CDC1 3 ) 1.02 (m, 6H) 2.38 (m, IH) 4.56 (d, d , IH) 5.14 (s , 2H) 5.30 (d, IH) 6.14 (s, 2H) 7.26-7.50 (m, 7H) 7.80(s, IH) 7.96 (d, IH) 71 Example A-I- 13 Iodomethyl 3-(N-benzyloxycarbonyl-L-valyloxyVpropionate 0 O I ^ O ^ oA NHCBz a) 3-buten- 1 -yl-3-(N-benzyloxycarbonyl)-propionate. To a solution of 3-buten-l-ol (2.16g, 30 mmole), N-benzyloxycarbonyl-1-valine (8.29g, 33 mmole) and 4-dimethylaminopyridine (0.37g, 3 mmole) in dichloromethane (80 ml) was added dicyclohexyl-carbodiimide (7.22g, 35 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated under reduced pressure and ethyl acetate (200 ml) was added. The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 8.3g = 90%. b) 3-(N-benzyloxycarbonyl-L-valyloxy)-propanoic acid. To a solution of 3-buten-l-yl -3-( N-benzyloxycarbonyl-L-valyloxy)-propionate (9.2g, 30 mmole) in 150 ml benzene was added tetrabutylammonium bromide (1.62g, 5 mmole) and 100 ml water. The mixture was cooled to about 5°C and potassium permanganate (14.82g, 90 mmole) was added in portions. The mixture was stirred 2 hours at room temperature, diluted with water and decolorized by the addition of sodium bisulfite. The mixture was acidified with 2M hydrogen chloride and extracted 3 times with ethyl acetate. The combined organic phases were washed with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 5.4g = 55%. 'H-NMR (DMSO d-6) 0.90 (m, 6H) 2.5 (m, 2H) 3.88 (d, d, IH) 4.32 (m, 2H) 5.03 (s, 2H) 7.36 (m, 5H) 7.68 (d, IH) 72 c) Chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-propionate. To a solution of 3-(N-benzyloxycarbonyl-L-valyloxy)propanoic acid (5.2g, 16.08 mmole) in 1,4-dioxane (50 ml) was added a 40% solution of tetrabutylammonium hydroxide (10.43g, 16.08 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 40 ml dichloromethane and chloroiodomethane (28.4g. 160 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Ethyl acetate (100 ml) was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2.2g = 35% d) Iodomethyl3-( N-benzyloxycarbonyl-L-valyloxy)-propionate. To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (2.05g, 5.51 mmole) in dry acetone (50 ml) was added sodium iodide (4.12g, 27.5 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl acetate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.35g = 92%. 'H-NMR (CDC1 3 ) 0.94 (m, 6H) 2.17 (m, IH) 2.68 (t, 2H) 4.40 (m, 3H) 5.12 (s, 2H) 5.91 (s, 2H) 7.26 (m, 5H). Example A-I-l 3 A 13-bis(JV-tert-butoxycarbonyl-L-valyloxyV2-propyl 1 -iodoethyl carbonate 73 a) l,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-chloroethyl carbonate. To a solution of l,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propanol (0.545 g, 1.11 mmol) in 5 mL dry CH 2 C1 2 were added pyridine (540 μL, 6.68 mmol), with cooling and stirring in an ice bath, followed by 1-chloroethyl chloro formate (242 μL, 2.22 mmol). After 1 h, the reaction mixture was diluted with 5 mL CH 2 C1 2 and washed with water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous Na;,SO 4 and concentrated on a rotavapor, coevapoating several times with toluene. Column chromatogaphy (silica, 4/1 petroleum ether - ethyl acetate) gave the chloride (596 mg, 90%) as a white solid. b) 1 ,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1 -iodoethyl carbonate. A mixture of the chloride (596 mg, 1.0 mmol) from step (a) and Nal (684 mg, 4.57 mmol) in 10 ml dry MeCN was refluxed at 80 °C for 4 h. The reaction mixture was concentrated under vacuum and then partitioned between 30 mL diethyl ether and 10 mL water. The organic phase was washed with 5% aqueous sodium thiosulfate (2 x 5 mL), and the last aqueous layer was reextracted with ether (5 mL). The organic phases were combined, washed with brine, dried over Na^O^ and concentrated. Flash column chromatography (silica, 4/1 petroleum ether - ethyl acetate) gave a fraction (275 mg) containing 80% iodide, as determined from 'H NMR, and small amounts of the starting chloride and alkene from the elimination side reaction. 'H NMR (250 MHz, CDC1 3 ) δ 0.81-0.85 (m, 6H), 0.88-0.92 (m, 6H), 1.37 (s, 18H), 2.05 (m, 2H), 2.17 (d, 3H, J= 6.1 Hz), 4.12-4.46 (m, 6H), 5.00 (d, 2H, J= 8.8 Hz), 5.11 (m, IH), 6.68 and 6.69 (2 sets of q, IH, J= 6.1 Hz). 74 Example A-I- 14 3-(N-benzyloxycarbonyl-L-valyloxyV2.2-dimethylpropyl iodomethyl carbonate (a) 3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethyl- 1 -propanol. A mixture of N-benzyloxycarbonyl-L- valine (2.50 g, 10.0 mmol), 2,2-dimethyl-l,3- propanediol (5.30 g, 50.9 mmol), dicyclohexylcarbodiimide (2.60 g, 12.6 mmol), and 4-dimethylaminopyridine (125 mg, 1.0 mmol) in 100 mL dry CH 2 C1 2 was stirred for 23 h. The reaction mixture was filtered and washed successively with 50 mL each of water, saturated aqueous ΝH 4 C1, saturated aqueous NaHCO 3 , and water. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated. The title compound (2.99 g, 87%) was isolated by flash column chromatography (silica, 2/1 petroleum ether - ethyl acetate) as a white waxy solid. (b) 3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropyl chloromethyl carbonate. Chloromethyl chloro formate (1.50 mL, 16.6 mmol) was added to a solution of the alcohol (2.74 g, 8.12 mmol) from step (a) and pyridine (4.9 mL, 61 mmol) in 40 mL dry CH 2 C1 2 , in an ice bath. After stirring for 1 h, the mixture was diluted with CH 2 C1 2 and washed successively with water, saturated ΝaHCO 3 , and brine. The organic phase was dried over anhydrous NajSO, and concentrated, coevaporating several times with toluene on a rotavapor. Flash column chromatography (silica, 2/1 petroleum ether - ethyl acetate) gave 3.31 g (95%) of the title compound. (c) 3 -(N-benzyloxycarbonyl-L- valyloxy)-2,2-dimethylpropyl iodomethyl carbonate. A mixture of the chloride (3.14 g, 7.30 mmol) from step (b) and Νal (4.37 g, 29.2 mmol) in 73 mL dry MeCΝ was refluxed at 80 °C for 3 h. After removal of solvent under vacuum, the mixture was partitioned between 80 mL ethyl acetate and 40 mL water. The organic phase was washed with 5% Νa^O^ and then brine, dried over 75 anhydrous Na ; ,SO 4 , and concentrated. Flash column chromatography (silica, petroleum ether - ethyl acetate) gave 3.68 g (97%) of the title compound. 'H NMR (250 MHz, CDC1 3 ) δ 0.88 and 0.96 (2d, 3H each), 0.98 (s, 6H), 2.18 (m, IH), 3.94 and 4.02 (2s, 2H each), 4.32 (dd, IH, J= 9.0, 4.7 Hz), 5.11 (s, 2H), 5.26 (d, IH), 5.92 and 5.93 (ABq, 2H, J AB = 5.1Hz), 7.35 (s, 5H). Example A-I- 15 1 -(N-benzyloxycarbonyl-L- valyloxy V2-methyl-2-propyl iodomethyl carbonate (a) 1 -(N-benzyloxycarbonyl-L- valyloxy)-2-methyl-2-propanol N-Benzyloxycarbonyl-L- valine (2.02 g, 8.0 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol), and ), and dicyclohexylcarbodiimide (2.04 g, 9.9 mmol, in 20 mL CH 2 C1 2 ) were added to 2-methyl-l,2-propanediol (12.2 mmol) in 30 mL dry CH 2 C1 2 , with cooling in an ice bath. DMF (5 mL) was added. After stirring for 5 h at 10 °C , the reaction mixture was filtered, concentrated, and then redissolved in ethyl acetate. The organic solution was washed with saturated ΝaCl, dried over anhydrous ΝajSO^ and concentrated. Flash column chromatography (silica, 2/1 petroleum ether - ethyl acetate) gave 2.3 g of the title compound. (b) 1 -(N-benzyloxycarbonyl-L- valyloxy)-2-methyl-2-propyl chloromethyl carbonate. All of the alcohol from above was dissolved in 35 mL dry CH 2 C1 2 and cooled in an ice bath. Pyridine (3.50 mL, 43.4 mmol) was added, followed by chloromethyl chloroformate (1.30 mL, 14.4 mmol). After 1 h, the ice bath was removed and stirring was continued for 2 h at ambient temperature.The mixture was diluted with CH 2 C1 2 (50 mL) and washed with water (50 mL), and then brine (2 x 25 mL).Drying over anhydrous Νa 2 SO 4 of the combined organic phases and concentration under vacuum, coevaporating several times with toluene, gave a yellow-brown oil that was subjected to flash column chromatography (silica, 2/1 petroleum ether - ethyl 76 acetate) to yield 2.86 g (86% from N-benzyloxycarbonyl-L-valine) of the title compound. (c) 1 -(N-benzyloxycarbonyl-L- valyloxy)-2-methyl-2-propyl iodomethyl carbonate. A mixture of the chloride (2.84 g, 6.84 mmol) from step (b) and Νal (4.15 g, 27.2 mmol) in 68 mL dry acetonitrile was refluxed at 75 °C for 4 h. After evaporation of solvent under vacuum, the residue was partitioned between ethyl acetate (80 mL) and water (40 mL), and the organic layer was washed with 5% Νa^O ; , (15 mL) and brine (25 mL). Drying the organic phase over anhydrous Νa^O,, and concentration gave a yellow oil that was subjected to flash column chromatography (silica, 2/1 petroleum ether - ethyl acetate) to furnish 3.29 g (95%) of the title compound. Η ΝMR (250 MHz, CDC1 3 ) δ 0.90 and 0.94 (2d, 3H each, J= 6.8 Hz), 1.52 (s, 6H), 2.17 (m, IH), 4.35 (m, IH), 4.22 and 4.39 (ABq, 2H, J AB = 11.7 Hz), 5.10 (s, 2H), 5.30 (d, IH), 5.86 (s, 2H), 7.34 (s, 5H) Example A-I- 16 Iodomethyl 3 ^-di-fl ' -CBZ-L-valyloxVlhvdrocinnamate a) 4-Methoxybenzyl-3 ,4-dihydroxyhydrocinnamate. 3,4-Dihydroxycinnamic acid (6.5 g, 35.7 mmol) was dissolved in DMF (50 ml) and cooled to 0°C on an ice-bath. 4-Potassium tert-butoxide (35.7 mmol), was then added and the mixture was left for approximately 30 min at 0°C, followed by dropwise adition of 4-methoxy-benzylchloride (39 mmol) in DMF (25 ml). The mixture was allowed to reach room temperature and left over-night. The solvent was then evaporated and the crude product was purified by chromatography (ethyl acetate- hexane, 1:1) to give 6 g of the title compound (55%). 77 b) 4-Methoxybenzyl-3 ,4-di-(N-CBZ-L-valyloxy)hydrocinnamate. 4-Methoxybenzyl-3,4-dihydroxyhydrocinnamate (5 g, 16.5 mmol), NN- dimethylaminopyridine (2g, 16.5 mmol), NN'- dicychlohexyl carbodiimide (8.5 g, 41.3 mmol) and Cbz-L-valine (10.4 g, 41.3 mmol) were dissolved in dichloromethane (50 ml). After 4 h, the the mixture was filtered and evaporated onto silica gel and purified by chromatography (hexane-EtOAc, 5:2 —> 3:2) to give pure title product (10.1 g, 79 %). c) 3,4-Di-(Ν-CBZ-L-valyloxy)hydrocinnamic acid. 4-Methoxybenzyl-3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (10 g, 13 mmol) was dissolved in dichloromethane and 1,1,1 trifluoroacetic acid (30 ml) and left at ambient temperature for 3.5 h. Evaporation under reduced pressure and purification by chromatography (chloroform-methanol, 10:1) yielded 6.7 g (80%) pure title product. Η NMR (CDC1 3 45 °C): 7. 24-7.0 (m, 13H), 5.65 (br s, IH), 5.55 (br s, IH), 5.1 (m, 4H), 4.46 (m, 2H), 2.95 (t, 2H), 2.66 (t, 2H), 2.35 (m, 2H). d) Chloromethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate. 3,4-Di-(N-CBZ-L-valyloxy)hydrocinnamic acid (4.2 g, 6.47 mmol) was dissolved in dioxane (70 ml). Tetrabutylammonium hydroxide was added dropwise until pH=8. The solvent was then removed under reduced pressure The solid was redissolved in dioxane (30 ml) and toluene (30 ml) and evaporated. The procedure was repeated twice (for removal of water). Dichloromethane (60 ml) and chloro-iodomethane was added in one portion and the mixture was left at ambient temperature for 6 h. Evaporation of the solvent and purification by chromatography yielded 1.7 g title product (38%). e) Iodomethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate. Chloromethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (1.9 g, 2.7 mmol) and sodium iodide (2 g, 13.3 mmol) were dissolved in acetonitrile (50 ml) and heated to 65° C for 60 min. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and filtrated. Removal of the solvent and 78 purification by chromatography (ethyl acetate-hexane, 2:5) gave pure title product (1.9 g, 90 %) Η NMR (CDC1 3 45 °C): 7.34-7.02 (m, 13H), 5.89 (s, 2H), 5.64 (br s, 2H), 5.14-5.02 (m, 4H), 4.47 (m, 2H), 2.96 (t, 2H), 2.64 (t, 2H), 2.33 (m, 2H), 1.08-0.99 (m, 12H) Example A-I- 17 3-(N-CBZ-L-valyloxy)phenyl iodomethyl carbonate a) 3-(N-CBz-L-valyloxy)phenol. CBz-L-valine (10 g, 40 mmol), 1,3-dihydroxybenzene (8.7g, 79 mmol) NN'dicychlohexylcarbodiimide (10.2g, 44 mmol) and 4-dimethylaminopyridine (2.4 g, 20 mmol) were dissolved in DMF (50 ml) and left at ambient temperature overnight. The reaction mixture was filtered, the solvent removed under reduced pressure and the crude product was taken up in dichloromethane and filtered. Removal of the solvent followed by purification by chromatography (chloroform- methanol, 10:1) yielded pure title product (10.9 g, 79%). b) (Ν-CBZ-L-valyloxy)phenyl chloromethyl carbonate. 3-(N-CBz-L-valyloxy)phenol (5.4 g, 15 7 mmol) was dissolved in dichloromethane (70 ml) and cooled in an ice-bath. Pyridine (1.2 g, 23.5 mmol was added followed by dropwise addition of 1-chloro-methylchloroformate (2.3 g, 18.8 mmol) in dichloromethane (10 ml). The mixture was left at room temperature for 4 h. Water (25 ml) was then added and the phases were separated. The organic layer was washed with 0.01 M aqueous hydrochloric acid (25 ml). Purification by chromatography (ethyl acetate-hexane, 1:1) gave the title compound (4.5 g, 65 %) c) 3-(N-CBZ-L-valyloxy)phenyl iodomethyl carbonate. 79 (N-CBZ-L-valyloxy)phenyl chloromethyl carbonate (1.5g, 3.44 mmol) and sodium iodide (2 g, 13.3 mmol) were stirred at 60°C in acetonitrile (50 ml) for 4.5 h.The mixture was filered, the solvent removed and the crude product was taken up in 100 ml hexane-ethyl acetate, 1:1, and filtered through a sintered glass funnel, packed with 2 cm silica gel. Removal of the solvent yielded pure title product (1.68 g, 92%) 'H NMR (CDC1 3 45 °C): 7.38-7.02 (m, 9H), 6.03 (s, 2H), 5.2 (br s, IH), 5.14 (s, 2H), 4.48 (m, IH), 2.30 (m, IH), 1.09-1.01 (m, 6H) Example A-I- 18 Iodomethyl 2-(N-CBZ-L-valyloxy)phenylacetate O a) 4-Methoxybenzyl 2-hydroxyphenylacetate. 2-hydroxyphenylacetic acid (10 g, 66 mmol) was dissolved in NN-dimethyl- formamide (100 ml) and cooled on ice-bath. Potassium tert-butoxide (8.85 g, 78 mmol) was added. The mixture was left for 30 min and allowed to reach room temperature. 4-Methoxy-benzylchloride (11.7 g, 72 mmol) in NN-dimethyl- formamide (30 ml) was then added dropwise, under nitrogen atmosphere and left over-night. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in ether (100 ml) and washed with water (25 ml), brine and dried over sodium sulphate. Chromatography (hexane-ethyl acetate, 2:1) followed by recrystallization (hexane-ethyl acetate) gave the title compound (7.6 g, 42%). b) 4-Methoxybenzyl 2-(Ν-CBz-L-valyloxy)phenylacetate. 4-Methoxybenzyl 2-hydroxyphenylacetate 3g, 11 mmol), NN-dichyclohexyl- carbodiimide (2.7 g, 13.2 mmol), dimethylaminopyridine (0.134 g, 1.1 mmol) and CBz-L-valine (3.3 g, 13.2 mmol) were dissolved in dichloromethane (50 ml). After the weekend the solid was filtered off, the solvent removed under reduced pressure 80 and the crude product purified by chromatography (ethyl acetate^eXane, ' ! :2) to give the title compound (5.2 g, 93%). c) 2-(N-CBz-L-valyloxy)phenylacetic acid. 4-Methoxybenzyl 2-(N-CBz-L-valyloxy)phenylacetate (4.25 g, 8.4 mmol), was dissolved in dichloromethane (40 ml). Triflouroacetic acid (8 ml) was added with cooling on ice. The mixture was allowed to reach room temperature and stirred for 40 min. The solvent was removed under reduced pressure and the crude product was recrystallized twice (hexan-ethyl acetate + a small amount of dichloromethane) to give the title compound (2.6 g, 80 %). 