PHOSPHOROUS CONTAINING COMPOUNDS AS INHIBITORS OF ENKEPHALINASES

Abstract: Compounds having the general formula in which W is R′ or OR′, R′ being hydrogen, alkyl, phenyl or benzyl X is (CH₂) p -CHR³ or CHR³-(CH₂) p - R₃³ is ohosen from various substituents, Y is -NH-, -NH-, -NH -NH, or -NH-O-, Z is chosen from various of organic groups, and R₂ forms, with the carbonyl group to which it is attached, car­ boxy or various esterified carboxy groups or is the group -NR⁸R⁹. The compounds inhibit the activity of etikephalinases. Intermediates of formula (Wa)₂-Xa-Ya are disclosed in which Wa is alkoxy, phenoxy or benzyloxy and Ya is -NH₂ or -NCO.

Description: PHOSPHOROUS CONTAINING COMPOUNDS AS INHIBITORS OF ENKEPHALINASES Enkephalin is a natural opiate receptor agonist and is believed to be a mixture of two pentapeptides: H-Tyr-Gly-Gly-Phe-Met-OH (methionine-enkephalin), and H-Tyr-Gly-Gly-Phe-Leu-OH (leucine-enkephalin). Hereinafter, the name enkephalin is used generically to embrace all such compounds. It has been reported by Beluzzi et al., Nature, 260, 625 (1976), that when enkephalin is injected into the brain ventricle of rats, a profound analgesia is obtained. It is also know in the art that enkephalin is acted upon by a group of enzymes known generically as enkephalinases, which are also naturally occurring and is inactivated thereby. The present invention is aimed at providing compounds capable of inhibiting the action of enkephalinases. European Patent Applications Nos. 81102770.5, 82108858.0, and 82402314.7 (publication Nos. 38046, 75334 and 820088, respectively) disclose certain phosphorous containing compounds which are described as possessing enkephalinase-inhibiting activity. The present invention provides compounds having the general formula EMI2.1 wherein R1 is hydrogen, alkyl having from 1 to 6 carbon atoms, EMI2.2 in which A is hydrogen, halogen, hydroxy, nitro, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms, 2- or 3- thienyl or phenyl which may be substituted with halogen, hydroxy, nitro, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, or alkyl having from 1 to 6 carbon atoms ; W is R1 or OR1 wherein R1 is as defined above ; ; X is - (CH2) p-CHR3 - or - -CHR3 - (CH2)p - wherein p is O or I, and R3 is 2- or 3-thienylmethyl, 3-indolylmethyl, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, EMI3.1 in which A is as defined above, Y is EMI3.2 Z is o-, m-. or p-phenylene, -(CHR4) r [wherein r 4 is 1,2,3, or 4 and R is independently chosen from hydrogen, alkyl having from 1 to 6 carbon atoms, hydroxy, alkoxy having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, 3-indolylmethyl, hydroxymethyl, 2-(methylthio)ethyl, EMI3.3 in which A is as defined above) or -Bq-B'-B"- [wherein q is O or 1, one of the groups, B, B' or B" is EMI3.4 in which A is as defined above and the remaining B, B' and/or B" is -CH2-], [with the following provisos : when W is OR1 and Y is -NHCO-, r mav not be 1: when Y is EMI3.5 r cannot be 1; when Y is Z may also be -CRa=CRb wherein Ra and Rb may be the same or different and are chosen from hydrogen, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, 3-indolylmethyl, hydroxymethyl, 2-(methylthio)ethyl, or together with the carbon atoms to which they are attached form a cycloalkenylene ring having from 5 to 8 carbon atoms; ; R2 is hydroxy, alkoxy having from 1 to 6 carbon atoms, EMI4.1 therein s is 0,1,2, or 3] EMI4.2 therein R5 and R may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms, and R7 is EMI4.3 or alkyl having from 1 to 6 carbon atoms, EMI4.4 [wherein t is 1 or 2], EMI5.1 [wherein u is 1 or 2], EMI5.2 or NR 8R9 wherein R8 is EMI5.3 R9 is hydrogen or alkyl having from 1 to 6 carbon atoms, and wherein A in the groups defined for R2 is as defined above; or a pharmaceutically acceptable salt thereof, in non sclvated form or a solvate thereof with a pharmaceutically acceptable solvent. As sed herein, unless stated otherwise, the terms alkyl ana alkoxy denote such groups having straight or branched carbon chains of from 1 to 6 carbon atoms. Halogen includes fluorine, chlorine, bromine and iodine. Preferred values for the above defined groups are: R1 is hydrogen, methyl, ethyl, phenyl or benzyl; R2 is hydroxy, methoxy, ethoxy, phenoxyethyloxy pivaloyloxymethyloxy, EMI6.1 or EMI6.2 W is hydroxy, ethoxy, methyl, or benzyl; X is EMI6.3 wherein A1 is hydrogen, phenyl, fluorine, chlorine or trifluoromethyl; Y is as defined above; Z is p-phenylene, or -CH2CHR41-, wherein R41 id hydrogen, hydroxy, me thoxy, methyl or benzyl; A is phenyl, hydrogen, fluorine or chlorine The most preferred values for such groups are: R1 is hydrogen; R2 is hydroxy, methoxy, ethoxy, phenoxyethyloxy EMI7.1 W is hydroxy; X is EMI7.2 wherein A1 is as defined above; Y is 41 41 Z is p-phenylene or -CH2CHR r wherein R is as defined above. Examples of preferred compounds having structural formula I are: N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss alanine N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss alanine ethyl ester N-[3-(1,1'-biphenyl-4-yl)-1-oxo-2-(phosphonomethyl)- propyl]-ss-alanine N-[3-(4-chloro)phenyl-1-oxo-2-(phosphonomethyl)propyl] ¯-alanine N-[3-(4-chloro)phenyl-1-oxo-2-(phosphonomethyl)propyl]- B-alanine ethyl ester N-[3-(4-fluoro)phenyl-1-oxo-2-(phosphonomethyl)propyl] B-alanine 3-[3-(1,1'-biphenyl-4-yl)-1-oxo-2-(phosphonomethyl)- propyl) amino-2-methylpropanoic acid 3-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2methylpropanoic acid 3-[3-(4-chloro)phenyl-1-oxo-2-(phosphonomethyl)propyl] amino-2-methylpropanoic acid 3-[3-(4-fluoro)phenyl-1-oxo-2-(phosphonomethyl)propyl]amino-2-methylpropanoic acid 4-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]aminobutanoic acid 4-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]aminobenzoic acid N-[1-oxo-3-phenyl-2-phosphonopropyl]-ss-alanine 3-oxo-3-[2-phenyl-1-(phosphonomethyl)ethyl]aminopropanoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]aminobutanoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]amino-Z2-butenoic acid 4-oXo-4-[2-phenyl-1-(phosphonomethyl)ethyllamino-E- 2-butenoic acid 4-[2-(1,1'-biphenyl-4-yl)-1-(phosphonomethyl)ethyl] amino-4-oxobutanoic acid 4-E2-(4-fluoro)phenyl]-1-(phosphonomethylwethyllamino- 4-oxobutanoic acid N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyllglycine N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl]alanine <RTI ID=8.6> N-[2-phenyl-1-(phosDhonomethyl)ethylaminocarbonyl]- ss-alanine N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl]- phenylalanine 4-[2-phenyl-1-(phosphonomethyl) ethylaminocarbonyl]aminobenzoic acid 2-[2-phenyl-1-(phosphonomethyl) ethyl aminoccarbonyloxyacetic acid 2-[2-phenyl-1-(phosphoomethyl)ethyl] aminocarbonyloxypropanoic acid 3-[2-phenyl-1-(phosphonomethyl)ethyl]aminocarbonylOxy- propanoic acid 4-[[2-phenyl-1-(phosphonomethyl)ethyl] aminocarbonyl]benzoic acid 3-[[2-phenyl-1-(phosphoomethyl)ethyl] aminocarbonyl]benzoic acid 2-[[2-phenyl-1-(phosphonomethyl)ethyl[aminocarbonyl]- benzoic acid N-[2-(Butylhydroxyphosphinyl)methyl-l-oxo-3-phenylpropyl -ss-alanine N-[2-(Butylhydroxyphosphinyl)methyl-l-oxo-3-phenylpropyl -ss-alanine Ethyl Ester N-[1-oxo-2-phosphonomethyl-3-(2-thienyl)propyl]-ssalanine N-[l-Oxo-2-phosphonomethyl-3-(3-thienyl)propyl]-ss- alanine N-[3-(3-IndOlyl)-l-oxo-a-(phosphonomethyl)propyl]-ss- alanine N-[1-Oxo-2-(phosphonomethyl)hexyl]-ss-alanine N-[3-Cyclohexyl-1-oxo-2-(phosphonomethyl)propyl]-ssalanine N-(2-Cyclohexyl-1-oxo-2-(phosphonomethyl)ethyl]-ssalanine N-[2-(4-Chloro)phenyl-l-oxo-a-(phosphonomethyl)ethyl]- i3-alanine 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2hydroxypropanoic Acid 3-[1-Oxo-3-phenyl-2-(phsophonomethyl)propyl]amino-2methoxypropanoic Acid N-[l-Oxo-3-phenyl--2-(phosnhonomethyl)propyl]-ss-alanine Piyaloyloxymethyl Ester N-]1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2-Phenoxyethyl Ester N-[l-Oxo-3-phenyl--2-(phosphonomethyl)propyl]-ss-alanine 4-Bromophenacyl Ester No[l-exo-3-phenyl-a-(phosphonomethyl)propyl]-ss-alanine 2, 3-Dihydroxypropyl Ester N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2-Naphthyloxyethyl Ester N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine Phthalidyl Ester N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2-Methylphenylamide N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2,3-Isopropylideneglycerol Ester 4- [l-Oxo-3-phenyl-2- (phosphpnomethyl) propyl) aminobenzoic Acid Ethyl Ester N-[a-oxo-2-phosphonomethyl-3-(4-trifluoromethyl)phen propyl]-ss-alanine N-[l-Oxo--2-phosphonomethyl-3-(4-trifluoromethyl)phenyl- <RTI ID=11.10> propyl)-J3-alanine Ethyl Ester N-[2-(n-Butoxyhydroxyphosphenyl)methyl-1-oxo-3-phenyl propyl]-ss-alanine Ethyl Ester 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl [amino-2 hydroxymethylpropano ic Acid 3-[l-Oxo-3-phenyl-2-(phosphonomethyl)propyllamino-2 cyclo-propylpropanoic Acid 3-[1-Qxo-3-phenyl-2-(phosphonomethyl)propylJamino-2- (cyclopropyl) methylpropanoi c Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 (3-indolyl)methylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyllamino-2- (2-methylthio)ethylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phospllonomethyl)propyl3amino-2- phenylpropanoi c Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl) propyl]amino-2 (4-chloro)phenylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphoomethyl)propyl]amino-2 (phenyl) niethylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propylÇamino-2- ((4-chloro)phenyl)methylpropanoic Acid N-[2-(Benzylhydroxyphosphinyl)methyl-l-oxo-3-phenylpropyl]-ss-alanine N-[2-(Benzylhydroxyphosphinyl)methyl-1-oxo-3-phenylpropyl]-ss-alanine Ethyl Ester 1-[-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminomethyl-3,4-benzo-cyclopentene-1-carboxylic Acid 1- [2- [1-Oxo-3-phenyl-2- (phosphonomethyl) propyl] amino] ethyl-3,4-benzocyclopentene-1-carboxylic Acid 2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminomethyl-3-phenyl-Z-2-propenoic Acid 2-[2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino] ethyl-3-phenyl-Z-2-propenoic Acid 2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino] <RTI ID=13.3> ethyl-3-phenyl-Z-2-propenoic Acid 3-(1H-Benzimidazol-2-yl)-2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminomethyl propanoic Acid 2-(lH-Benzimidazol-2-yl)-4-[1-Oxo-3-phenyl-2-(phospho- nometNyl) propyl] amino butanoic Acid A second aspect of the present invention comprises compounds having the structural formula Ia: EMI14.1 wherein Wa is alkoxy having from 1 to 6 carbon atoms, phenoxy or benzyloxy; Xa is EMI14.2 wherein A is de fined herein; Ya is -NH2 or -NCO, such compounds being novel intermediates useful in the preparation of compounds of the present invention. Certain compounds having formula I may contain (CHR4)r moieties wherein the R4 group may be chosen independently from those listed above. For example, when r equals 3 the substitution may be arranged as follows: EMI15.1 EMI15.2 in which, when two or more R4 substituents are present they may be the same or different; for instance groupings such as EMI15.3 EMI16.1 Compounds having structural formula I wherein R2 is hydroxy, form salts with pharmaceutically acceptable bases. Sodium, potassium and calcium hydroxide as well as sodium and potassium carbonate are examples of suitable bases for this purpose. In addition, salts formed with pharmaceutically acceptable amines such as for