PHOSPHONOPEPTIDES WITH COLLAGENASE INHIBITING ACTIVITY

Abstract: Phosphorus derivatives having structure (I), processes for their preparation and their use as collagenase inhibitors.

Description: Phosphoπopeptides with collagenase inhibiting activity. The present invention relates to novel phosphorus derivatives, processes for their preparation and their use in medicine. In particular, the present invention relates to their use as inhibitors of enzymes of the collagenase family of neutral metalloproteases, for treating arthritic and other diseases. The mammalian collagenase family of enzymes comprises a number of proteases, exemplified by interstitial (type I) collagenase itself, the stromelysins (also known as proteoglycanases or transins) , fibroblast and poly orphonuclear leucocyte gelatinases (also known as collagen-IV-ases) , and 'pump-l 1 (putative metalloprotease 1, uterine metalloprotease) [Goldberg βt al, J. Biol. Chem. 2610, 6600, 1986/ Whitham et al, Biochem. J. 240, 913, 1986; Breathnach βt al, Nucleic Acids Res., 15, 1139, 1987; Muller βt al, Biochem. J., 253, 187, 1988; Collier et al, J. Biol. Chem., 263, 6579, 1988; Murphy et al, Biochem. J., 258, 463, 1989; Quantin βt al, Biochem. (N.Y.), 28, 5327, 1989; Birkedal-Hansen, J. Oral Pathol., 17, 445, 1988; P. Basset et al, Nature 348, 699, 1990] . Membership of the mammalian collagenase family of proteases is evident by possession of a number of highly characteristic and experimentally verifiable properties as described in EPA 401963 (Beecham Group) , which can be adopted as criteria for allocation to this family of enzymes. As a particular example of the therapeutic value of inhibitors of the collagenase family of enzymes, such as are disclosed in the present invention, chronic arthritic diseases leading to extensive loss of the collagen, proteoglycan and elastin components of the cartilage, bone and tendons within the joints, should be amenable to treatment with inhibitors of the collagenases, proteoglycanases (stromelysins) and gelatinases currently thought to be the major enzymes involved. These enzymes have been detected in extracts of synovial and cartilage tissue, and have also been extensively studied in tissue cultures of a wide range of connective tissues. Apart from control of the biosynthesis, secretion and activation of the enzymes, the most important natural regulation of these enzymes in normal and diseased states, is considered to be the endogenous production of inhibitors such as the Tissue Inhibitor of Metalloproteinases and alpha-2 macroglobulin. An imbalance between the local levels of the proteolytic enzymes and of their natural inhibitors will allow destruction of connective tissue components to occur. The compounds described in the present invention, being synthetic and low molecular weight inhibitors of this family of enzymes, offer a therapeutically useful way in which a more normal or non-pathological balance between inhibition and enzymic activity can be restored: they thus act to complement and supplement the endogenous enzyme inhibitors. Indeed, because these enzymes usually act only within restricted pericellular environments, before being inactivated by inhibitors circulating in the blood and present in most inflammatory exudates, the low molecular weight inhibitors disclosed here may be more effective than endogenous proteinaceous inhibitors that are excluded by their size from the localized regions of connective tissue destruction. EPA-320118 (Beecham Group) discloses a class of phosphorus derivatives having activity as inhibitors of collagenase and utility in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is a contributing factor. Novel phosphorous derivatives have now been discovered, which are collagenase inhibitors and thus of potential utility in the treatment of diseases in which collagenolytic activity and tissue remodelling is implicated. According to the present invention there is provided a compound of general formula (I), or a salt thereof: in which, _ is -(CH2) n ~ w where n is 0-6 and W is amino, optionally-substituted phenyl, -CONR5R , - R5COR6, NR5CO2CH2R6 or NR5CONR5R6 where R5 is hydrogen or Cι_g alkyl and Rg is hydrogen, Cι_g alkyl, optionally-substituted phenyl or heteroaryl, or R5 and Rg together with the nitrogen atom to which they are bonded form a 5-, 6- or 7- membered ring with an optional oxygen or sulphur atom or an optionally substituted second nitrogen atom in the ring; or W is -S(0)p-R7 where p is 0, 1 or 2 and R7 is Cι_galkyl; or is a group of sub-formula (a) , (b) , (c) or (d) : (a) (b) where in sub-formula (a) , (b) and (c) A represents an optionally-substituted mono or bicyclic aryl or heteroaryl ring, and in sub-formula (c) and (d) q is an integer from 1 to 3; R2 is C3_ alkyl; R3 is hydrogen, Cι_galkyl, -CH2-Z where Z is optionally substituted phenyl or heteroaryl, -(CH2)r RgRg, -(CH 2 ) r NHCOR! 0 , -(CH 2 ) r NR l1^(=NR 12 ) R 8 R 9 , -(CH 2 ) r CO H(CH2) s NR8R9 or -(CH2) r _R 13 where r is 1 to 6, s is 2 to 4, each of Rg and R9 is independently hydrogen or C _galkyl or Rg and R9 together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-membered ring with an optional oxygen or sulphur atom or an optionally substituted second nitrogen atom in the ring, R*J_ Q is Cι_galkyl or -(CH2)t NR 8 R 9 where t is 1 or 2 and Rg and R9 are as defined above, R ] _]_ is hydrogen or C**__galkyl or R- j _ and Rg, together with the nitrogen atoms to which they are bonded, form an optionally substituted 5-, 6- or 7-membered ring, R-*_2 is hydrogen or C^-galkyl and R]_3 is an optionally substituted piperidyl ring or R3 is a group: -CHOR 14 where R ] _4 is hydrogen, C _galkyl or optionally substituted benzyl and R25 is hydrogen or C-]__galkyl; and R4 is hydrogen, C^-galkyl or -(CH2) r RgR9 in which r, Rg and R9 are as defined for R3; or R3 and R4 are joined together as -(CH2) m - where m is an integer from 4 to 12, or R3 and R4 are joined as - (CH2)χ- Rι - (CH2) y- where x is an integer from 1 to 9, y is an integer from 2 to 10, and the moiety - (CH2) X - is adjacent to the carbon atom bearing R3 marked with an asterisk in formula (I) , and R-j_g is selected from hydrogen, C-j__galkyl, C2-galkanoyl, C]__galkoxycarbonyl, aroyl, aralkyl or aralkyloxycarbonyl in each of which the aryl moiety is optionally substituted. Cι_galkyl groups (either alone or as part of another group) , may be a straight chain or branched. Optional substituents for aryl and heteroaryl groups may be selected from OH, C]__g alkyl, C ] __g alkoxy, halogen, -NHCO(C 1 _g)alkyl, -NHCOPh and -CONR 5 Rg, where Ph is optionally substituted phenyl and R5 and Rg are as defined above. The term aryl includes phenyl and naphthyl. It will be understood that the term heteroaryl includes aromatic heterocyclic groups containing one or more heteroatoms and includes 5- or 6-membered monocyclic and 9- or 10-membered bicyclic heteroaryl groups which preferably contain one or two heteroatoms selected from nitrogen, oxygen and sulphur. When Z is 9- or 10-membered bicyclic heteroaryl the two rings are fused with one 5- or 6-membered ring preferably containing a single heteroatom, for example indolyl. When R5 and Rg or Rg and R9 groups combined with their appended nitrogen atom to form a heterocyclic ring, typical examples of a suitable ring structure are piperidine, or pyrrollidine, piperazine and morpholine. When such groups contain a second nitrogen heteroatom this may be optionally substituted, for example, by a C-_galkyl group. Suitably Ri [ is -(CH2) n -W where n is 0, 1, 2 or 3. Suitably W is amino, phenyl, N-phthalimido or 1,8- naphthalenedicarboxa ido each of which may be optionally substituted, NHC02CH2 where Rg is optionally substituted phenyl or S(0) p CH where p is 0, 1 or 2. Preferably R-^ is 2-hydrox phenyl, -(CH.2) n ~ w where n is 2 and W is amino, phenyl, 2-hydroxyphenyl, NHCθ2CH2 , N-phthalimido, 4-bromo-l,8-naphthalenedicarboxamido, 7,9- dioxo-8-azaspiro[4,5]decyl, methylmercapto, methylsulphinyl or methylsulphonyl, or R* * _ is -(CH2) n "* w where n is 1, 2 or 3 and W is a 1,8-naphthalenedicarboxamido group. Suitably R2 is a C4 alkyl group, such as n-butyl, iso-butyl or sec-butyl. Preferably R2 is iso-butyl. Suitably R3 is benzyl, C*-__galkylamino, 4-hydroxybenzyl, C- j __galkoxybenzyl such as 4-methoxybenzyl, or 9- or 10- membered fused bicyclic heteroarylmethyl such as 3-indolylmethyl. Preferably R3 is benzyl, 4-methoxybenzyl, -(CH2)4 H2 or 3-indolylmethyl. Suitably R4 is methyl, ethyl or -(CH2) r NR 8 R 9 . Preferably R4 is methyl or -(CH2)2 NR8R ^ where R 8 and R 9 are both hydrogen or R 8 and R 9 together with the nitrogen atom to which they are bonded form a pyrrolidine or N- ethylpiperazine group. Suitably, when groups R3 and R4 are combined as -(CH2)*-*■*.- then = 10, resulting in a lactam structure based on a 13-membered ring. Suitably, when groups R3 and R4 are combined as -(CH2) χ - R]_5-(CH2)y- then x and y have values such that R3 and R4 form part of an 11- to 16-membered azalactam structure and R*-_g is hydrogen, methyl, benzyl, t-butoxy- carbonyl or benzyloxycarbonyl. Preferably, when groups R3 and R4 are combined they form a group - (CH 2 ) icr- Particular compounds of this invention include: N-[N-(1-phosphono-l-(2-hydroxyphenyl) ethyl)-leucyl] -N,0-dimethyl-(S)-tyrosinamide, N-[N- (l-phosphono-3-(1, 8—naphthalenedicarboximide)propyl)- (S)-leucyl]-N,O-dimethyl-(S)-tyrosinamide, N-[N-(l-phosphono-3-phthalimidopropyl)- (S) -leucyl]- (S) - phenylalanine-N-methylamide, N-[N-(l-phosphono-4-(1,8-naphthalenedicarboximido)butyl)-(S)- leucyl]- (S)-phenylalanine-N-methylamide, N-[N- (l-phosphono-2- (1, 8-naphthalenedicarboximido)ethyl- (S) - leucyl]- (S)-phenylalanine-N-methylamide, N-[N- (l-phosphono-3- (1,8-naphthalenedicarboximido)propyl) - (S)-leucyl]-(S)-phenylalanine-N-methylamide, N-[N-(l-phosphono-3-phenylpropyl)- (S)-leucyl]-(S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-3- (4-brom-o-1, 8-naphthalene- dicarboximido)propyl)-(S)-leucyl]- (S)-phenylalanine methylamide, N-[N- (l-phosphono-3- (benzyloxycarbonylamino)propyl) - (S) - leucyl]- (S)-phenylalanine methylamide, N-[N-(l-phosphono-3-(2-hydroxyphenyl)propyl)- (S)-leucyl]- (S)- phenylalanine methylami-de, N-[N-(l-phosphono-3- (methylmercapto)propyl) - (S)-leucyl]- (S)- phenylalanine-N-methylamide, N-[N- (l-phosphono-3-(methylsulphinyl) ropyl)- (S)-leucyl]- (S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-3- (methylsulphonyl)propyl- (S)-leucyl]- (S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-3- (1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]- (S) tryptophan-N-methylamide, N-[N- (l-phosphono-3- (1,8-naphthalenedicarboximido)propyl) - (S)-leucyl-(S)-lysine-N-methylamide, N-[N- (l-phosphono-3- (1, 8-naphthalenedicarboximido)propyl) - (S)-leucyl]- (-)-aminoazacyclotridecan-2-one, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(aminoethyl) amide, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(ethylpyrrolidine) amide, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(ethyl-N-methylpiperazine) amide, N-[N-(l-phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl) ]- propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide, or N-[N-(l-phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl) ]- propyl)-(S)-leucyl]-(S)-lysine-N-methylamide, and pharmaceutically acceptable salts thereof. The compounds of formula (I) may form salts with bases e.g. sodium hydroxide. The compounds of formula (I) have a basic nitrogen atom and may form acid addition salts e.g. hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, aleate, citrate, lactate, tartrate, oxalate and similar acid addition salts. Such compounds form part of the present invention. The compounds of formula (I) have at least two, and may have three or more asymmetric centres and therefore exist in more than one stereoisomeric form. The invention extends to all such forms and to mixtures thereof, including racemates, and