'H NMR (CDC1 3 45 °C): 7.35-7.08 (m, 9H), 5.35 (br s, IH), 5.13 (s, 2H), 4.48 (m, IH), 3.57 (s, 2H), 2.33 (m, IH), 1.08 (d, 3H), 1.02 (d, 3H). d) Chloromethyl 2-(N-CBZ-L- valyloxy )phenylacetate. This compound was prepared in poor yield from 2-(N-CBz-L- valyloxy )phenylacetic acid (5.5 g, 14.3 mmol) by an unoptimized procedure essentially as described in Example A-I- 16 d). Yield: 0.265 g Η NMR (CDC1 3 45 °C): 7.28-7.01 (m, 9H), 5.55 (s, 2H), 5.2 (br s, IH), 5.07 (s, 2H), 4.43 (m, IH), 3.53 (s, 2H), 2.26 (m, IH), 1.02 (d, 3H), 0.95 (d, 3H). e) Iodomethyl 2-(N-CBZ-L-valyloxy)phenylacetate. Chloromethyl 2-(N-CBZ-L- valyloxy )phenylacetate is treated with Nal and purified as described in the Examples above to yield the title compound. Example A-I- 19 Iodomethyl 4-(N-CBZ-L-valyloxyxy)phenylacetate 81 a) 4-Methoxybenzyl 4-hydroxyphenylacetate. Prepared from 4-hydroxyphenylacetic acid (10 g, 65.7 mmol) in 70 % yield by the same procedure as for Example A-I-l 8 a) above, but wherein the solvent for the recrystallization was changed to hexane-ether. b) 4-Methoxybenzyl 4-(N-CBz-L-valyloxy)phenylacetate. Prepared from 4-methoxybenzyl 4-hydroxyphenylacetate (3 g, 11 mmol) by the same procedure as for Example A-I- 18 b) in 87 % yield. Solvent for chromatography: ethyl acetate-hexane, 1:2. c) 4-(N-CBZ-L-valyloxy)phenylacetic acid. Prepared in 82 % yield from 4-methoxybenzyl 4-(N-CBz-L-valyloxy)phenylacetate (1.6 g, 288 mmol) by the procedure described for Example A-I-l 8 c). Solvent for recrystallization: hexane-ether and a small amount of dichloromethane. 'H NMR (CDC1 3 45 °C): 7.36-7.27 (m, 7H), 7.02 (d, 2H), 5.25 (d, IH), 5.14 (s, 2H), 4.52 (m, IH), 3.64 (s, 2H), 2.3 (m, IH), 1.08 (d, 3H), 1.02 (d, 3H). d) Chloromethyl 4-(N-CBZ-L-valyloxy)phenylacetate. Prepared from 4-(N-CBZ-L-valyloxy)phenylacetic acid (3 g, 7.8 mmol) in 26 % yield by the same procedure as described for Example A-I-l 8 d). Solvent for chromatography: hexane-ether, 3:2. e) Iodomethyl 4-(N-CBZ-L-valyloxy)phenylacetate. Chloromethyl 4-(N-CBZ-L-valyloxy)phenylacetate (0.83 g, 1.9 mmol) and sodium iodide (1.15 g, 7.6 mmol) were heated in acetonitril (45 ml) for 5 h. The mixture was filtrated, the solvent removed, taken up in dichloromethane and filtrated again. Evaporation and purification by chromatography (ether-hexane, 2:3) yielded the title product (0.8 g, 80 %). 'H NMR (CDC1 3 45 °C): 7.38-7.09 (m, 4H), 5.84 (s, IH), 5.30 (br s, IH), 5.15 (s, 2H), 4.5 (m, IH), 3.56 (s, 2H), 2.36 (m, IH), 1.10 (d, 3H), 1.00 (d, 3H). 82 Example A-I-20 Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethvD benzoate a) 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)-toluene. To a cooled solution of 4-methylphenylethanol-2 (5.0g, 36.7 mmole), 4- dimethylaminopyridine (0.98g, 8 mmole) and N-benzyloxycarbonyl-L-valine (10.05g, 40 mmole) in dichloromethane (120 ml) was added dicyclohexyl- carbodiimide (9.1g, 44 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated under reduced pressure and ethyl acetate (250 ml) was added. The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 13.3g = 97% b) 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)- benzoic acid. To a cooled mixture of chromic anhydride (7.55g, 75 mmole) in acetic acid (100 ml) was added dropwise a solution of 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)- toluene (9.3 g, 25.1 mmole) in acetone (50 ml). The mixture was stirred at room temperature for 3 days and reduced to about 100 ml. 600ml 10% sodium chloride solution was added and the mixture was extracted four times with ethyl acetate. The organic phase was washed with brine and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was islolated by silica gel column chromatography with dichloromethane/methanol. Yield : 2,lg = 21%. 'H-NMR (CDC1 3 ) 0.79 (d, 3H) 0.90 (d, 3H) 2.08 (m,lH) 3.04 (t, 2H) 4.28 (d, d,lH) 4.39 (m, 2H) 5.11 (s, 2H) 5.26 (d, IH) 7.34 (m, 7H) 8.04 (d, 2H) c) Chloromethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate. To a solution of 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoic acid (2.0g, 5.0 mmole) in 1,4-dioxane (20 ml)was added a 40% solution of tetrabutylammonium hydroxide (3.1g, 4.75 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and coevaporated 83 two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (10 ml) and iodochloromethane (13.2g, 75 mmole) was added The solution was stirred overnight at room temperature and evaporated under reduced pressure. About 50 ml ethyl acetate were added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography .Yield: 0.5g =23% d) Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl) benzoate. To a solution of chloromethyl 4-(2-N-benzyloxycarbonyl-L-valyloxy ethyl) benzoate (0.5g, 1.11 mmole). In dry acetone (10 ml) was added sodium iodide (0.75g, 5.0 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 0.53g = 88%. 'H-NMR (CDC1 3 ) 0.88 (d, 3H) 0.90 (d, 3H) 2.08 (m, IH) 3.02 (t, 2H) 4.28 (d, d, IH) 4.38 (m, 2H) 5.10 (s, 2H) 5.22 (d, IH) 6.15 (s, 2H) 7.35(m, 7H) 7.98 (d, 2H ) Example A-I-21 Iodomethyl 2-rN-benzyloxycarbonyl-L-isoleucyloxymethy 2-methyl propionate. a) 4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)- 2-methyl propionate. To a cooled solution of 4-methoxybenzyl 2-(hydroxymethyl)-2-methyl propionate (6.0g, 25 mmole), 4-dimethylaminopyridine (0.6 lg, 5 mmole) and N- benzyloxycarbonyl-L-isoleucine (6.90g, 26 mmole) in dichloromethane (100 ml) was added dicyclohexyl-carbodiimide (6.2g, 30 mmole) and the mixture was stirred overnight at room temperature.The mixture was cooled and the urethane was filtered. The solution was evaporated and 200 ml ethyl acetate was added, The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced 84 pressure. The product was isolated by silica gel column chromatography with toluene/acetone.Yield: 11.7g = 96%. 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-methyl) propionic acid. To a solution of 4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)- 2-methyl propionate (1 l.Og, 22.6 mmole) in 100 ml dichloromethane was added trifluoroacetic acid (15 ml) and the mixture was stirred overnight at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The residue was stirred 1 hour with 100 ml ethanol and the white solid was filtered (byproduct). The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 7.4g = 89%. 'H-NMR (CDC1 3 ) 0.90 (m, 6H) 1.26 (m, 8H) 1.88 (m, IH) 4.12 (d, d, 2H) 4.38 (d, d, IH) 5.10 (s, 2H) 5.32 (d, IH) 7.28 (m, 5H) c) Chloromethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)-2-methyl propionate. To a solution of 2-(N-benzyloxycarbony-L-isoleucyloxymethyl)-2-methyl propionic acid (7.0g, 19 mmole) in 80 ml 1,4-dioxane was added a 40% solution of tetrabutylammonium hydroxide (12.4g, 19 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 25 ml dichloromethane and iodochloromethane (33.7g, 190 mmole) was added . The solution was stirred overnight at room temperature and evaporated under reduced pressure. About 100 ml ethyl actate was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone.Yield: 4.2 = 54% d) Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-methyl propionate. 85 To a solution of chloromethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2- methyl propionate (3.0g, 7.2 mmole) in 50 ml dry acetone was added sodium iodide (4.8g, 32 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 3.3g = 90%. 'H-NMR (CDCl j ) 0.93 (m, 6H) 1.23 (m, 8H) 4.12 (m, 2H) 4.38 (d, d, IH) 5.10 (s, 2H) 5.26 (d, IH) 5.92 (m, 2H) 5.35 (m, 5H) Example A-I-22 Iodomethyl 4-fN-benzyloxycarbonyl-L-valyloxy)cvclohexanoate. a) 4-Methoxybenzyl 4-hydroxycyclohexanoate. To a solution of ethyl 4-hydroxycyclohexanoate (8.61g, 50 mmole) in 50 ml ethanol was added a solution of potassium hydroxide 85% (3.63g, 55 mmole) and the mixture was stirred for 6 hours at 70°C. The mixture was evaporated under reduced pressure, coevaporated two times with N,N-dimethylformamide and reduced to about 100 ml. 4-Methoxybenzyl chloride (9.4g, 60 mmole) was added and the mixture was stirred for 18 hours at 60°C. The mixture was evaporated under reduced pressure and 250 ml ethyl acetate was added. The organic phase was washed five times with water, dried with sodiun sulfate and evaporated under reduced pressure. Yield: 13.2g =100% (crude) b) 4-methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy)- cyclohexanoate. To a cooled solution of 4-methoxybenzyl 4-hydroxycyclohexanoate (7.5g, 28 mmole), 4-dimethylaminopyridine (0.73g, 6 mmole) and N-benzyloxycarbonyl-L- valine (7.54g, 30 mmole) in dichloromethane (90 ml) was added dicylohexyl- carbodiimide (6.8g, 33 mmole) and the mixture was stirred for 2 days at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated and 250 ml ethyl acetate was added.The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase 86 was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone.Yield : 13g = 93% c) 4-(N-benzyloxycarbonyl-L-valyloxy) cyclohexanoic acid. To a solution of 4-methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy)- cyclohexanoate (12g, 24.1 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred for 3 hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The residue was stirred 1 hour with about 100 ml ethanol and the white solid was filtered (byproduct). The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with toluene/acetone. Yield: 6.8g = 74%. 'H-NMR (CDC1 3 ) 0.91 (m, 6H) 1.52-2.54 (m, 10H) 4.28 (m, IH) 4.82-5.08 (m, IH) 5.11 (s, 2H) 5.28 (d, IH) 7.36 (m, 5H) d) Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate. To a solution of 4-(N-benzyloxycarbonyl-L-valyloxy) cyclohexanoic acid (6.6g, 20 mmole) in 1,4-dioxane (70 ml) was added a 40% solution of tetrabutylammonium hydroxide (11.34g, 17.5 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 60 ml dichloromethane and iodochloromethane (30.9g, 175 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. About 100 ml ethyl actate was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 4.1g = 55%. e) Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate. 87 To a solution of chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (4.0g, 9.4 mmole) in dry acetone (50 ml) was added sodium iodide (6.3g, 42 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield 4.5g = 93%. 'H-NMR (CDC1 3 ) 0.90 (m, 6H) 1.52-2.02 (m, 8H) 2.18 (m, IH) 2.43 (m, IH) 4.30 (m, IH) 4.76-5.08 (m, IH) 5.11 (s, 2H) 5.26 (d, IH) 5.91 (d, 2H) 7.34 (m, 5H) Example A-I-23 Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxymethylV2-ethyl butyrate N-CBz-Valyf-O a) 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethylbutan- 1 -ol. To a cooled solution of 2-ethyl-2-hydroxymethyl-butan- 1 -ol (33.1 g, 250 mmole), 4- dimethylaminopyridine (1.22g, 10 mmole) and N-benzyloxycarbonyl-L-valine (12.6g, 50 mmole) in 350 ml dichloromethane was added dropwise a solution of dicyclohexyl-carbodiimide (12.4g, 60 mmole) in 50 ml dichloromethane. The mixture was stirred 2 days at room temperature and cooled. The urethane was filtered and the solution evaporated under reduced pressure. 350 ml ethyl acetate was added and the organic phase was washed twice with 5% acetic acid, 5% sodium-hydrogencarbonate and water. The organic phase was dried with sodium sulfat and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 16.4g = 90%. c) 2-(N-benzyloxycarbonyl-L-valyloxymethyl )-2-ethyl-butyric acid. To a cooled mixture of chromic anhydride (8.5g, 85,2 mmole) in 100 ml acetic acid was added dropwise a solution of 2-(N-benzyloxycarbonyl-L-valyoxymethyl)-2- ethyl-butan-1-ol (10.4g, 28.4 mmole) in 50 m} acetone and the mixture was stirred 24 hours at room temperature. The mixture was added to 1000 ml 10% sodium chloride 88 solution and extracted four times with ethyl acetate. The organic phase was washed twice with brine, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 7g = 65%. 'H-NMR (CDC1 3 ) 0.88 (m, 12H) 1.67 (m, 4H) 2.14 (m, IH) 4.26 (m, 3H) 5.10 (s, 2H) 5.30 (d, 2H) 7.34 (m, 5H) d) Chloromethyl 2-(N-benzyoxycarbonyl-L-valyloxymethyl -2-ethyl butyrate. To a solution of 2-(N-benzyloxycarbony-L-valyloxymethyl)-2-ethyl-butyric acid (7.2g,18,9 mmole) in 1,4-dioxane (80 ml) was added a 40% solution of tetrabutylammonium hydroxide (12.26g, 18.9 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated once with 1,4-dioxane and two times with toluene. The dried product was dissolved in 30 ml dichloromethane and iodochloromethane (49.4g, 280 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. About 100 ml ethyl actate were added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 5.2g = 63%. e) Iodomethyl 2-( N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate. To a solution of chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate (5.0g, 11.7 mmole) in dry acetone (60 ml) was added sodium iodide (7.5g, 50 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 5.4g = 90%. 'H-NMR (CDCI 3 ) 0.92 (m, 12H) 1.65 (m, 4H) 2.18 (m, IH) 4.28 (m, 3H) 5.10 (s, 2H) 5.22 (d, IH) 5.92 (s, 2H) 7.36 (m, 5H) 89 Example A-I-24 2-rN-( " iodomethoxycarbonyl -amino -2-methyl-l-(N-benzyloxycarbonyl-L- valyloxyVpropane O O- o- CBzNH a) 2-(N-tert.-butyloxycarbonylamino)-2-methyl- 1 -(N-benzyloxycarbonyl- L-valyloxy)-propane. To a cooled solution of 2-(N-(tert.-butyloxycarbonyl)-amino)-2-methylpropan-l-ol (J. Am. Chem. Soc 113 (1991) p 8883) (4.73g, 25 mmole), 4-dimethylamino- pyridine (0.61g, 5 mmole) and N-benzyloxycarbonyl-L-valine (6.28g, 25 mmole) in dichloromethane (70 ml) was added dicyclohexyl-carbodiimide (6.19g, 30 mmole) and the mixture was stirred 2 days at roommtemperature. The mixture was cooled, the urethane was filtered and the solution evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with,sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 10.2g = 96%. b) 2-amino-2-methyl- 1 -(N-benzyloxycarbonyl-L-valyloxy)-propane. To a solution of 2-(N-(tert.-butyloxycarbonyl)-amino)-2 -methyl- 1 -(N- benzyloxycarbonyl-L-valyloxy)-propane (lOg, 23 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (30 ml) and the mixture was stirred for 1 hour at room temperature. The solution was evaporated under reduced pressure and 10% sodium carbonate solution was added. The product was extracted four times with dichloromethane, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 3.0g = 40% (crude) 90 c) 2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-l- (N- benzyloxycarbonyl-L-valyloxy)-propane. To a solution of 2-amino-2-methyl-l-(N-benzyloxycarbonyl-L-valyloxy)-ρropane (2.9g, 9 mmole) and pyridine (2 ml) in dichloromethane (50 ml) was added chloromethyl chloro formate(l.55g, 12 mmole) and the mixture was stirred for 3 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate was added. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: l.lg = 29%. d) 2-(N-(iodomethoxycarbonyl)-amino)-2 -methyl- 1 -(N- benzyloxycarbonyl-L-valyloxy)-propane. To a solution of 2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-l-(N- benzyloxycarbonyl-L-valyloxy)propane (1.05g, 2.53 mmole) in dry acetone (20 ml) was added sodium iodide (1.8g, 12 mmole) and the mixture was stirred for 36 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed with 10% sodium thiosulfate solution and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 1.04g = 81%. 