example ammonia, N-methylglucamine, ethanolamine, diethanolamine, lysine and arginine are also contemplated. Certain of the enkephalinase inhibiting compounds of the invention form solvates with, for example, pharmaceutically acceptable solvents such as water and ethyl alcohol. In formula I, certain atoms may be asymmetric (chiral) centers. Such centers will be readily apparent to those skilled in the art. The present invention contemplates all isomers at these centers both in stereochemically pure form and in admixture. The compounds having structural formula I and their pharmaceutically acceptable salts inhibit the activity of enzymes designated enkephalinases. The compounds are particularly useful for the inhibition of enkepha linase A. In in vitro tests, selected compounds having structural formula I in a concentration range from 10 to 10 M have been found to inhibit the activity of the aforementioned enzyme by 50% or more. The present invention thus includes within its scope pharmaceutical compositions containing an enkephalinaseinhibiting effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. Such pharmaceutical composition may be made up in dosage forms known in the art such as tablets, capsules or elexirs for oral administration, or in sterile solutions or suspensions for parenteral or transdermal administration. Typically a compound of formula Ior pharmaceutically acceptable salt thereof will demonstrate an enkephalinase inhibiting effect when administered in a preferred dosage range from about 0.01 to about 100 mg/kg body weight. The dosages are to be administered at intervals of from 3 to 8 hours. However, the quantity and frequency of dosage will depend upon such factors as the severity of the pain, the general physical condition of the patient and other factors which a physician will recognise. The compounds of formula I, their salts, and solvates thereof, can be prepared by a process characterized in that A) to produce a compound of formula I in which Y is EMI18.1 a compound of formula XX is condensed with a compound of formula XXI EMI18.2 m) to produce a compound of formula I in which Y is EMI18.3 a compound of formula XXII is reacted with 2 compound of formula XXIII EMI19.1 C) to produce E compound of formula I in which Y is EMI19.2 a compound o- formula XXIV is reacted with a compound of formula XXV EMI19.3 D) to produce a compound of formula I in which Y is EMI19.4 a compound of formula XXVI is reacted with a compound of formula XXVII EMI19.5 E) to produce a compound of formula I in which at least one of W, OR1 and R2 is hydroxy, a compound having the formula XXVIII EMI20.1 in which ' is R1 as defined in above or is an esterified hydroxy group which may be the group ORI, OR" is hydroxy or an esterified hydroxy group which may be the group OR1, R2' is hydroxy, -NR8R9 as defined above, or an esterified hydroxy group which may be an esterified hydroxy group as defined for Rê above, at least one of W', OR' and Rê' being an esterified hydroxy group, is subjected to a de-esterification reaction whereby at least one esterified hydroxy group W', OR" or OR2 (and essentially any esterified hydroxy group not being as defined by W, OR1 or R2 above), is converted to hydroxy, so as to produce a compound of formula I, in which at least one of W, OR1 and R2 is hydroxy; F) to produce a compound of formula I in which at least one of W, OR1 and R2 is an esterified hydroxy group, a compound of formula I as defined above, in which at least one of the group W, OR1 and R2 is a hydroxy group, is subjected to an esterification reaction whereby at least one such group is converted to an esterified hydroxy group as defined by W, OR1 or R2 respectively above. wherein in the above process A to F W,X,Y,Z,R1 and R are as defined above, and any functional groups are protected if necessary or desired, said process A,B,C, D,E or F being followed by removal of any protecting groups, if necessary or desired, from the resulting compound of formula I, and isolation of the compound of formula I as such or as a pharmaceutically acceptable salt, in non-solvated form or as a solvate with a pharmaceutically acceptable solvent. Processes A and D will generally be carried out by reacting compound XX with compound XXI, and compound XXVI with compound SXYII respectively, using standard, art recog nized coupling methods. Coupling procedures have been reviewed in, for example, "The Peptides: Analysis Synthesis Biology", Viol. 1 (Major Methods of Peptide Bond Formation), E Gross and J. Meienhoffer eds. Academic Press 1979. For example the condensation may be carried out in a suitable solvent for example an aprotic solvent e.g. N, dimethyl formamide preferably under an inert at mosphere using a condensing agent such as dicyclo hexylcarbodiimide or diphenylphosphenyl azide. Processes R and C will generally be carried out by con tacting compound SXII with compound XXIII, and compound XXIV with. compound XXV respectively, in a non-reactive solvent, for example dichloromethane or ethyl acetate at a temperature ranging from ambient to reflux temperature. The de-esterification procedures (process E) can be carried out according to art recognized procedures to effect preferential and/or sequential removal of ester groups so as to permit partial or complete ester hydro lysis. Preferably the de-esterification will be carried out on an ester compound as defined by formula I above. The preferential removal of ester groups are illustrated in the following diagram for the compound of formula I shown, in which C7H7 indicates the benzyl group. The skilled man will appreciate procedures illustrated and other art recognized procedures can be used to effect de-esterification of other ester derivatives of compounds of formula I EMI23.1 In this procedure compound XXX is subjected to catalytic reduction using a palladium on carbon catalyst in the presence of hydrogen under pressure using a suitable solvent e.g. ethanol. EMI23.2 In this reaction the compound XXX is contacted with potassium fluoride and 18-crown-6 in the presence of dioxane and with the addition of sodium hydroxide. The reaction is generally carried out at elevated temperature e.g. at reflux EMI24.1 In this reaction the ester XXX may be treated with hydrogen bromide in acetic acid, generally under an inert atmosphere, at ambient temperature. EMI24.2 This de-esterification may be carried out by treating the compound XXX with bromotrimethylsilane. The reaction will generally be carried out under an inert atmosphere at ambient temperature. Esterification of compounds of formula I in which W, OR1 and/or R2 are hydroxy can also be carried out using readily available art recognized methods, for example by converting the respective hydroxy group to an activated ester group e.g. a chloride, at elevated tempe rature, followed by reaction of the resulting compound in the presence of an organic base, with an alcohol R'OH or R2H, so as to give the desired ester. Salts of compounds of formula I may be formed by conventional means, such as by reacting the free acid or free base forms of a compound of formula I with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin. A compound of formula XX in which,in moiety X, p is O may be prepared for e:ça=.ple, by reacting a compound having structural formula II with a compound having structural formula III to produce a compound having the structural formula IV. This reaction proceeds efficiently in the presence of a base such as, for example, a metal alkoxide, or sodium hydrioe. EMI26.1 In the above formulas W, Rl and P3 have the meanings as herein defined, R may be any convenient alkyl group or a functionally equivalent group such as a benzyl group and L is a suitable group, leaving under the conditions of the reaction. Useful leaving groups are for example, halogen such as bromine or iodine and sulfonic acid ester groups such as p-toluenesulfonyloxy, trifluoromethylsulfonyloxy and the like. The product of this reaction, compound IV, may be converted to its corresponding free carboxylic acid (R=E) by any of a variety of methods known to those skilled in the art which differentiate between types of esters. For example, when R is benzyl and R1 is ethyl, R can be removed selectively by catalytic hydrogenation. Compounds of formula XX in which, in moiety X, p is 1 may be prepared by reacting a compound having structural formula II with a 2- or 3- substituted acrylic acid derivative, respectively compound VI or VII, EMI27.1 to produce the corresponding compounds respectively VIII or IX. The substitutents W, R1, R3 and R are as previously defined. For example, when W=OEt, R1=Et and R=R3 = benzyl this reaction may be carried out, by use of sodium hydride in toluene at ambient or reflux temperature. The products VIII or IX may then be converted to the free carboxylic acids (R=H) by, for example, the procedures menmentioned above. In an alternate method, a substituted propionic acid derivative XI or XII, L-CH2CHR3C02R L-CHR3CH2C02R XI XII may be condensed with II to produce, respectively, compound VIII or IX. Substituents L, R3 and R are as defined hereinabove. This reaction may be carried out in substantially the same manner as described above for the reaction of compounds II and III. Alternate processes for the synthesis of compounds IV, VIII and IX have been described in, for example Houben- Weyl's Methoden der Organischen Chemle, Vol. XII, part I (1963), and part II (1964). Compound XXII (including compounds of formula Ia, in which Ya is N:C:O) may be prepared from the corresponding com pound IV or VIII when R is H by, for example, the Curtius or Lossen rearrangement of the corresponding IVa,IVb and VIIIa or VIIb, respectively. EMI28.1 x=CHR3, IVb; x=CH2CHR3, VIIIb Generally the Cutuis rearrangement may be carried out by heating the acylazide IVa or VIIIa in a non-reactive solvent, for example benzene or toluene; the heating will usually be carried out until nitrogen evolution ceases. The rearrangement and reaction conditions therefor are described in "The Chemistry of the Azido Group" S. Patai, ed., pp 397-405, Wiley-Interscience, New York, 1971. The Loosen rearrangement can be carried out according to process conditions described in e.g. "Chemical Reviews", Viol. 58, p. 374 FF. (1958) and the various references cited therein. The conversion of compounds IV and VIII into IVa or YIIIa and IVb or ErIIIb can be accomplished by a variety of methods known to those of ordinary skill in the art. Some of these are described in, for example, the multi-volume series "Reagents for Organic Synthesis" originated by Fieser and Fieser. Compounds XXVI (including compounds of formula Ia, in which Ya is NH2) may be prepared by hydrolysing the correspondingly substituted compound having structural formula XIII. Such hydrolysis may be accomplished by treatment of compound XIII with a dilute aqueous acid, e.g. aqueous HCl. The compounds having structural formula XXVII are either known in the art or preparable by known procedures. All possible isomeric forms and mixtures thereof of the above described reactants end products are contemplated. For example, the cis and trans isomers of compound VII are intended to be included, as are the possible cis and trans isomers of compounds wherein Z is defined as One of ordinary skill in the art, will appre- ciate that not all of the compounds of this invention mav be readily prepared by any one process.However,it will be apparent that by selecting a particular process from those set forth above, all of the compounds of this invention may be prepared. Further, 2 number of the intermediates for preparing the compounds of this invention are commercially available or they may be readily prepared by art recognized methods, or by the method of the present invention described herein. Thtermediates for preparing the compounds of this invention are described or the preparation thereof is embodied in the following publications: a. Reaction of trialkylphosphites with c,- unsaturated acids, Izv. Akad. Nauk S.S.S.R, Ser. Khim., 1259 (1971) ; b. Reaction of trialkylphosphites with a,- unsaturated esters, Bull. Chem. Soc. Japan, This . 