PHOSPHONO DERIVATIVES AS ANTIINFLAMMATORY AND ANTIARTHRITIC AGENTS

Abstract: Various novel phosphono derivatives (XII) of amino acid esters such as the "nonphenyl-type" N-phosphono compounds of formula (IX): R6-CH(NR7-PO(OR4)(OR5))COOR3, the "phenyl-type" N-phosphono compounds of formula (X): R8-CH(NR9-PO(OR4)(OR5))COOR3, and the "phenylethylene-type" N-phosphono compounds of formula (XI): R10-CH(NR11-PO(OR4)(OR5))COOR3 are disclosed as being useful as antiinflammatory and antiarthritic agents. Further disclosed is a method of treating inflammatory and arthritic disease with known N-phosphono derivatives of amino acid esters, the "benzyl-type" N-phosphono compounds of formula (III): R1-CH(NR2-PO(OR4)(OR5))COOR3. Additionally disclosed are N,N'-diphosphonodiamine esters of formula (XV) and phosphonophosphinate esters of formula (XVIII): R14-X-(CW)m1-CR15R16-CH2-CM(P(O)(OR4)(OR5))(P(O)(OR4)(R19)) also useful for treating inflammatory and arthritic diseases.

Description: PHOSPHONO DERIVA TIVES AS ANTIINFLAMMATORY AND AISΓΠARTΉRΓΠC AGENTS BACKGROUND OF THE INVENTION 1. Field of the Invention The phosphono derivatives (XII) of amino acid esters are useful as antiinflammatory and antiarthritic agents. 2. Description of the Related Art French Patent M 6430 (1968) discloses derivatives of N-phosphoaspartic acid and their salts for treating psychic and physic asthenia. French Patents M 7690 (1970) and M3936 (1966) disclose salts of N-phosphohistidine and N-phospholysine for fatigue and as candiotonics. Synthesis 6 444-8 (1988) discloses synthesis of N-dimethylphosphoryl DL-phenylalanine ethyl ester. J. Am. Chem. Soc, 71, 1940 (1949) discloses synthesis of diphenylphosphoryl DL- phenylalanine ethyl ester. European Patent 0085488 (1983) discloses phosphono peptide derivatives as anti- hypertensive agents. Critical Reviews in Biochem., 16,51 (1984) reviews N-, O- and S-phosphoderivatives of amino acids, peptides and proteins. US Patent 5,720,274 discloses aryl etone bearing diphosphonates useful for aniinflammatory and/or antiarthritic use. WO 9,012,017 discloses pyrazoline diphosphonates useful for aniinflammatory and/or antiarthritic use. At the 203rd American Chemical Society National Meeting Spring 1992 (San Fransico) Medicinal Section; Abstract #210; pyrazoline diphosphonates were disclosed as being useful for antiinflammatory and/or antiarthritic use. J. Chem. Soc, 3614 (1971) discloses that diamines can be diphosphorylated with diphenylphosphite or diphenyl phosphorchloroidothionate to produce diphosphorylated diamines. J. Med. Chem., 27, 654 (1984) discloses how to prepare diphosphorylated diamine phenyl esters. The present invention does not include aromatic esters. J. Organomet. Chem., 312, 283 (1986) discloses the preparation of the ethylene phosphate ester (XVI) starting material for the preparation of the phosphonophosphinate esters (XVIII). Heterocycles, 30, 855 (1990) and EPO Publication 0 298 553 Al discloses phosphonophosphinate acids useful for promoting bone growth where the non-phosphate portion includes 2-pyridinyl substitution. The present invention includes esters but not acids, and are useful for a different purpose, namely treatment of inflammation and arthritis not bone growth. SUMMARY OF INVENTION Disclosed is a method of treating a human who has arthritis or an inflammatory disease with an antiarthritic effective amount or antiinflammatory effective amount of a "benzyl-type" N-phosphono compounds of formula (HI) R r CH[NR 2 -PO(OR 4 )(OR 5 )]COOR 3 (ffl) where R, is R 1 . 3 -(CR,. 1 R 1 . 2 ) n - where R and R^ are the same or different and are -H or C,-C 4 alkyl, where n = 1 and where R,. 3 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR where R is C, -C 3 alkyl or -CO-C r C 4 alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR M where R M is as defined above, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR where R M is as defined above, or combinations thereof; where R 2 is -H or C,-C 4 alkyl; where R 3 is -H or -Q, alkyl; where R 4 is -H or C,-C 6 alkyl; where R 5 is -H or C,-C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms and pharmaceutically acceptable salts thereof. Also disclosed are "Nonphenyl-type" N-phosphono compounds of formula (IX) R 6 -CH[NR 7 -PO(OR 4 )(OR 5 )]COOR 3 (IX) where R 3 is -H or - alkyl; where R 4 is -H or C,-C 6 alkyl; where R 5 is -H or - alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; where R 6 is R 6 . 