'H-NMR (CDC1 3 ) 0.92 (m, 6H) 1.35 (s, 6H) 2.10 (m,lH) 3.88 (m, IH) 4.35 (m, 2H) 5.11 (s, 2H) 5.32 (d, IH) 5.82 (s, IH) 5.91 (s, 2H) 7.35 (m, 5H) Example A-I-25 l-(2-N-CBz-L-valyloxyethylV6-oxo-1.6-dihvdro-pyridine-3-carboxylic acid iodomethyl ester 91 O O^N^ O-Cbz-Val a) 6-oxo-l,6-dihydro-pyridine-3 -carboxy lie acid 4-methoxybenzyl ester. To a solution of 6-hydroxynicotinic acid (4.87 g, 35 mmol) in DMF (100 mL) at room temperature, was added potassium tert-butoxide (3.93 g, 35 mmol). The reaction mixture was stirred at 60 °C for lh. 4-Methoxybenzylchloride (8.30 g, 53 mmol) was added and the reaction mixture was stirred at 60 °C for 4h. The DMF was evaporated under vacuum, the residue was dissolved in ether (200 mL) and washed with water (3 x 100 mL). The organic phase was dried with Na 2 SO 4 and evaporated to give 4.41 g of 6-oxo-l,6-dihydro-pyridine-3 -carboxy lie acid 4-methoxybenzyl ester. b) 1 -(2 -Hydroxyethyl)-6-oxo-l,6-dihydro-pyridine-3 -carboxylic acid 4- methoxybenzyl ester. To a solution of 6-oxo-l,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester (4.41 g, 17 mmol) and K 2 CO 3 (2.58 g, 18.7 mmol) in DMF (100 mL) at room temperature, was added 2-bromoethanol (2.02 g, 16.2 mmol). The reaction mixture was stirred at 80 °C for 30h, whereupon the DMF was evaporated under vacuum. The crude product was column chromatographed (silica gel, 2— »5% MeOH in CH 2 C1 2 ), to give 3.91 g of l-(2-hydroxyethyl)-6-oxo-l,6-dihydro-pyridine-3- carboxylic acid 4-methoxybenzyl ester. c) 1 -(2 -N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3 -carboxylic acid 4-methoxybenzyl ester. To a mixture of DCC (5.06 g, 24.5 mmol), DMAP (318 mg, 2.6 mmol) and N-CBz- L-valine (6.48 g, 25.8 mmol) in CH 2 C1 2 (200 mL) at 0 °C, was added dropwise a solution of l-(2-hydroxyethyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid 4- methoxybenzyl ester (6.40 g, 24 mmol) in CH 2 C1 2 (200 mL). After lh at 0 °C, the 92 temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH 2 C1 2 ), to give 6.81 g l-(2-N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3 -carboxylic acid 4-methoxybenzyl ester. d) 1 -(2 -N-CBz-L-valyloxyethyl)-2-pyridone-5 -carboxylic acid. To a solution of l-(2-N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3- carboxylic acid 4-methoxybenzyl ester (6.46 g, 12 mmol) in CH 2 C1 2 (85 mL) at room temperature, was added trifluoroacetic acid (15 mL). After lh at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3— 6% MeOH in CH 2 C1 2 ), to give 4.91 g 1- (2-N-CBz-L-valyloxyethyl)-2-pyridone-5-carboxylic acid. 'H-NMR (CDC1 3 ): 12.15 (br s, IH), 8.29 (d, J= 2.2 Hz, IH), 7.93 (dd, J= 9.5, 2.2 Hz, IH), 7.31 (m, 5H), 6.69 (d, J= 9.5 Hz, IH), 5.53 (d, IH), 5.07 (s, 2H), 4.52- 4.05 (m, 5H), 2.20-2.00 (m, IH), 0.90 (d, 3H), 0.81 (d, 3H). e) 1 -(2 -N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3 -carboxylic acid chloromethyl ester. To a solution of l-(2-N-CBz-L-valyloxyethyl)-2-pyridone-5 -carboxylic acid (4.91 g, 11.8 mmol) in dioxane (200 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (7.65 g). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (200 mL) and then chloroiodomethane (8.74 mL, 120 mmol) was added and the solution was stirred for 12h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane / ethyl acetate (1:1 v/v, 200 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 2-4% MeOH in CH 2 C1 2 ), to give 1.80 g of 93 1 -(2-N-CBz-L-valyloxyethyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid chloromethyl ester. f) 1 -(2-N-CBz-L-valyloxyethyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid iodomethyl ester To a solution of l-(2-N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3- carboxylic acid chloromethyl ester (1.80 g, 3.87 mmol) in acetonitrile (30 mL), was added sodium iodide (2.32 g, 15.5 mmol). The solution was stirred for 4 h at 60 °C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH 2 C1 2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na^O^ and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH 2 C1 2 ), to give 2.04 g 1 -(2 -N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3 -carboxy lie acid iodomethyl ester. 'H-NMR (CDC1 3 ): 8.19 (d, J= 2.5 Hz, IH), 7.79 (dd, J= 9.6, 2.5 Hz, IH), 7.32 (m, 5H), 6.52 (d, J= 9.6 Hz, IH), 6.04 (s, 2H), 5.38 (d, IH), 5.07 (s, 2H), 4.54-4.06 (m, 5H), 2.20-2.00 (m, IH), 0.91 (d, 3H), 0.81 (d, 3H). Example A-I-26 Iodomethyl 5-[(N-benzyloxycarbonyl-L-valyloxy methyl]-2-furoate O J Q 0 ~ < o (a) 5 - [(N-B enzyloxycarbonyl-L- valy loxy)methyl] -2-furaldehyde . A solution of 5-(hydroxymethyl)-2-furaldehyde (1.00 g, 7.69 mmol) in 5 mL dry CH 2 C1 2 was added to a mixture of N-benzyloxycarbonyl-L-valine (2.40 g, 9.57 mmol), N,N-dicyclohexylcarbodiimide (2.00 g, 9.69 mmol), and 4-dimethyl- aminopyridine (117 mg, 0.96 mmol) in 45 mL CH 2 C1 2 . After stirring overnight, the reaction slurry was filtered, concentrated under vacuum, and subjected to flash 94 column chromatography (silica, 2/1 petroleum ether - ethyl acetate to give the valine ester (quantitative yield). (b) 5-[(N-Benzyloxycarbonyl-L-valyloxy)methyl]-2-furoic acid A solution of ΝaClO 2 (2.8 mmol) in 3 mL water was added dropwise to a stirred solution of 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furaldehyde (798 mg, 2.22 mmol) from step (a) in 3 mL MeCΝ, with cooling in an ice bath. After 2.5 h, the ice bath was removed, 2 mL more MeCΝ was added, and the two-phase liquid reaction mixture was stirred at room temperature for 25 h. The reaction mixture was diluted with water, made basic with saturated ΝaHCO 3 , and extracted with ethyl acetate (3 x 50 mL). The separated aqueous solution was acidified to pH 2 with 5% aqueous HC1 and extracted with ethyl acetate (3 x 50 mL). This second ethyl acetate solution was washed with brine, dried over anhydrous Na^O^ and evaporated to dryness under vacuum to give the carboxylic acid (287 mg, 34%) which was used in the next step without further purification. (c) Chloromethyl 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furoate. Tetrabutylammonium hydroxide (40 wt. % solution in water, 0.55 mL, 0.84 mmol) was added to the carboxylic acid (286 mg, 0.76 mmol) from step (b) in 5 mL dioxane. The yellow solution was concentrated under vacuum, coevaporating several times with dioxane, toluene, and, lastly, CH 2 C1 2 . The residue was charged with 10 mL dry CH 2 C1 2 and chloroiodomethane (0.55 mL, 7.55 mmol) was added. After stirring for 20.5 h, the reaction mixture was concentrated and subjected to flash column chromatography (silica, 2/1 petroleum ether - ethyl acetate) to give the chloromethyl ester (137 mg, 42%). (d) Iodomethyl 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furoate. All of the chloromethyl ester (137 mg, 0.32 mmol) from step (c) was refluxed with Νal (195 mg, 1.3 mmol) in 3.2 mL dry MeCΝ at 70 °C for 4 h. The solvent was removed under vacuum and the residue was subjected to flash column chromatography (silica, 3/1 petroleum ether - ethyl acetate) to give the iodomethyl ester (152 mg, 92%). 95 'H NMR (250 MHz, CDC1 3 ) δ 0.84 and 0.93 (2d, 3H each, J= 6.8 Hz), 2.16 (m, IH), 4.33 (dd, IH, J= 9.1, 4.7 Hz), 5.09-5.21 (m, 4H), 5.36 (d, IH, J= 9.1 Hz), 6.08 (s, 2H), 6.52 (d, IH, J= 3.4 Hz), 7.19 (d, IH, J= 3.5 Hz), 7.33 (s, 5H). Example A-I-27 Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate a) 4-Methoxybenzyl 4-(2-hydroxyethoxy)benzoate. To a solution of 4-methoxybenzyl 4-hydroxybenzoate (7.0g, 27 mmole) in dry N,N- dimethylformamide (50 ml) was added potassium carbonate (4.15g, 30 mmole) and 2-bromoethanol.The mixture was stirred 48 hours at 80°C, evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed five times with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate.Yield: 6.8g = 83%. b) 4-methoxybenzyl 4-(2-N-benzyloxycarbonyl-L- valyloxyethoxy)benzoate. To a solution of 4-methoxybenzyl 4-(2-hydroxyethoxy) benzoate (6.6g, 21.8 mmole), 4-dimethylaminopyridine (0.6 lg, 5 mmole) and N-benzyloxycarbonyl-L- valine (6.3g, 25 mmole) in dichloromethane (80 ml) was added dicyclohexyl- carbodiimide (5.2g, 25 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled and the urethane was filtered.The solution was evaporated and ethyl acetate (200 ml) was added. The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 10.6g = 90 %. c) 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid. To a solution of 4-methoxybenzyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate (10.2g, 19.04 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred 3 hours at room temperature. 96 The solution was evaporated under reduced pressure and co-evaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 6.9g = 87%. 'H-NMR (CDC1 3 ) 0.94 (m, 6H) 2.18 (m, IH) 4.22- 4.68 (m, 5H) 5.10 (s, 2H) 6.94 (d, 2H) 7.35 (m, 5H) 8.05 (d, 2H) d) Chloromethyl 4-( 2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate. To a solution of 4-(2- N-benzyloxycarbonyl-L-valyloxyethoxy) benzoic acid (6.7g, 16.1 mmole) in 1,4-dioxane (80 ml) was added a 40% solution of tetrabutylammonium hydroxide (9.74g, 15 mmole) and the mixturewas stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and coevaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (30 ml) and iodochloromethane (42.5g, 241 mmole) was added. The solution was stirred overnight at room temperature and evaporated under reduced pressure. About 150 ml ethyl actate were added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 1.2g = 17% e) Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate. To a solution of chloromethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate (1.1 g, 2.37 mmole) in dry acetone (40 ml) was added sodium iodide (1.5g, 10.0 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure.Yield: 1.3g = 98%. 'H-NMR (CDCI 3 ) 0.88 (d, 3H) 0.95 (d, 3H) 2.18 (m, IH) 4.22 (m, 2H) 4.32 (d, d, IH) 4.50 (m, 2H) 5.10 (s, 2H) 5.22 (d, IH) 6.14 (s, 2H) 6.90 (d, 2H) 7.35(m, 7H) 7.98 (d, 2H) 97 Example A-I-28 Iodomethyl 4-[3-(Cbz-L-valyloxy -l-propyllbenzoate a) t-Butyl 4-[3-(Cbz-L-valyloxy)-l-propyl]benzoate. t-Butyl 4-(3-hydroxy-l-propyl)benzoate (Taylor et al J Org. Chem. 1995, 60, 7947) (3.3 g, 14 mmol), NN'-dicychlohexyl carbodiimide (3.3 g, 16.8 mmol), CBZ-L- valine (4.2 g, 16.8 mmol) and NN-dimethylaminopyridine (0.85 g, 7 mmol) were dissolved in a minimum amount of dichloromethane and left at ambient temperature over-night. The slurry was then filtrated and the solvent evaporated. Purification by chromatography (dichloromethane-ether, 20:1) gave pure title compound (7 g, 100 %). b) Chloromethyl 4-[3-(Cbz-L-valyloxy)-l-propyl]benzoate t-Butyl 4-[3-(Cbz-L-valyloxy)-l-propyl]benzoate (6.5 g, 13.8 mmol) was dissolved in dichloromethane (50 ml). Triflouroacetic acid (10 ml) was added and the mixture was left over-night. The solvent was then removed and the crude residue coevaporated with toluene and 1,4-dioxan and dried in vacuum over-night. The dried product was dissolved in 1,4-dioxane (100 ml) and tetrabutyl ammoniumhydroxide (40 w/w % in water) was added dropwise until the pH = 7-8. The solvent was co- evaported with toluene four times, and then dissolved in dichloromethane (100 ml) followed by addition of 100 g of molecular sieve (4 A) and the mixture was stirred for 30 minutes. Chloroiodomethane (15 ml) was added and the reaction mixture was left for five hours. Filtration and purification by chromatography (hexane-ethyl acetate, 3:1) gave pure title product (3.3 g, 52 %). 98 c) Iodomethyl 4-[3-(cbz-L-valyloxy)-l-propyl]benzoate Chloromethyl 4-[3-(Cbz-L-valyloxy)-l-propyl]benzoate (3 g, 6.5 mmol) and sodium iodide (4.9 g, 32 mmol) were dissolved in acetonitril (50 ml) and heated to 65 C for 4 hours. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and filtrated. Removal of the solvent and purification by chromatography (dichloromethane-ether, 20:1) gave pure title product (2.4 g, 67 %). Η NMR (CDC1 3 45 °C): 7.95 (d, 2H), 7.36-7.24 (m, 7H), 6.15 (s, 2H), 5.2 (br s, IH), 5.12 (s, 2H), 4.330-4.20 (m, IH), 4.15 (t, 2H), 2.74 (t, 2H), 2.2-2.1 (m, IH), 1.99 (m, t 2H), 0.98 (d, 3H), 0.91 (d, 3H) Example A-I-29 Iodomethyl 4-[3-(Cbz-L-isoleucyloxyVl-propyl " jbenzoate a) t-Butyl 4-[3-(Cbz-L-isoleucyloxy)-l-propyl]benzoate. Prepared from t-butyl 4-(3 -hydroxy- l-propyl)benzoate (3.5 g, 14.8 mmol) by the same procedure as described for Example A-I-28 to give the title compound (7 g, 97%). b) Chloromethyl 4-[3-(Cbz-L-isoleucyloxy)-l-propyl]benzoate. Prepared from the material of step a) (6.9 g, 14.4 mmol) by the procedure described in Example A-I-28 to give the title compound (3.8 g, 55%) as a colourless oil. c) Iodomethyl 4-[3-(Cbz-L-isoleucyloxy)-l-propyl]benzoate. 99 Prepared from the product of step b (3.26 g, 6.8 mmol) by the same procedure as for Example A-I-28 to give pure title compound. (3.46 g, 90 %). 'H NMR (CDC1 3 45 °C): 7.98-7.93 (m, 2H), 7.35-7.23 (m, 7H), 6.15 (s, 2H), 5.25- 5.15 (br s, IH), 5.13 (s, 2H), 4.32 (m, IH), 4.12 (t, 2H), 2.74 (t, 2H), 1.94 (m, 2H), 1.86 (m, IH), 1.5-1.4 (m, IH), 1.25-1.15 (m, IH), 0.95-0.86 (m, 6H). Example A-I-30 Iodomethyl 2-( N-benzyloxycarbonylamino-2-methylpropionyloxy- methyl V2 -methyl propionate a) 2-benzyloxycarbonylamino-2 -methyl propionic acid. To a solution of sodium carbonate (13.3g, 125 mmole) in water (100 ml) was added 2-amino-2-methylpropionic acid (5.0g, 50 mmole) and the mixture was stirred for 30 minutes. The solution was cooled to about 10°C and a 50% solution of benzyl chloroformiate (20.5g, 60 mmole) was added dropwise. The mixture was stirred at roomtemperature overnight and acidified with 2M hydrochloric acid. The mixture was extracted two times with ethyl acetate. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 7.7g = 64% b) 4-methoxybenzyl 2-(2-benzyloxycarbonylamino-2- methylpropionyloxymethyl)-2 -methyl propionate. To a cooled solution of 4-methoxybenzyl 2-(hydroxymethyl)-2-methyl propionate (3.6g, 15 mmol), 4-dimethylaminopyridine (0.37g, 3 mmole) and 2- benzyloxycarbonylamino-2-methylpropionic acid (3.8g, 16 m-mole) in dichloromethane (60 ml) was added dicyclohexyl-carbodiimide (3.7g, 18 mmole) and the mixture was stirred overnight at room temperature.The mixture was cooled and the urethane was filtered. The solution was evaporated and 150 ml ethyl acetate were added, The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and 100 evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene / acetone. Yield: 6,2g =91% c) 2-(benzyloxycarbonylamino-2-methylpropionyloxymethyl )-2- methylpropionic acid. To a solution of 4-methoxybenzyl 2-(2-benzyloxycarbonylamino-2- methylpropionyloxymethyl)-2methyl propionate (6,1 g, 13,3 mmole) dichloromethane (50 ml) was added trifluoro acetic acid (10 ml) and the mixture was stirred 3 hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 4.1g = 91% 'H-NMR (CDC1 3 ) 1.22 (s, 6H) 1.52 (s, 6H) 4.13 (m, 2H) 5.07 (s, 2H) 5.44 (s, IH) 7.33 (m, 5H) d) Chloromethyl 2-(2-benzyloxycarbonylamino-2- methylpropionyloxymethyl)-2-methyl propionate. To a solution of 2-(2-benzyloxycarbonylamino-2-methylpropionyloxymethyl)-2- methyl propionic acid (4.0g, 11.8 mmole) in 80 ml 1,4-dioxane was added a 40% solution of tetrabutylammonium hydroxide (7.5g, 11.5 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1 ,4-dioxane and two times with toluene. The dried product was dissolved in 20 ml dichloromethane and iodochloromethane (31.7g. 180 mmole) was added. The solution was stirred overnight at room temperature and evaporated under reduced pressure. About 100 ml ethyl actate were added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 2.0g = 45%. e) Iodomethyl 2-( N-benzyloxycarbonylamino-2- methylpropionyloxymethyl)-2-methyl propionate. 