303 (1981), Chem. Letters, 1265 (1981); c. Reaction of metal (sodium) dialkylphosphonates with &alpha;,ss-unsaturated esters, J. Org. Chem., 37, 4396 (1972); d. Reaction of phosphinate compounds with an ,B-unsaturated acid chloride, Zh. Obshch. Khim., 40,(9), 1995 (1976); e. Preparation of phosphonite half esters, Chem. Ber., 93, 1220 (1960); f. Hydrolysis of phosphonate esters, Synthesis, 409, 412 (1982); g. Curtius rearrangement of acyl azides, Int. J. Peptide Protein Res., 21, 258 (1983). h. Cleavage of alkyl phosphonate esters using bromo trimethylsilane, J. Chem. Soc Chem. Commun. 739(1979). EXAMPLE 7 N-rtR,S)-2-(Diethoxyphosphinyl)methyl-1-oxo-3-phenyl- propyl-fS-alanine benzyl ester A. 2-Benzylacrylic acid benzyl ester To a cooled solution (ice bath) of 2-benzyl-acrylic acid (24.0 g, 0.148 mole) in 200 ml benzyl alcohol under an inert atmosphere add dropwise 25 ml (0.343 mole) of thionyl chloride. After stirring for i5 minutes in the ice bath, heat the reaction mixture at 60-70 C. for five hours. Remove excess thionyl chloride under vacuum and distill the residue under reduced pressure: yield 22.0 g (59%). b.p. 130-135 C (0.26 mm Hg). PMR (CDl3, ppm relative to TMS internal standard): 3.53 (s,2H); 5.14 (s,2H); 5.47 (broad s,1H); 6.27 (broad s, 1H) ; 7.25 (broad s,5H); 7.32 (broad s,5H). IR 1715 cm-1, 1640 cm Mass Spectrum m/e 252 (M+). B. Benzyl (R,S)-2-(Diethoxyphosphinyl )methyl-3-phenyl- propanoate In a 500 ml 3 neck round bottomed flask fitted with addition funnel and N2 inlet place 0.20 g of 50% NaH in mineral oil (0.10 9, net, 4.16 mmoles), which then wash with 3 volumes (20 ml) of hexane. Introduce 200 ml toluene, then, dropwise, 12.1 ml of diethyl phosphite (13.0 9. 94.2 mmoles). Stir for 30 minutes, then add dropwise 21.5 g (113 mmoles) 2-benzylacrylic acid benzyl ester. Stir the reaction at ambient temperature for 45 minutes. Quench the reaction by adding 5.0 ml acetic acid, filter and concentrate to obtain 31.9 g of a syrup. Conduct thin layer chromatography on silica gel using 60% ethyl acetate in hexane whereupon a single compound is indicated having Rf 0.3. IR (FT, nujol mull, cm 1740 (s), 1600 (w), 1250 (s), 1060 (s), 1030 (s). PMR (CDC13, ppm relative to TMS internal standard): 1.26 (doublet of t, 6H, JH, H=7.5Hz, JH, H=7.5Hz, JH, P=2Hz) ; 5.08 (s,2H); 7.0-7.5 (m, 10H). CMR (CDCl3, ppm relative to TMS Internal standard) 1636(CH3, Jccop 6.21Hz) ; 27.20 (PCH2, Jpc=142.3Hz) ; 39.55 (CH, Jpcc = 13.10Hz); 42.04 (CH2Ar, J =3.67Hz); 64.08 (CH2, pccc J =6.34Hz); 66.61 (OCH2); 166.8 (COO); 174.0 (CON, cop Jpccc=6.9Hz). Mass Spectrum : m/e 390 (M+). C. (R,S)-2-(Diethoxyphosphinyl )methyl-3-phenylpropa- noic Acid Using a Parr Hydrogenation apparatus, hydrogenate 29.9 9 (76.7 mmoles) of the benzyl ester prepared in part B above, dissolved in 150 ml of methanol using 3.8 g of 10% Pd on carbon and a 3.45 bar pressure of hydrogen for 2.5 hours. Filter the catalyst through diatomaceous earth such as Celite (Trade Mark), and evaporate the solvent to obtain 23.3 c of an oil. IR (FR, nujol mull, cm-1) : 2900-2050(m), 1735(s), 1200!s), 1050(s). PMR (D6-GMSO, ppm relative to TMS Internal standard): 1.21 (t, 6H, JH JH,H=7.5Hz) ; 1.4-2.15 (M, 3H); 2.83 (m, 2H); 3.92 (m, 4H, JH,H=7.5Hz, J,p=2Hz); 7.20 (broad s, 5H). 13CMR(CDCl3, ppm relative to TMS Internal standard): 16.26 (CH3, Jccop=5.98Hz)s 26.55 (PCH2, Jpc=142,4Hz) ; 39.13 (CH, Jpcc=13.95Hz) ; 41.67 (CH2Ar, Jpccc=3.61Hz) ; 62.22 (CH20, '3 =6.56Hz); 126.7, 128.5, 129.2. 131.0 cop (Ar) ; 177 (CO, Jpccc=6.12Hz). Mass Spectrum : m/e 300 (M+). D. N-[(R,S)-2-(diethoxyphosphinyl)methyl-1-oxo-3 phenylpropyl-f3-alanine Benzyl Ester To a mixture of 3.00 g (10.0 mmoles) (R,S)-2-(diethoxy phosphinylmethyl)-3-phenylpropanoic acid, 3.51 g (10.0 mmoles) ss-alanine benzyl ester (p-tosylate salt), 3.06 g (20.0 mmoles) l-hydroxybenzotriazole (HOBT), and 1.39 ml (1.01 g, 10.0 mmoles) triethylamine (Et3N) in 50 ml of N,N-dimethylformamide (DMF), under an inert atmosphere and cooled with an ice water bath, add 1.92 g (10.0 mmoles) l-(3-dimethylaminopropyl)-3-ethyl-carbo- diimide hydrochloride (EDCI) and 1.39 ml triethylamine. Allow the reaction to warm up to room temperature and stir for 16 hours. After dilution with 100 ml ethyl acetate (EtOAc) wash the mixture in succession with saturated NaHC03 (50 ml), 1N citric acid (50 ml), saturated NaHC03 (50 ml), saturated NaCl (50 ml) and dry the organic solution with MgS04. Evaporate the solvent to obtain an oil, which purify by flash chromatography [0. Org. Che. 43, 2923 (1978)3 on SiO2 (4% CH3OH in CHCl3) to yield 2.4 g of oily product (52%). Analysis for C24H32N06P: 61.63% C; 6.81% H; 2.84% N (calculated 62.46%C; 6.77% H; 3.04% N). EXAMPLE 2 N-[(R,S)-1-Oxo-3-phenyl-2-(phosphonomethyl)propyl] B-alanine Add a solution (20 ml) of 33% HBr in acetic acid (HOAc) to 1.3 g (2.8 mmoles) of N-[(R,S)-2-diethoxy-phosphinyl)- methyl-1-oxo-3-phenylpropyl]-ss-alanine benzyl ester, under a nitrogen atmosphere, Stir the resulting solution at room temperature for 16 hours. Evaporate the solvent, and excess HBr under reduced pressure, then triturate with ether to afford a yellow solid. Recrystallize from water to obtain 0.66 g (75%) of a colourless solid, m.p. 132-136 C. Analysis for C13Hl8NO6P. H20: 47.28% C; 5.83% H, 4.04%N (calculated 46.85% C; 6.05% H; 4.20% N). EXAMPLE 3 N-[(S)-2-(Diethoxyphosphinyl)methyl-1-oxo-3-phenyl propyl3-ss-alanine Benzyl Ester A. Ethyl (R,S)-2-(Diethoxyphosphinyl)methyl-3-phenyl propanoate In a 2 1 3-neck round bottomed flask fitted with addition funnel and nitrogen inlet place 1.26 g of 50% NaH in mineral oil (0.63 g, net, 0.0263 mole), which then wash with 3 volumes (30 ml ) of hexane. Introduce toluene (1.2 l),then dropwise 74.5ml (79.9 g, 0.579 mole) of dimethyl phosphite. After stirring for 30 minutes add, dropwise, 100 g (0.526 mole) of 2-benzylacryclic acid ethyl ester unprepared as in, for example, Chem. Ber., 57, 1116 (1924)] at such a rate as to maintain the reaction temperature below 45 C. After the addition, allow the reaction to stir at room temperature for an additional 45 minutes. Quencn the reaction by adding 4 ml of glacial acetic acid. Filter and concentrate in vacuo to obtain a syrup (181 g), in which a small amount of diethylphosphite is retained. IR (FT, neat, cm 1): 1745 (s), 1600(w), 1250(s), 1030(s). PMR (CDC13, ppm relative to TMS Internal standard): 1.28 (t,3H,JHH=7.5hz); 1.3. (doublet of t, 6H, 'JMM= 8Hz, JHp=2Hz); 2.0(m, 3H, PCH2, CH); 2.95 (m,2H,CH2Ar); 4.00 (q,2H,J=7.5Hz); 4.05 (m,4H,JHH=8Hz, JHp=2Hz); 7.22 (m,5H,Ar). Mass Spectrum: m/e 328 (M+). B. (S)-2-(DiethoxvDhosDhinyl)methYl-3-phenylDroDanoic acid Method 1 SteD 1 In a 4 1., 3 neck round bottomed flask fitted with a magnetic stirrer, pH probe, and a piece of small diameter Teflon (Trade Mark) tubing (NaOH inlet), suspend 21.3 g (54.6 mmoles) of benzyl (R,S)-2- (diethoxyphosphinyl)methyl-3-phenyl-propanoate (Example I) in 2.0 1. of deionized water containing 1.4 g of bovine a-chymotrypsin, at ambient temperature. Adjust the pH of the medium and maintain at pH 7.2 to 7.4 by adding lN NaOH via a pH-controlling device. When the pH ceases to drop, add 200 ml of saturated NaCl and 500 ml of EtOAc and stir the mixture vigorously for 30 minutes. After separating the phases, dry the organic layer with Na2SO4, and concentrate to a mobile liquid, which purify on SiO2 by flash chromatography (using a mixture containing equal parts by volume ethylacetate/hexane) to yield 7.89g (74%) of pre dominantly benzyl (R)-2-(diethoxyphosphinyl)methyl 3-phenylpropanoate. [&alpha;]26D = -8.5 (C=1,CH3OH) SteD 2 Acidify the aqueous phase from step 1 to pH 1 with concentrated HCl, and filter through diatomaceous earth. Extract the resulting solution three times (150 ml each) with EtOAc, and after pooling the extracts dry them with Na2SO4 to obtain 7.38 g (90%) of (S)-2-(diethoxy-phosphinyl)methyl-3-phenylpropa- noic acid as a low melting solid. m-p- = 39-40 C. [&alpha;]26D = +8.9 (C=1,CHCl3). Analysis for C14 H21 PO5 : 55.71% C; 6.97S H (calculated 56.00% C; 7.05% H). Method 2 step I Suspend ethyl (R,S)-2-(diethoxyphosphinyl)methyl-3phenylpropanoate (173 g 0.53 mole) obtained from part A in 20 1. of deionized water containing 13.6 g of bovine a-chymotrypsin, at ambient temperature, using an overhead mechanical stirrer at medium speed. Adjust the pH of the reaction and maintain it at 7.2 to 7.4 by adding 2N NaOH with a pH controlling device. After 135 ml of base have been consumed, add 4 1 of ethyl acetate, and after stirring 30 minutes separate the phases. Dry the organic layers over Na2SO4 and evaporate the solvent to obtain 83.9 g (97%) of ethyl (R)-2-(di ethoxyphosphinyl) methyl-3-phenylpropanoate. [a)25D = 0 -18.0 (C=l, CHCl3). Step 2 Acidify the aqueous layer to pH 2.5 with concentrated HC1, and filter through Celite. Add 1 kg of NaCl and wash the clear solution twice with 4 l of EtOAc. Dry the organic phases with Na2SO4, and concentrate to obtain 79 g of a yellow oil, which solidifies on cooling. [a) 25D +8.9 (C=l, CHCl3), m.p. = 39-4O0C. C. N-[(S)-2-(Diethoxyphosphinyl)methyl-1-oxo-3 phenvl-propvll--alanine Benzyl Ester To a mixture of 7.80 g (26.2 mmoles) of (S)) -2-(diethoxyphosphinyl)methyl-3-phenylpropanoic acid, 9.22 g (26.2 mmoles) ss-alanine benzyl ester (p-tosylate salt), 8.04 g (52.5 mmoles) HOBT, and 3.65 ml (.26.2 mmoles) Et3N in 150 ml DMF, under an inert atmosphere and cooled with an ice-water bath, add 5.03 g (26.2 mmoles).of EDCI and 3.65 ml (26.2 mmoles) ht3N. Allow the reaction to warm up to room temperature and stir for 16 hours. Dilute with 250 ml EtOAc, then wash the mixture sequentially with saturated NaHCO3 (75 ml), 1N citric acid (75 ml), saturated NaHCO3 (75 ml), saturated NaCl (100 ml), and dry the organic solution with Na2SO4 Evaporate the solvent to obtain an oil, which purify on SiO2 by flash chromatography (1% CH3OH/CHCl3) 26 0 to yield 10.3 g (87X) of an oil. [a] D = 23.7 (c=l, CH3OH). IR (FT, neat, cm-1) : 3280 (m), 1740 (s), 1675 (s), 1550 (m), 1250 (s), 1060 (s), 1030 (s). 