diastereoisomeric mixtures. Preferred iso ers are those having the (S)- or (-)- configuration at the chiral centre bearing R3 when R3 is other than hydrogen, and those having the (S)-configuration at the chiral centre bearing R2, both marked with an asterisk in formula (I) . The present invention also provides a process for the preparation of a compound of formula (I) which comprises cleaving a group R20 from a compound of formula (II) : wherein R 2 o is Cι_galkyl, optionally substituted phenyl or optionally substituted benzyl and R χ is hydrogen, C-j__galkyl or optionally substituted benzyl and R]_, R 2 , R3 and R4 are as defined in formula (I) , and where necessary, converting R21 to hydrogen by a further cleavage reaction. Cleavage of R20 and, where necessary, 21 may be carried out in aqueous acid or alkali or using a trimethylsilyl halide, preferably bromotrimethylsilane, in an inert solvent, for example dichloromethane. Benzyl esters may alternatively be removed by hydrogenolysis or other standard debenzylation procedures. When both R20 and R21 are C^-galkyl, cleavage of R20 or -Jy - to give to a compound of formula (II) in which R o is hydrogen and R21 is Cι_galkyl, may be carried out by treatment with excess alkali under mild conditions, for example with aqueous sodium hydroxide in an alcoholic solvent at room temperature. Similarly, where R20 is optionally substituted benzyl and R21 is Cχ_galkyl, the benzyl group only may be cleaved by hydrogenolysis to give a compound of formula (II) in which R20 is hydrogen and R21 is C-_galkyl. Cleavage of an R 2 ι C^-galkyl group may thereafter be carried out as described above to give the compound of formula (I) . When R21 is not hydrogen, then cleavage of both R21 and R 2 o is conveniently effected in a single reaction. Preferably R20 and R21 are both C]__galkyl, such as methyl or ethyl, or R Q and R21 are both benzyl. Compounds of formula (II) are believed to be novel and form a further aspect of the invention. Compounds of formula (II) may be prepared by treating a compound of formula (III) : in which R- * _, R2, 20 an( i R 21 are as defined in formula (II) (except that R21 is not H) , with a compound of formula (IV) in which R3 and R4 are as defined in formula (I) . The reaction is preferably carried out in the presence of a coupling agent, such as dicyclohexylcarbodiimide or l-ethyl-3-[3-(dimethylamino) ropyl]carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, or using l,l l -carbonyldiimidazole, in an inert solvent such as dichloromethane or acetonitrile. Selective cleavage of the group R 2 χ may then be carried out using the procedures described above for the preparation of compounds of formula (I) to give compounds of formula (II) in which R 2 χ is hydrogen. Alternatively, compounds of formula (II) in which R20 and R21 are Cχ_galkyl or optionally substituted benzyl may be prepared by the reaction of a compound of formula (V) : in which R 2 , R3 and R 4 are as defined in formula (I) , with a compound of formula (VI) : 7 in which R__ is as defined in formula (I) , R 2 o and R 2 1 are C*]__galkyl or optionally substituted benzyl and R17 is a leaving group such as halogen, methanesulphonyloxy or trifluoromethanesulphonyloxy, in the presence of a base such as triethylamine or Proton Sponge (1, 8-bis (dimethylamino) - naphthalene) , or using anhydrous potassium carbonate in an alcoholic solvent. Where R17 is an oxygen-based leaving group, for example trifluoromethanesulphonyloxy, which is preferred, displacement of the leaving group is conveniently carried out in the presence of Proton Sponge in an inert solvent such as acetonitrile or dichloromethane, over a period of several days in the absence of light. As a further alternative, compounds of formula (II) in which R20 and R 21 are c l-6 alk y 1 ' optionally substituted aryl or optionally substituted benzyl may be prepared by reaction of a compound of formula VII: R- (VII) in which R ] _, R2, R3 and R4 are as defined for formula (I) with a compound of formula (VIII) : in which R-*_g is C-^-galkyl and R20 and R21 are as defined for formula (II) provided that R21 is not hydrogen and thereafter removing the phosphonic acid protecting group. The reaction is suitably carried out in an organic solvent such as dichloromethane at reduced temperature, e.g. -10 to 5°C. The intermediate compounds of formula (III) may be prepared by treating a compound of formula (IX) or a salt thereof: in which R-j_, R20 and - R 21 are as defined in formula (III) , with a compound of formula (XA) or (XB) or a salt thereof: in which R 2 is as defined in formula (I) , R^η is as defined in formula (VI) and R^g is hydrogen or a carboxyl protecting group, and thereafter removing the R^g carboxyl protecting group. When a compound of formula (XB) is used, the reductive amination may be carried out by hydrogenation over a noble metal catalyst such as palladium on carbon or by reaction with sodium cyanoborohydride at pH 6 to 7. Lower alkyl alcohol solvents such as methanol and ethanol are suitable for both reactions. These reactions may be carried out in the presence of molecular sieves. A hydrogenation reaction is preferred but this process precludes the use of compounds of formulae (IX) and (XB) in which any of R20* R 21 or R 19 * 3 benzyl. Preferably a carboxyl protecting group is a methyl or ethyl ester. Ester protecting groups may be removed under standard basic hydrolysis conditions using dilute base such as 1 Normal aqueous sodium hydroxide in methanol. When the compound of formula (IX) is in the form of the free base, the compound of formula (XB) is suitably an α-keto ester (Rjg = C-_galkyl) . When the compound of formula (IX) is a salt, such as the hydrochloride salt, the compound of formula (XB) is suitably a salt of an α-keto acid ( 19 = H) , for example the sodium salt. The preparation of compounds of formula (III) using a compound of formula (XA) may be carried out under standard alkylation conditions. A halogen leaving group is preferably bromine and an oxygen-based leaving group is preferably trifluoromethanesulphonyloxy. Compounds of formula (III) may alternatively be prepared by condensing a compound of formula (XI) or a salt thereof: R 19 (XI) in which R2 is as defined in formula (I) and Rig is a carboxyl protecting group with an aldehyde, R -CH0 in which Rl is as defined in formula (I) and treating the condensation product with an appropriate phosphite, for example dimethyl phosphite, diphenyl phosphite or dibenzyl phosphite and thereafter removing the carboxyl protecting group. The carboxyl group is conveniently protected as an alkyl or benzyl ester which may be removed using standard hydrolysis or hydrogenation conditions. As described above in connection with reductive amination of compounds of formula (XB) , where a benzyl protecting group R 9 is removed by hydrogenation then R 2 o and R21 are restricted to Cι_galkyl. As a- further alternative, compounds of formula (III) may be prepared by treating a compound of formula (XII) : in which R*-_ and R 2 are as defined in formula (I) and R-*_g is a carboxyl protecting group as defined for formula (XI) with a compound of formula (VIII) as hereinbefore defined using conditions as described for the reaction of compounds of formulae (VII) and (VIII) . A further alternative preparation of compounds of formula (III) may be carried out by reacting a compound of formula (VI) as hereinbefore defined with a compound of formula (XI) as hereinbefore defined, using conditions as described for the reaction of compounds of formula (V) with compounds of formula (VI) , and thereafter removing the protecting group R 19 . Suitable carboxyl protecting groups include alkyl, benzyl and trialkylsilyl groups. A trialkylsilyl protecting group. for example trimethylsilyl, is especially useful in that it may be readily incorporated, in situ, for example by addition of hexamethyldisilazane to the reactants in acetonitrile in the presence of triethylamine, and selectively removed in aqueous methanol, without imposing any limitations on the value of R 2 Q anci R 21- Other silylating agents include trimethylsilyl chloride and N,N-diethyltrimethylsilylamine. An R-_9 alkyl carboxyl protecting group may be removed by base hydrolysis, for example using sodium hydroxide in aqueous methanol . It will be appreciated that where the carboxyl protecting group R-*_g is alkyl, R 2 o and R21 may be alkyl or benzyl derivatives, but where R_g is a benzyl group, R20 an d 21 are limited to alkyl. When compounds of formula (III) are prepared by this route, it is preferred that R20 and R21 are benzyl and R17 is trifluoromethanesulphonyloxy in the compound of formula (VI) and R19 is trimethylsilyl or methyl in the compound of formula (XI) . Compounds of formula (V) may be prepared by treating a compound of formula (XIII) : in which R 2 is as defined in formula (I) and wherein the amino group is optionally protected, with a compound of formula (IV) as hereinbefore defined, in the presence of a coupling agent as hereinbefore described for the preparation of compounds of formula (II) from compounds of formulae (III) and (IV) . Compounds of formula (VII) may be prepared by reaction of an aldehyde R-^-CHO in which R-j_ is as defined in formula (I) with an amine of formula (V) as hereinbefore defined in an organic solvent such as dichloromethane at reduced temperature (e.g. -10 to 5°C) in the presence of magnesium sulphate. Compounds of formula (VIII) may be prepared by reaction of the corresponding phosphite, for example dimethylphosphite or dibenzylphosphite with a trialkylsilylhalide, for example trimethylsilyl chloride, in an inert solvent such as dichloromethane at reduced temperature (e.g. -10 to 5°C) in the presence of a base such as a trialkylamine. Compounds of formula (VI) may be prepared from hydroxyalkylphosphonate derivatives by conversion of the hydroxyl group to the leaving group R17 by conventional methods. For example, where χ7 is trifluoro¬ methanesulphonyloxy, trifluoromethanesulphonic anhydride may be added to a solution of the hydroxyalkylphosphonate in an inert solvent such as dichloromethane, the reaction being carried out at reduced temperature under an inert atmosphere, according to the general method of E. Vedejs et al., Journal of Organic Chemistry 50, 2165, (1985). Hydroxyalkylphosphonate compounds may in turn be prepared by reaction of the corresponding phosphite, for example dibenzylphosphite, with an aldehyde R^-CHO in which R-*_ is as defined in formula (I) according to the general method of F. Texier-Boullet and A. Foucaud, Synthesis, 916 (1982) . Benzyl and alkyl phosphites are either commercially available compounds or can be prepared from commercially available starting materials by standard methods. Intermediate compounds of formula (IX) are either known compounds or may be prepared from known aminoalkyl phosphonic acid derivatives using standard procedures to introduce the R 2 Q d R21 as required. Protection of the amine function during these reactions may be necessary. Introduction of an R20 or R21 methyl group may be effected by reaction with diazomethane in a suitable inert solvent. Compounds of formula (IX) of fixed configuration may be prepared by the general method of R. Jacquier et al., Phosphorus and Sulfur 36, 73, 1983. The compounds of formulae (IV) and (XIII) are either known amino acid derivatives or can be made from these derivatives by known methods. Compounds of formula (XA) and (XB) are either known compounds or may be prepared from known compounds by known methods. Compounds of formula (XII) may be prepared from an aldehyde R^-CHO as hereinbefore defined and a compound of formula (XI) as hereinbefore defined by a procedure analogous to that described for the preparation of compounds of formula (VII) . The intermediates of formulae (II), (III), and certain intermediates of formula (IX) disclosed herein are novel compounds and form an aspect of the