101 To a solution of chloromethyl 2-(N-benzyloxycarbonylamino-2- methylpropionyloxymethyl)-2 -methyl propionate (1.9g, 4.92 mmole) in 50 ml dry acetone was added sodium iodide (3.0g, 20 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 2,lg. 'H-NMR (CDC1 3 ) 1.20 (s, 6H) 1.53 (s, 6H) 4.13 (s, 2H) 5.07 (s, 2H) 5.30 (s, IH) 5.90 (s, 2H) 7.35 (m, 5H) Example A-I-31 Iodomethyl 2-methyl-2-(N-benzyloxycarbonyl-L-alanyloxymethvπpropionate The title compound (alternative nomenclature 2,2-dimethyl-3-(CBz-alanyloxy)- propioic acid iodomethyl ester) is prepared in a similar manner as described in Example A-I- 10 using N-CBz protected L-alanine in place of N-CBz-D- valine. 'H-NMR (CDC1 3 ): 7.33 (m, 5H), 5.91 (m, 2H), 5.11 (s, 2H), 4.38 (m, IH), 4.14 (m, 2H), 1.40 (d, 3H), 1.21 (d, 6H). Example A-I-32 Iodomethyl 3 -(N-CBz-L-valyloxy >2-methyl-propionate N-CBz-L-Val— O a) 3-(N-CBz-L-valyloxy)-2 -methyl- 1 -propanol. To a mixture of DCC (16.5 g, 80 mmol), DMAP (0.977 g, 8 mmol) and N-CBz-L- valine (20.1 g, 80 mmol) in CH 2 C1 2 (400 mL) at 0 °C, was added dropwise a solution of 2-methyl- 1,3-ρropanediol (72.1 g, 800 mmol) in CH 2 C1 2 (100 mL). After lh at 0 102 °C, the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 16h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 5% MeOH in CH 2 C1 2 ), to give 20.3 g 3-(N-CBz-L-valyloxy)-2-methyl-l-propanol. b) 3-(N-CBz-L-valyloxy)-2-methyl-propionic acid. To a solution of CrO 3 (4.29 g, 42.9 mmol) in HO Ac (50 mL) at 20 °C, was added dropwise a solution of 3-(N-CBz-L-valyloxy)-2-methyl-l-propanol (4.61 g, 14.3 mmol) in aceton (25 mL). After stirring for 24h, water (300 mL) was added and the reaction mixture was extracted with CH 2 C1 2 (4x200 mL) . The combined organic layers was concentrated under reduced pressure. The residue was column chromatographed (silica gel, 5-10% MeOH in CH 2 C1 2 ), to give 3.10 g of 3-(N-CBz- L-valyloxy)-2-methyl-propionic acid. 'H-NMR (CDC1 3 ): 11.54 (br s, IH), 7.33 (s, 5H), 5.48 (d, IH), 5.11 (s, 2H), 4.40- 4.00 (m, 3H), 2.95-2.70 (m, IH), 2.25-2.05 (m, IH), 1.30-1.12 (m, 3H), 0.95 (d, 3H), 0.87 (d, 3H). c) Chloromethyl 3-(N-CBz-L-valyloxy)-2-methyl-propionate. To a solution of 3-(N-CBz-L-valyloxy)-2-methyl-propionic acid (3.10 g, 9.2 mmol) in dioxane (100 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (5.97 g). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (100 mL) and then chloroiodomethane (6.70 mL, 92 mmol) was added and the solution was stirred for 6h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane / ethyl acetate (1:1 v/v, 200 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 0.5-2% MeOH in CH 2 C1 2 ), to give 1.90 g of chloromethyl 3-(N-CBz-L-valyloxy)-2-methyl-propionate. 103 d) Iodomethyl 3-(N-CBz-L-valyloxy)-2-methyl-propionate. To a solution of chloromethyl 3-(N-CBz-L-valyloxy)-2-methyl-propionate (1.84 g, 4.77 mmol) in acetonitrile (50 mL), was added sodium iodide (2.86 g, 19.0 mmol). The solution was stirred for 3.5 h at 60 °C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH 2 C1 2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (NajSO and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH 2 C1 2 ), to give 1.78 g of iodomethyl 3- (N-CBz-L- valyloxy)-2-methyl-propionate. 'H-NMR (CDC1 3 ): 7.35 (s, 5H), 5.90 (s, 2H), 5.25 (d, IH), 5.10 (s, 2H), 4.36-4.18 (m, 3H), 2.94-2.73 (m, IH), 2.26-2.08 (m, IH), 1.28-1.18 (m, 3H), 0.96 (d, 3H), 0.87 (d, 3H). Example A-I-33 Iodomethyl 3-(N-CBz-L-t-butylglvcyloxyV2.2-dimethylpropionate CBzHN Y' O Λ O°- a) 4-Methoxybenzyl 3-(N-CBz-L-t-butylglycyloxy)-2,2- dimethylpropionate. To a mixture of DCC (4.95 g, 24 mmol), DMAP (293 mg, 2.4 mmol) and N-CBz-L- t-butylglycine (6.37 g, 24 mmol) in CH 2 C1 2 (100 mL) at 0 °C, was added dropwise a solution of 4-methoxybenzyl 2,2-dimethyl-3-hydroxypropionate (2.86 g, 12 mmol) in CH 2 C1 2 (50 mL). After lh at 0 °C, the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 48h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 1-2% MeOH in CH 2 C1 2 ), to give 5.60 g 4-methoxybenzyl 3-(N-CBz-L-t- butylglycyloxy)-2,2-dimethylpropionate. 104 b) 3-(N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionic acid To a solution of 4-methoxybenzyl 3-(N-CBz-L-t-butylglycyloxy)-2,2- dimethylpropionate (5.60 g, 11.5 mmol) in CH 2 C1 2 (90 mL) at room temperature, was added trifluoroacetic acid (10 mL). After lh at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3→5% MeOH in CH 2 C1 2 ), to give 2.70 g of 3-(N-CBz- L-t-butylglycyloxy)-2,2-dimethylpropionic acid. 'H-NMR (CDC1 3 ): 11.2 (br s, IH), 7.34 (s, 5H), 5.44 (d, IH), 5.11 (s, 2H), 4.25-4.03 (m, 3H), 1.32-1.22 (m, 6H), 0.97 (s, 9H). c) Chloromethyl 3-(N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionate. To a solution of 3-(N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionic acid (2.70 g, 7.38 mmol) in dioxane (100 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (4.79 g). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (100 mL) and then chloroiodomethane (5.37 mL, 73.8 mmol) was added and the solution was stirred for 6h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane / ethyl acetate (1 :1 v/v, 200 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 0.5-1% MeOH in CH 2 C1 2 ), to give 2.44 g of chloromethyl 3-(N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionate. d) Iodomethyl 3-(N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionate. To a solution of chloromethyl 3-(N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionate (2.44 g, 5.90 mmol) in acetonitrile (50 mL), was added sodium iodide (3.54 g, 23.6 mmol). The solution was stirred for 3.5 h at 60 °C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH 2 C1 2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (NajSO^ and concentrated under reduced pressure. The crude product was column 105 chromatographed (silica gel, 1% MeOH in CH 2 C1 2 ), to give 2.61 g of iodomethyl 3- (N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionate. 'H-NMR (CDCl j ): 7.32 (s, 5H), 5.89-5.82 (m, 2H), 5.40 (d, IH), 5.07 (s, 2H), 4.17 (d, IH), 4.11 (s, 2H), 1.22-1.19 (m, 6H), 0.95 (s, 9H). Example A-I-34 N-benzyloxycarbonyl-t » -4-(N-benzyloxycarbonyl-L-valyloxyVL-proline iodomethyl ester. \ Λ CBzΝH O^/ (a) N-benzyloxycarbonyl-trατw-4-hydroxy-L-proline ?-methoxybenzyl ester. Cesium carbonate (1.23 g, 3.78 mmol) was added to a stirred solution of N- benzyloxycarbonyl-traM.s-4-hydroxy-L-proline (2.00 g, 7.54 mmol) in 20 mL dry DMF. After 15 min, jo-methoxybenzyl chloride (1.25 mL, 9.21 mmol) was added and the mixture was stirred for 17 h. The solvent was evaporated under vacuum, and the residue was partitioned between EtOAc (100 mL) and water (50 mL).The organic phase was washed with water (2 x 25 mL), dried over anhydrous Νa^O^ and concentrated. Flash column chromatography (silica gel, 2/1 EtOAc - petroleum ether) gave 2.69 g (92%) of the/?-methoxybenzyl ester. (b) N-benzyloxycarbonyl-trα«5-4-(N-benzyloxycarbonyl-L-valyloxy)-L- proline/>-methoxybenzyl ester. A mixture of N-benzyloxycarbonyl-trαrø-4-hydroxy-L-proline ?-methoxybenzyl ester (2.54 g, 6.59 mmol), N-benzyloxycarbonyl-L-valine (1.82 g, 7.24 mmol), 4- dimethylaminopyridine (90 mg, 0.7 mmol), and dicyclohexylcarbodiimide (1.64 g, 7.95 mmol) in 26 mL dry CH 2 C1 2 was stirred overnight. The slurry was filtered, and the filtrate was concentrated under vacuum to give an oil that was subjected to flash column chromatography (silica gel, 3/1 and " then 2/1 petroleum ether - EtOAc) to yield 3.70 g ( 91 %) of the title compound. 106 (c) N-benzyloxycarbonyl-trøns-4-(N-benzyloxycarbonyl-L-valyloxy)-L- proline chloromethyl ester. The 7-methoxybenzyl group was removed by stirring a solution of the compound (2.47 g, 4.0 mmol) from step (b) and 8 mL CF 3 COOH in 40 mL CH 2 C1 2 for 30 min. The reaction mixture was concentrated under vacuum, coevaporating several times with more CH 2 C1 2 and toluene. A second sample (1.14 g, 1.84 mmol) was treated similarly. The crude products obtained from both samples were combined and subjected to flash column chromatography (silica gel, 15% methanol in CH 2 C1, to give 2.58 g of cream-colored solids containing N-benzyloxycarbonyl-tra«^-4-(N- benzyloxycarbonyl-L-valyloxy)-L-proline (TLC 15/85 MeOH/CH 2 Cl 2 Rf = 0.25). This material (1.14 g) was dissolved in 10 mL dioxane. Tetrabutylammonium hydroxide (1.15 mL of a 40 wt % solution in H 2 O, 1.76 mmol) was added, the mixture was evaporated to dryness, and the residue was coevaporated several times with toluene and, lastly, CH 2 C1 2 . The resulting Q salt was stirred with chloroiodomethane (1.30 mL, 17.8 mmol) in dry CH 2 C1 2 (20 mL) for 20 h. The solvent was removed under vacuum, 25 mL of 2/1 petroleum ether - EtOAc was added, and the precipitates which formed were filtered. Concentration of the filtrate, followed by flash column chromatography (silica gel, 4/1 and then 2/1 petroleum ether - EtOAc) gave the chloromethyl ester (580 mg) as white solids. (d) N-benzyloxycarbonyl-trøHs-4-(N-benzyloxycarbonyl-L-valyloxy)-L- proline iodomethyl ester. The chloromethyl ester (533 mg, 0.974 mmol) from step (c) and Νal (594 mg, 3.96 mmol) were refluxed in dry MeCΝ (10 mL) at 75 °C for 4 h. After removal of solvent under vacuum, the mixture was partitioned between 20 mL EtOAc and 10 mL water. The organic phase was washed with 5% ΝajS^ and then brine, dried over anhydrous Νa^SO^ and concentrated. Flash column chromatography (silica gel, 3/1 petroleum ether - EtOAc) gave the iodomethyl ester (526 mg, 84%) as white solids. 'H ΝMR (250 MHz, CDC1 3 ) δ 0.86 and 0.94 (2d, 3H each, J= 6.8 Hz), 2.13 (m, 2H), 2.31 (m, IH), 3.65-3.80 (m, 2H), 4.24 (m, IH), 4.43 (m, IH), 5.03-5.19 (m, 4H), 5.30 107 (br s, IH), 5.54 (br d, IH), 5.70 and 5.83-5.97 (s and ABq, 2H total), 7.30-7.32 (m, 10H). Prodrugs of the invention EXAMPLE A-l 4-amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid. tri(2-methyl-2-(L- valyloxymethyD propionyloxymethvD ester. a) 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, tri(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl) propionyloxymethyl) ester and 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1- bisphosphonic acid, di(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl) propionyloxymethyl) ester. 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid is prepared by the methodology in Kieczykowski et al, J Org Chem 1995, 60, 8310-8312, and the 4-amino group CBz protected as shown in US 5 227 506. To a solution thereof (195 mg, 0.51 mmole) in dry N,N-dimethylformamide (2 ml), was added diisopropylethyl- amine (0.27 ml, 1.53 mmole), followed by an injection of a solution of iodomethyl 2- methyl-2-(N-benzyloxycarbonyl-L- valyloxymethyl) propionate (626 mg, 1.27 mmole) in N,N-dimethylformamide (2 ml). After stirring under argon for 2,5 h at room temperature, the solution was concentrated on rotavapor and treated with ethyl acetate (1 ml). Crystals were filtered off and the filtrate was extracted with brine containing a small amount of sodium thiosulfate. The organic phase was filtered through anhydrous sodium sulfate and evaporated. The title compounds were isolated by silica gel column chromatography (0-4, 7-8, 20-30% ethanol in dichloromethane). Triester (70 mg). R f (10%MeOH/ CHC1 3 ) 0.45. 'H-NMR (CDC1 3 ): 7.30 (m, 20H), 5.85-5.43 (m, 9H), 5.08 (m, 8H), 4.36-3.95 (m, 9H), 3.10 (m, 2H), 2.15-1.75 (m, 7H), 1.19 (s, 18H), 0.86 (m, 18H). 31 P-NMR (CDCl 3 +l%CD 3 OD) (H 3 PO 4 reference): δ 23.8 (d), 11.8(d); 108 Diester (185 mg), R f (10%MeOH/ CHC1 3 ) 0.10 (at the center of oval spot from baseline). 'H-NMR (CDCl 3 +l%CD 3 OD): 7.31 (m, 15H), 5.79-5.63 (m, 4H), 5.08 (m, 6H), 4.35-4.10 (m, 6H), 3.10 ( , 2H), 2.18-1.70 (m, 6H), 1.19 (m, 12H), 0.87 (m, 12H). 31 P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 16.6 (s). b) 4- Amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, tri(2-methyl-2- (L- valyloxymethyl) propionyloxymethyl) ester. A solution of 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid tri(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl) propionyloxymethyl) Ester (203 mg, 0.136 mmol) in methanol / ethyl acetate / acetic acid (2:1 :1 v/v/v) (8.7 ml) was hydrogenated over a Pd-black catalyst (93 mg) at 40 psi of hydrogen for 16 h. The suspension was filtered through Celite on a fine pore sized glassinter and washed with methanol/ethyl acetate (2:1). The filtrate was evaporated to dryness in vacuo and the title compound as the tetra acetate was obtained as a white solid after a few co-evaporations with dioxane and hexane. 31 P-NMR (CDCl 3 +5%CD 3 OD)(H 3 PO 4 reference): δ 23.1 (m), 11.1 (m). Example A-2 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid, di(2-methyl-2-(L- valyloxymethvD propionyloxymethvD ester. 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di(2- methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl) propionyloxymethyl) ester (130 mg, 0.112 mmol) was hydrogenated over Pd-black (48 mg) by the method of Example A-l b), to give the title compound as the triacetate as a white solid (90 mg). 31 P-NMR (CDCL+5%CD 3 OD)(H 3 PO 4 reference): δ 16.2 (br, s). Example A-3 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid. di(2-methyl-2-( " L-valyloxy) propionyloxymethyl ester 109 a) 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxy) propionyloxymethyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (306 mg, 0.80 mmole) was esterified by the method described in Example A-l-a. After silica gel column chromatography (2-4, 6-12, 15-20% ethanol in dichloromethane), the pure fractions containing the title compound were pooled together and evaporated. The residue was then dissolved in ethyl acetate and the solution extracted twice with aqueous saturated sodium bicarbonate and then twice with 5% aqueous EDTA- disodium salt. (116 mg of title compound). R f (20%MeOH/CHCl 3 ) 0.20 (at the center of oval spot from baseline). 'H-NMR (CDCl 3 +l%CD 3 OD): 7.28 (m, 15H), 5.60 (m, 4H), 5.05 (m, 6H), 4.13 (m, 2H), 3.09 (m, 2H), 2.19-1.72 (m, 6H), 1.49 (m, 12H), 0.89 (m, 12H). 31 P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 15.3 (s). b) 4- Amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di(2-methyl-2- (L- valyloxy) propionyloxymethyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid, di(2- methyl-2-(N-benzyloxycarbonyl-L-valyloxy) propionyloxymethyl) ester (116 mg, 0.107 mmol) was hydrogenated over Pd-black (46 mg) by the method of Example A- 1-b, to give the title compound as the triacetate as a white solid (71 mg). 31 P-NMR (CDCL+5%CD 3 OD)(H 3 PO 4 reference): δ 14.9 (s). Example A-4 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid, di (2-(L- valyloxy 3-methyl- (S +Vbutyryloxymethyπ ester. a) 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di (2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester. 