13CMR (CDCl3, ppm relative to TMS internal standard): 16.36 (CH3, J = ccop 6.07 Hz); 61.72 (CH2O, Jcop=6.22 Hz); 27.71(PCH2, J = 2 pc 140.3 Hz) ; 40.28 (CH, Jpcc=14.17 Hz) ; 43.71 (CH2Ar, J =3.07 Hz); 34.63(CH2CH2); 33.87(CH2CH2)i 66.39 pccc 2p (OCH2); 173.1 (CONH, J =6.13 Hz); 172.0 (COO). pccc Mass Spectrum: m/e 461 (M+). EXAMPLE 4 N-[(S)-1-Oxo-3-phenyl-2-(phosphonomethyl)propyl] ss-alanine calcium salt Add a solution (50 ml) of 33% HBr in HOAc to 9.30 g (20.0 mmoles) of N-[(S)-1-oxo-2-(diethoxyphos- phinyl)methyl-3-phenylpropyl]-a-alanine benzyl ester, under a N2 atmosphere. Stir the resulting orange solu tion at room tepmerature for 16 hours. Evaporate the solvent andexcess HBr (in vacuo) to obtain an oil, which dissolve in 50 ml of H2O and wash twice (50 ml) with ether. Evaporate the aqueous solution to obtain 7.4 g of an oil. Dissolve the oil in 300 ml of H2O, add 1.49 g of Ca(OH)2 and warm at 500C for a few minutes. Filter the resulting solution, concentrate it and tri turate with CH3OH to yield 5.84G (82%) of a white solid. [&alpha;]26D = 26.30 (c-l,lNHCl). m.p. > 2200C. Analysis for C13H16 NO6P.Ca.H2O : 41.66% C, 4.75%H ; 3.44 % N (calcu lated 42.052 C; 4.89%H; 3.77%N). IR (FT,nujol mull, cm-1) : 3280(m), 2800-2200(m), 1730(m), 1640(s), 1570(m,), 1060(s). 13CMR (DCI, ppm relative to TMS, dioxane internal standard)- : 29.66 (PCH2m Jpc=138.0 Hz) : 40.67(CH, 1 =15.41 Hz); 44.02 (CH2Ar, J =2.92 Hz); pcc 2 pccc 33.83(CH2CH2); 35.43(CH2CH2); 16.5 (CON, J = 6.49 Hz); 175.0 (COO). Mass Spectrum (FAB, Xe, glycerol): m/e 354 (M+ +1). EXAMPLE 5 3-[(S)-2-(Diethoxyphosphinyl)methyl-1-oxo-3-phenyl Dropvll-amino-2-(R,S)methvlropanoic acid benzvl ester A. Benzvl 3-.amino-2-(R,S) -methvloropanoate hydrochlor- ide salt To a cooled suspension of 10.0 g (97 mmoles) of (R,S)-P-aminoisobutyric acid in 150 ml of benzyl alcohol add,dropwise, 25 ml of ml of thionyl chloride, then heat for 5 hours at 55-65 C. Cool the solution, dilute with ether, and cool to -100C. Collect the white crystalline material to obtain 18.7 g (84%) m.p. 89-900C. Analysis for C11H15N02 .HCl.0.5(H2O) 55.60%C; 6.84% H; 6.13% N (calculated 55.35% C; 7.18% H; 5.87% N). Mass Spectrum: m/e 193 (M+). B. 3-[(S)-2-(Diethoxyphosphinyl)methyl-1-oxo-3-phenyl propyl]amino-2-(R,S)-methylpropanoic acid Benzyl Ester To a mixture of 3.00 g (10.0 mmoles) of (S) -2-diethoxyphosphinylmethyl-3-phenylpropanoic acid, 2.30 g (10.0 mmoles) benzyl 3-amino-2-(R,S)-methylpropanoate (hydrochloride salt), 3.06 g (20.0 mmoles) HOBT, and 1.39 ml (10.0 mmoles) Et3N in 50 ml DMF, under an inert atmosphere and cooled with an ice-water bath, add 1.92 g (10.0 mmoles) of EDCI and 1.39 ml (10.0 mmoles) Et3N. Allow the reaction mixture to warm up to room temperature and stir for 16 hours. After diluting with 100 ml EtOAc wash the mixture sequentially with saturated NaHCO3(50 ml), 1N citric acid (50 ml), saturated NaHCO3 (50 ml), and dry the organic solution with Na2SO4. Evaporate the solvent to afford an oil, which purify on SiO2 by flash chromatography (1%CH30H/ CHC13) to yield 3.53 g (74%) of product. [a) D26 20.40 (c=l, CH30H). IR(FT, neat, cm ): 3285(m), 1735(s), 1675(s),1555(m), 1250(s), 1060(s), 1030(s). PMR(CDC13, ppm relative to TMS internal standard): 0.94(d,1/2 of 3H, CH3, J=8 Hz); 1.08(d, 1/2 of 3H, CH3, J= 8 Hz); 1.28 (t,6H, CH3 ,J=7 Hz); 2.0 (m, 2H, CH2P); 2,85 (m, 5H, CH2Ar, NCH2, CH) ; 3.29 (m, 1H, CH) ; 3.99(m,4H,CH20,J=7 Hz); 5.07(d,2H,OCH2); 6.04 (m, 1H, NH) ; 7.16 (broad s, 5H, Ar); 7.45 (broad s, 5H, Ar).13CMR (CDCL3, ppm relative to TMS internal standard: 14.58, 14.93 (CH3) ; 16.36 (CH3, Jccop=6.1 Hz) ; 27.74 (PCH2, J =140.4 Hz); 39.40(signals for diasteromeric R pc alanine C's); 41.0(CH, J =18.0 Hz); 43.77 (CH2Ar, pcc J pccc=2.1 Hz); 61.73 (CH2OP, J =6.4 Hz); 66.36 cop (OCH2Ar); 172.6 (CONH, J=6 Hz); 174 (COO). Mass Spectrum: m/e 475 (M+). EXAMPLE 6 3-[(S)-2-(Diethoxyphosphinyl)methyl-1-oxo-3-phenyl propyl]amino-2-(R,S)-methylpropanoic acid calcium salt Add a solution (40 ml) of 33% HBr in HOAc to 3.5 g (7.37 mmoles) of the ester from Example 5, B., under a N2 atmosphere. Allow the resulting orange solution to stir at room temperature for 16 hours. Evaporate the solvent and excess HBr (in vacuo) to obtain an oil, which dissolve in 50 ml H2O, and wash twice (50 ml) with ether. Evaporate the aqueous solution to afford 2.4 g of a glassy material, which redissolve in 200 ml H20. To this solution add 0.585 g of Ca(OH)2 then warm it to 50 C. Filter and concentrate the solution, then triturate with CH3OH to obtain 1.61 g (61%) of a white powder. m-p. > 2000 C. [&alpha;]26D = 33.00 (c=l, IN (HCl). Analysis for (C14H18NO6P)2 Ca3.H2O : 42.51% C; 4.72X H; 3.31% N (calculated 42.53% C; 4.59% H; 3.54%N). IR (FT, nujol mull, cm-1) : 3280 (m), 2800-2200(m), 1635(s), 1560(m), 1060 (s). 13CMR(DCl, ppm relative to TMS, dioxane internal standard): 14.90, 15.15 (diastereomeric CH3); 29.90 (PCH2, J =137.2 Hz); 39.76 (CH-CH3); 40.60(CH, pc 3' P =14.71 Hz); 42.24(NCH2); 44.16(CH2Ar); 127.75, pcc 2 ' .16(CH2At); 127.75, 129.53, 129k72, 139.06 (Ar); 176.87 (diastereomeric COO); 179.7(CON, J =3.7 Hz). pccc EXAMPLE 7 N-[(R)-2-(Diethoxyphosphinyl0methyl-1-oxo-3-phenyl propyl]-ss-alanine benzyl ester A. (R)-2-(Diethoxyphosphinyl)methyl-3-phenylpropanoic acid Dissolve 7.8 g (20.0 mmoles) of benzyl (R)-2 (diethoxyphosphinyl)methyl-3-phenylpropanoate (Example 3, B. step I)in 40 ml of CH30H, and hydrogenate in Parr hydrogenation apparatus over 2.0 g of 10% Pd on carbon at 3.45 bar hydrogen pressure for 2.5 hours. Filter the catalyst using Celite, and concentrate to obtain 5.8 g (96%) of an oil. [&alpha;]26= -8.2 (c=1, CHCl3). B. N-[(R)-2-(Diethoxyphosphinyl)methyl-1-oxo-3-phenyl propyl]-ss-alanine benzyl ester To a mixture of 3.00 g (10.0 mmoles) of (R)2-(diethoxyphosphinyl)methyl-3-phenylpropanoic acid, 3..51 g (10.0 mmoles) ss-alanine benzyl ester (p-tosylate salt), 3.06 g (20.0 mmoles) HOBT, and 1.39 ml (10.0 mmoles) Et3N in 50 ml DMF, under an inert atmosphere and cooled with an ice-water bath, add 1.92 g (10.0 mmoles) EDCI and 1.39 ml Et3N. Allow the reaction to warm up to room temperature and stir for 16 hours. After dilution with 100 ml EtOAc wash the mixture with saturated NaHC03 (50 ml), 1N citric acid (50 ml), saturated NaHCO3 (50 ml), saturated NaCl (50 ml), and dry the organic solution with Na2SO4. Evaporate the solvent to obtain an oil, which purify on SiO2 by flash chromatography to yield 4.5 g (98%) of an oil. [&alpha;]26=-21.0 (c=l, CH3OH). EXAMPLE 8 N-[(R)-1-oxo-3-phenyl-2-)phosphonomethyl)propyl] -ss-alanine calcium salt Add a solution (50 ml) of 33% HBr in HOAc to 4.5 g (9.76 mmoles) of N-[(R)-2-(diethoxyphosphinyl) methyl-1-oxo-3-phenylpropyl] -ss-alanine bezyl ester under a N2 atmosphere. Stir the resulting orange solution at room temperature for 16 hours. Evaporate the solvent and excess HBr in vacuo to afford an oil, which dissolve in 50 ml of H20 and then wash twice with 50 ml portions of ether. Evaporate the aqueous solution to yield 3.2 g of an oil. Dissolve the oil in 400 ml of H2O, add 0.8 g of Ca(OH)2 and warm to 500 C for a few minutes. Filter the resulting solution and lyophilize to give a white powder. m.p. > 200 C [&alpha;]D26 = -22.2 (c=1, 1N HCl) EXAMPLE 9 N-[(S)-2-(Diethoxyphosphinyl)methyl-1-oxo-3-phenyl propyl]-ss-alanine ethyl ester To a mixture of 5.00 g (16.7 mmoles) of (S) -2-( diethoxyphosphinyl) methyl-3-phenylpropanoic acid, 2.56 g (16.7 mmoles) ss-alanine ethyl ester (hydrochloride salt), 5.10 g (33.3 mmoles) HOBT, and 2.32 ml (16.7 mmoles) Et3N in 75 ml DMF, under an inert atmosphere and cooled with an ice-water bath, add 3.19 g (16.7 mmoles) of EDCI and 2.32 ml Et3N. Allow the reaction mixture to warm up to room temperature and stir for 16 hours. After dilution with 100 ml EtOAc wash the mixture sequentially with saturated NaHCO3 (50 ml), 1N citric acid (50 ml), saturated NaHCO3 (50 ml), saturated NaCl (50 ml), and dry the organic solution with Na2S04. Evaporate the solvent to yield an oil, which purify on SiO2 by flash chromatography (EtOAc/Hexane) to yield 5.8 g (88%) of an oil. [&alpha;]26=11.9 (c=l, CHCl3). IR(FT, neat, cm ) : 3280(m), 1733(s), 1670(s), 1545(m), 1240(s), 1220(s), 1180(s), 1050(s), 1030(s). PMR (CDC13, ppm relative to TMS internal standard 1.24(t,3H); 1.28(t,6H); 1.97(m,2H, PCH2), 2.33(m, 2H, CH2CO); 2.54(m, lH, CH); 2.85(m, 2H, CH2Ar); 3.36 (m, 2H, NCH2) ; 4.06 (m, 6H, CH2O) ; 6.03 (m, 1H, NH) ; 6.98 (m, 5H, Ar). 13CMR (CDCL3, ppm relaTIVE TO TMS internal standard): 14.16(CH3); 16.34(CH3, J ccop =6.36 Hz); 27.69(PCH2, Jpc=140.2 Hz); 33.86, 34,65 (ss-ala Ch2's) ; 40.32 (CH, Jpcc=14.53 Hz) ; 43.70 (CH2) Ar, Jpccc=3.1 Hz) ; 60.52 (CH2O) ; 61.72 (CH2O, Jcop= 6.5 Hz); 126.6, 128.5, 129.1, 138.8(Ar's); 172.2(COO); 173.1 (con, Jpccc=6.2 Hz). Mass Spectrum : m/e 399 (M+). EXAMPLE 10 N-[(S)-1-Oxo-3-phenyl-2-(phosphonomethyl)propyl] -ss-alanine ethyl ester calcium salt Add bromotrimethylsilane (10.0 ml, neat) (TMS -Br) dropwise to 4.77 g (12.0 mmoles) of N-[(S)-2- (diethoxyphosphinyl)methyl-1-phenylpropyl-ss- alanine ethyl ester, cooled in a ice-water bath under a N2 atmosphere. Allow the solution to warm up to room temperature and stir for 2 hours. Remove (in vacuo) TMS-Br and ethylbromide (in vacuo), and to the residual oil add 10 ml of aqueous acetone. After stirring this mixture for 15 minutes remove the solvent and obtain 5 g of a glass. Dissolve the oil and 0.89 g of Ca(OH)2 in 500 ml of H2O at 500C. Filter and evaporate the solvent to afford a solid, which subsequently wash with CH3OH and Et2O Yield 2.4 g (53%). m.p. > 220 C. [&alpha;]D26=20.0 (c=1, IN HCl). Analysis for C15H22NO6P.Ca.l.1.(H2O) :43.72% C ; 5.12% H; 3.18% N (calculated 44.11%C ; 5.68%h ; 3.43%N) IR(FT, nujol mull, cm ): 3350(m), 2750-2500(w), 1735(s), 1635 (s), 1570(s), 1100 (s), 1070(s). PMR(DCl ppm relative to TSP internal standard): 1.22 (t, 3H); 2.04(m,2H, PCH2); 2.15(m, 2H, CH2CO); 2.90(m, 3H, CH2Ar, CH) ; 3.14 (m, NCH2) ; 4.04 (q, 2H) ; 7.30 (m, 5H, Ar). 13CMR (D2O, ppm relative to TMS, dioxane internal standard: 17.72 (CH3) ; 29.74 (PCH2 ; Jpc-136.9 Hz) ; 33.84, 35.38 (ss-ala CH2's ; 40.65 (CH, Jpcc=15.1 Hz) ; 44.08 (CH2Ar, Jpccc=3.2 Hz) : 58.39 (OCH2); 127.7, 129,5, 12,8, 139.0(Ar's) ; 174.7(CCO) : 176.5 (CON. @ = 5.6 Hz). Mass Specteur : tccc ¯ (FAB, Xe, glycerbl). @/e 382 (M +1). EXAMPLE 11 N-[(S)-2-(Diethoxyphosphinyl)methyl-l-oxo-3-phenyl propyl]-ss-alanine-2-phenoxyethyl ester To a mixture of 4.0 g (13.3 mmoles) of (S)-2-(diethoxyphosphinyl)methyl-3-phenylpropanoic acid, 5.08 9 (13.3 mmoles) ss-alanine 2-phenoxyethyl ester (p-tosylate salt), 4.08 9 (26.6 mmoles) HOBT, and 1.85 ml (13.3 mmoles) Et3N in 75 ml DMF, under an inert atmosphere and cooled with an ice-water bath, add 2.56 EDCI and 1.85 ml Et3N. Allow the reaction to warm up to room temperature and stir for 16 hours. After dilution with 100 ml EtOAc wash the mixture sequentially with saturated NaHC03 (50 ml), 1N citric acid (50 ml), saturated NaHC03 (50 ml), saturated NaCl (50 ml), and dry the organic solution with Na2S04. Evaporate the solvent to afford an oil, which purify on SiO2 by flash chromatography (EtOAc/Hexane) to yield 1.6 g (25%) of an oil. [&alpha;]D26=6.3 (c=1, CHCl3). IR (FT, neat, cm-1): 3290(m), 1740(s), 1675(s), 1600(m), 1590(m), 1550(m), 1250(s), 1170(s), 1055(s), 1030(s). PMR (CDC13, ppm relative to TMS internal standard): 1.30 (t,6H,CH3); 1.95(m, 2H, PCH2); 2.35(m, 3H, CH2CO, CH); 2.83(m, 2H, CH2Ar), 3.37(m, 2H, NCH2); 4.04 (m, 4H, CH20D); 4.17 (m, 2H, CH2O) ; 4.38 (m, 2H, CH2O) ; 6.10 (m, 1H, NH); 6.96(m, 5H, OAr); 7.18(m, 5H, Ar). 