present invention as do the described processes for their preparation. Where obtainable, pharmaceutically acceptable salts of the compounds of formula (I) may be formed conventionally by reaction with the appropriate acid or base. As mentioned previously, the compounds of formula (I) exist in more than one diastereoisomeric form. Where the processes of the invention produces mixtures thereof, the individual isomers may be separated one from another by chromatography e.g. column chromatography or HPLC. Alternatively, separate diastereoisomeric compounds of formula (I) can be obtained by using stereoisomerically pure starting materials or by separating desired isomers of intermediates at any stage in the overall synthetic process, and converting these intermediates to compounds of formula (I) . It will be appreciated that where a single diastereoisomer of a compound of formula (I) is prepared by more than one process variant as hereinbefore described, each of which allows a different chiral centre to be defined, it may be possible to deduce the configuration at a chiral centre which is not pre-determined using a particular process variant. Furthermore, it will be appreciated that although the absolute configuration at a particular chiral centre may not be known, it is possible to characterise a given diastereoisomer relative to its epimer or to another diastereoisomer using MNR spectroscopy or optical rotation. In a further aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use as active therapeutic agents, particularly as agents for treatment of conditions in which degradation of connective tissue and other proteinaceous components of the body occurs, such as musculo-skeletal disorders resulting from collagenolytic activity, particularly rheumatism and/or arthritic conditions, and tissue remodelling. Compounds of formula (I) also have potential utility in the treatment of cancer; for preventing myelin degradation in the central and peripheral nervous system; for the treatment or prevention of colonic damage such as irritable bowel disease; and in other conditions in which members of the collagenase family of neutral metalloproteases have pathological or other roles. The present invention further provides a pharmaceutical composition, which comprises a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A composition of this invention is useful in the treatment of usculo-skeletal disorders, particularly arthritic diseases and for modulation of tissue remodelling as well as having potential utility in the treatment of the diseases described above. A composition of the invention, which may be prepared by admixture, may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner. These conventional excipients may be employed in conventional manner, for example as in the preparation of compositions of related peptide enzyme inhibitors, such as the ACE inhibitor enalapril. A composition of the invention may be adapted for oral, topical, rectal or parenteral administration but oral administration is preferred. Parenteral compositions may be administered intravenously, intramuscularly, intra- articularly, intradermally, sub-cutaneously or into the cerebro-spinal fluid. Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment or prophylaxis of any of the disorders mentioned above. The suitable dosage range for the compounds of the invention may vary from compound to compound and may depend on the condition to be treated. It will also depend, inter alia, upon the relation of potency to absorbability and the mode of administration chosen. The compound or composition of the invention may be formulated for administration by any route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories. The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate. Solid compositions may be obtained by conventional methods of blending, filling, tableting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients. For example, in a hard gelatin capsule containing the required amount of a compound of the invention in the form of a powder or granulate in intimate mixture with a lubricant, such as magnesium stearate, a filler, such as macrocrystalline cellulose, and a disintegrant, such as sodium starch glycollate. Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavouring or colouring agents. The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository or for parenteral administration in an injectable form. For injection, for example by intra-articular injection or by injection into the cerebro-spinal fluid or via other routes which will gain access to sites of demyelination, such as by intramuscular, intradermal or subcutaneous injection, as freely soluble solutions or as poorly dispersed depot stores, the compounds of the invention may be presented in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in sterile unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation. For topical and percutaneous administration, the preparations may also be presented as an ointment, cream, lotion, gel, spray, aerosol, wash, skin paint or patch. A unit dose for treating diseases in which enzymes of the collagenase family are involved will generally contain from 10 to 1000 mg and preferably will contain from 10 to 500 mg, in particular 10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition may be administered one or more times a day, for example 2, 3 or 4 times daily, so that the total daily dose for a 70 kg adult will normally be in the range 10 to 3000 mg. Such a dosage corresponds to approximately 0.15 to 50 mg/kg per day. Alternatively, in particular for injection, the unit dose will contain from 2 to 200 mg of a compound of the invention and be administered in multiples, if desired, to give the desired daily dose. The present invention additionally provides a method of treating conditions in which degradation of connective tissue and other proteinaceous components of the body occurs which comprises administering to the mammal in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of conditions in which degradation of connective tissue and other proteinaceous components of the body occurs. The following Descriptions and Examples illustrate the preparation of compounds of the invention. All temperatures are expressed in °C. Description 1 N- [I- (D e-thoxyphosph±nyl) —1- ( 2 -hydroxyphβnyl) methyl] - leucine, benzyl ester (Dl) Salicylaldehyde (1.83g), leucine benzylester p-toluene sulfonate salt (5.9g) and triethylamine (2.1 ml) in toluene (100 ml) were heated at reflux for 2 h in a Dean-Stark apparatus. The solution was cooled and solvent removed in vacuo. Diethyl phosphite (3.2g) was added and the solution heated at 120°C for 24 h. The reaction mixture was cooled and column chromatography on silica gel, eluting with ethyl acetate, gave the title compound as a yellow oil (2.8g) . Description 2 N-[1-(Diethoxyphosphinyl)-1-(2-hydroacyphenyl)methyl]-leucine (D2) The title compound (l.Og) was prepared from (Dl) (1.4g) by hydrogenation at atmospheric pressure over 10% palladium on charcoal in ethanol. Description 3 N-[N-(1-Diethoxyphosphinyl-l-(2-hydroxyphenyl)methyl)- leucyl]-N,O-dimβthyl-L-tyrosinamide (D3) A solution of N-[1-(diethoxyphosphinyl)-1-(2-hydroxy- phenyl) ethyl-leucine (D2) (0.5g) in dry acetonitrile was cooled to 0°C in an ice-bath and l,l'-carbonyldiimidazole added. The mixture was kept at 0°C for 1 h and then 0-methyl-(S)-tyrosine N-methylamide in the minimum volume of acetonitrile was added dropwise with stirring. The mixture was allowed to warm to room temperature and stirred for a further 2 days and then evaporated to dryness. The residue was taken up in chloroform and washed with dilute citric acid and water. The organic layer was dried with anhydrous sodium sulphate, filtered and evaporated to dryness to give the crude product. Purification by column chromatography on silica gel with initially chloroform rising to 10% methanol/chloroform as eluant gave the title compound (0.43g). Observed El M+563. Description 4 3-(1,8-Naphthalenedicarboximide)propanol (D ) 3-Amino-l-propanol (3.75g) was dissolved in dichloromethane (500 ml) and dimethylformamide (50 ml) and naphthalic anhydride (9.9g) added, followed by triethylamine (6.9 ml) . The solution was stirred at room temperature for 2h and 1- hydroxybenzotriazole (8.75g) and l-ethyl-3 (3-dimethylamino- propyl)carbodiimide hydrochloride (13. g) added and the solution stirred at room temperature for 24h. The solution was filtered, washed with water, IN hydrochloric acid, saturated sodium bicarbonate solution and dried with anhydrous sodium sulphate. The solution was filtered and the solvent evaporated in vacuo to give the title compound as a pale yellow solid (7.5g) . Description 5 3-(1,8-Naphthalenedicarboximido)propanal (D5) A solution of oxalyl chloride (3.5 ml) in dichloromethane (100 ml) was cooled to -60°C and dimethylsulphoxide (5.95 ml) in dichloromethane (10 ml) added slowly over 15 min. The alcohol (9g) (D4) in dichloromethane (100 ml) was added dropwise over 30 min, and the solution stirred at -60°C for 15 min. The reaction mixture was allowed to warm to -15°C, cooled to -60°C and triethylamine (24.5 ml) added. The solution was allowed to warm to room temperature, washed with water, dilute hydrochloric acid, 10% sodium carbonate solution and dried with anhydrous sodium sulphate. The solution was filtered and the solvent evaporated in vacuo to give the title compound as a white solid (8.3g) . δ (CDCI3) : 2.86 (2H, dt) , 4.53 (2H, t) , 7.75 (2H, t) , 8.22 (2H, d), 8.56 (2H, d) , 9.90 (1H, s) . Description 6 N-[N-(1-(Dibenzyloxyphosphinyl)-3-(1,8-naphthalene- dicarboximido)propyl)-(S)-leucyl]-N,O-dimethyl-(S)- tyrosinamide (D6) 3-(l,8-Naphthalenedicarboximido)propanal (3.2g) (D5) in dichloromethane (50 ml) was added to a solution of N-((S)- leucyl)-N,O-dimethyl-(S)-tyrosinamide (4.04g) in dichloromethane (50 ml) at 0°C. Magnesium sulphate was added and the reaction mixture stirred at 0°C for 15 min, then at room temperature for 15 min. Dibenzyl trimethylsilylphosphite (4.25g), prepared by the method of J.I.G. Cadogan et al. [Tetrahedron 1990, 46, 7175], was added via syringe to the above reaction mixture under nitrogen at 0°C. The solution was allowed to warm to room temperature and stirred for 18h, washed with water, 10% citric acid solution and saturated sodium chloride solution. The solution was dried with anhydrous sodium sulphate, filtered and the solvent evaporated in vacuo to give an orange oil. Purification by column chromatography on silica gel, eluting with ethyl acetate, gave a single diastereoisomer. Isomer D6A (0.9g) δ (CDCI3) : 0.81 (6H, dd) , 0.90-2.35 (6H, m) , 2.77 (3H, d) , 2.87 (2H, m), 3.22 (2H, m) , 3.67 (3H, s) , 4.12 (2H, t) , 4.74 (1H, m), 4.95 (4H, m) , 6.78 (2H, d) , 7.10 (2H, d) , 7.31 ( 10H, s ) , 7 . 60 ( IH, d) , 7 . 74 ( 3H, t ) , 8 . 22 (2H, d) , 8 .5 ! (2H, d) . Observed FAB (M+H) + 819. C4gH 51 N 4 0gP requires M 818. Further elution gave a slower running single diastereoisomer. Isomer D6B (1.8g) δ (CDCI3) : 0.82 (6H, dd) , 1.12-2.24 (6H, m) , 2.69 (3H, d) , 2.83 (IH, m) , 3.13 (2H, m) , 3.62 (IH, ) , 3.68 (3H, s) , 4.15 (IH, ) , 4.27 (IH, m) , 4.60 (IH, t) , 4.95 (4H, m) , 6.59 (IH, d) , 6.76 (2H, d) , 7.15 (2H, d) , 7.30 (10H, m) , 7.62 (IH, d) , 7.76 (2H, t), 8.23 (2H, d) , 8.60 (2H, d) . Observed FAB (M+H) + 819. C4gH 51 N 4 0gP requires . 