110 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (383 mg, 1 mmole) was esterified by the method described in Example A-3-a to yield 184 mg of title compound. R f (20%MeOH/CHCl 3 ) 0.20 (at the center of oval spot from baseline). 'H-NMR (CDC1 3 + l%CD 3 OD): 7.27 (m, 15H), 5.62 (m, 4H), 5.15-4.72 (m, 8H), 4.32 (m, 2H), 3.08 (m, 2H), 2.16-1.73 (m, 6H), 0.88 (m, 24H). 31 P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 15.5 (s). b) 4-Amino-l -hydroxybutylidene- 1,1 -bisphosphonic acid, di (2-(L- valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid, di (2-(N- benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester (184 mg, 0.166 mmol) was hydrogenated over Pd-black (71 mg) by the method of Example A- 1-b, to give the title compound as the triacetate as a white solid (95 mg). 31 P-NMR (CDCl 3 +5%CD 3 OD)(H 3 PO 4 reference): δ 14.6 (s). Example A-5 4-amino-l -hydroxybutylidene- 1.1 -bisphosphonic acid, mono (2-methyl-2-( " L- valyloxymethyl propionyloxymethyl) ester. a) 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, tribenzyl mono (2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl) propionyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (1.54 g, 4 mmole) in dry N,N-dimethylformamide (24 ml), heated at 50 °C, was added diisopropylethylamme (2.78 ml, 16 mmole), followed by dropwise addition of benzylbromide (1.9 ml, 16 mmole). After stirring under argon for 4 h, the solution was concentrated on rotavapor and treated with ethyl acetate (20 ml). Crystals were filtered off and the filtrate was extracted with brine. The organic phase was filtered through anhydrous sodium sulfate and evaporated. The 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid, tribenzylester was isolated by silica gel i l l column chromatography (2-4, 7-10, 15-20% ethanol in dichloromethane). The pure fractions containing the pure triester were pooled together and evaporated. The residue was then dissolved in ethyl acetate and the solution extracted three times with 2M aqueous solution of citric acid. Triester (990 mg); R f (20%MeOH/ CHC1 3 ) 0.15 (at the center of oval spot from baseline); 3 'P-NMR (CDC1 3 ) (H 3 PO 4 reference): δ 20.4(d), 13.3 (d); 'H-NMR (CDC1 3 ): 7.35- 7.10 (m, 20H), 5.20-4.91 (m, 8H), 4.60 (br, IH), 3.00 (m, 2H), 2.12-1.75 (m, 4H). b) Dried tribenzyl ester (395 mg) was dissolved in dry N,N- dimethylformamide (3 ml), followed by addition of diisopropylethylamme (99 ml) and a solution of iodomethyl 2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl) propionate (737 mg) in N,N-dimethylformamide (1 ml). After stirring under argon for 4 h at 30 °C, the solution was concentrated to dryness on rotavapor and treated with ethyl acetate (10 ml). Crystals were filtered off and the filtrate was extracted with brine brine containing a small amount of sodium thiosulfate. The organic phase was filtered through anhydrous sodium sulfate and evaporated. The title compound (84 mg) was isolated by silica gel column chromatography (1, 2, 3% ethanol in dichloromethane). R f (2%MeOH/ CHC1 3 ) 0.60; 3 'P-NMR (CDCI 3 ) (H 3 PO 4 reference): δ 16.4(m). 'H-NMR (CDC1 3 ): 7.28 (m, 25H), 5.22 (d, IH), 5.62-5.53 (m, 3H), 5.07, 5.04 (2xs, 10H), 4.93 (br, IH), 4.27 (d,d, IH), 4.15 (d,d, 2H), 3.11 (m, 2H), 2.13-1.77 (m, 5H), 1.17 (s, 6H), 0.92 (d, 3H), 0.83 (d, 3H). c) 4-amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, mono (2- methyl-2-(L -valyloxymethyl) propionyloxymethyl) ester. 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid tribenzyl mono (2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl) propionyloxymethyl) ester (84 mg, 0.083 mmol) was hydrogenated over Pd-black (60 mg) by the method of Example A-l-b, to give the title compound as a white solid (35 mg). 112 3 'P-NMR (CDCl 3 +5%CD 3 OD)(H 3 PO 4 reference): δ 14.5 (m). Example A-6 4-amino-l -hydroxybutylidene- 1.1 -bisphosphonic acid, di (2-(-L-valyloxy)-2-phenyl- DL-acetyloxymethyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (192 mg, 0.5 mmole) was esterified with the corresponding iodomethyl ester by the method described in Example A-3-a to yield 72 mg of the title compound as the tri-N-CBz protected form, ready for deprotection. R f (20%MeOH/CHCl 3 ) 0.20 (at the center of oval spot from baseline). 'H-NMR (CDC1 3 + l%CD 3 OD): 7.44-7.10 (m, 25H), 5.94 (m, 2H), 5.59 (m, 2H), 5.18-4.85 (m, 6H), 4.36 (m, 2H), 3.00 (m, 2H), 2.12-1.63 (m, 6H), 0.95 (m, 12H). 3l P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 15.5 (s). Example A-7 4-amino-l -hydroxybutylidene- 1.1 -bisphosphonic acid, di ((1.3-di-varyloxy)propyl-2- oxycarbonyloxy methyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (141 mg, 0.37 mmole) was esterified from the corresponding iodomethyl ester by the method described in Example A-l -a to yield 90 mg of title compound as the tri CBz protected form, ready for deprotection. R f (10%MeOH/CHCl 3 ) 0.20 (at the center of oval spot from baseline). (153 mg of mixture of the diester and triester). 'H-NMR (CDC1 3 + l%CD 3 OD) of title compound: 7.29 (m, 25H), 5.65 (m, 4H), 5.14- 4.85 (m, 12H), 4.45-4.05 (m, 12H), 3.11 (m, 2H), 2.14-1.76 (m, 8H), 0.87 (m, 24H). 31 P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 16.7 (s). Example A-8 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid, di (2-L-valyloxy -DL- propionyloxymethyl) ester. 113 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (158 mg, 0.41 mmole) was esterified from the corresponding iodomethyl ester by the method described in Example A-3-a to yield 110 mg of the title compound as the tri N-Boc protected from, ready for deprotection. R f (20%MeOH/CHCl 3 ) 0.15 (at the center of oval spot from baseline). 'H-NMR (CDCl 3 +l%CD 3 OD): 7.29 (m, 15H), 5.65 (m, 4H), 5.15-4.95 (m, 8H), 4.33 (m, 2H), 3.09 (m, 2H), 2.22-1.74 (m, 6H), 1.52 (m, 6H), 0.92 (m, 12H). 31 P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 16.8 (s). Example A-9 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid di-(5-CL- valyloxy)-2.2- dimethylvaleryloxymethyl) ester a) 4-Benzyloxy carbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di-(5-(N-CBz-L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (575 mg, 1.50 mmol) in DMF (10 mL), was added diisopropylamine (0.78 mL, 4.5 mmol), followed by an injection of a solution of give iodomethyl 5-(N-CBz-L- valyloxy)-2,2-dimethylvalerate (1.95 g, 3.75 mmol) in DMF (5 mL). After stirring under argon for 1.5 h at room temperature, the solution was concentrated on rotavapor and treated with ethyl acetate (100 mL). Crystals were filtered off and the filtrate was extracted with brine containing a small amount of sodium thiosulfate. The organic phase was filtered through anhydrous sodium sulfate and evaporated. After silica gel column (silica gel, 4— »20% MeOH in CH 2 C1 2 ), the pure fractions containing the title compound were combined and evaporated. The residue was then dissolved in ethyl acetate and the solution extracted twice with aqueous saturated sodium bicarbonate and then twice with 5% aqueous EDTA-disodium salt. The ethyl acetate phase was evaporated, to give 171 mg of 4-benzyloxy carbonylamino- 1- hydroxybutylidene- 1 , 1 -bisphosphonic acid di-(5-(N-CBz-L-valyloxy)-2,2- dimethylvaleryloxymethyl) ester. 114 'H-NMR (CDCI 3 ): 7.30 (br s, 15H), 5.85-5.25 (m, 4H), 5.20-4.95 (m, 6H), 4.30- 3.95 (m, 6H), 3.18-3.00 (m, 2H), 2.20-1.75 (m, 6H), 1.7-1.4 (m, 8H), 1.3-1.0 (s, 12H), 1.0-0.8 (m, 12H). 3 'P-NMR (CDCl 3 )(H 3 PO 4 reference): 16.0 (s). b) 4- Amino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid di-(5-(L- valyloxy)-2,2-dimethylvaleryloxymethyl) ester. A solution of 4-benzyloxy carbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di-(5-(N-CBz-L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester (171 mg, 0.147 mmol) in methanol / ethyl acetate / acetic acid (2:1:1 v/v/v) (20 mL) was hydrogenated over a Pd-black catalyst (30 mg) at 40 psi of hydrogen for 6 h. The suspension was filtered through celite and the filtrate was evaporated to dryness under reduced pressure, to give 95 mg of 4-amino- 1 -hydroxybutylidene- 1,1- bisphosphonic acid di-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester was obtained as a white solid. 'H-NMR (CDCI 3 ): 5.75-5.30 (m, 4H), 5.20-4.95 (m, 6H), 4.20-3.80 (m, 6H), 3.00- 2.80 (m, 2H), 2.20-1.40 (m, 14H), 1.3-1.0 (m, 12H), 1.0-0.8 (m, 12H). 31 P-NMR (CDCl 3 +CD 3 OD)(H 3 PO 4 reference): δ 17.3 (br s) Example A- 10 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid di-((2-(L-valyloxy)- ethoxycarbonyloxy) methyl) ester a) 4-benzyloxy carbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di-((2-(N-CBz-L-valyloxy)-ethoxycarbonyloxy) methyl) ester To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (550 mg, 1.44 mmol) in DMF (10 mL), was added diisopropylamine (0.75 mL, 4.32 mmol), followed by an injection of a solution of 2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate (1.40 g, 3.60 mmol) in DMF (5 mL). After stirring under argon for 1.5 h at room temperature, the solution was concentrated on rotavapor and 115 treated with ethyl acetate (100 mL). Crystals were filtered off and the filtrate was extracted with brine containing a small amount of sodium thiosulfate. The organic phase was filtered through anhydrous sodium sulfate and evaporated. After silica gel column (silica gel, 4— »20% MeOH in CH 2 C1 2 ), the pure fractions containing the title compound were combined and evaporated. The residue was then dissolved in ethyl acetate and the solution extracted twice with aqueous saturated sodium bicarbonate and then twice with 5% aqueous EDTA-disodium salt. The ethyl acetate phase was evaporated, to give 160 mg of 4-benzyloxy carbonylamino- 1 -hydroxybutylidene- 1,1- bisphosphonic acid di-((2-(N-CBz-L-valyloxy)-ethoxycarbonyloxy) methyl) ester. 'H-NMR (CDC1 3 ): 7.29 (br s, 15H), 5.90-5.30 (m, 4H), 5.15-4.90 (m, 6H), 4.50- 4.00 (m, 10H), 3.18-3.00 (m, 2H), 2.20-1.50 (m, 6H), 1.05-0.80 (m, 12H). 31 P-NMR (CDCl 3 )(H 3 PO 4 reference): 16.5 (s). b) 4- Amino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid di-((2-(L- valyloxy)-ethoxycarbonyloxy) methyl) ester. A solution of 4-benzyloxy carbonylamino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid di-((2-(N-CBz-L-valyloxy)-ethoxycarbonyloxy) methyl) ester (160 mg, 0.147 mmol) in methanol / ethyl acetate / acetic acid (2:1:1 v/v/v) (20 mL) was hydrogenated over a Pd-black catalyst (30 mg) at 40 psi of hydrogen for 7 h. The suspension was filtered through celite and the filtrate was evaporated to dryness under reduced pressure, to give 100 mg of 4-amino-l -hydroxybutylidene- 1,1- bisphosphonic acid di-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester was obtained as a white solid. 'H-NMR (CDCI 3 ): 5.80-5.40 (m, 4H), 4.70-4.05 (m, 10H), 4.4-4.2 (m, 4H), 3.00- 2.80 (m, 2H), 2.20-1.50 (m, 6H), 1.05-0.80 (m, 12H). 31 P-NMR (CDCl 3 +CD 3 OD)(H 3 PO 4 reference): δ 17.5 (br s). Example A-l 1 4- Amino- 1-hydroxybutyliden- 1.1 -bisphosphonic acid bis [ ~ 2.2-dimethyl-3-(D- valyloxyVpropionyloxymethyll ester 116 a) 4-Benzyloxycarbonylamino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid bis [2,2-dimethyl-3-(N-CBZ-D-valyloxy)-propionyloxymethyl] ester To a solution of 4-benzyloxycarbonylamino-l -hydroxybutyliden- 1,1 -bisphosphonic acid (382 mg, 1 mmole) and diisopropylethyl (0.43 ml, 2.5 mmole) in DMF (3 ml) at -40° C was added 2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid iodomethyl ester (1.23 g, 2.5 mmole) in DMF (4 ml). The reaction was kept at 0° C for 2.5 hr and then at 4° C for 18 hr. The reaction mixture was evaporated in vacuo and ethyl acetate (20 ml) was added. The precipitate was filtered off and the organic phase was washed with sodium bicarbonate aqueous solution and dried. The product was isolated with silica gel column chromatography. 125 mg. 'H-NMR (CDC1 3 ): 7.31 (m, 15 H) 5.71 (m, 4 H) 5.58 (d, 2 H) 5.12 (s, 4H) 5.05 (s, 2H) 4.30 (dd, 2H) 4.12 (m, 4 H) 3.18 (m, 2H) 2.05 (m, 6 H) 0.92 (dd, 12 H). 31 P-NMR (CDC1 3 ): 15.1 b) 4- Amino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid bis [2,2-dimethyl-3- (D-valyloxy)-propionyloxymethyl] ester. 4-Benzyloxycarbonylamino-l -hydroxybutyliden- 1,1 -bisphosphonic acid bis [2,2- dimethyl-3-(N-CBZ-D-valyloxy)-propionyloxymethyl] ester (130 mg) was dissolved in a mixed solvent of EtOAc/MeOH/AcOH (6 ml/3 ml/1.5 ml). To the solution was added palladium black (60 mg). The reaction was kept under hydrogen atmosphere (40 psi) until sampling showed the complete deprotection of the benzyloxycarbonyl groups. The reaction mixture was filtered, and then dried and coevaporated with toluene and methanol, giving the titled product. 102 mg. 31 P-NMR ( CDC1 3 + CD 3 OD ) : 14.1 Example A- 12 4- Amino- 1 -hydroxybutyliden- 1.1 -bisphosphonic acid bis [4-(N-CBz-L-valyloxy)- butanoyloxymethyll ester 117 a) 4-Benzyloxycarbonylamino- 1 -hydroxybutyliden- 1 , 1 -bisphosφHέriϊy ^acitFtffs [4-(N-CBz-L-valyloxy)-butanoyloxymethyl] ester. 4-Benzyloxycarbonylamino-l -hydroxybutyliden- 1,1 -bisphosphonic acid (573 mg, 1.5 mmole) was dissolved in dioxane (10 ml). To the solution was added tetrabutylammonium hydroxide (40 %, 2.43 ml, 3.75 mmole). The solution was evaporated and coevaporated with DMF several times. The residue was dissolved in DMF (5 ml). To the solution was added 4-(N-CBz-L- valyloxy) butyric acid iodomethyl ester (1.79 g, 3.75 mmole) in DMF (5 ml) portionwise in one hour. The reaction was kept at room temperature for 3 hr and then evaporated in vacuo. Later, ethyl acetate (20 ml) was added. The precipitate was filtered off and the organic phase was washed with sodium bicarbonate aqueous solution and dried. The product was isolated with silica gel column chromatography. 135 mg. 'H-NMR (CDC1 3 ):7.25 (m, 15 H) 5.60 (m, 6 H ) 5.05 (m, 8H) 4.30-3.90 (m, 6 H) 3.10 (m, 2 H) 2.50-1.80 (m, 14 H) 0.85 (m, 12 H). 31 P-NMR (CDC1 3 ): 13.7. b) 4-amino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid bis 4-(L- valyloxy)-butanoyloxymethyl] ester. 4-Benzyloxycarbonylamino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid bis [4-(N- CBz-L-valyloxy)-butanoyloxymethyl] ester (100 mg) was dissolved in a mixed solvent of EtOAc/MeOH/AcOH (6 ml/3 ml/ 1.5 ml). To the solution was added palladium black (80 mg). The reaction was kept under hydrogen atmosphere (40 psi) until sampling showed the complete deprotection of the benzyloxycarbonyl groups. The reaction mixture was filtered, and then dried and coevaporated with toluene and methanol, giving the titled product. 