13CMR (CDC12, ppm relative to TMS): 16.36(CH3, Jccop=S.lHz); 27.69(PCH2, Jpc=140.3Hz); 33.79, 34.56 [ss-ala CH2's); 40.32 (CH, Jpcc=14.6Hz) ; 43.69 (CH2Ar, Jpccc=3.3 Hz) ; 61.72(CH20P, J =6.4Hz); 62.96, 65.66 (CH20); 114.6, cop 121.3, 126.6, 128.5, 129.1, 129.6, 138.8 (Ar's); 158.4 (OAr) ; 172.1 (COO) ; 173.1 (CON, Jpccc=5.8Hz). Mass Spectrum : m/e 491 (M+). EXAMPLE 12 N-[(S)-1-Oxo-3-phenyl-2-(phosphonomethyl(propyl)-ss alanine 2-phenoxyethyl ester Add bromotrimethylsilane (TMS-Br) (2.4 ml, neat) dropwise to a cooled (ice-water bath) 1.49 g (3.00 mmoles) of N-[(S)-2-(diethoxyphosphinyl)methyl-1-oxo-3-phenylpropyl-ss-alanine 2-phenoxyethyl ester, under a N2 atmosphere. Allow the solution to warm to room temperature and stir 2 hours. Remove (in vacuo) excess TMS-Br and ethylbromide, and to the residual oil add 5 ml of aqueous acetone. After stirring this mixture for 15 minutes remove the solvent, and wash the solid obtained with 25 ml of cold Et2O. Yield 1.1 g (85%). m.p.=142-143 C. [&alpha;]26=14.2 (c=1, DMSO). Analysis for C21 H26NO7P: 57.61%C; 5.86%H; 2.92%N (calculated 57.93%C; 6.02%H; 3.22%N). IR(FT, nujol mull, cm 3405(s), 2800-1800(w), 1735(s), 1625(s), 1600(m), 1585(m), 1545(s), 1185(s), 1175(s), 1125(s). PMR(d6DMSO, ppm relative to TMS internal standard: 1.71(m, 2H, PCH2); 2.35(m, 3H, CH2CO, CH); 2.82(m, 2H, CH2Ar); 3.19(m, 2H, NCH2); 4.24(m, 4H, CH2O) ; 6.95(m, 5H, OAr); 7.20(m, 5H, Ar); 7.82(t, 1H, NH); 9.01(broad 5, 2K, OH). 13CMR (d6-DMSO, ppm relative to TMS internal standard): 29.66 (PCH2, '3 =138.0 Hz); 33.46; pc 34.48 (ss-ala CH2's) ; 39.00 (CH, Jpcc = 15.0 Hz) ; 42.19 (CH2Ar, Jpccc=2.7Hz) ; 62.47, 65,48 (CH2O) ; 114.4, 120.8, 125.9, 128.0, 128.9, 129.3, 129.5(Ar's); 158.1 (OAr); 171.2(COO); 173.4(CON, '3 =9.6Hz). pccc Mass Spectrum: m/e 417 (M+ -18). EXAMPLE 13 N-[(R,S)-3-(1-1'-Biphenyl-4-yl)-2-(diethoxyphosphinyl) methyl-l-oxopropyl--alanine benzyl ester A. Ethyl 3-(1,1'-biphenyl-4-yl)-2-ethoxycarbonyl propanoate Add dimethyl malonate (33.6 9, 0.21 mole) dropwise over a 15 minute period to a solution of Na (4.6 9, 0.2 g-atom) in 125 ml absolute EtOH. Stir the suspension for 15 minutes, and to it add over a 10 minute period a warm solution of 4-chloromethylbiphenyl (40 g 0.197 mole) in 50 ml EtOH; After refluxing the reaction for 4 hours allow it to stand overnight (16 hours). Then concentrate the reaction mixture to a syrup, and partition between H20 and Et2O. Wash the etheral layer with H20, saturated NaCl, dry over MgSO4, and concentrate to an oil (61.7 g). Distill under reduced pressure to afford 24.0 g (37%) of desired product. b.p.=182-192 C/0.2 mm Hg. B. Potassium 3-(l,l'-biphenyl-4-yl)-2-ethoxycdrbonyl- propanoate To 15.0 g (46.0 mmoles) of the diester from the preceding step in 50 ml of anhydrous EtOH add a freshly prepared solution of 3.00 g (2.58 9 net, 46.0 mmoles) KOH in 46 ml of anhydrous EtOH. Allow the reaction to stir at room temperature, under a N2 atmosphere for 5 hours. Filter the resulting precipitate and wash with several volumes of Et2 0 to yield 13.52 (87.2%) of product. m.p. 1700C (decomposition). C. Ethyl 2-[(1,1'-biphenyl-4-yl)methyl]-2-propenoate To a mixture of 13.5 9 (40.1 mmoles) of the salt from the preceding step 4.54 ml (3.23 g, 44.1 mmoles) di ethyl amine, and 5.5 ml of 37% aqueous formaldehyde, cooled with an ice-water bath, add dropwise 22.0 ml (44.0 mmoles) of 2N HC1. Allow the reaction mixture to warm up to room temperature and stir 4 hours. Extract with 4 x 50 ml Et20, then wash the combined organic layers with 50% HC1 (100 ml), saturated NaCl (100 ml), 5% NaHC03 (lOOmI) and saturated NaCI (100 ml). Evaporate the solvent after drying with MgS04 to afford 8.83 g of a clear oil. b.p. 150-158 C/0.2-0.3 mm Hg. PMR (CDCl3, ppm relative to TMS Internal standard): 1 .24(t, 3H); 4.67(s, 2H); 4.11 (q, 2H; 5.54(d, lH); 6.29(d, TH) ; 7.47(m, 9H). D. (R,S)-3-(1,1'-Biphenyl-4-yl)-2-(diethyoxyphos phinyl)methylpropanoic acid ethyl ester In a 250 ml 3 neck round bottomed flask fitted with an addition funnel and N2 inlet place 0.10 g of 50% NaH in oil (2.1 mmoles), which then wash with 3 volumes (20 ml) of hexane. Introduce toluene (100 ml) then add dropwise 4.00 ml (4.29 g, 31.0 mmoles) diethylphosphite. After stirring 15 minutes 8.27 g (31.0 mmoles) add the ethyl ester from the preceding step. Stir the reaction mixture at room temperature for 16 hours under an inert atmosphere. After quenching the reaction with 5.0 ml HOAc, filter the mixture and evaporate the solvent to an oil. Chromatography on SiO2 (3 CH3OH/ CHCl3) affords 7.1 g of desired product (57%). E. (R,S)-3-(1,1'-Biphenyl-4-yl)-2-(diethoxyphosphinyl)- methylpropanoic acid To 7.1 9 (17.6 mmoles)of the ethyl ester (from the preceding step) suspended in 30 ml H20 add 17.6 ml of 1 DON NaOH at room temperature under an inert atmosphere. After 5 days, work up the reaction mixture by first extracting with 50 ml EtOAc (from which are recovered 2.4 9 of starting material), followed by acidification to pH 3.0 and re-extracting with two volumes (50 ml) of EtOAc. Combine the latter organic layers, dry with MgS04, and evaporate the solvent to give 4.0 9 (61%) of a thick oil. Analysis for C20H2505P: 64.39%C; 6.41%H (calculated 63.82%C, 6.70%H). IR(FT, neat, cm1): 2850-2400(m), 1733(s), 1605(w), 1490(m), 1200(s), 1170(s), 1055(s), 1030(s). PMR(CDCl3, ppm relative to TMS internal standard): 1.25 (doublet of t, 6H, JHH=7.5Hz, JHp=1.5Hz); 2.02(m, 2H, PCH2); 2.99(m, 3H, CH2Ar, CH); 4.03(m, 4H, JHH=7.5Hz, JHP=1.5Hz) ; 7.41 (m, 9H, Ar). 13CMR (CDCl3, ppm relative to TMS internal standard) : 16.26 (CH3, Jccop=6.2Hz) ; 26.58(PCH2, Jpc=142.7Hz) ; 38.75 (CH, Jpcc=14.1Hz) ; 41.60 (CH2Ar, Jpccc=3.1Hz) ; 62.26 (CH2O, Jcop=6.7Hz) ; 177.1 (CO@ JPCCC=6.2Hz). pccc + Mass Spectrum: m/e 376 (M ). F. N-[(R,S,)-3-(1,1'-Biphenyl-4-yl)-2-(diethoxyphos phinyl)-methyl-1-oxopropyl]-ss-alanine benzyl ester To a mixture of 3.90 9 (10.4 mmoles) of the propanoic acid of the preceding step, 3.64 9 (10.4 mmoles) ss-alanine benzyl ester (p-tosylate salt), 2.81 g (20.8 mmoles) HOBT, and 1.45 ml (10.4 mmoles) Et3N in 50 ml DMF, under an inert atmosphere and cooled with an ice-water bath, add 2.00 g (10.4 mmoles) of EDCI and 1.45 ml Et3N. Allow the reaction to warm up to room temperature and stir for 16 hours. After dilution with 100 ml EtOAc wash the mixture sequentially with saturated NaHC03 (50 ml), 1N citric acid (50 ml), saturated NaHC03 (50 ml), saturated NaCl (50 ml), and dry the organic solution with MgS04. Evaporate the solvent to afford an oil, which purify by chromatography on SiO2 (3% CH30H/CHC13) to yield 4.91 g (88%) of a thick oil. IR(FT, neat, cm-1) : 3280(m), 1740(s), 1675(s), 1600(w), 1550(m), 1245(s), 1220(s), 1170(s), 1055(s), 1030(s). PMR(CDC13, ppm relative to TMS internal standard): 1.35(t, 6H); 1.98(m, 2H, PCH2); 2.40(m, 2H, CH2CO); 2.90(m, 3H, CH2Ar, CH); 3.39(m, 2H, NCH2); 4.04(m, 4H, CH20); 4.96(q, 2H, OCH2Ar); 6.22(t, lH, NH); 7.36 (m, 9H, Ar). 13CMR(CDC13, ppm relative to TMS): 16.35(CH3, Jccop=6.02Hz) ; 27.69 (PCH2, Jpc=140.3Hz) ; 33.81, 34.64 (ss-ala CH2's) ; 39.85 (CH, Jpcc=14.58Hz) ; 43.6(CH2Ar, Jpccc=3.47Hz; 6l.76('CH20, Jcop=6.68Hz) ; 66.32(0CH2Ar); 126.9, 127.1, 128.1, 128.3, 128.5, 128.8, 129.5, 135.6, 137.8, 139.5, 140.7 (Ar's); 172.0 (COO); 173.0(CON, JpCcc=6.28Hz). Mass Spectrum: m/e 537 (M+). EXAMPLE 14 N-[(R,S)-3-(1,1'-Biphenyl-4-yl)-1-oxo-2-(phosphono- methyl)-propyl]-ss-alanine Add a solution (100 ml) of 33% HBr in HOAc to 4.7 9 (8.7 mmoles) of the ester from the preceding step under a N2 atmosphere. Allow the resulting orange solution to stir at room temperature for 16 hours. Evaporate the solvent and excess HBr in vacuo to afford a solid, which crystallises when partitioned between 100 ml H20 and 50 ml EtOAc. Filter, then wash with 250 ml EtOAc and dry at high vacuum (at room temperature) to afford 2.54 9 (75%) of product. m.p.=193-1940C. Analysis for C19H22NO6P: 58.41%C; 5-61%H; 3-11%N (calculated 58.31%C, 5.67%H, 3.58%N). IR(FT, nujol mull, cm ): 3300(m), 2850-2000(m), 1695(s), 1642(s), 1570(m). 13CMR(D20, ppm relative to TMS, dioxane internal standard) : 32.85 (PCH2, Jpc=130.2Hz) ; 37.25 (CH, Opcc=4.7Hz); 39.52, 39.87(ss-ala CH2's); 45.96(CH2Ar, J =2.4Hz); 127.7, 128.4, 130.0, 130.5, 139.4, 140.0, pccc 141.3 (Ar's) ; 178.6 (CON, Jpccc=11.6Hz) ; 180.9 (COOH). Mass Spectrum : m/e 391 (M+). EXAMPLE 15 N-[(RbS)-2-diethoxyphosphinyl-1-oxo-3-phenylpropyl]- ss-alanine benzyl ester A. (R,S)-2-Diethoxyphosphinyl-3-phenylpropanoic acid In a 250 ml 3 neck round bottomed flask fitted with a magnetic stirrer, dropping funnel, and N2 inlet place 7.5 ml (58 mmoles) of dimethyl phosphite and 150 ml 1,2-dimethoxyethane. To the cooled solution (O-100C) add 4.2 g (110 mmoles) of 60% NaH (oil dispersion). Stir the resulting slurry at 5 C for 20 minutes, and to it add 12.2 g (53 mmoles) of 2-bromo-3-phenylpropanoic acid in 50 ml of 1,2-dimethoxy-ethane over a 20 minute period. After 1 .5 hours add 7 ml EtOH, and pour the reaction mixture into 100 ml H20 and extract with Et20. Acidify the aqueous solution to pH 4 with dilute HCl, and extract with several portions of Et2O. Dry the combined ethereal extracts with Na2S04 and concentrate to 13.2 g of an oil. Triturate with cold (-70 C) Et2Q to obtain 8.0 g of a solid, which recrystallizes from Et2 0 to yield 6.85 g (45.470) of white crystals. m.p. = 69-71 C. Analysis for C13Hl905P: 54.62%C; 6.56%H; 11.02%P (calculated 54.55%C, 6.69%H, 10.82%P). PMR(CDC13, ppm relative to TMS internal standard) : 1.30 (doublet of t, 6H, JHH=8Hz, JHP=3Hz) ; 3.19(m, 2H, CH2Ar); 3.22(m, lH, CH); 4.15(m, 4H, CH20); 7.24(broad s, 5H, Ar); 10.8 (broad s, IH, OH). Mass Spectrum: m/e 286 (M+). B. N-LeR,S)-2-Diethoxyphosphinyl-l-oxo-3-phenylpropyl]- ss-alanine benzyl ester Treat a mixture of 3.5 g (12.2 mmoles) (R,S)-2-diethoxyphosphinyl-3-phenylpropanoic acid, 4.66 g (13.3 mmoles) ss-alanine benzyl ester (p-tosylate salt), 1.9 g (12.2 mmoles) HOBT, 2.3 g (12.2 mmoles) EDCI, and 50 ml DMF with 4.0 ml N-ethylmorpholine, and stir at room temperature 16 hours. Pour the resulting solution into H2O and extract with several portions of Et2O. Wash the combined ethereal layers with several volumes of H20, dry over MgS04 and concentrate to a yellow oil. Chromatograph on SiO2 (EtOAc/CH3CN/HOAc) to obtain 4.5 g of product. Analysis for C@@H@@NO@P 61.88%C; 6.82%H; 2.77%N. (calculated 61.74%C, 6.75%H, 3.13%N). PMR(CDC13, ppm relative to TMS internal standard): 1.32(t, 6H); 2.45(t, 2H, CH2CO); 2.6-3.6 (m, 5H, NCH2, CH2Ar, CH); 4.13(m, 4H, CH20); 5.10(s, 2H, OCH2Ar); 6.50(m, 1H, NH); 7.22(s, 5H, Ar); 7.35(s, 5H, Ar). Mass Spectrum: m/e 447 (M+). EXAMPLE 16 N-[(R,S)-2-diethoxyphosphinyl-1-oxo-3-phenylpropyl] ss-alanine Hydrogenate 0.9 g (2 mmoles) of N-[(R,S)-2-diethoxyphosphinyl-1-oxo-3-phenylpropyl-ss-alanine benzyl ester dissolved in 50 ml EtOH, in a Parr hydrogenation apparatus over 0.1 g of 10% Pd on carbon at 3.45 bar hydrogen pressure for 4 hours. Filter the catalyst using diatomaceous earth (celite) and concentrate to yield an oil, which crystallizes. Recrystallize from EtOAc to yield 0.485 g of a white solid. m.p. = 66-68 C. Analysis for C16H24NO6P: 53.66%C; 6.69%H; 3.51N (calculated 53.78%C, 6.77%H, 3.92%N). PMR(CDC13, ppm relative to TMS internal standard): 1.35(doublet of t, 6H, JHH=8Hz, JHp=3Hz); 2.23(m, 2H, CH2CO); 2.85-3.95(m, 5H, NCH2, CH2Ar, CH); 4.18(m, 4H, CH20); 7.20(s, 5H, Ar); 7.47(m, 1H, NH). Mass Spectrum: m/e 357 (M+). EXAMPLE 17 N-[(R,S)-1-Oxo-3-phenyl-2-phosphonopropyl]-ss-alanine calcium salt Add a solution (40 ml) of 33% HBr in HOAc to 3.2 g (7.15 mncles) of N-[(R,S)-2-diethoxyphosphinyl-1-oxo- 3-phenylpropyl-ss-alanine benzyl ester, under a N2 atmosphere. Stir the resulting orange solution at room temperature for 16 hours. Evaporate the solvent and excess HBr (in vacuo' to