818. Description 7 3-(Phthalimido)propanol (D7) 3-Amino-l-propanol (7.5g) was dissolved in ethanol (200 ml), N-carbethoxyphthalimide (21.9g) was added and the solution stirred at room temperature for 24h. The solvent was evaporated in vacuo and the residue dissolved in chloroform and washed with water (2x) . The chloroform solution was dried with sodium sulphate, filtered and the solvent evaporated in vacuo to give the title compound (12.7g) . Description 8 3-(Phthalimido)propanal (D8) The title compound (11.5g) was prepared from 3- (phthalimido)propanol (D7) (12.7g) by the procedure described in Description 5. δ (CDC1 3 ) : 2.89 (2H, dt) , 4.05 (2H, t) , 7.74 (2H, m) , 7.86 (2H, m), 9.83 (IH, s) . Description 9 N-[N-(1-(Dimethoxyphosphinyl)-3-phthalimidopropyl)-(S)- leucyl]-(S)-phenylalanine-N-methylamide (D9) 3-(Phthalimido)propanal (4.06g) (D8) in dichloromethane (50ml) was added to a solution of (S)-leucyl-(S)- phenylalanine-N-methylamide (5.82g) in dichloromethane (50ml) at 0°C. Magnesium sulphate was added and the reaction mixture stirred at 0°C for 15 min, then at room temperature for 15 min. Dimethyl trimethylsilylphosphite (3.3g), prepared by the method of J.I.G. Cadogan et al. [Tetrahedron 1990, 46, 7175] was added via syringe to the above reaction mixture under nitrogen at 0°C. The solution was allowed to warm to room temperature and stirred for 18h, washed with water, 10% citric acid solution and saturated sodium chloride solution. The solution was dried with anhydrous sodium sulphate, filtered and the solvent evaporated in vacuo to give an orange oil. Purification by column chromatography on silica gel, eluting with ethyl acetate, followed by 10% methanol/ethyl acetate gave the title compound as a mixture of 2 diastereoisomers (8g) (D9) . δ (CDCI3) : 0.85 (6H, m) , 0.95-2.18 (5H, m) , 2.67 (1- H, d) , 2.75 (H4H, d) , 2.80-3.32 (3H, ) , 3.55 (-vf-H, t) , 3.72 (8H, m) , 3.84 ( _E, m) , 4.60 (V6H, q) , 4.75 (VδH, m) , 6.22 (^H,d) 7.22 (5-4H, m) , 7.53 (IH, t) , 7.74 (3H, m) , 7.85 (2H, m) . Observed FAB (M+H) + 587 C29H39N4O7P requires . 586 The title compound was also prepared as a single diastereoisomer (D9A) (0.09g) from the acid (D24A) (O.lg) and (S)-phenylalanine-N-methylamide (0.05g) by the procedure described in Description 19. δ (CDCI3) : 0.88 (6H, d) , 1.28 (2H, m) , 1.60 (2H, m) , 1.84 (IH, m) , 2.08 (IH, m) , 2.67 (3H, d) , 3.14 (2H, m) , 3.55 (IH, t), 3.75 (8H, m) , 3.84 (IH, m) , 4.60 (IH, q) , 6.26 (IH, d) , 7.23 (5H, m),7.51 (IH, d) , 7.73 (2H, m) , 7.85 (2H, m) Description 10 4-(1,8-Naphthalenedicarboximido)butanol (D10) The title compound (4.5g) was prepared from 4-amino-l- butanol (4.45g) by the procedure described in Description 4. Description 11 4-(1,8-Naphthalenedicarboximido)butanal (Dll) The title compound (3.96g) was prepared from 4-(1,8- naphthalenedicarboximido)butanol (D10) (4.38g) by the procedure described in Description 5. δ (CDCI3) : 2.10 (2H, 2 overlapping t) , 2.60 (2H, t) , 4.20 (2H, t), 7.70 (2H, t), 8.17 (2H, d) , 8.58 (2H, d, 9.83 (IH, s) . Description 12 N-[N-(1-(Dibenzyloxyphosphinyl)-4-(1,8-naphthalene- dicarboximido)butyl)-(S)-leucyl]-(S)-phenylalanine-N- methylamide (D12) The title compound (3.33g) was prepared as a mixture of 2 diastereoisomers from 4-(1,8-naphthalenedicarboximido)- butanal Dll) (3.96g), (S)-leucyl-(S)-phenylalanine-N- methylamide (4.32g) and dibenzyl trimethylsilylphosphite (4.99g) by the procedure described in Description 6. δ (CDC1 3 ) : 0.67 (3H, dd), 0.79 (3H, dd) , 0.99-2.03 (8H, m) , 2.56 (l--iH, d) , 2.74 (1-^H, d) , 2.70-3.69 (4H, m) , 4.12 (2-H, m), 4.50 (*H, q) , 4.93 (4H, m) , 6.23 (-VέH, d) , 7.23 (15H, m) , 7.74 (3H, m) , 8.22 (2H, m) , 8.61 (2H, d) . Observed FAB (M+H) + 803. 4 H5 4θ7P requires M 802. Description 13 2-(1,8-Naphthalenβdicarboximido)ethanol (D13) The title compound (7g) was prepared from ethanolamine (3.05g) by the procedure described in Description 4. Description 14 2-(1,8-Naphthalenedicarboximido)βthanal (D14) The title compound (3.15g) was prepared from 2-(1,8- naphthalenedicarboximido)ethanol (D13) (3.21g) by the procedure described in Description 5. δ (CDCI3) : 5.05 (2H, s) , 7.73 (2H, t) , 8.24 (2H, d) , 8.60 (2H, d) , 9.74 (IH, s) . Description 15 N-[N-(1-(Dibenzyloxyphosphinyl)-2-(1,8-naphthalene- dicarboximido)ethyl)-(S)-leucyl]-(S)-phenylalanine-N- methylamide (D15) The title compound (3.0g) was prepared as a mixture of 2 diastereoisomers from 2-(1, 8-naphthalenedicarboximido) - ethanal (D14) (3.13g), (S)-leucyl- (S)-phenylalanine-N- methylamide (3.81g) and dibenzyl trimethylsilylphosphite (4.4g) by the procedure described in Description 6. δ (CDC1 3 ) : 0.19 (1-V4H, d) , 0.39 (1-Vffl, d) , 0.70 (3H, dd) , 0.70- 1.48 (3H, m) , 2.22 (--iH, dd) , 2.68 (1-fcH, d) , 2.74 (Hffl, d) , 2.74-3.65 (3-4H, m) , 4.30 (IH, m) , 4.49 (1* * 4H, m) , 4.74 (**iH, m) , 4.98 (4H, m), ' 6.20 (Vffl, m) , 6.78 (IH, dd) , 6.86 (-H, d) , 7.22 (15H, m) , 7.76 (2H, t) , 8.22 (2H, d) , 8.57 (2H, d) . Observed FAB(M+H) + 775. C44H47N4O7P requires M 774. Description 16 N-[N-(1-(Dibenzyloxyphosphinyl)-3-(1,8-naphthalene- dicarboximido)propyl)-(S)-leucyl]-(S)-phenylanine-N- methylamide (D16) The title compound (2.5g) was prepared from 3-(l,8- naphthalenedicarboximido)propanal (D5) (3.5g), (S)-leucyl- (S)-phenylalanine-N-methylamide (4.03g) and dibenzyl trimethylsilylphosphite (4J 65g) by the procedure described in Description 6. Purification by column chromatography on silica gel, eluting with a gradient of 0-5% methanol/ethyl acetate gave a single diastereoisomer. Isomer D16A δ (CDCI3) : 0.77 (6H, dd) , 0.83-2.03 (5H, m) , 2.17 (IH, m) , 2.77 (3H, d), 2.77-3.37 (3H, m) , 4.21 (2H, t) , 4.78 (IH, m) , 4 . 96 (4H, ) , 7 .24 (15H, m) , 7 .62 (IH, d) , 7 .76 (2H, t) , 8.23 (2H, d) , 8.57 (2H, d) . Observed FAB (M+H) + 789. C45H N 0 7 P requires M 788. Analysis: C45H4 N4θ7P requires C, 68.51; H, 6.26; N, 7.10%. Found C, 68.44; H, 6.17; N, 7.55%. Further elution gave a slower running diastereoisomer. Isomer D16B δ (CDC1 3 ) : 0.79 (6H, dd) , 1.05-2.28 (5H, ) , 2.66 (3H, d) , 2.78 (IH, m), 3.17 (2H, m) , 3.58 (IH, t) , 4.20 (2H, m) , 4.63 (IH, m), 4.93 (4H, ) , 6.63 (IH, d) , 7.21 (15H, m) , 7.65 (IH, d) , 7.75 (2H, t) , 8.21 (2H, d) , 8.58 (2H, d) . Observed FAB (M+H) + 789. C45H49N4O7P requires M 788. Analysis: C 4 5H4 4θ7P requires C, 68.51; H, 6.26; N, 7.10%, Found C, 68.83; H, 6.18; N, 7.40%. Description 17 N-[l-(Dibenzyloxyphosphinyl)-3-phenylpropyl]-(S)-leucine, methyl ester (D17) Hydrocinnamaldehyde (4.62g) in dichloromethane (50 ml) was added to a solution of (S)-leucine methyl ester (5.0g) in dichloromethane (50 ml) at 0°C. Magnesium sulphate was added and the reaction mixture stirred at 0°C for 15 min, then at room temperature for 15 min. Dibenzyl trimethylsilylphosphite (11.6g) , prepared by the method of J.I.G. Cadogan et al. [Tetrahedron 1990, 46, 7175], was added via syringe to the above reaction mixture under nitrogen at 0°C. The solution was allowed to warm to room temperature and stirred for 18h, washed with water, 10% citric acid solution and saturated sodium chloride solution. The solution was dried with anhydrous sodium sulphate, filtered and the solvent evaporated in vacuo to give a yellow oil. Purification by column chromatography on silica gel, eluting with a mixture of pentane:ether:acetone (10:9:1), gave a single diastereoisomer. Isomer D17A (1.47g) δ (CDC1 3 ) : 0.88 (6H, dd) , 1.40 (IH, m) , 1.61-1.90 (2H, m) , 2.10 (IH, m) , 2.56-2.92 (5H, m) , 3.63 (3H, s) , 3.75 (IH, t) , 4.97 (4H, ) , 7.25 (15H, m) . Observed El M + 524. Further elution gave a slower running single diastereoisomer Isomer D17B (O.βlg) δ (CDCI3) : 0.87 (6H, dd) , 1.40 (2H, m) , 1.75 (2H, m) , 2.05 (IH, m) , 2.66 (IH, m) , 2.84 (2H, m) , 3.42 (IH, t) , 3.58 (3H, s), 4.93 (4H, m) , 7.26 (15H, m) . Observed El M + 524. Analysis: C30H3-3NO5P requires C, 68.82; H, 7.73; N, 2.68% Found C, 68.87; H, 7.23; N, 2.37%. Description 18 N-[1-(Dibenzyloxyphosphinyl)-3-phenylpropyl]-(S)-leucine (D18) The methyl ester (D17A) (1.35g) was dissolved in dioxan (30 ml) and water (15 ml) . Sodium hydroxide (0.12g) was added and the solution was stirred at room temperature for 24h. The dioxan was evaporated in vacuo and the aqueous solution washed with ether, acidified with 2N hydrochloric acid and extracted with ethyl acetate (2x) . The organic extracts were dried with sodium sulphate and the solvent evaporated in vacuo to give the title compound, as a white solid (0.65g), as a single diastereoisomer (D18A) . δ (CDCI3) : 0.87 (6H, dd) , 1.48 (2H, m) , 1.77 (2H, m) , 2.13 (IH, ) , 2.86 (2H, ) , 3.76 (IH, t) , 5.02 (4H, m) , 7.16 (5H, m) , 7.33 (10H, s) . Observed El M + 510 [α] D 22 ■= -12.08° (c=l% in methanol) Analysis: C2 H3 N0 5 P.1/2H 2 0 requires C, 67.17; H, 7.19; N, 2.70%. Found C, 67.13; H, 6.93; N, 2.79%. Similarly, the title compound was prepared, as a pale yellow oil (0.22g), as a single diastereoisomer (D18B) from the methyl ester (D17B) (0.52g). δ (CDCI3) : 0.88 (6H, t) , 1.38 (IH, m) , 1.62 (2H, )*, 1.85 (IH, m), 2.10 (IH, m) , 2.75 (3H, m) , 3.37 (IH, t) , 5.03 (4H, m) , 7.16 (5H, m) , 7.33 (10H, s) . Observed El M + 510 Description 19 N-[N-(1-(Dibenzyloxyphosphinyl)-3-phenylpropyl)-(S)-leucyl]- (S)-phenylalanine-N-methylamide (D19) The acid (D18A) (0.6g) was dissolved in dichloromethane (20 ml), cooled to 0°C and 1-hydroxybenzotriazole (0.23g) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33g) were added. The solution was stirred at 0°C for 15 min, then at room temperature for 15 min, cooled to 0°C and (S)-phenylalanine-N-methylamide (0.24g) in dichloromethane (20 ml) added. The solution was stirred at room temperature for 24h, washed with water, 10% citric acid solution and saturated sodium chloride solution. The organic solution was dried with anhydrous sodium sulphate and the solvent evaporated in vacuo to give a beige solid (0.69g) . Purification by column chromatography on silica gel, eluting with ethyl acetate gave the title compound, as a white solid (0.52g), as a single diastereoisomer (D19A) . δ (CDC1 3 ) : 0.80 (6H, d) , 1.20 (2H, m) , 1.50 (IH, m) , 1.73 (2H, m) , 2.00 (IH, m) , 2.54 (IH, m) , 2.65 (3H, d) , 2.73 (2H, m) , 3.02 (2H, m) , 3.57 (IH, t) , 4.54 (IH, q) , 4.97 (4H, m) , 6.05 (IH, broad s) , 7.19 (10H, m) , 7.33 (10H, s) . Observed FAB (M+H) + 670. C3gH 4 8 3θ5P requires M 669. [α] D 22 = -30.85° (c=0.98% in methanol) Analysis: C3 H4gN 3 θ5P requires C, 69.94; H, 7.22; N, 6.27%. Found C, 70.05; H, 7.28; N, 6.38%. Similarly, the title compound was prepared from the acid (D18B) (0.20g), as a pale yellow oil (0.23g), as a single diastereoisomer (D19B) . δ (CDCI3) : 0.78 (6H, dd) , 1.02-1.32 (3H, m) , 1.65-2.14 (3H, m), 2.60 (3H, m) , 2.76 (3H, d) , 2.92 (IH, dd) , 3.14 (IH, dd) , 3.32 (IH, dd), 4.80 (IH, m) , 5.00 (4H, m) , 7.00 (IH, d) , 7.20 (10H, m) , 7.33 (10H, m) , 7.63 (IH, broad d) . Observed FAB (M+H) + 670. C3gH4 8 N 3 0 5 P requires M 669. Description 20 N-[1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido)propyl]-(S)-leucine, benzyl ester (D20) 3-(1,8-Naphthalenedicarboximido)propanal (D5) (9.5g) was added to a solution of (S)-leucine benzyl ester, p-toluene sulphonate salt (14.75g) and triethylamine (5.8ml) in dichloromethane (100ml) . Molecular sieves and magnesium sulphate were added and the mixture stirred under nitrogen for 18h. The solution was filtered and added dropwise to dimethyl trimethylsilylphosphite (7.5g), prepared by the method of J.I.G.Cadogan et al [Tetrahedron 1990, 46, 7175], under nitrogen at 0°C. The solution was allowed to warm to room temperature and stirred for 18h, washed with water, 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The solution was dried with anhydrous sodium sulphate, filtered and the solvent evaporated in vacuo to give a yellow oil. Purification by column chromatography on silica gel, eluting with a mixture of ether:ethyl acetate (1:1) gave a single diastereoisomer (D20A) (5.51g) . δ (CDC1 3 ) : 0.95 (6H, dd) , 1.53 (2H, t) , 1.75 - 2.00 (3H, m) , 2.27 (IH, m), 2.98 (IH, m) , 3.72 (3H, d) , 3.80 (3H, d) , 3.90 (IH, t) , 4.20 (IH, m) , 4.46 (IH, ) , 5.65(2H,m), 7.35 (5H, m), 7.77 (2H, t) , 8.23 (2H, d) , 8.62 (2H, d) . 31 P: δ (CDCI3) : 28.73 Observed CI (M+H) + 567, C30H35N2O7P requires M.566 [α] D 22 = -14.94 (c=0.38, MeOH) Analysis: C30H35N2O7P requires C, 63.60; H, 6.23; N,4.94% Found C, 63.28; H,6.20; N, 4.83% Further elution gave a slower running single diastereoisomer. Isomer D20B (5.23g) δ (CDCI3) : 0.93 (6H, dd) , 1.53 (2H, t) , 1.80 (2H, ) , 2.17 (IH, m) , 3.10 (IH, m) , 3.63 (IH, t) , 3.71 (3H, d) , 3.77 (3H, d) , 4.29 (IH, m) , 4.44 (IH, m) , 5.15 (2H, m) , 7.36 (5H, m) , 7.75 (2H, t), 8.21 (2H, d) , 8.59 (2H, d) . 