70 mg. 3 'P-NMR (CD 3 OD): 17.7 Example A- 13 4-amino- 1 -hydroxybutyliden- 1.1 -bisphosphonic acid. di-(3-(L-valyloxy) benzoyloxymethyl) ester 118 a) 4-Benzyloxycarbonylamino- 1 -hydroxybutyliden- 1 , 1 -bisphonic acid, di-(3 -(N-benzyloxycarbonyl-L- valyloxy) benzoyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutyliden- 1,1 -biphosphonic acid (0.59g, 1.5 mmole) and diisopropylethyl-amine (0.64g, 5 mmole) in N,N- dimethylforrnamide (40 ml) was added dropwise a solution of iodomethyl-3-(N- benzyloxycarbonyl-L-valyloxy)-benzoate (2.2g, 4.3 mmole) in N,N- dimethylformamide (5 ml). The mixture was stirred 2 hours at room temperature under argon. The mixture was evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the mixture was filtered after 2 hours. The organic phase was washed twice with 5% sodium hydrogencarbonate solution and dried with sodium sulfate. The product was isolated by silica gel column chromatography. Yield: 0.23g = 15% 'H-NMR (CDC1 3 + 5% CD 3 OD) 0.89 (m, 12H) 1.58-2.28 (m, 6H) 2.92 (m, 2H) 4.26 (m, 2H) 5.00 (m, 6H) 5.46-6.02 (m, 4H) 6.78- 7.86 (8m, 23H) 31 P-NMR (CDC1 3 + 5% CD 3 OD) 16.5 (s) b) 4-amino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid, di-(3-(L- valyloxy) benzoyloxymethyl) ester. Deprotection of the CBz groups of 4-benzyloxycarbonylamino-l-hydroxybutyliden- 1,1 -bisphonic acid, di-(3-(N-benzyloxycarbonyl-L-valyloxy) benzoyloxymethyl) ester using mild conditions as specified in Greene, "Protecting Groups in Organic Synthesis, (John Wiley & Sons, New York, 1981) yields the title compound. Example A- 14 4- Amino- 1 -hydroxybutyliden- 1.1 -bisphosphonic acid. di-(3-(L-valyloxy)- propionyloxymethyl) ester a) 4-Benzyloxycarbonylamino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid, di-(3-( N-benzyloxycarbonyl-L-valyloxy)-propionyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l-hydroxybutyliden-l,l-bisphosphonic acid (0.88g, 2,5 mmole) and diisopropylethyl-amine (0.78g, 6 mmole) in N,N- dimethylformamide (40 ml) was added dropwise a solution of iodomethyl-3-(N- 119 benzyloxycarbonyl-L-valyloxy)-propionate (2.3g, 4.95 mmole) in N,N- dimethylformamide (5 ml). The mixture was stirred 2 hours at room temperature under argon and evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the mixture was filtered after 2 hours. The organic phase was washed twice with 5% sodium hydrogencarbonate solution and dried with sodium sulfate. The product was isolated by silica gel column chromatography. Yield: 0.19g = 8% 'H-NMR (CDC1 3 + 5% CD 3 OD) 0.89 (m, 12H) 1.62-2.16 (m, 6H) 2.60 (m, 4H) 3.08 (m, 2H) 4.12 (m, 2H) 4.30 (m, 4H) 5.02 (m, 6H) 5.42-5.64 (m, 4H) 7.24 (m, 15H) 3 'P-NMR (CDC1 3 + 5% CD 3 OD) 16,9 (s) b) 4- Amino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid, di-(3-(L- valyloxy)-propionyloxymethyl) ester. Deprotection of the CBz groups of 4-benzyloxycarbonylamino-l-hydroxybutyliden- 1,1 -bisphosphonic acid, di-(3-(N-benzyloxycarbonyl-L-valyloxy)- propionyloxymethyl) ester using mild conditions as specified in Greene, "Protecting Groups in Organic Synthesis, (John Wiley & Sons, New York, 1981) yields the title compound. Example A- 15 4-amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid. di-(4-CL-varyloxy) benzoyloxymethyl) ester. a) 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di-(4-(N-benzyloxycarbonyl-L-valyloxy) benzoyloxymethyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (141 mg, 0.37 mmole) was esterified from the corresponding iodomethyl ester by the method described in Example A-3-a) to yield 55 mg of title compound. R f (20%MeOH/CHCl 3 ) 0.15 (at the center of oval spot from baseline). 'H-NMR (CDC1 3 + l%CD 3 OD): 7.82 (m, 4H), 7.29 (m, 15H), 6.97 (m, 4H), 5.85 (m, 4H), 5.11 (m, 6H), 4.46 (m, 2H), 3.10 (m, 2H), 2.30-1.77 (m, 6H), 1.52 (m, 6H), 0.99 (m, 12H). 120 3 'P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 15.6(s). b) 4- Amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di-(4-(L- valyloxy) benzoyloxymethyl) ester. 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di-(4-(N- benzyloxycarbonyl-L-valyloxy) benzoyloxymethyl) ester is CBz deprotected using mild conditions as prescribed in Greene, "Protecting Groups in Organic Synthesis, (John Wiley & Sons, New York, 1981) to yield the title compound. Example A- 16 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid, di-f 3-(3.4-di-(L-valyloxy) phenyl) propionyloxymethyl) ester. a) 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di-(3-(3,4-di(N-benzyloxycarbonyl-L-valyloxy) phenyl) propionyloxy- methyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (143 mg, 0.37 mmole) was esterified from the corresponding iodoemthyl ester by the method described in Example A-3-a) to yield 169 mg of the title compound. R f (20%MeOH/CHCl 3 ) 0.15 (at the center of oval spot from baseline). 'H-NMR (CDC + l%CD 3 OD): 7.40-6.85 (m, 31H), 5.62 (m, 4H), 5.02 (m, 10H), 4.43 (m, 4H), 3.10 (m, 2H), 2.84 (m, 4H), 2.61 (m, 4H), 2.35-1.73 (m, 8H), 1.52 (m, 6H), 0.99 (m, 24H). 31 P-NMR (CDCl 3 +l%CD 3 OD)(H 3 PO 4 reference): δ 14.3 (s). b) 4- Amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di-(3-(3,4-di- (L- valyloxy) phenyl) propionyloxymethyl) ester. 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di-(3-(3 ,4- di(N-benzyloxycarbonyl-L-valyloxy) phenyl) propionyloxy- methyl) ester is CBz deprotected using mild conditions as prescribed in Greene, "Protecting Groups in Organic Synthesis, (John Wiley & Sons, New York, 1981) to yield the title compound. 121 Example A- 17 4-Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid. tri(3-(L-valyloxy)-2.2- dimethylpropoxycarbonyloxymethyl) ester a) 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid tri(3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropoxycarbonyl oxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (174 mg, 0.45 mmol) in dry DMF (1 mL) were added diisopropylethylamme (240 μL, 1.38 mmol), followed by 3-(N-benzyloxycarbonyl-L-valyloxy)-2,2- dimethylpropyl iodomethyl carbonate (592 mg, 1.14 mmol). After stirring for 5 h at ambient temperature, under nitrogen, the reaction mixture was concentrated on a rotavapor, freated with ethyl acetate (15 mL), and filtered. The organic solution was washed with 5% Νa^O^ followed by brine. Drying over anhydrous Νa 2 SO 4 and concentration gave a yellow oil that was subjected to column chromatography (silica, 2/1 petroleum ether - ethyl acetate, 2.5 - 20% methanol in CH 2 C1 2 ) to give fine, white solids (147 mg) enriched in the triester. The solids were dissolved in ethyl acetate, washed twice with 5% aqueous EDTA-disodium salt, dried over anhydrous Na j SO^ and evaporated to dryness under vacuum. R f (10% methanol in CH 2 C1 2 ) 0.30; ' H NMR (250 MHz, CDC1 3 + 1% CD 3 OD) δ 0.85-0.95 (m, 36 H), 1.70-2.20 (m, 7H), 3.10 (br s, 2H), 3.85-3.95 (br, 12 H), 4.25 (m, 3H), 5.05 (s, 8H), 5.52-6.0 (m, 10H), 7.30 (s, 20H); 3 'P NMR (101 MHz, CDC1 3 + 1% CD 3 OD) δ 13.6 and 24.6 (2d, J= 47 Hz). The diester was a minor component: 31 P NMR δ 18.6 (s). b) Removal of benzyloxycarbonyl protecting groups. The triester (110 mg) from step (a) was hydrogenated at 40 psi over Pd black (14 mg) in 4.2 mL solvent (2/1/1 ethyl acetate - methanol - acetic acid) for 18.5 h. The suspension was filtered through a small column of celite and washed with ethyl acetate - methanol. The filtrate was evaporated to dryness under vacuum to give 122 white solids (97 mg). Because proton NMR showed incomplete deprotection, the material was resubmitted for hydrogenation (14 mg Pd, 10 mL solvent) overnight to give the deprotected triester (as the acetate salt, 79 mg) as shown by the disappearance of peaks for the benzyloxy group at δ 5.05 and 7.30. 31 P NMR (101 MHz, CDCL δ 12.5 and 24.0. Example A- 18 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid, di-f 2 -methyl- 1 -(L-valyloxy)- 2-propoxycarbonyloxymethyl) ester a) 4-Benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di( 1 -(N-benzyloxycarbonyl-L- valyloxy)-2-methyl-2-propoxycarbonyloxymethyl) ester. 4-Benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (460 mg, 1.2 mmol) was esterified by the method described in Example A- 17 a) with 1-(N- benzyloxycarbonyl-L-valyloxy)-2-methyl-2-propyl iodomethyl carbonate (1.54 g, 3.0 mmol) for 2h. After column chromatography (silica, 4-20% methanol in CH 2 C1 2 ), the pure fractions containing the title compound were pooled together and concentrated. The residue was dissolved in ethyl acetate, washed twice with 5% aqueous EDTA- disodium salt, and then, water, dried over Νa;,SO 4 , and evaporated to dryness under vacuum to give the diester as off-white solids (92 mg). 3 'P NMR (101 MHz, CDC1 3 + 1% CD 3 OD) δ 19.5 (s); 'H NMR (250 MHz, CDC1 3 + 1% CD 3 OD) δ 0.76-1.41 (m, 24H), 1.74 (br s, 4H), 2.05 (m, 2H), 3.02 (br s, CH 2 N), 3.90-4.30 (m, CH 2 OC=O and CHα valine), 4.93-5.01 (m, 6H), 5.30-5.90 (m, OCH 2 O and NHC=O), 7.22 (s, 15H). (b ) 4- Amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid, di(2 -methyl- 1 - (L-valyloxy)-2-propoxycarbonyloxymethyl) ester. 123 The benzyloxycarbonyl-protected diester (86 mg) from step (a) was hydrogenated by the method described in Example A- 17 b) to give the title compound (as the acetate salt) as a white powder (72 mg). 31 P NMR (101 MHz, CDC1 3 ) δ 19.2 (s). Example A- 19 4-amino-l -hydroxybutylidene- 1.1 -bisphosphonic acid di (2 -methyl -2-(L- isoleucyloxymethvDpropionyloxymethyl) ester. a) 4-N-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di (2-methyl-2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)propionyl- oxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (824mg, 2.1 mmole) and diisopropylethylamme (0.8g, 6.3 mmole) in dry N,N- dimethylformamide (15 ml) was added dropwise a solution of iodomethyl 2-methyl- 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl) propionate (3.1g, 5.21 mmole) in N,N-dimethylformamide (6 ml). The mixture was stirred 2 hours at room temperature and evaporated under reduced pressure. Ethyl acetate (70 ml) was added and after 1 hour the crystals were filtered. The organic phase was washed two times with saturated sodium hydrogencarbonate solution, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 0.36g 'H-NMR (CDC1 3 ) 0.86(m, 12H) 1.20 (m, 16H) 1.60-2.20 (m, 6H) 3.10 (m, 2H) 3.80- 4.40 (m, 6H) 5.08 (m, 6H) 5.45 (m, 4H) 7.29 (m, 15H) 31 P-NMR (CDC1 3 +5% CD 3 OD) 14.2 (s) b) 4-amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di (2-methyl- 2-(isoleucyloxymethyl)propionyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid di (2-methyl-2-(N-benzyloxycarbonylamino-L-isoleucyloxymethyl)propionyl- oxymethyl) ester (0.195g, 0.171 mmole) in ethyl acetate (10 ml), methanol (10 ml) 124 and acetic acid (5 ml) was added palladium black (lOOmg). The mixture was hydrogenated overnight at 45 psi. The catalyst was filtered and washed with ethyl acetate, methanol and acetic acid. The solution was evaporated under reduced pressure and the product was dried in vacuo to yield the title compound as the triacetate salt. Yield: 15 Omg. 31 P-NMR (CDC1 3 +5% CD 3 OD) 18.1 (s) Example A-20 4-amino-l -hydroxybutylidene- 1.1 -bisphosphonic acid di (4-CL-valyloxy)- cyclohexanoyloxymethyl) ester a) 4-N-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di (4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -biphosphonic acid (0.706g, 1.8 mmole) and diisopropylethylamme (07g, 5.4 mmole) in N,N- dimethylformamide (15 ml) was added dropwise a solution of iodomethyl 4-(N- benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (2.35g, 4.5 mmole) in N,N- dimethylformamide (5 ml). The mixture was stirred 2 hours at room temperature under argon. The mixture was evaporated under reduced pressure. Ethyl acetate (60 ml) was added and the solid was filtered after 2 hours. The organic phase was washed twice with saturated sodium hydrogencarbonate and brine. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The products were isolated by silica gel column chromatography with dichloromethane/ methanol. After silica gel column chromatography the fractions were dissolved in ethyl acetate and washed three times with 5% aqueous EDTA-disodium salt solution, dried with sodium sulfate, evaporated under reduced pressure and dried in vacuo to yield 298mg 'H-NMR (CDC1 3 ) 0.84 (m, 12H) 1.35-2.35 (m, 24H) 3.10 (m, 2H) 4.08 (m, 2H) 5.02 (m, 8H) 5.55 (m, 4H) 7.24 (m, 15H) 31 P-NMR (CDC1 3 + 5% CD 3 OD) 15.2 (s) 125 b) 4-amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di (4-(L- valyloxy)-cyclohexanoyloxymethyl) ester. 4-N-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di (4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoyloxymethyl) ester is de- CBz protected using conventional conditions as exemplified above to yield the title compound. Example A-21 4-amino-l -hydroxybutylidene- 1.1 -bisphosphonic acid tri (4-fL-valyloxy)- cyclohexanoyloxymethyl) ester The appropriate fraction of Example A-20, step a) was dissolved in ethyl acetate and washed three times with 5% aqueous EDTA-disodium salt solution, dried with sodium sulfate, evaporated under reduced pressure and dried in vacuo to yield 320 mg which is deprotected using conventional conditions as exemplified above to yiled the title compound. 'H-NMR (protected form) (CDC1 3 ) 0.86 (m, 18H) 1.3-2.5 (m, 34H) 3.10 (m, 2H) 4.22 (m, 3H) 4.55-5.10 (m, 11H) 5.50 (m, 6H) 7.28 (m, 20H) 31 P-NMR (CDC1 3 + 5% CD 3 OD) 20.8 (d) 10.0 (d) Example A-22 4-amino-l -hydroxybutylidene- 1.1 -bisphosphonic acid di [N-C2-L- valyloxy- 1.1- dimethyl-ethyl)aminocarbonyloxymethyl]ester. a) 4-N-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di [N-(2-L-valyloxy- 1 , 1 -dimethyl-ethyl)aminocarbonyloxymethyl]ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene 1,1 -biphosphonic aid (O.lg, 0. mmole) and diisopropylethylamme (0.3 lg, 2.4 mmole) in N,N- dimethylformamide (5 ml) was added dropwise a solution of 2-(N-( iodomethoxy- carbonyl)-amino)-2-methyl- 1 -(N-benzyloxycarbonyl-L-valyloxy)-propane in N,N- dimethylformamide (2.5 ml). The mixture was stirred 2 hours at room temperature under argon. The mixture was evaporated under reduced pressure. Ethyl acetate (40 126 ml) was added and the solid was filtered after 2 hours. The organic phase was washed twice with saturated sodium hydrogencarbonate and brine. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol acetic acid. After silica gel column chromatography the fractions were dissolved in ethyl acetate and washed three times with 5% aqueous EDTA-disodium salt solution, dried with sodium sulfate, evaporated under reduced pressure and dried in vacuo. Yield: 165mg. 'H-NMR (CDC1 3 ) 0.80 (m, 12H) 1.20 (m, 12H) 1.88 (m, 6H) 3.00 (m, 2H) 3.64 (m, 4H) 4.20 (m, 2H) 5.00 (m, 6H) 5.50 (m, 4H) 7.26 (m, 15H) 3 'P-NMR (CDC1 3 + 5% CD 3 OD) 14.8 (s) b) 4-amino-l -hydroxybutylidene- 1,1 -bisphosphonic acid di [N-(2-L- valyloxy- l,l-dimethyl-ethyl)aminocarbonyloxymethyl] ester. A solution of 4-N-benzyloxycarbonylamino- 1 -hydroxybutyliden- 1 , 1 -bisphosphonic acid di[N-(2-L-valyloxy-l,l-dimethyl-ethyl)aminocarbonyloxymethyl] ester (0.16g 0.14mmole) in ethyl acetate (5ml), methanol (10 ml) and acetic acid (5 ml) was hydrogenated with palladium black O.lg) at room temperature and 45 psi overnight . The catalyst was filtered and washed with ethyl acetate and methanol. The solution was evaporated under reduced pressure and the product was dried in vacuo to yield the triacetate salt. Yield: lOOmg 31 P-NMR (CDC1 3 + 5% CD 3 OD) 14.7 (s) Example A-23 4-amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid di-(T -C2-L-valyloxyethyl)-6- oxo-1.6-dihvdro-pyridine-3-carbonyloxymethyl) ester a) 4-Benzyloxy carbonylamino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid di-(l-(2-N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3- carbonyloxymethyl) ester. 