afford a gassy residue. Dissolve tis material in water, and wash with Et2O. Re-concentrate the aqueous fraction to give 2.1 g of a clear glass. Mass Spectrum: m/e 256 (M+-CO2H). Dissolve 0.5 g of the glassy product and O.il7 g Ca(OH)2 in 30 ml H20 at 40 C. Filter the solution, and lyophilize to give 0.41 g of a white solid. m.p. > 220 C. Analysis for C12H14NO6P. Ca. H2O : 40.41%C ; 3.89%H ; 3.22%H (calculated 40.33%C, 4.51%H, 3.92%N). PMR(D20, ppm relative to TMS): 2.20(t, 2H, CH2CO); 2.65-3.5(m, 5H, NCH2, CH2Ar, CH); 7.30ts, SM, Ar). Mass Spectrum (FAB, Xe, glycerol) : m/e 302 (M+ +1). EXAMPLE 18 N rl-Oxo-2-phosPhonomethYl-3-(4-trifluoromethyl)phenYl- propyl-ss-alanine ethyl ester Add bromotrimethylsilane (8 ml, 0.06 mole), with cooling, to 4.4 g (0.0094 mole) of N-[2-(diethoxyphosphinyl)methyl-l-oxo-3-(4-trifluoromethyl)phenylpropyl] -aralanine ethyl ester under a N2 atmosphere, and stir at room temperature for 2.5 hours. After removing excess bromotrimethylsilane and other volatiles in vacuo add aqueous acetone (20 ml of 90:10 v/v) and stir the mixture for 15 minutes. Collect the solid by filtration and wash with acetone. Recrystallize from methanol to obtain the title compound,m.p. 144-1460C. EXAMPLE 19 4-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]aminobenzoic acid ethyl ester Add bromotrimethylsilane (13.5 ml, 0.10 mmole) with cooling to 7.4 g (0.0165 mole) of 4-[2-(diethoxyphosphinyl)methyl-1-oxo-3-phenylpropyl]aminobenzoic acid ethyl ester under a N2 atmosphere, and stir at room temperature for 16 hours. After removing excess bromo trimethyl-silane and other volatiles ir. vaccc: add a; ous acetone (20 ml of 90:10 v/v), and stir the mixtur for 15 minutes. Filter the mixture and concentrate t gum, which triturate with EtOAc/hexane overnight. Filter the solid thereby obtained and wash with hexane m.p. 178-179 C. EXAMPLE 20 4-[2-(Ethoxyhydroxyphosphinyl)methyl-1-oxo-3-phenylpropyl]-aminobenzoic acid ethyl ester To a mixture of 2.00 g (4.47 mmoles) of 4-[2-(diethoxy- phosphinyl)methyl-1-oxo-3-phenylpropyl]aminobenzoic acid ethyl ester, 2.60 g (45.0 mmoles) ct potassium fluoride, and 50 mg of 18-crown-6 in 50 ml of dioxane add 30 ml of 1N NaOH and reflux the reaction for 45 minutes. After reducing the volume of the reaction to 1/3 of the original, acidify the residue with dilute HC to pH 1. Extract with EtOAC, dry with MgSO4 and evaporate the solvent to obtain the title product. EXAMPLE 21 N-[2-(Di-n-butoxyphosphinvl)methyl-1-oxo-3-phenylpropyl]-ss-alanine ethyl ester Heat 3.4 g 910 mmoles) of N-[1-oxo-3-phenyl-2-(phosph@@@) methyl-propyl]-ss-alanine ethyl ester with 7.5 ml (100 mmoles) of thionyl chloride (SOC12) for between 2 to 6 hours. At the end of this period remove excess S0C12 and other volatiles in vacuo. To the residue, cooled with an ice-salt bath, add excess (10 ml) nbutanol, and 3 ml (20 mmoles) Et3N. Stir the mixture at room temperature for 16 hours. To the residue add 0.5N HC1 (40 ml) and EtOAc (100 ml). After separating the phases, wash the organic layer with saturated NaCl, saturated NaHC03, dry with MgS04, and evaporate the solvent. Purify the residue by chromatography on Si02 using EtOAc/hexane to obtain the title product. EXAMPLE 22 N-[2-(n-Butoxyhydroxyphosphinyl)methyl-1-oxo-3-phenylpropyl-ss-alanine ethyl ester Heat 6.9 g (20 mmoles) of N-[l-oxo-3-phenyl-2-(phospho no)methyl-propyl]--alanine ethyl ester with 15 mm (206 mmoles) of thionyl chloride (SOC12) for between 2 and 6 hours. At the end of this period remove excess S0C12 and other volatiles in vacuo. Cool the residue with an ice-salt bath, then treat with .8 ml (20 mmoles) of n-butanol in 50 ml of dichloromethane containing 6 ml (43 mmoles) of Et3N. After stirring between 1 to 2 hours quench the reaction with 1N HC1, and extract with 200 ml EtOAc. Wash the organic phase with saturated NAC1, dry with MgS04, and evaporate the solvent to yield an oil, which chromatograph on SiO2 using EtOAc/ hexane to obtain the title product in pure form. The following test procedure was utilized to assay the enkephalinase A inhibiting effectiveness of the com pounds of formula I and their pharmaceutically accept able salts: Enkephalin (ENK) degrading activity was separated into the following three fractions according to the method of Gorenstein and Snyder [Life Sci., 25 2065 (1979)]: Enkephalinase A (Gly3-Phe4), Aminopeptidase, (AP) (Tyr1-Gly2), and Enkephalinase B (Gly2-Gly3). Enzyme activity was separated by taking the brain tissue (minus cerebellum) from Sprague-Dawley rats and homogenizing it in 30 volumes of 50 mM Tris buffer, pS 7.4, using a Brinkmann Polytron. The resulting homo genate is centrifuged at 50,000 x g for 15 minutes. The pellet, constituting the membrane bound enzyme material, was washed by resuspending it in Tris and re centrifuging it 4 times. Following washing, solubilization of the membrane pellet was achieved by incubating it for 45 minutes et 37 C in the presence of 15 volumes (based on initial brain weight) of 50 mM Tris-1% Triton X-100 buffer, pH 7.4. After centrifugation at 100,000 x g for 60 minutes to remove non-solubilized material, the Triton soluble supernatant was layered on a 1.5 x 30 cm DEAE Sephacel column previously equilibrated with 50 mM Tris-0.12 Triton, pH 7.4. Material was eluted from the column using a 1 liter linear NaCl gradient running from 0.0 to 0.4 M. Effluent was collected in 7 ml fractions, each of which was assayed for enkephalin degrading activity. Under these conditionsEnkephalinas A activity was found to elute between 120 and 200 ml. followed by AP activity (260 to 400 ml) and finally by Enkephalinase B activity between 420 and 450 ml. Enkephalin degrading activity was monitored using a radiometric assay. The substrate was 3H-Met5-ENK (50.1 Ci/mmol, New England Nuclear) diluted in 0.05 M Tris bluffer, pH 7.4, such that the f-inal reaction mixture concentration was 4Q nM. Total reaction mixture volume including enzyme and substrate was 250ul. Incubation was carried out for 90 minutes at 37 0C. To stop the reaction, tubes were transferred to a boilirg water bath for 15 minutes. Assay products were separated form one another using thin layer chromatography. A 4/Ul aliquot of the reaction mixture was spotted on a Baker-flex Silica Gel 1B plate t20 x 20 cm) along with unlabelled standards 5 (Met -ENK, tyrosine, tyrosylglycine, tyrosyl-glycyl- glycine) and the components co-chromatographd in an isopropanol:ethyl acetate: 5% acetic acid solvent system (2.2:1), which is capable of resolving Met5-ENK from its breakdown products. Total running time was approximately 17 hours. TLC tanks are gassed with nitrcgen prior to starting the run. Following the run, markers are visualized with ninhydrin spray. These spots, along with remaining plate regions, are cut from the plate and the radioactivity corresponding to each monitored using liquid scintillation counting. IC50's are determined using linear regression techniques. By way of example, utilizing this procedure, the following nanomolar (nM) concentrations for the specified compounds were found to inhibit the action of enkephalinase A by 50% (IC50) TABLE A Compound EMI64.1 EMI64.2 <tb> <SEP> Enkepha <tb> <SEP> linase <SEP> In <tb> <SEP> hibition <tb> <SEP> * <SEP> A <SEP> Y <SEP> Z <SEP> R2 <SEP> IC50 <SEP> nM <tb> <SEP> S <SEP> -H <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OH <SEP> 19.0 <tb> <SEP> S <SEP> -Cl <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OH <SEP> 11.0 <tb> <SEP> R,S <SEP> -C6H5 <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OH <SEP> 1.3 <tb> <SEP> S <SEP> -H <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OC2H5 <SEP> 60 <tb> <SEP> S <SEP> -H <SEP> -CONH- <SEP> -(CH2)2- <SEP> -O(CH2)2OC6H5 <SEP> 210 <tb> S <SEP> -H <SEP> -CONH- <SEP> -(CH2)3- <SEP> -OH <SEP> 80 <tb> <SEP> ** <tb> <SEP> S <SEP> -H <SEP> -CONH- <SEP> -CH2CH(CH3)- <SEP> -OH <SEP> 25.5 <tb> <SEP> R <SEP> -H <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OH <SEP> 600 <tb> <SEP> R,S <SEP> -CH3 <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OH <SEP> 60 <tb> <SEP> R,S <SEP> -CH3 <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OC2H5 <SEP> 2.200 <tb> <SEP> S <SEP> -H <SEP> -CONH- <SEP> p-C6H4- <SEP> -OC2H5 <SEP> 63 <tb> <SEP> ** <tb> <SEP> R,S <SEP> -H <SEP> -NHCOO- <SEP> -CH(CH3)- <SEP> -OH <SEP> 100 <tb> <SEP> ** <tb> <SEP> S <SEP> -H <SEP> -CONH- <SEP> -CH2CH(OH)- <SEP> -OH <SEP> 25 <tb> * : stereochemistry (as indicated by RS, or R,S) ** : R,S stereochemistry R stereochemistry The following test procedure was utilized to assess the noted compounds' potentiation of the analgesic effects of (D-A1a2-Met5)enkephalinamide (DAEAM). Background for the use of this procedure is given in Chipkin, R.E., Iorio, L.C., Barnett, A., Berger, J., and Billard, W., Regulators Pentides: From Molecular Biology to Function, edited by E. Costa and M. Trabucchi, Raven Press, New York, 1982, pp. 235-242. Male CFl mice (19-23 g) from Charles River Breeding Labs, Mass., were used (N=10/dose or dose combination). Tailflick testing was carried out in a manner similar to that of Dewey and Harris, Methods in Narcotic Research, Eds., S. Ehrenpreis and A. Neidle, pp. 101-109, Marcel Dekker, Inc., New York, 1975 using a radiant heat noxious stimulus. Following determination of control latencies (typically 2-3 sec), the mice were first administered (sc or po) either vehicle or drug and after an appropriate interval injected intracerebroventricularly (icv) with either vehicle (10 ul of saline) or DAEAM according to Haley and McCormick, Br., J. Pharmacol., 12,12 (1957). Tailflick latencies were re-determined 30 minutes later, as this has previously been determined to be the time of peak analgesia for DAEAM, and a cut-off of 10 seconds is employed. By way of example, utilizing this procedure, the fcllowing parenteral and/or oral ED50 values (the dose at which half the test animals displayed analgesia) were obtained for compounds having the formulae indicated below n Table B, TABLE B Compound EMI66.1 EMI66.2 <tb> <SEP> Oral <SEP> ED50, <SEP> in <tb> * <SEP> A <SEP> Y <SEP> Z <SEP> R2 <SEP> mice <SEP> (mg/kg) <tb> S <SEP> -H <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OH <SEP> 3 <tb> S <SEP> -H <SEP> -CONH- <SEP> -(CH2)2- <SEP> ! <SEP> -OCH2CH3 <SEP> 2.5 <tb> S <SEP> -H <SEP> -CONH- <SEP> -CH2-CH(CH3)- <SEP> -OH <SEP> 20 <tb> S <SEP> -Cl <SEP> -CONH- <SEP> -(CH2)2- <SEP> -OH <SEP> 25 <tb> * stereochemistry