31 P: δ (CDCI3) : 29.65 Observed CI (M+H) + 567 C30H35N2O7P requires M 566 [α] D 22 = -13.20 (c=0.44, MeOH) Analysis: C30H35N2O7P.H2O requires C, 61.64; H, 6.38; N, 4.79% Found C, 61.56; H, 6.35; N, 4.62%. Description 21 N-[1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido)propyl]-(S)-leucine (D21) The benzyl ester (D20A) (3.7g) was dissolved in methanol (100ml) and hydrogenated over 10% palladium on charcoal at atmospheric pressure for 3h. The solution was filtered and the solvent evaporated in vacuo to give the title compound as a single diastereoisomer (2.7g) (D21) . δ (CDCI3) : 0.96 (6H, t) , 1.58 (2H, m) , 1.89 (2H, m) , 2.26 (IH, m), 3.12 (IH, m), 3.76 (3H, d) , 3.83 (3H, d) , 4.29 (IH, m), 4.47 (IH, m) , 7.67 (2H, t) , 8.14 (2H, d) , 8.49 (2H, d) 31 P: δ (CDCI3) : 29.22 Observed FAB (M+H) + 477 C23H2gN 2 θ7P requires M 476 [α] D 22 = -1 .50 (c = 1 .00, MeOH) Analysis: C23H29N2O7P. H 2 0 requires C, 55.87; H, 6.31; N, 5.66% Found C, 55.67; H, 5.84; N, 5.66% Description 22 N-[N-(1-(Di ethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido)propyl)-(S)-leucyl]-(S)-phenylalanine-N- methylamide (D22) The title compound (1.2g) was prepared from the acid (D21) (0.95g) and (S)-phenylalanine-N-methylamide (0.24g) by the procedure described in Description 19. δ (CDCI3) : 0.89 (6H, dd) , 1.26 (2H, m) , 1.62 (IH, m) , 1.84 (2H, m), 2.11 (IH, brond s) , 2.60 (3H, d) , 2.85 (IH, m) , 3.20 (2H, m), 3.55 (IH, t) , 3.71 (3H, d) , 3.78 (3H, d) , 4.19 (IH, m), 4.33 (IH, m) , 4.65 (IH, q) , 6.56 (IH, d) , 7.23 (5H, m) , 7.71 (IH, d) , 7.76 (2H, t) , 8.23 (2H, d) , 8.60 (2H, d) . Description 23 N-[l-(Dimethoxyphosphinyl)-3-phthalimidopropyl]-(S)-leucine, benzyl ester (D23) The title compound was prepared from 3-(phthalimido- propyl)propanal (3.36g) and (S)-leucine benzyl ester, p-toluene sulphonate salt (6.51g) by the procedure described in Description 20. Purification by column chromatography on silica gel, eluting with a mixture of ether:ethyl acetate (1:1) gave a single diastereoisomer. Isomer D23A (1.62g) δ (CDCI3) : 0.92 (6H, m) , 1.38 - 1.92 (5H, m) , 2.13 (IH, m) , 2.93 (IH, m) , 3.47 - 4.06 (3H, m) , 3.73 (3H, d) , 3.79 (3H, d) , 5.13 (2H, m) , 7.33 (5H, m) , 7.70 (2H, m) , 7.83 (2H, m) . Further elution gave a slower running single diastereoisomer. Isomer D23B (1.52g) δ (CDCI3) : 0.90 (6H, dd) , 1.50 (2H, t) , 1.70 - 2.20 (4H, m) 2.95 (IH, m) , 3.53 (IH, t) , 3.70 (3H, d) , 3.75 (3H, d) , 3.75 - 4.03 (3H, m) , 5.14 (2H, ) , 7.35 (5H, m) , 7.70 (2H, m) , 7.83 (2H, m) Description 24 N-[1-(Dimethoxyphosphinyl)-3-phthalimidopropyl]-(S)-leucine (D24) The title compound was prepared as a single diastereoisomer (D24A) (0.97g) from the benzyl ester (D23A) (1.52g) by the procedure described in Description 21. δ (CDCI3) : 0.96 (6H, dd) , 1.55 (2H, m) , 1.85 (2H, m) , 2.20 (IH, m) , 3.03 (IH, dt) , 3.78 (8H, m) , 3.98 (IH, m) , 7.70 (2H, m) , 7.83 (2H, m) Similarly, the title compound was prepared as a single diastereoisomer (D24B) (0.83g) from the benzyl ester (D23B) (1.4g) δ (CDCI3) : 0.96 (6H, d) , 1.55 (2H, ) , 1.85 (2H, m) , 2.15 (IH, m), 2.98 (IH, m) , 3.44 (IH, m) , 3.78 (8H, m) , 7.73 (2H, m) , 7.85 (2H, m) 31 P: δ (CDCI3) : 29.01 Description 25 3-(4-Bromo-l,8-naphthalenedicarboximido)propanol (D25) A mixture of 4-bromophthalic anhydride and 3-amino-l- propanol (12g) in ethanol (200ml) was heated under reflux for 30 min. The solution was allowed to cool to room temperature and the solvent evaporated in vacuo to give a solid which was washed with ester to give the title compound (12.2g) (D25) . δ (CDC1 3 ) : 2.00 (2H, dt) , 3.60 (2H, t) , 4.35 (2H, t) , 7.88 (IH, t), 8.07 (IH, d) , 8.44 (IH, d) , 8.60 (IH, d), 8.70 (IH, d) Description 26 3-(4-Bromo-l,8-naphthalenedicarboximido)propanal (D26) The title compound (10.3g) (D26) was prepared from the alcohol (12.2g) (D25) by the procedure described in Description 5. δ (CDCI3) : 2.90 (2H, dt) , 4.54 (2H, t) , 7.85 (IH, t) , 8.04 (IH, d), 8.40 (IH, d) , 8.59 (IH, dd) , 8.66 (IH, dd) , 9.90 (IH, s) Description 27 N-[1-(Dimethoxyphosphinyl)-3-(4-bromo-l,8-naphthalene dicarboximido)propyl]-(S)-leucine, trimethylsilylethyl ester (D27) The title compound (D27) was prepared from 3-(4-bromo-l, 8- naphthalenedicarboxamido)propanal (D26) (3.0g) and (S)- leucine, trimethylsilylethyl ester (2.17g) by the procedure described in Description 20. Purification by column chromatography on silica gel, eluting with 40 - 60° petrol, increasing to 20% ethyl acetate/40 - 60° petrol gave a single diastereoisomer Isomer D27A (l.Og) δ (CDC1 3 ) : 0.96 (8H, m) , 1.48 (2H, t) , 1.82 (2H, m) , 2.25 (IH, m) , 2.94 (IH, m) , 3.75 (8H, m) , 4.15 (2H, m) , 4.24 (IH, m) , 4.52 (IH, dt) , 7.81 (IH, t) , 8.02 (IH, d) , 8.39 (IH, d) , 8.56 (IH, d) , 8.63 (IH, d) Further elution gave a slower running single diasterisomer. Isomer D27B (0.95g) δ (CDCI3) : 0.91 (8H, m) , 1.47 (2H, t) , 1.8 (2H, m) , 2.13 (IH, m) , 3.06 (IH, m) , 3.51 (IH, t) , 3.73 (3H, d) , 3.79 (3H, d) , 4.12 (3H, m) , 4.26 (IH, m) , 4.41 (IH, m) , 7.80 (IH ,t), 8.00 (IH, d) , 8.38 (IH, d) , 8.54 (IH, d) , 8.62 (IH, d) Description 28 N-[1-(Dimethoxyphosphinyl)-3-( -bromo-1,8-naphthalene dicarboximido)propyl]-(S)-leucine (D28) The trimethylsilylethyl ester (l.Og) (D27A) was dissolved in tetrahydrofuran (50 ml) and the solution cooled to 0°C. A solution of IM tetrabutylammonium fluoride (1.5ml) in tetrahydrofuran (10ml) was added dropwise under nitrogen and the solution stirred at room temperature for 24h. Water (20ml) was added and the solution cooled to 0°C and acidified with 2N hydrochloric acid. The solution was extracted with ethyl acetate (3x) and the combined organic extracts washed with water, dried with anhydrous sodium sulphate and the solvent evaporated in vacuo to give the title compound as a single diastereoisomer (0.8g) (D28A) δ (CDCI3) : 1.04 (6H, m) , 1.73 (2H, m) , 2 . 00 - 2 . 60 (3H, m) , 3 .88 (7H, m) , 4.21 (2H, ) , 4.40 (2H, ) , 7.55 (IH, t) , 7. 82 (IH, t) , 8 .05 (IH, d) , 8 .32 (2H, t) Similarly the title compound was prepared as a single diastereoisomer (0.28g) (D28B) from the trimethylsilylethyl ester (0.33g) (D27B) . δ (CDCI3) : 0.98 (6H, d) , 1.20 - 2.20 (5H, m) , 3.07 (IH, m) , 3.34 (IH, m) , 3.50 (IH, t) , 3.82 (6H, t) , 4.34 (2H, t) , 7.87 (IH, t), 8.06 (IH, t), 8.40 (IH, d) , 8.60 (IH, d) , 8.66 (IH, d) Description 29 N-{N-(1-(Dimethoxyphosphinyl)-3-(4-bromo-l,8- naphthalenedicarboxjmido) ropyl]-(S)-leucyl]-(S)- phenylalanine-N-methylamide (D29) The title compound was prepared from the acid (l.Og) (D28A) and (S)-phenylalanine-N-methylamide (0.65g) by the method described in Description 19. Purification by column chromatography on silica gel, eluting with 5% methanol/ethyl acetate gave the title compound as a single diastereoisomer (0.3g) (D29A) δ (CDCI3) : 0.89 (6H, d) , 1.27 (2H, m) , 1.62 (IH, m) , 1.69 (2H, m), 2.26 (IH, m) , 2.70 (3H, d) , 2.84 (IH, m) , 2.93 - 3.25 (IH, m), 3.56 (IH, t) , 3.72 (3H, t) , 3.79 (3H, d) , 4.17 (IH, m), 4.31 (IH, m) , 4.58 (IH, m) , 6.48 (IH, d) , 7.23 (5H, ), 7.68 (IH, d) , 7.87 (IH, t) , 8.06 (IH, d) , 8.42 (IH, d) , 8.60 (IH, d), 8.68 (IH, d) Similarly, the title compound was prepared as a single diastereoisomer (O.lg) (D29B) from the acid (0.28g) (D28B) and (S)-phenylalanine-N-methylamide (O.lδg). δ (CDCI3) : 0.85 (6H, dd) , 1.13 (2H, m) , 1.57 (2H, m) , 1.90 - 2.24 (2H, m) , 2.80 (3H, d) , 3.00 (2H, m) , 3.28 (2H, m) , 3.70 (3H, d) , 3.75 (3H, d) , 4.27 (2H, t) , 4.77 (IH, m) , 7.23 (5H, m) , 7.50 (IH, d) , 7.62 (IH, d) , 7.87 (IH, t) , 8.05 (IH, d) , 8.40 (IH, d) , 8.60 (IH, d) , 8.65 (IH, d) Description 30 N-[N-(1-(Dibenzyloxyphosphinyl)-3-(2-bβnzyloxy- phenyl)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide (D30) The title compound (4.0g) was prepared from 3-(2-benzyloxy- phenyl) propanol (4.8g), (S)-leucyl- (S)-phenylalanine-N- methylamide (5.82g) and dibenzyltrimethylsilyl phosphite (6..7g) by the procedure described in Description 6. Observed FAB (M+H) + 776 H 5 N 3 0 P requires . 775 Description 31 N-[N-(1-(Dimethoxyphosphinyl)-3-(methylmercapto)propyl)-(S)■ leucyl]-(S)-phenylalanine-N-methylamide (D31) The title compound (4.1g) (D31) was prepared from 3-(methyl¬ mercapto)propanal (2.08g) , (S)-leucyl-(S)-phenylalanine-N- methylamide (5.82g) and dimethyltrimethylsilyl phosphite (3.3g) by the procedure described in Description 9. Purification by column chromatography on silica gel, eluting with 3% methanol/ethyl acetate gave the title compound as a mixture of 2 diastereoisomers (4.1g) (D31) δ (CDCJ3) : 0.90 (6H, m) , 0.90-1.95 (6H, m) , 2.08 (1-JftH, s) , 2.10 (Ilia, s) , 2.60 (2H, t) , 2.73 (1-VtSH, d) , 2.76 (1UH, d) , 2.82-3.12 (2H, m) , 3.26 (l-*ffi, m) , 3.57 (-Vffl, m) , 3.74 (3H, d), 3.78 (3H, d), 4.55 (-4H, q) , 4.76 (V_R, m) , 6.14 (-V4H, broad s) , 7.22 (5H, m) , 7.38 (--iH, broad s) , 7.53 (-VέH, d) , 7.64 OSH, d) . Observed FAB (M+H) + 488 C22H38N3O5PS requires M 487 Description 32 N-[N-(1-(Dimethoxyphosphinyl)-3-(methylsulphinyl)propyl)- (S)-leucyl]-(S)-phenylalanine-N-methylamide (D32) Sodium periodate (0.86g) in water (5ml) was added to a solution of N-[N-(1-(dimethoxyphosphinyl)-3-(methyl¬ mercapto)propyl)-(S)-leucyl]-(S)-phenylalanine-N- methylamide(0.98g) (D31) in methanol(50ml) . The solution was stirred at room temperature for 2h and the solvent evaporated in vacuo. The residue was dissolved in chloroform, washed with water, saturated sodium chloride solution and dried with anhydrous sodium sulphate. The solution was filtered and the solvent evaporated in vacuo to give the title compound. Purification by column chromatography on silica gel, eluting with 5% methanol/chloroform gave the title compound as a mixture of 2 diastereoisomers (0.63g) (D32) δ(CDCl 3 ) : 0.87 (6H, m) , 1.03-2.35 (6H, m) , 2.60 (1-V6H, d) , 2.66 (H4H,d), 2.70 (1^6H, d) , 2.73 (1-4H, d) , 2.77-3.10 (4--4H, m) , 3.22 (IH, dd) , 3.60 (^H, m) , 3.77 (3H, d) , 3.80 (3H, d) , 4.53-4.77(lH, m) , 6.14 (- * *H, broad s) , 7.10 (V4H, broad s) , 7.22(5H, m) , 7.50(*^H, d) , 7.57 (V4H, d) . Observed FAB (M+H) + 504 C22 H 38 N 3°6 PS requires M 503 Description 33 N-[N-(1-(Dimethoxyphosphinyl)-3-(methylsulphonyl)propyl)- (S)-leucyl]-(S)-phenylalanine-N-methylamide (D33) A solution of sodium periodate (4.26g) in water (20ml) was added to N-[N-(1-(dimethoxyphosphinyl)-3-(methyl¬ mercapto)propyl)-(S)-leucyl]- (S) -phenylalanine-N- • methylamide(0.98g) (D31) in methanol (50ml) . The solution was stirred at room temperature for 72h and the solvent evaporated in vacuo. The residue was dissolved in chloroform, washed with water, saturated sodium chloride solution and dried with anhydrous sodium sulphate. The solution was filtered and the solvent evaporated in vacuo to give the title compound. Purification by column chromatography on silica gel, eluting with 10% methanol/ethylacetate gave the title compound as a mixture of 2 diastereoisomers (0.52g) (D33) δ(CDCl 3 ) : 0.84 (6H, m) , 1.02-2.40 (7H, m) , 2.70 (1-Vffl, d) , 2.74 (1-V4H, d), 2.93 (U4H, s) , 3.01 (l^H, s) , 3.03 (2H, m) , 3.20 (2H, m) , 3.40 (-UH, m) , 3.58 (-4H, m) , 3.78 (6H, m) , 4.56 ( 1 /2H, q) , 4.66 { _K, m) , 5.73 (^H, d) , 6.80 (-Vffl, d) , 7.23 (5H, m) , 7.44 (IH, t) Observed FAB (M+H) + 520 C22H38N3O PS requires M 519 Description 34 N-[N-(1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido) propyl)-(S)-leucyl]-(S)-phenylalanine-N- methylamide (D34) The title compound (0.53g) was prepared as a single diastereoisomer (D34) from the acid (0.6g) (D21) and (S)- tryptophan-N-methylamide (0.31g) by the procedure described in Description 19. δ(CDCl 3 ) : 0.89 (6H, dd) , 1.35 (2H, m) , 1.72 (3H, m) , 1.96 (IH, m) , 2.71 (3H, d) , 2.78 (IH, m) , 3.27 (IH, dd) , 3.44 (IH, dd), 3.55 (IH, m) , 3.62 (3H, d) , 3.75 (3H, d) , 3.94 (IH, m), 4.17 (IH, m) , 4.74 (IH, q), 6.42 (IH, d) , 6.97 (2H, m), 7.14 (IH, d), 7.27 (IH, s) , 7.62 (2H, dd) , 7.77 (2H, t) , 8.24 (2H, d), 8.43 (IH, broad s) , 8.59 (2H, d) Description 35 N-[N-(1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido)propyl)-(S)-N ε -benzyloxycarbonyllysine-N- methylamide (D35) The title compound (1.4g) was prepared as a single diastereoisomer (D35) from the acid (0.95g) (D21) and (S)-N ε - benzyloxycarbonyllysine-N-methylamide (0.42g) by the procedure described in Description 19. δ(CDCl ): 0.99 (6H, t) , 1.32-2.04 (11H, m) , 2.23 (IH, m) , 2.74 (3H, d) , 3.00 (IH, m) , 3.73 (3H, d) , 4.22-4.55 (3H, ), 5.09 (2H, s) , 5.18 (IH, m), 6.50 (IH, d) , 7.33 (5H, ), 7.57 (IH, d) , 7.75 (2H, t) , 8.23 (2H, d) , 8.60 (2H, d) 31 P δ(CDCl 3 ) : 29.96 m.p. 128-132°C Observed FAB (M+H)+ 742 C38H5()N5θgP requires 751 [α] D 22 = -22.49 (c=0.98%,MeOH) Analysis: C38H 5 oN 5 OgP requires C, 60.71; H, 6.70; N, 9.32% Found C, 60.37; H, 6.47; N, 9.12% Description 36 N-[N-(1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido) propyl)-(S)-leucyl]-(-)-aminoazacyclo tridecan-2-one (D36) The title compound (0.75g) was prepared as a single diastereoisomer (D36) from the acid (0.6g) (D21) and (-)-3- aminoazacyclotridecan-2-one (0.3g) ([α]-*-, 2 " = -63.6 (c=l% in methanol) by the procedure described in Description 19. δ(CDCl 3 ): 0.95 (6H, dd) , 1.28 (16H, m) , 1.52 (2H, m) , 1.65- 2.11 (5H, ) , 2.25 (IH, m) , 2.85 (IH, m) , 3.04 (IH, broad s), 3.62 (2H, m) , 3.71 (3H, d) , 3.79 (3H, d) , 4.36 (2H, m) , 4.54 (IH, m) , 6.43 (IH, m) , 7.63 (IH, d) , 7.76 (2H, t) , 8.22 (2H, d) , 8.60 (2H, d) Observed FAB (M+H) + 671 3sH5 1 N θ7P requires M 670 Description 37 (S)-N α -t-Butyloxycarbonyl-N ε -benzyloxycarbony1lysine-N- (benzyloxycarbonyl aminoethyl) amide (D37) The title compound (7.2g) was prepared from N α -£.