127 To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (565 mg, 1.44 mmol) in DMF (10 mL), was added diisopropylamine (0.75 mL, 4.32 mmol), followed by an injection of a solution of give l-(2-N-CBz-L- valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid iodomethyl ester (2.00 g, 3.60 mmol) in DMF (5 mL). After stirring under argon for 1.5 h at room temperature, the solution was concentrated and treated with ethyl acetate (100 mL). Crystals were filtered off and the filtrate was extracted with brine containing a small amount of sodium thiosulfate. The organic phase was filtered through anhydrous sodium sulfate and evaporated. After silica gel column (silica gel, 4→20% MeOH in CH 2 C1 2 ), the pure fractions containing the title compound were combined and evaporated. The residue was then dissolved in ethyl acetate and the solution extracted twice with aqueous saturated sodium bicarbonate and then twice with 5% aqueous EDTA-disodium salt. The ethyl acetate phase was evaporated, to give 205 mg of 4- benzyloxy carbonylamino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid di-(l-(2-N- CBz-L-valyloxyethyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carbonyloxymethyl) ester. 'H-NMR (CDC1 3 ): 8.35-7.95 (m, 2H), 7.85-7.50 (m,2H), 7.26 (br s, 15H), 6.60-6.20 (m,2H), 5.90-5.35 (m, 4H), 5.15-4.80 (m, 6H), 4.50-4.00 (m, 10H), 3.18-3.00 (m, 2H), 2.45-1.55 (m, 6H), 1.00-0.80 (m, 12H). 31 P-NMR (CDCl 3 )(H 3 PO 4 reference): 16.8 (s). b) 4-amino-l -hydroxybutylidene- 1,1 -bisphosphonic acid di-(l-(2-L- valyloxyethyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carbonyloxymethyl) ester. A solution of 4-benzyloxy carbonylamino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid di-(l-(2-N-CBz-L-valyloxyethyl)-6-oxo-l,6-dihydro-pyridine-3- carbonyloxymethyl) ester (180 mg, 0.145 mmol) in methanol / ethyl acetate / acetic acid (2:1 :1 v/v/v) (20 mL) was hydrogenated over a Pd-black catalyst (30 mg) at 40 psi of hydrogen for 10 h. The suspension was filtered through celite and the filtrate was evaporated to dryness under reduced pressure, to give 85 mg of 4-amino-l- hydroxybutylidene- 1 , 1 -bisphosphonic acid di-( 1 -(2-L-valyloxyethyl)-6-oxo- 1 ,6- dihydro-pyridine-3-carbonyloxymethyl) ester was obtained as a white solid. 128 'H-NMR (CDCI 3 ): 8.65-8.20 (m, 2H), 7.95-7.65 (m, 2H), 6.65-6.30 (m, 2H), 5.90- 5.35 (m, 4H), 4.70-4.00 (m, 10H), 3.18-3.00 (m, 2H), 2.45-1.55 (m, 6H), 1.00-0.80 (m, 12H). 3 'P-NMR (CDCl 3 )(H 3 PO 4 reference): 13.9 (s). Example A 24 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid di (d.3-di-(Valyloxy)propyl- 2-oxycarbonyloxy methyl) ester a) 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di ((l,3-di-(N-benzyloxycarbonyl)valyloxy)propyl-2-oxycarbonyloxy methyl) ester. 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (141 mg, 0.37 mmole) was esterified by the method described in Example A-l a using the corresponding iodomethyl ester to give 90 mg of the title compound. R f (10%MeOH/CHCl 3 ) 0.20 (at the center of oval spot from baseline). 'H-NMR (CDC1 3 + l%CD 3 OD): 7.29 (m, 25H), 5.65 (m, 4H), 5.14-4.85 (m, 12H), 4.45-4.05 (m, 12H), 3.11 (m, 2H), 2.14-1.76 (m, 8H), 0.87 (m, 24H). 31 P-NMR (CDCI 3 +I %CD 3 OD)(H 3 PO 4 reference): δ 16.7 (s). b) 4-Amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di (( 1 ,3-di- (valyloxy)propyl-2-oxycarbonyloxy methyl) ester. A solution of 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di ((l,3-di-(N-benzyloxycarbonyl)valyloxy)propyl-2-oxycarbonyloxy methyl) ester (162 mg, 0.1 mmol) in methanol / ethyl acetate / acetic acid (2:1 :1 v/v/v) (6 ml) was hydrogenated over a Pd-black catalyst (70 mg) at 40 psi of hydrogen for 16 h. The suspension was filtered through Celite on a fine pore sized glass sinter and washed with methanol/ethyl acetate (2:1). The filtrate was evaporated to dryness in vacuo and the title compound was obtained as the pentacetate, a white solid after a few co-evaporations with dioxane and hexane. 31 P-NMR (CDCI 3 + 5%CD 3 OD)(H 3 PO 4 reference): δ 13.5 (br). 129 Example A 25 4- Amino- 1 -hydroxybutyliden- 1.1 -bisphosphonic acid di-(2-f L-valyloxymethyl)-2- ethyl butyroyloxymethyl) ester a) 4-N-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di-(2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl )-butyroyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutyliden- 1,1 -biphosphonic acid (0.777g, 2.0 mmole) and diisopropylethylamme (0.78g, 6.0 mmole) in N,N- dimethylformamide (15 ml) was added dropwise a solution of iodomethyl 2-(N- benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate (2.6g, 5 mmole) in N,N- dimethylformamide (5 ml). The mixture was stirred 2 hours at room temperature under argon. The mixture was evaporated under reduced pressure. Ethyl acetate (60 ml) was added and the solid was filtered after 2 hours. The organic phase was washed twice with saturated sodium hydrogencarbonate and brine. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The products were isolated by silica gel column chromatography with dichloromethane/methanol. After silica gel column chromatography the pure fractions were dissolved in ethyl acetate and washed three times with 5% aqueous EDTA-disodium salt solution, dried with sodium sulfate, evaporated under reduced pressure and dried in vacuo.Yield: 320mg 'H-NMR (CDC1 3 ) 0.84 (m, 24H) 1.5-2.2 (m, 14H) 3.10 (m, 2H) 4.20 (m, 2H) 5.0 (m, 6H) 5.50 (m, 4H) 7.26 (m, 15H) 31 P-NMR (CDC1 3 + 5% CD 3 OD) 14.5 (s) b) 4-amino- 1 -hydroxybutyliden- 1,1 -bisphosphonic acid di-(2-(L- valyloxymethyl)-2-ethyl butyroyloxymethyl) ester. A solution of 4-benzyloxycarbonylamino- 1 -butylidene- 1 , 1 -bisphosphonic acid di- (2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyroyloxymethyl) ester (0.195g, 0.167 mmole) in methanol (15 ml), ethyl acetate (5 ml) and acetic acid (10 ml) was hydrogenated with palladium black (120mg) at room temperature overnight with 45 psi. The catalyst was filtered and washed with ethyl acetate, methanol and acetic acid. The solution was evaporated under reduced pressure and solidified with ether. The product was filtered and dried in vacuo to yield the tri acetate salt. 130 Yield: 0.125g. 31 P-NMR (CDC1 3 + 5% CD 3 OD) 14.9 (s) Example A 26 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid bis f3-(L-valyloxy)-2- methyl-propionyloxymethyl) ester a) 4-Benzyloxy carbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid bis (3-(N-CBz-L-valyloxy)-2-methyl-propionyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid (580 mg, 1.48 mmol) in DMF (10 mL), was added diisopropylamine (0.773 L, 4.44 mmol), followed by an injection of a solution of iodomethyl 3-(N-CBz-L- valyloxy)-2-methyl-propionate (1.77 g, 3.70 mmol) in DMF (5 mL). After stirring under argon for 1.5 h at room temperature, the solution was concentrated on rotavapor and treated with ethyl acetate (100 mL). Crystals were filtered off and the filtrate was extracted with brine containing a small amount of sodium thiosulfate. The organic phase was filtered through anhydrous sodium sulfate and evaporated. After silica gel column (silica gel, 4→20% MeOH in CH 2 C1 2 ), the pure fractions containing the title compound were combined and evaporated. The residue was then dissolved in ethyl acetate and the solution extracted twice with aqueous saturated sodium bicarbonate and then twice with 5% aqueous EDTA-disodium salt. The ethyl acetate phase was evaporated, to give 189 mg of 4-benzyloxy carbonylamino- 1 - hydroxybutylidene- 1,1 -bisphosphonic acid bis (3-(N-CBz-L-valyloxy)-2-methyl- propionyloxymethyl) ester. Η-NMR (CDCl 3 +l%CD 3 OD): 7.32 (br s, 15H), 5.85-5.30 (m, 4H), 5.18-4.93 (m, 6H), 4.30-3.95 (m, 6H), 3.22-3.00 (m, 2H), 2.93-2.70 (m, 2H), 2.20-1.65 (m, 6H), 1.35-1.05 (m, 6H), 1.00-0.75 (m, 12H). 31 P-NMR (CDCl 3 )(H 3 PO 4 reference): 15.1 (s). b) 4- Amino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid bis (3-(L- valyloxy)-2-methyl-propionyloxymethyl) ester. 131 A solution of 4-benzyloxy carbonylamino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid bis (3-(N-CBz-L-valyloxy)-2-methyl-propionyloxymethyl) ester (189 mg, 0.175 mmol) in methanol / ethyl acetate / acetic acid (2:1:1 v/v/v) (20 mL) was hydrogenated over a Pd-black catalyst (35 mg) at 50 psi of hydrogen for 7h. The suspension was filtered through celite and the filfrate was evaporated to dryness under reduced pressure, to give 110 mg of 4-amino-l -hydroxybutylidene- 1,1- bisphosphonic acid bis (3-(L-valyloxy)-2-methyl-propionyloxymethyl) ester as the acetate salt, a white solid. 3 'P-NMR (CDCl 3 +CD 3 OD)(H 3 PO 4 reference): δ 14.7 (br s) 132 Example A 27 4- Amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid bis (3-(L-t-butylglvcyloxy)- 2.2-dimethylpropionyloxymethyl) ester a) 4-Benzyloxy carbonylamino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid bis (3-( N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionyloxymethyl) ester. To a solution of 4-benzyloxycarbonylamino-l -hydroxybutylidene- 1,1 -bisphosphonic acid (588 mg, 1.50 mmol) in DMF (10 mL), was added diisopropylamine (0.783 mL, 4.50 mmol), followed by an injection of a solution of iodomethyl 3-(N-CBz-L-t- butylglycyloxy)-2,2-dimethylpropionate (1.90 g, 3.75 mmol) in DMF (5 mL). After stirring under argon for 1.5 h at room temperature, the solution was concentrated on rotavapor and treated with ethyl acetate (100 mL). Crystals were filtered off and the filtrate was extracted with brine containing a small amount of sodium thiosulfate. The organic phase was filtered through anhydrous sodium sulfate and evaporated. After silica gel column (silica gel, 5→20% MeOH in CH 2 C1 2 ), the pure fractions containing the title compound were combined and evaporated. The residue was then dissolved in ethyl acetate and the solution extracted twice with aqueous saturated sodium bicarbonate and then twice with 5% aqueous EDTA-disodium salt. The ethyl acetate phase was evaporated, to give 158 mg of 4-benzyloxy carbonylamino- 1- hydroxybutylidene- 1,1 -bisphosphonic acid bis (3-( N-CBz-L-t-butylglycyloxy)-2,2- dimethylpropionyloxymethyl) ester. 'H-NMR (CDCl 3 +l%CD 3 OD): 7.26 (br s, 15H), 5.85-5.40 (m, 4H), 5.15-4.88 (m, 6H), 4.20-3.95 (m, 6H), 3.20-3.00 ( , 2H), 2.10-1.65 (m, 4H), 1.22-1.05 (m, 12H), 1.00-0.75 (m, 18H). 3 'P-NMR (CDCl 3 )(H 3 PO 4 reference): 15.1 (s). b) 4- Amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid bis (3-( L-t- butylglycyloxy)-2,2-dimethylpropionyloxymethyl) ester. A solution of 4-benzyloxy carbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid bis (3-( N-CBz-L-t-butylglycyloxy)-2,2-dimethylpropionyloxymethyl) ester (158 mg, 0.139 mmol) in methanol / ethyl acetate / acetic acid (2:1:1 v/v/v) (20 mL) was hydrogenated over a Pd-black catalyst (40 mg) at 50 psi of hydrogen for 16h. 133 The suspension was filtered through celite and the filtrate was evaporated to dryness under reduced pressure, to give 100 mg of 4-amino-l -hydroxybutylidene- 1,1- bisphosphonic acid bis (3-( L-t-butylglycyloxy)-2,2-dimethylpropionyloxymethyl) ester as a white solid. 3 'P-NMR (CDCl 3 +CD 3 OD)(H 3 PO 4 reference): δ 14.6 (br s) Example A 28 4-amino- 1 -hydroxybutylidene- 1.1 -bisphosphonic acid di| " tra«5 , -4-(L-valyloxy)-L- prorvoxymethyl] ester a) 4-benzyloxycarbonylamino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di[N-benzyloxycarbonyl-tra«j"-4-(N-benzyloxycarbonyl-L-valyloxy)-L- prolyoxymethyl] ester. Diisopropylethylamme (195 μL, 1.12 mmol) was added to a solution of 4- benzyloxycarbonylamino-1 -hydroxybutylidene- 1,1 -bisphosphonic acid (144 mg, 0.38 mmol) in 1 mL dry DMF, followed by the dropwise addition of a solution of the iodomethyl ester (520 mg, 0.814 mmol) from step (d) in 3 mL DMF. After stirring at ambient temperature for 5.5 h, the reaction mixture was concentrated on a rotavapor, treated with EtOAc (20 mL), and filtered. The precipitates were washed with 10 mL more EtOAc. The organic solution was washed with 10 mL saturated aqueous ΝaHCO 3 containing a small amount of Na 2 S 2 O 3 , followed by reextraction of the aqueous phase with 10 mL EtOAc. The organic phases were combined, washed with 10 mL brine, dried over anhydrous Na^O^ and concentrated. Flash column chromatography (silica gel, 5 - 25 % MeOH in CH 2 C1 2 (20 mL) yielded a fraction that gave light yellow solids (59 mg) enriched in the diester. The solids were dissolved in 25 mL EtOAc, washed with 5% aqueous EDTA-disodium salt (2 x 2 mL), dried over anhydrous Na-,SO 4 , and evaporated to dryness under vacuum. Η NMR (250 MHz, CDC1 3 + 1% CD 3 OD) δ 0.81-0.97 (m, 12H), 1.60-2.50 (br, 10H), 3.09 (br s, 2H), 3.55-3.77 (m, 4H), 4.20 (br s, 2H), 4.43 (m, 2H), 4.80-5.40 (m, 12H), 5.64 (br, 4H), 7.28-7.35 (m, 25H); 134 31 P NMR (101 MHz, CDC1 3 + 1% CD 3 OD) δ 18.3. b) 4-amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonic acid di[trans-4-(N- benzyloxycarbonyl-L-valyloxy)-L-prolyoxymethyl] ester. The product of step a) is deCBz protected by gentle conditions as described in Greene supra to yield the title compound. 135 Biological Example 1 The bioavailability of prodrugs of the invention built on the Z>w-phosphonate alendronate was assayed in rats. The prodrugs of the invention were orally administered at a dose corresponding to 0.1 mmol/kg to triplicate rats in a propylene glycol vehicle. The mother compound was also administered IV at 1/10 of that does for the calculation of absolute oral bioavailability. Urine was collected over 24 hours in a metabolic cage and analysed as shown in Kline et al J Chromat. 534 (1990) 139-149, but modified as follows: 1 ml of urine is mixed with 50 μl or 1.25 M calcium chloride and 100 μl of IM sodium hydroxide. After centrifugation, the urine was aspirated off and the pellet redissolved in 0.8 ml 0.2 M acetic acid, 0.4 ml of 0.01 M EDTA and 0.4 ml of 0.2 m sodium acetate. 1 ml of water was added and the solution loaded onto a preconditioned DEA cartridge. The cartridge was washed with 1 ml of water and alendronate eluted with 1 ml of IM carbonate buffer, pH 10.4. A part of the eluent, 150 μl was mixed with 5 μl of 0.05 M potassium cyanide and 5 μl of NDA solution (1 mg/ml) in methanol. 50 μl was injected into the chromato graph. Absolute bioavailability is determined as the ratio between the AUC for the mother compound administered IV against the AUC for the prodrug administered orally. Results are presented in table 1 below: 136 Table 1 compound absolute bioavailability (%) alendronate 2.2 Example A-2 42 Example A- 11 34 Example A-3 25 Example A-5 14 Example A-4 12 Example A- 18 10 Example A- 10 5 Example A-l 9 8 Example A-24 11 Example A-22 8 Example A-23 10 Example A- 12 9 The compounds of the invention exhibit substantially enhanced oral bioavailability relative to the alendronate. The pivaloyloxymethyl alendronate ester presented as the preferred prodrug in US 5 227 506 provided no better bioavailability than the mother compound in this assay (results not shown). Although the invention has been illustrated by reference to a number of examples built on the phosphorous-containing drug alendronate and employing various linkers and amino acids, it will be appreciated that the invention is not so limited to these values but extends throughout the spirit and scope of the accompanying claims.