Claims: CLAIMS (for all designated Countries other than Austria) 1. A compound having the structural formula I: EMI67.1 wherein RI is hydrogen, alkyl having from 1 to 6 carbon atoms, EMI67.2 in which A is hydrogen, halogen, hydroxy, nitro, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms, 2- or 3- thienyl or phenyl which may be substituted with halogen, hydroxy, nitro, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, or alkyl having from 1 to 6 carbon atoms ; W is R1 or OR1 wherein R1 is as defined above ; ; X is -(CH2)@-CHR3 - or - CHR3 - (CH2)@- wherein 2P 2p p is O or 1, and R3 is 2- or 3-thienylmethyl, 3-indolylmethyl, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, EMI68.1 in which A is as defined above, Y is EMI68.2 Z is o-, m- or p-phenylene, -(CHR4)r - [wherein r is 1,2,3, or 4 and R4 is independently chosen from hydrogen, alkyl having from 1 to 6 carbon atoms, hydroxy, alkoxy having from I to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, 3-indolylmethyl, hydroxymethyl, 2- (methylthio) ethyl, EMI68.3 in which A is as defined above] or -Bq-B'-B"- [wherein q is O or 1, one of the groups, B, B' or B" is EMI68.4 in which A is as defined above and the remaining B, B' and/or B" is -CH2-]. [with the following provisos : when W is OR1 and Y is -NHCO-, r cannot be 1; when Y is EMI68.5 r cannot be l; when Y is Z may also be -CRa=CRb- wherein Ra and Rb may be the same or different and are chosen from hydrogen, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, 3-indolylmethyl, hydroxymethyl, 2-(methylthio)ethyl, or together with the carbon atoms to which they are attached form a cycloalkenylene ring having from 5 to 8 carbon atoms; ; R2 is hydroxy, alkoxy having from 1 to 6 carbon atoms, EMI69.1 [wherein s is 0,1,2, or 3], EMI69.2 [wherein R5 and R may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms, and R7 is EMI69.3 or alkyl having from 1 to 6 carbon atoms], EMI69.4 [wherein t is 1 or 21, EMI70.1 [wherein u is 1 or 21, EMI70.2 or NR 8R9 wherein R8 is EMI70.3 R9 is hydrogen or alkyl having from 1 to 6 carbon atoms, and wherein A in the groups defined for R2 is as defined above; or a pharmaceutically acceptable salt thereof, in nonsolvated form or a solvate thereof with a pharmaceutically acceptable solvent. 2. A compound of formula I, as defined in claim I, characterised in that R is hydrogen, methyl, ethyl, phenyl or benzyl; R2 is hydroxy, methoxy, ethoxy, phenoxyethyloxy, pivaloyloxymethyloxy, EMI70.4 EMI70.5 W is hydroxy, ethoxy, methyl, or benzyl; X is EMI71.1 wherein A1 is hydrogen, phenyl, fluorine, chlorine or trifluoromethyl; Y is as defined in claim 1; Z is p-phenylene, or -CH2CHR41-, wherein R41 is hydrogen, hydroxy, methoxy, methyl or benzyl; or a pharmaceutically acceptable salt thereof, in non-solvated form or a solvate thereof with a pharmaceutically acceptable solvent. 3. A compound of formula I, as defined in claim 2, characterised in that R1 is hydrogen; R2 is hydroxy, methoxy, ethoxy, phenoxyethyloxy, pivaloyloxymethoxy, -OCH2CHCH2OH or OH EMI71.2 W is hydroxy; X is EMI72.1 wherein A1 is as defined in claim 2; Y is EMI72.2 and Z is p-phenylene or -CH2CHR41-, wherein R41 is as defined in claim 2; or a pharmaceutically acceptable salt thereof, in non=solvated form or a solvate thereof a pharmaceutically acceptable solvent. 4. A compound as defined in claim 1, namely N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-B- alanine, N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-ssalanine ethyl ester N-[3-(1,1'-biphenyl-4-yl)-1-oxo-2-(phosphonomethyl) propyl) --alanine, N-[3-(4-chloro)phenyl-1-oxo-2-(phosphonomethyl)propyl] ss-alanine, N-[3-(4-chloro)phenyl-1-oxo-2-(phosphonomethyl)propyl] B-alanine ethyl ester, N-[3-(4-fluoro)phenyl-1-oxo-2-tphosphonomethyl)propyl]- ss-alanine. 3-[3-(1,1'-biphenyl-4-yl)-1-oxo-2-(phosphonomethyl)- propyl]amino-2-methylpropanoic acid, 3-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2methylpropanoic acid, 3-13-(4-chloro)phenyl-1-oxo-2-(phosphonomethyl)propyl]- amino-2-methylpropanoic acid, 3-[(4-fluoro)phenyl-1-oxo-2-(phosphonomethyl)propyl]- amino-2-methylpropanoic acid, 4-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-aminobutanoic acid, 4-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl)amino benzoic acid N-[1-oxo-3-phenyl-2-phosphonopropyl]-ss-alanine 3-oxo-3-[2-phenyl-1-(phosphonomethyl)ethyl) amino propanoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]amino butanoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]amino-Z 2-butenoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]amino-E 2-butenoic acid 4-oxo-4-[2-(1,1'-biphenyl-4-yl)-1-(phosphonomethyl) ethyl]amino-butanoic acid 4-oxo-4-[2-(4-fluoro)phenyl]-1-(phosphonomethyl)ethyl] amino-butanoic acid N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] glycine N-[2-pher.ya phosphonome'hyl)ethylaminocarbonyltl- alanine N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] ss-alanine N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] phenylalanine 4-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] arninobenzoic acid, 2-[2-phenyl-1-(phosphonomethyl)ethyl]aminocarbonyloxyacetic acid, 2-[2-phenyl-1-(phosphonomethyl)ethyl]aminocarbonyloxypropanoic acid, 3-[2-phenyl-1-(phosphonomethyl)ethyl]aminocarbonyloxypropanoic acid, 4-[[2-phenyl-1-(phosphonomethyl)ethyl]aminocarbonyl]benzoic acid, 3-[[2-phenyl-1-(phosphonomethyl)ethyliaminocarbonyll- benzoic acid, or 2-[[2-phenyl-1-(phosphonomethyl)ethyl[aminocarbonyl]benzoic acid, N-[2-(Butylhydroxyphosphinyl)methyl-1-oxo-3-phenylpropyl -ss-alanine N-[2-(Butylhydroxyphosphinyl)methyl-l-oxo-3-phenylpropyi -ss-alanine Ethyl Ester N-[1-Oxo-2-phosphonomethyl-3-(2-thientyl)propyl]-ss alanine N-C1-Oxo-2-phosphonomethyl-3-(3-thiecyl) alanine N-[3-(3-IndOlyl)-l-oxo-a-(phosphonomethy1)propyl]-ss- alanine N-[1-Oxo-2-(phosphonomethyl)hexyl]-ss-alanine N-[3-Cyclohexyl-1-oxo-2-(phosphonomethyl)propyl]-ssalanine N-[2-Cyclohexyl-l-oxo-2-(phosphonomethyllethy1]-ss- alanine N-[2-(4-Chloro)phenyl-1-oxo-&alpha; ;-(phosphonomethyl)ethyl]- ss-alanine 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 hydroxypropanoic Acid 3-[1-Oxo-3-phenyl-2-iphosphonomethyL)propyllamino-2- methoxypropanoic Acid N-[l-Oxo-3-phenyl-2-(phosnhonomethyl)propyl]-ss-alanine Pivaloyloxymethyl Ester N-]1-Oxo-3-phenyl-2-(phosphonomethyl)propyl)-ss-alanine 2-Phenoxyethyl Ester N-[l-Oxo-3-phenyl-2-(ph4sphonomethyl)propyl]-ss-alanine 4-.Bromophenacyl Ester N-[1-Oxo-3-phenyl-a-(phosphonomethyl)propyl]-ss-alanine 2, 3-Dihydroxypropyl Ester N-[l-Oxo-3-phenyl-2-Xphosphonomethyl)propyl]-ss-alanine 2-Naphthyloxyethyl Ester N--[l-Oxo--3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine Phthali.dyl Ester N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2-Methylphenylamide N-[l-aso-3-phenyl-2-(.phosphonomethyl)propyl]-b-alanine 2,3-Isopropylideneglycerol Ester 4-[1-Oxo-3-phenyl-2-(phosphpnomethyl)propyl]aminobenzOic Acid Ethyl Ester N-[l-Oxo-2-phosphonomethyl-3-(4-trifluoromethyl)phenyl propyl]-ss-alanine N-[l-Oxo-2-phosphonomethyl-3-(4-trifluoromethyl)phenyl- propyl]-ss-alanine Ethyl Ester N-[2-(n-Butoxyhydroxyphosphenyl)methyl-1-oxo-3-phenyl propyl]-ss-alanine Ethyl Ester 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 hydroxymethylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2cyclo-propylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propylEamino-2- (cyclopropyl) methylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 (3-indolyl) methylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 ±2-methylthio) ethylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2phenylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl) propyl]amino-294-chloro)phenylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 CphenylEmethylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 CC4-chloro)phenyl)methylpropanoic Acid <RTI ID=78.6> N-[2-(BenzylhydroxyphosphinylJmeth-7-l-oxo-3-phenyl- propyl]-ss-alanine N-[2-(Benzylhydroxyphosphinyl)methyl-1-oxo-3-phenylpropyl]-ss-alanine Ethyl Ester 1-[-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminomethyl-3,4-benzo-cyclopentene-1-carboxylic Acid 1-[2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino] ethyl-3,4-benzocyclopentene-1-carboxylic Acid 2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino- methyl-3-phenyl-Z-2-propenoic Acid 2-[2-[1-Oxo-3-phenyl-2-(phosphonomethyl0propyl]amino] ethyl-3-phenyl-Z-2-propenoic Acid 2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino] ethyl-3-phenyl-Z-2-propenoic Acid 3-(1H-Benzimidazol-2-yl)-2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminomethyl propanoic Acid 2-(1H-Benzimidazol-2-yl)-4-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino butanoic Acid or a pharmaceutically acceptable salt.of any of the foregoing, in non-solvated form, or a solvate thereof with a pharmaceutically acceptable solvent. 5. A compound having the structural formula Ia: EMI80.1 wherein Wa is alkoxy having from 1 to 6 carbon atoms, phenoxy or benzyloxy; Xa is EMI80.2 wherein A is defined in claim 1 ; and Ya is -NH2 or -N:C:O. 6, A pharmaceutical composition comprising a compound of formula I, as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in solvated or non-solvated form, together with a pharmaceutically acceptable carrier or excipient. 7. A compound of formula I, or a pharmaceutically acceptable salt, in solvated or non-solvated form, as defined in any one of claims 1 to 4, for use in the inhibition of the action of enkephalinases in a mammal. 8. A process for the preparation of a compound of formula I as defined in claim 1, characterized in that A) to produce a compound of formula I in which Y is EMI81.1 a compound of formula XX is condensed. with a compound of formula XXI EMI81.2 B) to produce a compound of formula I in which Y is EMI81.3 a compound of formula XXII is reacted with a compound of formula XXII I EMI82.1 C) to produce a compound of formula I in which Y is EMI82.2 a compound of formula XXIV is reacted with a compound of formula XXV EMI82.3 D) to produce a compound of formula I in which Y is EMI82.4 a compound of formula XXVI is reacted with a compound of formula XXVII EMI82.5 E) to produce a compound of formula I in which at least 2 one of W, OR1 and R is hydroxy, a compound having the formula XXVIII EMI83.1 in which W' is R1 as defined in claim 1 or is an esterified hydroxy group which may be the group OR1, OR" is hydroxy or an esterified hydroxy group which may be the group OR1, R2' is hydroxy, -NR8R9 as defined in claim 1, or an esterified hydroxy group which may be an esterified hydroxy group as defined for R2 in claim 1, at least one of W', OR" and R2' being an esterified hydroxy group, is subjected to a de-esterification reaction whereby at least one esterified hydroxy group W', OR" or OR2, (and essentially any esterified hydroxy group not being as defined by W, OR1 or R2 in claim 1), is converted to hydroxy, so as to produce a compound of formula I, in which at least one of W, OR1 and R2 is hydroxy; F) to produce a compound of formula I in which at least one of W, OR1 and R2 is an esterified hydroxy group, a compound of formula I as defined in claim I, in whit at least one of the group W, OR1 and R2 is a hydroxy group, is subjected to an esterification reaction wh-- e- by at least one such group is converted to an esterified hydroxy group as defined by W, OR1 or R2 respectively in claim I, wherein in the above process A to F W,X,Y,Z,R1 and are as defined in claim 1 and any functional groups are protected if necessary or desired, said process A1B,C D,E or F being followed by removal of any protecting groups if necessary or desired, from the resulting compound of formula I, and isolation of the compound of formula I as such or as a pharmaceutically acceptable salt, in non-solvated form or as a solvate with a pharmaceutically acceptable solvent. CLAIMS for Austria 1. A process for the preparation of a compound of the general formula I EMI85.1 wherein R1 is hydrogen, alkyl having from 1 to 6 carbon atoms, EMI85.2 in which A is hydrogen, halogen, hydroxy, nitro, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms, 2- or 3- thienyl or phenyl which may be substituted with halogen, hydroxy, nitro, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, or alkyl having from 1 to 6 carbon atoms ; W is R1 or OR1 wherein