-butyloxy- carbonyl-N ε -benzyloxycarbonyllysine (5.3g) and 2- (benzyloxycarbonylamino) ethylamine(2.72g) by the procedure described in Description 19. δ(CDCl 3 ) : 0.90 (15H, m) , 1.75 (IH, m) , 3.17 (2H, q) , 3.32 (4H, broad s), 4.00 (IH, q) , 5.10 (4H, s) , 5.39 (IH, d) , 5.56 (IH, t), 6.76 (IH, broad s) , 7.33 (10H, S) Description 38 N-[N-(1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido) propyl)-(S)-leucyl]-(S)-(N ε -benzyloxy carbony1)lysine-N-(benzyloxycarbonylaminoethyl)amide (D38) N α -i.-Butyloxycarbonyl-N ε -benzyloxycarbonyllysine-N- (benzyloxycarbonyl aminoethyl) amide (1.22g) (D37) was dissolved in dichloromethane (20ml) and trifluoroacetic acid (15ml) added. The solution was stirred at room temperature for 2h and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (25ml) and triethylamine added to pHIO to give N ε -benzyloxycarbonyllysine-N- (benzyloxycarbonylaminoethyl) amide. The title compound was prepared from the above amine (l.Og) and the acid (0.95g) (D21) by the procedure described in Description 19. Purification by column chromatography on silica gel, eluting with 5% methanol/ethyl acetate gave the title compound as a single diastereoisomer (l.Og) (D38) . δ(CDCl 3 ) : 0.93 (3H, d) , 0.97 (3H, d) , 1.30-2.10 (11H, m) , 2.20 (IH, m) , 3.15 (2H, m) , 3.30 (4H, broad s) , 3.64 (3H, d) , 3.74 (3H, d) , 4.32 (4H, m) , 5.04 (4H, s) , 5.15 (IH, broad s) , 5.78 (IH, broad s) , 7.08 (IH, broad s) , 7.28 (10H, m) , 7.65 (IH, d) , 7.74 (2H, t) , 8.22 (2H, d) , 8.59 (2H, d) . Observed FAB (M+H) + 915 C H5gN 0 11 P requires M 914 Description 39 N-[N-(1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido) propyl)-(S)-leucyl]-(S)-(N ε -benzyloxycarbonyl) lysine-N-(ethylpyrrolidine) amide (D39) The title compound was prepared from (S)- (N ε -benzyloxy- carbonyl) lysine-N-(ethylpyrrolidine) amide (0.73g) and the acid (0.83g.) (D21) by the procedure described in Description 19. Purification by column chromatography on silica gel, eluting with 10% methanol/chloroform gave the title compound as a single diastereoisomer (1.2g) (D39) δ(CDCl 3 ) : 0.97 (6H, t) , 1.34-1.66 (6H, m) , 1.66-2.08 (9H, m) , 2.25 (IH, m) , 2.58 (6H, m) , 3.03 (IH, m) , 3.20 (2H, q) , 3.30 (2H, q) , 3.69 (IH, m) , 3.72 (3H, d) , 3.80 (3H, d) , 4.21-4.44 (2H, m) , 4.50 (IH, m) , 5.09 (2H, s) , 5.31 (IH, t) , 6.78 (IH, broad s) , 7.32 (5H, m) , 7.54 (IH, d) , 7.74 (2H, t), 8.22 (2H, d) , 8.60 (2H, d) . 31 P δ(CDCl 3 ) : 30.05 Observed FAB (M+H) + 835 C43H 5 NgOgP requires M 834 [α] D 22 = -17.21 (c=1.00, MeOH) Description 40 (S)-N α -t-Butyloxycarbonyl-N ε -bβnzyloxycarbonyllysine-N- (ethyl-N-methylpiperazine) amide (D40) The title compound (4.2g) was prepared from N α -£.- butyloxycarbonyl-N ε -benzyloxycarbonyl lysine (3.8g) and 1- aminoethyl-4-methyl piperazine (1.43g) by the procedure described in Description 19. δ(CDCl3): 1.42 (9H, s) , 1.50 (7H, m) , 1.80 (IH, m) , 2.30 (3H, s), 2.50 (10H, m), 3.19 (2H, q) , 3.23 (2H, q) , 4.05 (IH, m) , 4.95 (IH, m) , 5.08 (2H, s) , 5.17 (IH, m) , 6.55 (IH, ) , 7.36 (5H, s) . Observed FAB (M+H) + 506 C26 H 43 N 5°5 requires M 505 Description 41 N-[N-(1-(Dimethoxyphosphinyl)-3-(1,8-naphthalene dicarboximido) propyl)-(S)-leucyl]-(S)-(N ε -benzyloxy- carbonyl)lysine-N-(ethyl-N-methylpiperazine) amide (D41) The title compound was prepared from (D40) (l.lg) and the acid (0.92g) (D21) by the procedure described in Description (38). Purification by colum chromatography on silica gel, eluting with 10% methanol/ethyl acetate gave the title compound as a single diastereoisomer (D41) (1.2g) . δ(CDCl 3 ) : 0.93 (6H, t) , 1.30-2.05 (12H, m) , 2.26 (3H, s) , 2.40 (10H, m), 3.00 (IH, m) , 3.22 (4H, m) , 3.67 (IH, m) , 3.73 (3H, d), 3.80 (3H, d) , 4.20-4.42 (2H, ) , 4.50 (IH, m) , 5.06 (2H, s) , 5.25 (IH, ) , 6.52 (IH, broad t) , 7.30 (5H, s), 7.50 (IH, d), 7.70 (2H, t) , 8.20 (2H, d) , 8.58 (2H, d) . 31 P δ(CDCl 3 > : 29.99 Observed FAB (M+H) + 864 C 4Hg 2 N 7 0gP requires M. 863 [α] D 22 = -18.80 (c= 0.74, MeOH) Description 42 3-[8-(7,9-dioxo-8-a∑aspiro[4,5]decyl) ]propanol (D42) 3,3-Tetramethylene glutaric anhydride (8.4g) was dissolved in toluene (200ml) and 3-aminopropan-l-ol (4.5g) in toluene (50ml) added over 5 minutes. The solution was stirred at room temperature for 2h then heated at reflux for 3h. The solution was allowed to cool and solvent evaporated in vacuo to yield the title compound as a pale yellow oil (13.8g) (D42) . δ(CDCl 3 ) : 1.53 (4H, m) , 1.72 (6H, m) , 2.65 (4H, s) , 3.51 (2H, t), 3.92 (2H, t) Description 43 3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl) ]propanal (D43) The title compound (3.3g) (D43) was prepared from the alcohol (3.4g) (D42) by the procedure described in Description 5. δ(CDCl 3 ) : 1.50 (4H, m) , 1.71 (4H, m) , 2.60 (4H, s) , 2.64 (2H, dt), 4.12 (2H, t), 9.75 (IH, s) Observed CI M+H 224 Description 44 N-[1-(Dimethoxyphosphinyl)-3-[8-(7,9-dioxo-8- azaspiro[4,5]decyl)] propyl]-(S)-leucine, benzyl ester (D44) The title compound was prepared from the aldehyde (3.2g) (D43) , (S)-leucine, benzyl ester p-toluene sulphonate salt (5.7g) and dimethyl trimethylsilyl phosphite (2.6g) by the procedure described in Description 20. Purification by colu chromatography on silica gel, eluting with a mixture of 2:1 ether: ethyl acetate, increasing to 1:1 ether:ethyl acetate, gave a single diastereoisomer. Isomer D44A (2.14g) δ(CDCl 3 ) : 0.92 (6H, t) , 1.37-1.87 (13H, m) , 1.96 (IH, m) , 2.57 (4H, s), 2.82 (IH, m) , 3.71 (3H, d) , 3.78 (3H, d) , 3.83 (2H, m) , 4.00 (IH, m) , 5.13 (2H, m) , 7.34 (5H, m) 31 P δ(CDCl 3 ) : 28.74 Observed El MH+ 537 [α] D 22 = -13.33 (c=1.00, MeOH) Analysis: C27H4 1 N 2 O7P. 1 /2H 2 0 requires C, 59.44; H, 7.76; N, 5.13% Found: C, 59.42; H, 7.65; N, 4.99% Further elution gave a mixture of 2 diastereoisomers (3.l2g) Further elution gave a slower running single diastereoisomer Isomer D44B (0.70g) δ(CDCl 3 ) : 0.91 (6H, dd) , 1.50 (6H, broad t) , 1.70 (7H, m) , 1.94 (IH, m), 2.59 (4H, s) , 2.93 (IH, m) , 3.53 (IH, t) , 3.74 (6H, d), 3.84 (IH, m) , 4.00 (IH, m) , 5.16 (2H, s) , 7.34 (5H, m) . 31 P δ(CDCl 3 ) : 29.55 Observed El MH + 537 [α] D 22 = -11.47 (c=0.78, MeOH) Analysis: C 7 H 41 N 2 θ7P. 1 /2H 2 0 requires C, 59.44; H, 7.76; N, 5.13% Found C, 59.27; H, 7.58; N, 4.87% Description 45 N-[1-(Dimethoxyphosphinyl)-3-[8-(7,9-dioxo-8- azaspiro[4,5]decyl)] propyl]-(S)-leucine (D45) The--title compound was prepared as a single diastereoisomer (D45A) (1.7g) from the benzyl ester (D44A) (2.1g) by the procedure described in Description 21. δ(CDCl 3 ) : 0.96 (6H, dd) , 1.50 (6H, m) , 1.70 (6H, m) , 1.74 (IH, m) , 2.06 (IH, broad s) , 2.60 (4H, s) , 2.98 (IH, m) , 3.76 (3H, d) , 3.81 (3H, d) , 3.90 (2H, m) , 4.03 (IH, m) . 31 P δ(CDCl 3 ) : 29.13 Observed FAB (M+H) + 447 C20H35N2O7P requires M 446 [α] D 22 = -9.11 (c=0.48, MeOH) Similarly, the title compound was prepared as a single diastereoisomer (D45B) (0.5g) from the benzyl ester (D44B) (0.7g) δ(CDCl 3 ) : 0.96 (6H, dd) , 1.50 (6H, broad s), 1.60-1.90 (7H, m) , 2.00 (IH, m) , 2.59 (4H, s) , 2.92 (IH, m) , 3.41 (IH, t) , 3.73 (IH, m) , 3.80 (3H, d) , 3.84 (3H, d) , 3.92 (IH, m) Description 46 N-[1-(Dimethoxyphosphinyl)-3-£8-(7,9-dioxo-8- azaspiro[4,5]decyl)] propyl)-(S)-leucyl]-(S)-phenylalanine- N-methylamide (D46) The title compound was prepared as a single diasteroiso er (0.43g) (D46A) from the acid (D45A) and (S)-phenylalanine-N- methylamide (0.2g) by the procedure described in Description 19. δ(CDCl 3 ) : 0.87 (6H, dd) , 1.20 (2H, ) , 1.51 (5H, m) , 1.73 (6H, broad s), 1.90 (IH, ) , 2.61 (4H, s) , 2.73 (3H, d) , 3.12 (2H, m), 3.49 (IH, m) , 3.72 (3H, d) , 3.77 (3H, d) , 3.74 (2H, m), 3.90 (IH, m) , 4.57 (IH, q) , 6.32 (IH, broad d) , 7.25 (5H, m), 7.48 (IH, d) . 31 P δ(CDCl 3 ) : 30.10 Observed FAB (M+H) + 607 C30H47N4O7P requires M 606 [α] D 22 = -25.38 (c=0.76,MeOH) Analysis: C3 Q H47N407P 1 /2H 2 0 requires C, 58.52; H, 7.86; N, 9.10% Found C, 58.67; H, 7.50; N; 9.17% Similarly, the title compound was prepared as a single diastereoisomer (D46B) (0.46g) from the acid (0.5g) (D45B) and (S)-phenylalanine-N-methylamide (0.22g) δ(CDCl 3 ) : 0.82 (6H, t) , 1.00 (l,Hm), 1.16 (IH, m) , 1.50 (5H, ) , 1.70 (6H, m) , 1.95 (IH, m) , 2.60 (4H, s) , 2.70 (3H, d), 2.98 (IH, dd) , 3.10 (IH, m) , 3.30 (IH, dd) , 3.73 (3H, d), 3.78 (3H, d), 3.85 (3H, m) , 4.77 (IH, m) , 7.22 (5H, m), 7.34 (IH, broad d) , 7.47 (IH, d) Description 47 N-[N-(1-(Dimethoxyphosphinyl)-3-[8-(7,9-dioxo-8- azaspiro[4,5]decyl) ] propyl)-(S)-leucyl]-(S)- bβnzyloxycarbonyllysine-N-mβthylamidθ (D47) The title compound was prepared as a single diastereoisomer (0.5g) (D47) from the acid (0.45g) (D45A) and (S)-N ε - benzyloxycarbonyllysine-N-methylamide (0.29g) by the procedure described in Description 19. δ(CDCl 3 ) : 0.96 (6H, dd) , 1.47 (8H, m) , 1.75 (11H, m) , 1.98 (IH, m) , 2.59 (4H, s) , 2.75 (3H, d) , 2.80 (IH, m) , 3.20 (2H, m) , 3.60 (IH, t) , 3.72 (3H, d) , 3.79 (3H, d) , 3.85 (IH, m) , 4.00 (IH, m) , 4.30 (IH, q) , 5.09 (2H, s) , 5.17 (IH, broad s) , 6.40 (IH, broad d) , 7.34 (5H, s) , 7.44 (IH, d) . 