Claims: 137 Claims 1 A pharmaceutical compound with the formula: Drug-P(=O)-O-Linker (-R 2 ') k -R 2 where Drug-P(=O)-O- is the residue of a drug comprising a phosphonate, phosphinate or phosphoryl function, R 2 and R 2 ' (if present) are independently the acyl residue of an aliphatic amino acid; Linker is an at least difunctional moiety comprising a first function ester-bonded to the phosphonate, phosphinate or phosphoryl function spaced from a second function ester-bonded to R 2 ; and k is 1 or zero. 2 A compound according to claim 1 , wherein Drug-P(=O)-O- is derived from the group consisting of phosfestrol, (E)-(α,β-diethyl-4,4'- stilbenylen)bis(dihydrogenphosphate), nucleoside analogue phosphonates, nucleotide analogue mono-, di or triphosphates, phosphonoformic acid, phosphonoacetic acid, bis phosphonate bone metabolism agents, fosinoprilate, β-phosphonocarboxylic acid farnesyl protein transferase inhbitors, α-phosphonosulfonate squalene synthase inhibitors, phosphonomethylamine neutral endopeptidase (24.11) inhibitors. 3 A compound according to claim 1, wherein the structure of the formula -linker (-R 2 ') k -R 2 has one of the formulae: 138 R '4L R o '4R R -O - Qql- Qqr-T o- R '4L R 4R or R o ■ 4 R„ — O — ()ql — Ring — ()qr-T o- R 4R where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,. 3 alkyl, C 3 -C 6 cycloalkyl, C,-C 3 alkyl- - cycloalkyl, phenyl or benzyl, R 4R and R 4R ' are independently H, C,. 3 alkyl or phenyl, ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C,. 3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle. A compound according to claim 3, wherein R 4R and R 4R ' are hydrogen. A compound according to claim 3, with the structure: R '4L o R • 4R R - O- Qql- ()qr-T o- R 4L R '.4R 6. A compound according to claim 5, wherein R 4L and R 4L ' are respectively: methyl, methyl; 139 7. A compound according to claim 5, wherein R 4L and R 4L ' are respectively methyl, hydrogen; or ethyl, ethyl. 8 A compound according to claim 3, wherein ql and qr are respectively 1,0; 2,0 3,0; or 4,0 9 A compound according to claim 8, wherein ql and qr are respectively 1,0. 10 A compound according to claim 3, wherein ql and qr are respectively ι,i; 2,1; 3,1; 4,1; or 2,2. 11 A compound according to claim 3 wherein -ring- is phenyl, furyl, pyridyl, cyclobutyl cyclopentyl or cyclohexyl. 12 A compound according to claim 3, wherein the optional substituent to -ring- comprises a structure of the formula: R 2 -( ) ql -. 13 A compound according to claim 3, wherein R 2 is derived from valyl. 14. A compound according to claim 13, wherein R 2 is derived from L-valine. 15 A compound according to claim 3, wherein T is a bond. 140 16 A compound according to claim 3, wherein T is -NH-. 17 A compound according to claim 3, wherein T is -O-. 18 A compound according to claim 2, wherein the bz ' s-phosphonate is derived from a compound of the formula: Y O O HO-V- -P-OH HO OH X where X is H, halo, hydroxy; and Y is a) C,_ 10 alkyl, optionally substituted with heterocycle, -NR j R b , where R a and R b are independently hydrogen, C 6 alkyl or join together to form a 5 to 7 membered ring, optionally containing a further hetero atom, OH, halo, -S(C]„ 6 alkyl), phenyl, -C,. 7 cycloalkyl, (optionally substituted with -NELA or OH); b) C 3 . 7 cycloalkyl, optionally substituted with -NR_,R b , OH, halo, -S(C,_ 6 alkyl), phenyl, morpholino or pyridyl; c) halo; d) piperidinyl; e) pyrrolidinyl; f) -S(C,. 6 alkyl), optionally substitued with -NR-Pv,,, OH, halo or phenyl; g) -S-phenyl, optionally substituted with halo, nitro, Cj_ 6 alkyl, C,_ 6 alkoxy, trifluormethyl, -CONRaR b or -COOH. 141 19 A compound according to claim 18 wherein the bisphosphonate has the formula A-l. YY O O Ra1— O- P P- O — Ra2 O O / XX \ Ra3 Ra4 A-1 wherein YY and XX have the following values: NH 2 (CH 2 ) 3 - OH (alendronate) NH 2 (CH 2 ) 2 - OH (pamidronate) cycloheptylamino- H (cimadronate) chloro- chloro (clodronate) pyrrolidin-l-ylCH 2 CH 2 - OH (EB 1053) CH 3 - OH (etidronate) methylpentylaminoCH 2 CH 2 - OH (ibandronate) dimethylaminoCH 2 CH 2 - OH (olpadronate) pyridin-3-ylCH 2 - OH (risedronate) (4-chlorophenyl)-thio- H (tiludronate) imidazo-( 1 ,2-a)pyridin-3-ylCH 2 - OH (YH 529) lH-imidazol-lylCH 2 - OH (zoledronate) ; at least one of Ral-Ra4 is a structure of the formula -linker (-R 2 ') k -R 2 and the remainder are H. 20 A compound according to claim 19, wherein at least one of Ral-Ra4 is a structure of the formula 142 R 4L o R '4R R - O - ()ql- Qqr-T _IL ■ o - R 4L R 4R Ila or R o ■ 4R R — O — Qql — Ring — Qqr -T o - R '4R lib where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,. 3 alkyl, C 3 - 6 cycloalkyl, C 1 - 3 alkyl-C,C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C,. 3 alkyl or phenyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C,. 3 alkyl; -ring- is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; and the remainder of Ral-Ra4 are hydrogen or conventional pharmaceutically acceptable esters. 21 A compound according to claim 20, wherein Ral and Ra2 are each a structure Ila or lib as defined in claim 20 and Ra3 and Ra4 are H. 22 A compound according to claim 19, derived from alendronate, zoledronate or risedronate. 23 A compound according to claim 22, selected from: alendronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester alendronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester alendronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, 143 alendronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester alendronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, alendronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester risedronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester, risedronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester risedronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester risedronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester risedronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester zoledronate mono-(2-methyl-2-(D-valyloxymethyl) propionyloxymethyl) ester zoledronate di-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, zoledronate mono-(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, zoledronate mono-(2-methyl-2-(D-valyloxy) propionyloxymethyl) ester, 24 A compound according to claim 19, selected from: alendronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, risedronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, zoledronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, pamidronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, cimadronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, clodronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, [ 1 -hydroxy-3-( 1 -pyrrolidinyl)-propylidine]-bz ' s-phosphonate di-(2-methyl-2-(L- valyloxymethyl) propionyloxymethyl) ester, etidronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, ibandronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, olpadronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, tiludronate di-(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester, [ 1 -hydroxy-2imidazo-( 1 ,2-a)pyridin-3-ylethylidine]-bz ' s-phosphonate di-(2-methyl-2- (L- valyloxymethyl) propionyloxymethyl) ester, 144 and pharmaceutically acceptable salts thereof. 25 A compound according to claim 2 with the formula: R k 4L ■ 4R O O O F -0 - ()qi- Qqr-T O o-p Rf2 I -^o- O R R '4L 4R Rf1 or R '4. O R O O R, O— ql — Ring — Qqr-T O - -o- p- O Rf2 R O 4R I Rf1 where R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C L3 alkyl, C 3 - 6 cycloalkyl, C 1 - 3 alkyl-C,C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C,_ 3 alkyl or phenyl, ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C, .3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; Rfl is H or a further -linker-(R 2 ') k -R 2 structure as defined in claim 3, and Rf2 is H, a conventional pharmaceutically acceptable ester or a further -linker- (R 2 ') k -R 2 structure as defined in claim 3, and pharmaceutically acceptable salts thereof. 26 A compound according to claim 25, wherein Rfl is H 145 27 A compound according to claim 25, wherein Rfl is the same linker (-R 2 ') k -R 2 structure as depicted in claim 25. 28 A compound according to claim 25, wherein Rf2 is H, methyl or ethyl. 29 A compound according to claim 2 of the formula: R 4L R '.4R O O R - O - Qql- Qqr-T O O- P — nuc O R '4L R 4R I Rn10 or R O 4R O R 2 — O — Qql — Ring — Qqr -T O - O - P — nuc I R O 4R I Rn10 wherein nuc is a cyclic or acyclic nucleoside analogue phosphonate; RnlO is H or a further -linker(R 2 ') k -R 2 structure as defined in claim 3; R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C 1-3 alkyl, C 3 - 6 cycloalkyl, C 1 - 3 alkyl-C 1 C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C j _ 3 alkyl or phenyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C, .3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle; and pharmaceutically acceptable salts thereof. 146 30 A compound according to claim 29, wherein RnlO is identical to the linker-(R 2 ') k -R 2 structure in the depicted formula. 31 A compound according to claim 29, wherein RnlO is H. 32 A compound according to claim 29, wherein the nucleoside analague is derived from adefovir, cidefovir, PMPA, HPMP, HPMPA, HPMPG or HPMPDAP. 33 A compound according to claim 2 of the formula PF3: O H — Rf2 R, - O - or R — O — Qql -ring- Qqr-T — π- O O where R 2 is the acyl residue of an aliphatic amino acid, Rf2 is H, a pharmaceutically acceptable ester or a further linker(R 2 ')-R 2 structure as defined in claim 3, R 4L and R 4L ' are independently H, C,. 3 alkyl, C 3 - 6 cycloalkyl, C 3 alkyl-C,C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C,. 3 alkyl or phenyl, 147 ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C,. 3 alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle, and pharmaceutically acceptable salts thereof. 34 A compound according to claim 33, wherein Rf2 is H, methyl or ethyl. 35 A compound according to claim 2 wherein the neutral endopeptidase inhibitor has the structure: Rf2 R 4L R 4R O O I N O R - O - Qql- Qqr -T O O- P I ^ N O O O R 4. L R. 4R Rfl or Rf2 R O 4R O I N o R 2 — O — Qql — Ring — Qqr -T O -O- P N O O o R 4 ' I Rf1 where Rfl is H or a further structure as depicted in claim 3 Rf2 is H or a pharmaceutically acceptable ester, R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C,_ 3 alkyl, C 3 - 6 cycloalkyl, C j ^alkyl-C j CgCycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C,. 3 alkyl or phenyl, ql is 0-3, qr is 0-3, 148 T is a bond, -NR 4 - or -O- R 4 is H or C^ alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle, and pharmaceutically acceptable salts thereof. 36 A compound according to claim 35, wherein Rfl is H. 37 A compound according to claim 35, wherein Rfl is the same -Linker (-R 2 ') k R 2 structure as depicted in claim 35. 38 A compound according to claim 35, wherein Rf2 is hydrogen, methyl or ethyl. 39 A compound according to claim 2, wherein the α-phosphonosulphonate has the formula PF5: R R o,9.o Rf2 4L 4R O O I I R -O - Qql- Qqr -T O O- P Rf3 O R R '4L 4R I Rf1 or O R4R O s R 2 - O - Qql — Ring — Qqr -T OH — O-P ' Rf3 R4R ' ° | Rf1 where Rfl is H or a further -linker(R 2 ') k -R 2 structure as depicted in claim 3, Rf2 is H or a pharmaceutically acceptable ester, Rβ is a polyunsaturated, branched C 6 . 22 alkyl, R 2 is the acyl residue of an aliphatic amino acid, 149 R 4L and R 4L ' are independently H, C,_ 3 alkyl, C 3 - 6 cycloalkyl, C r3 alkyl-CιC 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H or C,. 3 alkyl ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C^alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle, and pharmaceutically acceptable salts thereof. 40 A compound according to claim 39, wherein the polyunsaturated alkyl Rf3 has the formula: wherein the asterisk denotes the point of attachment. 41 A compound according to claim 39, wherein Rfl is H. 42 A compound according to claim 39, wherein Rfl is the same -Linker (-R 2 ') k R 2 structure as depicted in claim 39. 43 A compound according to claim 39, wherein Rf2 is H, methyl or ethyl. 44 A compound according to claim 2 wherein the β-phosphonocarboxylic acid has the formula PF4: 150 R R. C\ O— Rf2 '4L O 4R O R - O - Qql- Qqr -T O - O- P I O Rf3 R R '4L 4R O Rf1 or R O x O— Rf2 O • 4R R 2 — O — Qql — ing — Qqr -T O - ? r H R o π Rf3 4R ι o Rf1 Rfl is H or a further -linker (-R 2 ') k R 2 structure as depicted in claim 3, Rf2 is H or a pharmaceutically acceptable ester , Rβ is a polyunsaturated, branched C 6 . 22 alkyl, R 2 is the acyl residue of an aliphatic amino acid, R 4L and R 4L ' are independently H, C j _ 3 alkyl, C 3 - 6 cycloalkyl, C 1 - 3 alkyl-C 1 C 6 cycloalkyl phenyl or benzyl, R 4R and R 4R ' are independently H, C,_ 3 alkyl or phenyl, ql is 0-3, qr is 0-3, T is a bond, -NR 4 - or -O- R 4 is H or C^alkyl; ring is an optionally substituted aromatic or non-aromatic, hetero-or carbocycle. 45 A compound according to claim 44, wherein the polyunsaturated alkyl Rβ has the formula: wherein the asterisk denotes the point of attachment. 46 A compound according to claim 44, wherein Rfl is H. 151 47 A compound according to claim 44, wherein Rfl is a further -Linker(R 2 ') k -R 2 structure. 48 A compound according to claim 44, wherein Rf2 is H, methyl or ethyl.

Inventors: JOHANSSON NILS GUNNAR, LINDSTROEM STEFAN, SALVADOR LOURDES, SUND CHRISTIAN, WAEHLING HORST, WALLBERG HANS, ZHOU XIAO-XIONG, JOHANSSON, NILS, GUNNAR, LINDSTROEM, STEFAN, SALVADOR, LOURDES, SUND, CHRISTIAN, WAEHLING, HORST, WALLBERG, HANS, ZHOU, XIAO-XIONG
Applicants: JOHANSSON NILS GUNNAR, LINDSTROEM STEFAN, MEDIVIR AB, SALVADOR LOURDES, SUND CHRISTIAN, WAEHLING HORST, WALLBERG HANS, ZHOU XIAO XIONG, JOHANSSON, NILS, GUNNAR, LINDSTROEM, STEFAN, SALVADOR, LOURDES, SUND, CHRISTIAN, WAEHLING, HORST, WALLBERG, HANS, ZHOU, XIAO-XIONG
Application year: 1999
Main classification: C07F9
IPC codes: A61K31, A61P31, A61P43, C07D213, C07F9, C12N9