R1 is as defined above ; ; X is (CH2)pCRR3 or -CHR -(CH2) - wherein p is O or 1, and R3 is 2- or 3-thienylmethyl, 3-indolylmethyl, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, EMI86.1 in which A is as defined above, Y is EMI86.2 Z is o-, m- or p-phenylene, -(CHR4)r- [wheerein r is 1,2,3, or 4 and R4 is independently chosen from hydrogen, alkyl having from 1 to 6 carbon atoms, hydroxy, alkoxy having from. I to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, 3-indolylmethyl, hydroxymethyl, 2- (methylthio) ethyl, EMI86.3 in which A is as defined above) o -Bq-B'-B"- Iwherein q is O or 1, one of the groups, B, B' or B us is EMI86.4 in which A is as defined above and the remaining B, B' and/or B" is -CR2-), [with the following provisos: when W is OR1 and Y is EMI86.5 r may not be 1; when Y is EMI86.6 r cannot be 1; when Y Z may also be -CRa=CRb wherein Ra and Rb may be the same or different and are chosen from hydrogen, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, 3-indolylmethyl, hydroxymethyl, 2-(methylthio)ethyl, or together with the carbon atoms to which they are attached form a cycloalkenylene ring having from 5 to 8 carbon atoms; ; R2 is hydroxy, alkoxy having from 1 to 6 carbon atoms, EMI87.1 [wherein s is 0,1,2, or 3] EMI87.2 [wherein R5 and R6 may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms, and R7 is EMI87.3 or alkyl having from 1 to 6 carbon atoms], EMI87.4 [wherein t is 1 or 2], EMI88.1 [wherein u is 1 or 2], EMI88.2 or NR BR9 wherein R8 is EMI88.3 R9 is hydrogen or alkyl having from 1 to 6 carbon atoms, and wherein A in the groups defined for R2 is as defined above; or of a phermaceutically acceptable salt, in solvate or non-solvate form, said process being characterised in that A) to produce a compound of formula I in which Y is EMI88.4 a compound of formula XX is condensed with a compound of formula XXI EMI88.5 B) to produce a compound of formula I in which Y is EMI88.6 a compound of formula XXII is reacted with a compound of formula XXII I EMI89.1 C) to produce a compound of formula I in which Y is EMI89.2 a compound of formula XXIV is reacted with a compound of formula XXV EMI89.3 D) to produce a compound of formula I in which Y is EMI89.4 a compound of formula XXVI is reacted with a compound of formula XXVII EMI89.5 E) to produce a compound of formula I in which at least one of W, OR1 and R2 is hydroxy, a compound having the formula XXVIII EMI90.1 in which W' is R' as defined in claim L or is an esterified hydroxy group which may be the group OR', OR" is hydroxy or an esterified hydroxy group which may be the group OR', R2' is hydroxy, -NR8R9 as defined in claim 1, or an esterified hydroxy group which may be an esterified hydroxy group as defined for R2 in claim 1, at least one of W', OR'i and R2' being an esterified hydroxy group, is subjected to a de-esterification reaction whereby at least one esterified hydroxy group W, OR" or OR' Cand essentially any esterified hydroxy group not bein as defined by W, OR' or R in claim 1), is converted to hydroxy, so as to produce a compound of formula in which at least one of W, OR' and R is hydroxy; F) to produce a compound of formula I in which at least one of W, OR' and R2 is an esterified hydroxy group, a compound of formula I as defined in claim 1, in which at least one of the group W, OR' and R2 is a hydroxy group, is subjected to an esterification reaction whereby at least one such group is converted to an esterified hydroxy group as defined by W, OR' or R respectively in claim 1, wherein in the above process A to F W,X,Y,Z,R' and R2 are as defined in claim 1 and any functional groups are protected if necessary or desired, said process A,B,C, D,E or F being followed by removal of any protecting groups., if necessary or desired, from the resulting compound of formula I, and isolation of the compound of formula I as such or as a pharmaceutically acceptable salt, in non-solvated form or as a solvate with a pharmaceutically acceptable solvent. 2. A process. as defined in claim 1, characterised in that there is produced a compound of formula I as defined in claim 1, in which R1 is hydrogen, methyl, ethyl, phenyl or benzyl; R2 is hydroxy, methoxy, ethoxy, phenoxyethyloxy, pivaloyloxymethyloxy, EMI91.1 EMI91.2 W is hydroxy, ethoxy, methyl, and benzyl; X is EMI92.1 wherein A1 is hydrogen, phenyl, fluorine, chlorine or trifluoromethyl; Y is as define: in claim 1; and Z is p-phenylene, or -CH2CHR41-, wherein R41 is hydrogen, hydroxy, methoxy, methyl or benzyl; or a pharmaceutically acceptable salt thereof, in solvated or non-solvated form. 3. A process as defined in claim 2, characterised in that there is produced a compound of formula I as defined in claim 2, in which R is hydrogen; R2 is hydroxy, methoxy, ethoxy, phenoxyethyloxy, pivaloyloxymethoxy, -OCH2CHCH2OH or OH EMI92.2 W is hydroxy; X is EMI93.1 wherein A1 is as defined in claim 2 ; Y is EMI93.2 and Z is p-phenylene or -CH2CHR -, wherein R@@ is as defined in claim 2; or a pharmaceuti.cally acceptable salt thereof, in solvated or non-solvated form. 4. A process as defined in claim 1, wherein there is produced compound N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss alanine, N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl)-ssalanine ethyl ester, N-[3-(1,1'-biphenyl-4-yl)-1-oxo-2-(phosphonomethyl) propyl)-±'-alanine, N-[3-(4-chloro)phenyl-1-oxo-2-(phosphonomethyl)propyl] B-zlanine, N-[3-(4-chloro)phenyl-1-oxo-4-(phosphonomethyl)propyl) ss-alanine ethyl ester, N-[3-(4-fluoro)phenyl-1-oxo-2-(phosphonomethyl)propyl] B-alanine, 3-[3-(1,1'-biphenyl-4-yl)-1-oxo-2-(phosphonomethyl)propyl]amino-2-methylpropanoic acid, 3-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2methylpropanoic acid, 3-f3-(4-chloroZphenyl-l-oxo-2-(phosphonomeohylapropyll- amino-2-methylpropanoic acid, 3-[(4-fluoro)phenyl-1-oxo-2-(phosphonomethyl)propyl] amino-2-metbylpropanoic acid/ 4-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl)eminobutanoic acid, 4-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]amino benzoic acid N-[1-oxo-3-phenyl-2-phosphonopropyl]-ss-alanine 3-oxo3-[2-phenyl-1-(phosphonomethyl)ethyl]amino propanoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]amino butanoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]amino-Z 2-butenoic acid 4-oxo-4-[2-phenyl-1-(phosphonomethyl)ethyl]amino-E 2-butenoic acid 4-oxo-4-[2-(1,1'-biphenyl-4-yl)-1-(phosphonomethyl) ethylzamino-butanoic aci 4-oxo-4-[2-(4-fluoro)phenyl]-1-(phosphonomethyl)ethyl] amino-butanoic acid N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] glycine N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] alanine N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] ss-alanine N-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl] phenyl al anine 4-[2-phenyl-1-(phosphonomethyl)ethylaminocarbonyl]aminobenzoic acid, 2-[2-phenyl-1-(phosphonomethyl)ethyl)aminocarbonyloxy acetic aci, 2-[2-phenyl-1-(phosphonomethyl)ethyl)aminocarbonyloxypropanoic acid, 3-[2-phenyl-1-(phosphonomethyl)ethyl)aminocarbonyloxypropanoic acid, 4-[[2-phenyl-1-(phosphonomethyl)ethyl)aminocarbonyl]benzoic acid, 3- [ [2-phenyl-i - (phosphonomethyl) ethyl) aminocarbonyl - benzoic acid 2-[[2-phenyl-1-(phosphonomethyl)ethyl [aminocarbonyl]benzoic acid, N-[2-(Butylhydroxyphosphinyl)methyl-1-oxo-3-phenylpropyl -ss-alanine N-[2-(Butylhydroxyphosphinyl)methyl-l-oxo-3-phenylpropyl -ss-alanine Ethyl Ester N-[l-Oxo-2-phosphonomethyl-3-(2-thienyl)propyl]-ss- alanine N-[1-Oxo-2-phosphonomethyl-3-(3-thienyl)propyl]-ss alanine N-[3-(3-Indolyl)-l-oxo-a-(phosphonomethyl)propyl]-ss- alanine N-[1-Oxo-2-(phosphonomethyl)hexyl]-ss-alanine N-[3-Cyclohexyl-1-oxo-2-(phosphonomethyl)propyl]-ss- alanine N-[2-Cyclohexyl-l-oxo-2-(phosphonomethyl)et'nyl]-ss- alanine N-[2-(4-Chloro)phenyl-l-oxo-a-(phosphonomethyl)ethyl] ss-alanine 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2hydroxypropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2- methoxypropanoic Acid N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl] Piyaloyloxymethyl Ester N-]1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2-Phenoxyethyl Ester N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 4-Bromophenacyl Ester N-tl-Qxo-3-phenyl-a-(phosphonomethy7)propyl3-ss-alanire 2, 3-Dihydroxypropyl Ester N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2-Naphthyloxyethyl Ester N-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine Phthalidyl Ester N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-ss-alanine 2-Methylphenylamide N-[l-Oxo--3-phenyl-2-(.phosphonomethylpropyn -aranine 2,3-Isopropylideneglycerol Ester 4-[1-Qxo-3-phenyl-2-(phosphpnosethyl)propyllaminobenzOic Acid Ethyl Ester N-[1-Oxo-2-phosphonomethyl-3-(4-trifluoromethyl)phenyl propyl]-ss-alanine N-[l-Oxo-2-phosphonomethyl-3-t4-trifluoromethyl)phenyl- propyl]-ss-alanine Ethyl Ester N-[2-(n-Butoxyhydroxyphosphenyl)methyl-1-oxo-3-phenyl propyl]-ss-alanine Ethyl Ester 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl[amino-2hydroxymethylpropanoic Acid 3-[l-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 cyclo-propylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2- (cyclopropyl)methylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2- (3-indolyl)methylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2 (2-methylthio) ethylpropanoic Acid 3- [1-0xo-3 -phenyl-2- (phosphonomethyl) propyl 1 amino-2- phenylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl) propyl]amino-2 (4- chloro) phenylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2- (phenyl) methylpropanoic Acid 3-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino-2- ((4-chloro)phenyl)methylpropanoic Acid N-[2-(Benzylhydroxyphosphinyl)methyl-l-oxo-3-phenylpropyl]-ss-alanine N-[2-Benzylhydroxyphosphinyl)methyl-1-oxo-3-phenylpropyl]-ss-alanine Ethyl Ester 1-[-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminomethyl-2,3-benzo-cyclopentene-1-carboxylic Acid 1-[2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino] ethyl-3,4-benzocyclopentene-1-carboxylic Acid 2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino methyl-3-phenyl-Z-2-propenoi c Acid 2-[2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]amino] ethyl-3-phenyl-Z-2-propenoic Acid 2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]am,ino] ethyl-3-phenyl-Z-2-propenoic Acid 3-(1H-Benzimidazol-2-yl)-2-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminomethyl propanoic Acid 2-(1H-Benzimidazol-2-yl)-4-[1-Oxo-3-phenyl-2-(phosphonomethyl)propyl]aminobutanoic Acid or a <RTI ID=100.4> Pharmaceutically acceptable salt of any of the foregoing, in solvated or non-solvated form. 5. A process for the preparation of a pharmaceutical composition, characterised in that a compound of formula I as defined in any of the preceding claims, or a pharmaceutically acceptable salt thereof in solvated or non-solvated form, is mixed with a pharmaceutically acceptable carrier or excipient. 6. A process for the preparation of a pharmaceutical composition, characterised in that a compound of formula I or a pharmaceutically acceptable salt thereof, in solvated or non-solvated form, prepared by the process of any one of claims 1 to 4, is mixed with a pharmaceutically acceptable carrier or excipient.

Inventors: GAETA, FEDERICO CARLOS AREJOLA
Applicants: SCHERING CORPORATION
Application year: 1984
Main classification: C07F9
IPC codes: C07F9