31 P δ(CDCl 3 ) : 30.01 Observed FAB (M+H) + 722 C3 5 H 5 gN 5 0gP requires M 721 [α] D 22 = -28.87 (c=0.95,MeOH) Analysis: C35H5gN5θgP-*-/2H 2 0 requires C, 57.72; H, 7.86; N, 9.58% Found C, 57.22; H.7.37; N, 9.54 Description 48 N-[N-(1-(Dimethoxyphosphinyl)-3-aminopropyl)-(S)-leucyl]- (S)-phenylalanine-N-methylamide (D 8) N-[N-(1-Dimethoxyphosphinyl)-3-phthalimidopropyl)-(S)- leucyl]-(S)-phenylalanine-N-methylamide (lg) (D9) was dissolved in a 0.2M methanol solution of hydrazine (50ml) and the solution stirred at room temperature for 24h. The solvent was evaporated in vacuo and the mixture treated with methanol, filtered and the solvent evaporated in vacuo to give the title compound as a mixture of 2 diastereoisomers (0.7g) (D48) which was used in the next stage without further purification. Description 49 N-[N-(1-(Dimethoxyphosphinyl)-3-(benzyloxycarbonylamino) propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide (D49) N-[N-(1-(Dimethoxyphosphinyl)-3-aminoρropyl)-(S)-leucyl]- (S)-phenylalanine-N-methylamide (4.5g) (D48) was dissolved in water (20ml) and dioxan (20ml) . Benzyl chloroformate (1.8ml) was added and the pH maintained at 9 - 9.5 by the addition of 10% sodium hydroxide solution. After stirring at room temperature overnight, the solution was extracted with chloroform. The organic extracts were washed with water, dried with anhydrous sodium sulphate, filtered and the solvent evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with 10% methanol/ethyl acetate gave the title compound as a mixture of 2 diastereoisomers (4.7g) (D49) δ (CDC1 3 ) : 0.87 (6H, ) , 0.96 - 2.17 (6H,m) , 2.59 (1-VέH, d) , 2.62 (l^H ,d), 2.62 (V R, d) , 2.80 (IH, m) , 3.00 (2H, ) , 3.24 (2H, m), 3.44 (IH, m) , 3.70 (6H, t) , 4.66 (IH, m) , 5.07 (2H, m) , 5.36 ( _H, broad t) , 6.12 (-viH, d) , 6.41 (--iH, broad t), 7.24 (11H, m) , 7.60 (^έH,d) Observed FAB (M+H + ) 591 C 2 gH43 4 θ7P requires M 590 Example 1 N-[N-(1-Phosphono-l-(2-hydroxypheny1)methyl)leucyl]-N,O- dimethyl-(S)-tyrosinamide (El) The diethyl ester (D3) (0.2g) was dissolved in dichloromethane (10ml) and treated with bromotrimethyl- silane (0.5ml). The solution was stirred at room temperature for 4 days, methanol (20ml) was added and the solvent evaporated in vacuo to give the crude product. Column chromatography on reverse phase silica, eluting with a gradient of 5% to 30% methanol in water gave the title compound (O.lβg) as a mixture of diastereoisomers. Observed FAB (M+H) + 508. C24H34N3O7P requires M 507. Example 2 N-[N-(l-Phosphono-3-(1,8-naphthalenedicarboximide)propyl)- (S)-leucyl]-N,O-dimethyl-(S)-tyrosinamide (E2) The dibenzyl ester (D6A) (0.5g) was dissolved in ethanol (100 ml) and hydrogenated over 10% palladium on charcoal at atmospheric pressure for 24h. The solution was filtered and the solvent evaporated in vacuo to give the title compound as a single diastereoisomer (E2A) (0.38g). Observed FAB (M+H) + 639. C3 2 H3gN θ8P requires M 638. Similarly, the dibenzyl ester (D6B) gave the title compound as a single diastereoisomer (E2B) . Observed FAB (M+H) + 639. C3 2 H 3 gN θ8P requires M 638. Example 3 N-[N-(l-Phosρhono-3-phthalimidopropyl)-(S)-leucyl]-(S)- phenylalanine-N-methylamide The dimethyl ester (D9) (lg) was dissolved in dichloromethane (10ml) and bromotrimethylsilane (1.56g) added under nitrogen at room temperature. The solution was stirred at room temperature for 3h, then refluxed for 1.5h. The solution was allowed to cool and solvent evaporated in vacuo to give a colourless oil which was dissolved in dioxan (5ml) and water (0.5ml) and refluxed for lh. The solvent was evaporated in vacuo to give the title compound as a white crystalline compound (0.7g) as a mixture of 2- diastereoisomers. δ(CD 3 OD) : 0.98 (6H, m) , 1.55-2.40 (5H, m) , 2.65 (3H, s) , 2.80-3.25 (3H, m) , 3.68 (Uffl, m), 3.84 (-H, m) , 4.21 ( _E, m), 4.43 (--2Ϊ, t) , A .61 (IH, m) , 7.27 (5H, m) , 7.84 (4H, m) Observed FAB (M+H) + 559 C27H35N4O7P requires M.558 The dimethyl ester (D9A) (0.06g) was dissolved in dichloromethane (10ml) and the solution cooled to -20°C. Iodotrimethylsilane (0.1ml) was added under nitrogen at - 20°C and the solution stirred for 30 min. The solution was allowed to warm to room temperature and stirred for 3h. The solvent was evaporated in vacuo and the residue dissolved in methanol (20ml) and stirred for 2h. Solvent was evaporated in vacuo to give the title compound (0.05g) as a single diastereoisomer. δ(CD 3 OD): 1.00 (6H, t) , 1.70 (3H, m) , 2.06 (IH, m) , 2.42 (IH, m) , 2.69 (3H, s) , 2.83-3.20 (3H, m) , 3.70 (IH, m) , 3.86 (IH, m), 4.42 (IH, t) , 4.68 (IH, dd) , 7.30 (5H, m) , 7.85 (4H, m) Observed FAB (M+H) + 559 C27H35N4O7P requires M 558 Example 4 N-[N-(l-Phosphono-4-(1,8-naρhthalenedicarboximido)butyl)- (S)-leucyl]-(S)-phenylalanine-N-methylamide (E4) The title compound (2.7g) was prepared from the dibenzyl ester (D12) (3.23g) by the procedure described in Example 2 δ(CD 3 OD): 0.68 (3H, dd) , 0.83 (3H, dd) , 1.06-1.90 (7H, m) , 2.25-3.15 (4H, m) , 2.53 (1-Vffl, s) , 2.60 (1-V4H, s) , 3.94 (1-H, m) , 4.24 ( Α, t), 4.50 (IH, m) , 7.06 (5H, m) , 7.51 (2H, t) , 8.14 (2H, d) , 8.22 (2H, d) . Observed FAB (M+Na) + 645. C 3 2H 3 gN4θ7P requires M. 622. Example 5 N-[N-(l-Phosphono-2-(1,8-naphthalβnedicarboximido)ethyl-(S)- leucyl]-(S)-phenylalanine-N-methylamide (E5) The title compound (0.69g) was prepared from the dibenzyl ester (D15) (1.14g) by the procedure described in Example 2, δ(CD 3 OD) : 0.27 (H4H, d) , 0.42 (H4H, d) , 0.96 (3H, d) , 0.96- 1.80 J3H, m) , 2.46 (l--iH, s) , 2.74 (l H, s) , 2.50-3.30 (3H, m) , 4.14 (--iH, t), 4.50 (2H, m) , 4.66 (IH, m) , 4.81 ( _\i, m) , 7.17 (5H, m) , 7.76 (2H, t) , 8.32 (2H, t) , 8.50 (2H, d) . Observed FAB (M+H) + 595. C30H35N4O7P requires M 594. Example 6 N-[N-(l-Phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-phenylalaninβ-N-methylamide (E6) The title compound (0.63g) was prepared as a single diastereoisomer (E6A) from the dibenzyl ester (D16A) by the procedure described in Example 2. The title compound (0.4g) was also prepared as a single diastereoisomer (E6A) from the dimethyl ester (D22) by treatment with bromotrimethylsilane (1ml) in dichloromethane (50ml) at room temperature under nitrogen for 48h. The solvent was evaporated in vacuo and the residue dissolved in methanol (25ml) and water (5ml) and stirred for 2 h. The solvent was evaporated in vacuo to give the title compound (E6A) (0.4g) as a white solid. δ(CD30D) : 1.02 (6H, dd) , 1.78 (4H, m) , 2.14 (IH, m) , 2.70 (3H, s) , 2.96 (IH, dd) , 3.12 (IH, dd) , 3.99 (IH, m) , 4.10 (1H,„. m) , 4.34 (IH, m) , 4.78 (IH, dd) , 7.22 (5H, m) , 7.78 (2H, t), 8.34 (2H, d) , 8.53 (2H, d) . 31 P: δ(CD 3 OD) : 18.47 Observed FAB (M+H) + 609 C31H37N4O7P requires M 608 [α] D 22 = -25.39 (c=0.81, MeOH) Similarly, the dibenzyl ester (D16B) gave the title compound as a single diastereoisomer (E6B) . δ(CD 3 OD) : 1.00 (6H, m) , 1.76 (3H, m) , 2.03 (IH, m) , 2.41 (IH, m), 2.68 (3H, s) , 2.95 (2H, m) , 3.14 (IH, dd) , 4.16 (2H, ), 4.46 (IH, t) , 4.69 (IH, dd) , 7.30 (5H, m) , 7.75 (2H, t), 8.30 (2H, d) , 8.46 (2H, d) Observed FAB (M+H) + 609 C31H37N4O7P requires M 608 Example 7 N- [N- (l-Phosphono-3-phβnylpropyl) - (S) -leucyl] - (S) - phenylalanine-N-methylamide (E7) The dibenzyl ester (D19A) (0.46g) was dissolved in ethanol (100 ml) and hydrogenated over 10% palladium on charcoal at atmospheric pressure for 24h. The solution was filtered and the solvent evaporated in vacuo to give the title compound, as a white solid, as a single diastereoisomer (E7A) (0.35g) . δ(CD 3 OD) : 0.95 (6H, dd) , 1.66 (3H, m) , 1.85 (IH, m) , 2.14 (IH, m) , 2.36 (IH, m) , 2.50-2.84 (2H, m) , 2.70 (3H, s) , 2.92 (IH, dd) , 3.07 (IH, dd) , 4.40 (IH, t) , 4.63 (IH, dd) , 7.23 (10H, m) . [α] D 22 = -26 .24° (c=l% in methanol ) m.p . = 147-150°C . Observed FAB (M+H) + 490. C2sH3 N3θ5P requires M. 489 Analysis: C25H 3 gN 3 θ5P.l/2H2θ requires C, 60.23; H, 7.48; N, 8.43%. Found C, 59.84; H, 7.29; N, 8.43%. Similarly, the title compound was prepared from the dibenzyl ester (D19B) (0.14g),as a white solid, as a single diastereoisomer (E7B) (0.10g). δ(CD 3 OD) : 0.81 (6H, dd) , 1.52 (3H, m) , 1.78 (IH, m) , 2.07 (IH, m) , 2.52 (3H, s) , 2.60 (IH, m) , 2.65-3.04 (4H, m) , 3.91 (IH, broad s) , 4.49 (IH, t) , 7.13 (10H, m) . [α] D 22 = -13.71° (c=l% in methanol). Observed FAB (M+H) + 490. C25H3 N3U5P requires -M 489. Example 8 N-[N-(l-Phosphono-3-(4-bromo-l,8-naphthalβnedicarb ximido)- propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide (E8) The title compound was prepared as a single diastereoisomer (0.08g) (E8A) from the dimethyl ester (0.2g) (D29A) by the procedure described in Example 6. δ(CD 3 OD) : 1.02 (6H, dd) , 1.76 (3H, broad d), 2.02 (IH, broad s), 2.40 (IH, m) , 2.68 (3H, s) , 2.84 (IH, m) , 2.94 (IH, dd) , 3.11 (IH, dd) , 4.04 (IH, m) , 4.16 (IH, m) , A . A1 (IH, t) , 4.67 (IH, dd), 7.30 (5H, m) , 7.79 (IH, t) , 7.98 (IH, d) , 8.20 (IH, d), 8.45 (2H, t) . Similarly, the title compound was prepared as a single diastereoisomer (E8B) from the dimethyl ester (D29B) . δ(CD 3 OD) : 0.97 (6H, dd) , 1.78 (4H, m) , 2.16 (IH, m) , 2.94 (IH, dd) , 3.08 (IH, dd) , 3.20 (IH, m) , 3.93 (IH, broad s) , 4.05 (IH, broad s) , 4.47 (IH, m) , 4.70 (IH, t) , 7.77 (IH, t), 7.95 (IH, d), 8.20 (IH, d) , 8.42 (2H, t) Example 9 N-[N-(l-Phosphono-3-(benzyloxycarbonylamino)propyl)-(S)- leucyl]-(S)-phenylalanine-N-methylamide (E9) The title compound was prepared from the dimethyl ester (D49) by treatment with bromotrimethylsilane for 3h as described in Example 6. δ(CD 3 OD) : 0.96 (6H, m) , 1.55-2.30 (5H, m) , 2.70 (3H, m) , 2.88-3.21 (5H, m) , 3.65 (IH, m) , 4.05-4.45 (IH, m) , 5.10 (2H, m) , 7.30 (10H, ) Observed FAB (M+H) + 563 C27H 3 gN 4 θ7P requires M. 562 Example 10 N-[N-(l-Phosphono-3-(2-hydroxyphenyl)propyl)-(S)-leucyl]- (S)-phenylalanine-N-methylamide (ElO) The title compound was prepared as a mixture of 2 • diastereoisomers (2.5g) (ElO) from the dibenzyl ester (4g) (D30) by the procedure described in Example 2. Observed FAB(M+H) + 506 C2sH3g 3θgP requires M 505 Example 11 N-[N-(l-Phosphono-3-(methylmercapto)propyl)-(S)-leucyl]-(S)- phenylalanine-N-methylamide (Ell) The title compound was prepared as a mixture of 2 diastereoisomers (0.15g) (Ell) from the dimethyl ester (0.19g) (D31) by treatment with bromotrimethylsilane for 24h as described in Example 6. Observed FAB (M+H) + 460 C20 H 34 N 3θ5 p S requires M 459 Ξxample 12 N-[N-(l-Phosphono-3-(methylsulphinyl)propyl)-(S)-leucyl]- (S)-phenylalanine-N-methylamide (E12) The title compound was prepared as a mixture of 2 diastereoisomers (0.42g) (E12) from the dimethyl ester (0.52g) (D32) by treatment with bromotrimethylsilane for 24h as described in Example 6. δ(CD 3 0D) : 0.99 (6H, m) , 1.60-2.47 (5H, m) , 2.70 (3H, m) , 2.77-3.53 (8H, m) , 4.36 (**iH, m) , 4.45 (--iH, m) , 4.70 (IH, m) , 7.31 (5H, ) Example 13 N-[N-(l-Phosphono-3-(methylsulphonyl)propyl)-(S)-leucyl]- (S)-phenylalanine-N-methylamide (E13) The title compound was prepared as a mixture of 2 diastereoisomers (0.4g) (E13) from the dimethyl ester (0.5g) (D33) by treatment with bromotrimethylsilane for 48h as described in Example 6. δ(DMSO) : 0.80 (6H, m) , 1.22-1.54 (5H, m) , 2. 3 (IH, m) , 2.50 (BiH, d) , 2.57 (Uffl, d), 2.84 (IH, m) , 2.90 (1-ϋH, s) , 2.94 (1-ViH, s) , 2.94-3.40 (4H, m) , 4.50 (IH, m) , 7.22 (5H, m) , 8.06 (-iH, d), 8.14 (-V6H, d) , 8.33 (-*iH, d) , 8.49 (-*iH, d) Observed FAB (M+H) + 492 C20H34N3O7PS requires M 491 Example 14 N-[N-(l-Phosphono-3-(1,8-naphthalβnedicarboximido)propyl)- (S)-leucyl]-(S) tryptophan-N-methylamide (E14) The title compound was prepared as a single diastereoisomer (0.4g) (E14) from the dimethyl ester (0.52g) (D34) by treatment with iodotrimethylsilane as described in Example 3. δ(CD 3 OD) : 0.65 (3H, d) , 0.73 (3H, d) , 1.20 (3H, m) , 1.52 (IH, m) , 1.72 (IH, m) , 2.00 (IH, m) , 2.45 (IH, m) , 2.50 (3H, s) , 2.58 (IH, ) , 3.45 (IH, t) , 4.06 (2H, m) , 4.50 (IH, dd) , 6.77 (2H, m) , 7.07 (IH, s) , 7.10 (IH, t) , 7.45 (IH, d) , 7.70 (2H, t), 8.23 (2H, d) , 8.42 (2H, d) 31 P : δ(CD 3 OD) : 24.58 Observed FAB (M+Na) + 670 C33H38N5O7P requires . 647 [α] D 22 = -20.41 (c=0.8%, MeOH) Example 15 N-[N-(l-Phosphono-3-(1,8-naphthalβnedicarboximido)propyl)- (S)-leucyl-(S)-lysine-N-methylamide hydrocholoride (E15) The title compound was prepared as a single diastereoisomer (0.62g) (E15) from the dimethyl ester (l.Og) (D35) by treatment with bromotrimethylsilane for 48h as described in Example 6. The product was dissolved in methanol and treated with ether/HCl to give the hydrochloride salt. δ(CD 3 OD) : 0.90 (6H, t) , 1.44 (2H, m) , 1.54-1.80 (7H, m) , 2.08 (IH, m) , 2.40 (IH, m) , 2.60 (3H, s) , 2.92 (2H, m) , 3.26 (IH, m) , 4.24 (2H, m) , 4.34 (IH, m) , 4.45 (IH, t) , 7.73 (2H, t), 8.27 (2H, d) , 8.45 (2H, d) 31 P δ(CD 3 OD) : 17.00 [α] D 22 = -9.03 (c=0.89, MeOH) Observed FAB (M+H) + 590 C 2 8H 4 oN5θ 7 P requires 589 Example 16 N-[N-(l-Phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(-)-aminoazacyclotridecan-2-one, di-sodium salt (El6) The title compound was prepared as a single diastereoisomer (0.6g) (E16) from the dimethyl ester (0.7g) (D36) by treatment with bromotrimethylsilane for 48h as described in Example 6. The product was dissolved in methanol/water and converted to the di-sodium salt by the addition of two equivalents of sodium hydroxide. δ(CD 3 0D) : 0.98 (6H, m) , 1.10-1.98 (22H, m) , 2.18 (IH, broad S), 2.68 (2H, m) , 3.63 (IH, q) , 4.30 (3H, m) , 7.75 (2H, q) , 8.24 (2H, t), 8.46 (2H, t) Observed FAB (M+H) + 687 C33H47N4θ 7 PNa 2 requires M 686 Example 17 N-[N-(l-Phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(aminoethyl) amide dihydrochloride (E17) The dimethyl ester (0.4g) (D38) was dissolved in dichloromethane (40ml) and a l.OM ether solution of hydrogen chloride (1.2ml) added. Bromotrimethylsilane (4ml) was added, the solution stirred at room temperature for 48h and the solvent evaporated in vacuo. The residue was dissolved in methanol (20ml) and the solution stirred for 2h. The addition of acetone gave the title compound (0.75g) as a single diastereoisomer (E17) . δ(CD 3 OD) : 1.02 (3H, d) , 1.05 (3H, d) , 1.47-2.03 (10H, m) , 2.20 (IH, ), 2.54 (IH, m) , 3.08 (4H, m) , 3.37-3.63 (3H, m) , 4.40 (2H, m), 4.58 (IH, t) , 7.88 (2H, t), 8.41 (2H, d) , 8.62 (2H, d) Observed FAB (M+H) + 619 C 2 gH 43 Ngθ7P requires M 618 Example 18 N-[N-(l-Phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(ethylpyrrolidine) amide dihydrochloride (El8) The title compound was prepared as a single diastereoisomer (0.4g) (E18) from the dimethyl ester (0.6g) (D39) by the procedure described in Example 17. δ(CD 3 OD) : 1.03 (3H, d) , 1.06 (3H, d) , 1.50-2.22 (13H, m) , 2.55 (IH, m) , 3.03 (2H, q) , 3.12 (2H, m) , 3.32 (4H, m) , 3.54 (IH, m) , 3.66 (IH, m) , 3.75 (2H, m) , 4.34 (2H, m) , 4.62 (IH, t), 7.87 (2H, t), 8.40 (2H, d) , 8.50 (2H, d) 31 P δ(CD 3 OD) : 15.71 Observed FAB (M+H) + 673 C33H gNgOgP requires M. 672 Example 19 N-[N-(l-Phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(βthyl-N-methylpiperazine) amide trihydrochloride (El9) The title compound was prepared as a single diastereoisomer (0.9g) (E19) from the dimethyl ester (l.lg) (D41) by the procedure described in Example 17. δ(CD 3 OD) : 1.03 (6H, dd) , 1.55 (2H, m) , 1.69-2.03 (7H, m) , 2.25 (IH, m) , 2.53 (IH, m) , 3.01 (IH, t) , 3.05 (3H, s) , 3.50 (4H, m) , 3.65 (IH, m) , 3.74 (IH, m) , 3.81 (8H, broad s) , 4.31-4.47 (4H, m) , 4.55 (IH, t) , 7.82 (2H, t) , 8.35 (IH, d) , 8.54 (IH, d) lp δ(CD 3 OD) : 17.45 Observed FAB (M+H) + 702 C34H52N7O7P requires M 701 [α] D 22 = +1.79 (c=0.78, MeOH) Example 20 N-[N-(l-Phosρhono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]- propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide (E20) The title compound was prepared as a single diastereoisomer (0.37g) (E20A) from the dimethyl ester (0.4g) (D46A) by treatment witn bromotrimethylsilane for 48h as described in Example 6. δ(CD 3 OD) : 0.97 (6H, d) , 1.50 (4H, m) , 1.72 (8H, m) , 2.17 (IH, m), 2.65 (4H, s) , 2.69 (3H, s) , 2.75 (IH, m) 2.98 (IH, m), 3.12 (IH, m), 3.77 (2H, m) , 4.39 (IH, q) , 4.68 (IH, q) , 7.28 (5H, m) . 31 P δ(CD 3 OD) : 18.54 Observed FAB (M+H) + 579 C28H43N4O7P requires M 578 [α] D 22 = -23.45 (c=0.64, MeOH) Similarly, the title compound was prepared as a single diastereoisomer (0.41g) (E20B) from the dimethyl ester (0.46g) (D46B) Example 21 N-[N-(l-Phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]- propyl)-(S)-leucyl]-(S)-lysine-N-methylamide hydrochloride (E21) The title compound was prepared as a single diastereoisomer (0.3g) (E21) from the dimethyl ester (0.5g) (D47) by the procedure described in Example 17. δ(CD 3 OD) : 1.02 (6H, t) , 1.55 (6H, m) , 1.66-1.87 (11H, m) , 1.95 (IH, m) , 2.28 (IH, m) , 2.72 (4H, s) , 2.74 (3H, s) , 3.00 (2H, t), 3.23 (IH, m) , 3.90 (IH, m) , 4.09 (IH, m) , 4.42 (IH, q), 4.49 (IH, t) 31 P δ(CD 3 OD) : 18.04 Observed FAB (M+H) + 560 C25H 4 N 5 θ7P requires M.559 [α] D 22 = -16.72- (c=0.66, MeOH) Example 22 Pharmaceutical compositions for oral administration may be prepared by combining the following: 1) Solid Dosage Formulation % w/w Compound of formula 1 10% Magnesium stearate 0.5% Starch 2.0% HPM cellulose 1.0% Microcrystalline cellulose 86.5% The mixture may be compressed to tablets, or filled into hard gelatin capsules. The tablet may be coated by applying a suspension of film former (e.g. HPM cellulose), pigment (e.g. titanium dioxide) and plasticiser (e.g. diethyl phthalate) and drying the film by evaporation of the solvent. The film coat can comprise 2.0% to 6.0% of the tablet weight, preferably about 3.0%. 2) Capsule %w/w Compound of formula 1 20% Polyethylene glycol 80% The medicinal compound is dispersed or dissolved in the liquid carrier, with a thickening agent added, if required. The formulation is then enclosed in a soft gelatin capsule by suitable technology. Example 23 A pharmaceutical composition for parenteral administration may be prepared by combining the following: Preferred Level Compound of formula 1 1.0% Saline 99.0% The solution is sterilised and sealed in sterile containers COLLAGENASΞ INHIBITOR ASSAY The test is performed essentially as in Cawston and Barrett, Anal. Biochem. 99, 340-345 (1979) . Compounds for testing are dissolved in methanol by sonication and added to collagenase (purified from culture supernatants from the human lung fibroblast cell line, I-38) in buffer. After a 5 min pre-incubation at 37°C, the assay tubes are cooled to 4°C and H-acetylated rat skin type I collagen is added. The assay tubes are incubated at 37°C overnight. The H- collagen forms insoluble fibrils, which are the substrate for the enzyme. To terminate the assay, the assay tubes are spun at 12000 rpm for 15 minutes. Undigested 3 H-collagen is pelleted, while digested H-collagen is found as soluble peptides in the supernatant. A sample of the supernatant is taken for liquid scintillation counting. The activity of collagenase inhibitors (IC50: 50% inhibitory concentration) is expressed as that concentration of compound that inhibits a known (standard) concentration of enzyme by 50%. The compounds of Examples 2-12 had IC50 values in the range 2.3 x 10~ 6 - 1.3 x 10 "8 M.

Claims: Claims: A compound of the formula (I) or a salt thereof in which, R-*_ is -(CH 2 ) n -W where n is 0-6 and W is amino, optionally-substituted phenyl, -CONRsR , -NRsCORg, R5C0 2 CH 2 R or NRsCONRsR where R5 is hydrogen or C]__g alkyl and Rg is hydrogen, C ] __g alkyl, optionally-substituted phenyl or heteroaryl, or R5 and Rg together with the nitrogen atom to which they are bonded form a 5-, 6- or 7- membered ring with an optional oxygen or sulphur atom or an optionally substituted second nitrogen atom in the ring; or is -S(0)p-R7 where p is 0, 1 or 2 and R7 is Cι_galkyl; or W is a group of sub-formula (a) , (b) , (c) or (d) : (a) (b) where in sub-formula (a) , (b) and (c) A represents an optionally-substituted mono or bicyclic aryl or heteroaryl ring, and in sub-formula (c) and (d) q is an integer from 1 to 3; R2 is C3_g alkyl; R3 is hydrogen, Cχ_galkyl, -CH2-Z where Z is optionally substituted phenyl or heteroaryl, -(CH ) r NRgRg, -(CH 2 ) r NHCOR 10 , -(CH 2 )r^llC(=N l2) RgRg, -(CH2) r CONH(CH 2 ) s NR 8 Rg or -(CH2) r - R 13 where r is 1 to 6, s is 2 to 4, each of Rg and Rg is independently hydrogen or Cχ_galkyl or Rg and Rg together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-membered ring with an optional oxygen or sulphur atom or an optionally substituted second nitrogen atom in the ring, R-^Q i Cι_galkyl or -(CH2)t NR 8 R 9 where t is 1 or 2 and Rg and Rg are as defined above, R ι is hydrogen or C _galkyl or R ι and Rg, together with the nitrogen atoms to which they are bonded, form an optionally substituted 5-, 6- or 7-membered ring, R 2 s hydrogen or Cχ_galkyl and Rχ3 is an optionally substituted piperidyl ring or R3 is a group: -CH-0-R 14 where R 4 is hydrogen, C _galkyl or optionally substituted benzyl and R 5 is hydrogen or Cχ_galkyl; and R4 is hydrogen, C _galkyl or -(CH 2 ) r NRgRg in which r, Rg and Rg are as defined for R3; or R3 and R4 are joined together as -(CH2) m - where m is an integer from 4 to 12, or R3 and R4 are joined as -(CH2) x - R -(CH2)y~ where x is an integer from 1 to 9, y is an integer from 2 to 10, and the moiety -(CH2) X - is adjacent to the carbon atom bearing R3 marked with an asterisk in formula (I) , and R-*_g is selected from hydrogen, C-^-galkyl, C2-galkanoyl, Cχ_galkoxycarbonyl, aroyl, aralkyl or aralkyloxycarbonyl in each of which the aryl moiety is optionally substituted. 2. A compound according to claim 1 in which R**_ is 2- hydroxyphenyl, -(CH 2 ) n -w where n is 2 and W is amino, phenyl, 2-hydroxyphenyl, NHCθ2CH2Ph, N-phthalimido, 4-bromo- 1, 8-naphthalenedicarboxamido, 7,9-dioxo-8- azaspiro[4,5]decyl, methylmercapto, methylsulphinyl or methylsulphonyl, or R__ is -(CH2) n - where n is 1, 2 or 3 and W is a 1, 8-naphthalenedicarboxamido group. 3. A compound according to claim 1 or 2 in which R2 is n- butyl, iso-butyl or sec-butyl. 4. A compound according to any one of claims 1 to 3 in which R3 is benzyl, C*_galkylamino, 4-methoxybenzyl, -(CH 2 )4NH2 or 3-indolylmethyl and R4 is methyl or -(CH2)2 NR 8 R 9 where Rg and Rg are both hydrogen or together with the nitrogen atom to which they are bonded, form a pyrrolidine or N-methylpiperazine group, or R3 and R4 are combined to form a group -(CH2)ιo~- 5. A compound according to any one of claims 1 to 5 in which the chiral centres marked with an asterisk in formula (I) have the (S)-configuration when R3 is other than hydrogen. 6. A compound according to claim 1 which is: N-[N-(1-phosphono-l-(2-hydroxyphenyl)methyl)-leucyl] -N,O-dimethyl-(S)-tyrosinamide, N-[N-(l-ρhosphono-3-(l,8-naphthalenedicarboximide)propyl) - (S)-leucyl]-N,O-dimethyl-(S)-tyrosinamide, N-[N-(l-phosphono-3-phthalimidopropyl)-(S) -leucyl]-(S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-4-(1, 8-naphthalenedicarboximido)butyl) - (S)-leucyl]-(S)-phenylalanine-N-methylamide, N-[N-(l-phosphono-2-(1, 8-naphthalenedicarboximido)ethyl- (S) - leucyl]-(S)-phenylalanine-N-methylamide, N-[N-(l-phosphono-3-(1, 8-naphthalenedicarboximido)propyl) - (S)-leucyl]-(S)-phenylalanine-N-methylamide, N-[N-(l-phosphono-3-phenylpropyl)-(S)-leucyl]-(S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-3-(4-bromo-l,8-naphthalene- dicarboximido) ropyl)-(S)-leucyl]-(S)-phenylalanine methylamide, N-[N-(l-phosphono-3-(benzyloxycarbonylamino)propyl)-(S)- leucyl]-(S)-phenylalanine methylamide, N-[N-(l-phosρhono-3-(2-hydroxyphenyl) ropyl)-(S)-leucyl]-(S)- phenylalanine methylamide, N-[N-(l-phosphono-3-(methylmercapto)propyl)-(S)-leucyl]-(S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-3-(methylsulphinyl)propyl)-(S)-leucyl]-(S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-3-(methylsulphonyl)propyl-(S)-leucyl]-(S)- phenylalanine-N-methylamide, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S) tryptophan-N-methylamide, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl-(S)-lysine-N-methylamide, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(-)-aminoazacyclotridecan-2-one, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(aminoethyl) amide, N-[N-(l-phosphono-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(ethylpyrrolidine) amide, N-[N-(l-phosphόno-3-(1,8-naphthalenedicarboximido)propyl)- (S)-leucyl]-(S)-lysine-N-(ethyl-N-methylpiperazine) amide, N-[N-(l-phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl) ]- propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide, or N-[N-(l-phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl) ]- propyl)-(S)-leucyl]-(S)-lysine-N-methylamide, and pharmaceutically acceptable salts thereof. 7. A process for the preparation of a compound according to claim 1 which process comprises cleaving a group R20 from a compound of formula (II) :

Inventors: HUNTER DAVID JAMES, MARKWELL ROGER EDWARD, WARD ROBERT WILLIAM, HUNTER, DAVID, JAMES, MARKWELL, ROGER, EDWARD, WARD, ROBERT, WILLIAM
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1992
Main classification: C07K5
IPC codes: A61K38, A61P29, A61P43, C07K1, C07K5, C07K14, C12N9