3 -(CR 6 .,R 6 . 2 ) - where -f i and R^ are the same or different and are -H or C,-C 4 alkyl, where m = 1-4 and where R^ is ortho-(-CH 2 -R 64 )-phenyl- where R^ and R 7 are taken together to form a ring selected from the group consisting of 5 thru 9 atoms, 2- or 3-thienyI optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OR^ where R^ is - alkyl or -CO-C,-C 4 alkyl or combinations thereof and where R 7 is -H or C r C 4 alkyl, 2-, 3- and 4-pyridinyl optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -ORs- 6 where R^ is as defined above, or combination thereof and where R 7 is -H or C r C 4 alkyl, 3-methyl-6-phenyl-pyrimidin-4-one-2-yl where the phenyl portion is optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH. -OR^ where R M is as defined above and where R 7 is -H or C,-C 4 alkyl, 2- or 4-quinolinyl optionally substituted with 1 thru 6 -F, -Cl, -Br, -OH, -OR^ where R M is as defined above, or combinations thereof and where R 7 is -H or C r C 4 alkyl, 2-triazinyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR^ where R^ is as defined above, or combinations thereof and where R 7 is -H or C,-C 4 alkyl; -OH and -O-R^s where R^s is C r C 4 alkyl; -SH and is as defined above; and pharmaceutically acceptable salts thereof. Further disclosed are "Phenyl-type" N-phosphono compounds of formula (X) R 8 -CH[NR 9 -PO(OR 4 )(OR 5 )]COOR 3 (X) where R 3 is -H or C r C Λ alkyl; where R 4 is -H or C r C 6 alkyl; where R 5 is -H or C r C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; where R 8 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR M where R w is C, -C, alkyl or -CO- - alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, where R M is -C 3 alkyl or -CO-C,-C 4 alkyl, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR M where R M is as defined above, or combinations thereof; where R 9 is -H or C r C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms and pharmaceutically acceptable salts thereof. Additionally disclosed are "Phenylethylene-type" N-phosphono compounds of formula (XI) R 10 -CH[NR π -PO(OR 4 )(OR 5 )]COOR 3 (XI) where R 3 is -H or C r C 4 alkyl; where R 4 is -H or C r C 6 alkyl; where R 5 is -H or C,-C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; where R 10 is Rιo- 3 -(CR 10 . ι Rι o . 2 ) p - where R 10 _, and R 10 _ 2 are the same or different and are - H or C,-C 4 alkyl, where p = 2-4 and where R 10 . 3 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR 1CM where R 1(M is C, -C 3 alkyl or -CO-C r C 4 alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR 1CM where R 1C is C, -C, alkyl or -CO-C,-C 4 alkyl, or combinations thereof, 2- or 3-indoIyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR 1(M where R 1(M is as defined above, or combinations thereof; 2-[3-methyl-6-phenylpyrimidin-4-one]yI; where R u is -H or -C 4 alkyl and pharmaceutically acceptable salts thereof. Also disclosed are N,N'-diphosphonodiamine esters of formula (XV) R 12 -CR 17 [NH-PO(OR 4 )(OR 5 )] (XV) I R 13 -CR 18 [NH-PO(OR 4 )(OR 5 )] where R 4 is -H or C,-C 6 alkyl; R 5 is -H or C C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; R 12 is C r C 4 alkyl, C r C, cycloalkyl, Ri 2 - 3 "(CRi 2 -ιRi 2 - 2 ) D - where Rj 2 ., and R 12 . 2 are the same or different and are -H or C r C 4 alkyl, where n = 0 or 1 and where R . 3 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR^ where R 12J , is Cj -C 3 alkyl or -CO-C r C 4 alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR 12-4 where R is as defined above, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR^ where R 12J) is as defined above, or combinations thereof; R 13 is C,-C 4 alkyl, Cj-C cycloalkyl, R j3 . 3 -(CRι 3 . 1 R 13 . 2 ) n - where R 13 ., and R 13 . 2 are the same or different and are -H or C,-C 4 alkyl, where n = 0 or 1 and where R 13 . 3 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR 13J( where R 1W is C, -C 3 alkyl or -CO-C r C 4 alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR IW where R 13J) is as defined above, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR 13 ^ where R 1 is as defined above, or combinations thereof and where R ]2 and R 13 are taken together with the attached carbon atoms to form (1) a phenyl ring - R, 7 and R 18 are taken together to form a double bond, (2) a 2,2'-naphthyl ring - R I7 and R lft are taken together to form a double bond, or (3) a cycloalkyl ring of C r C 8 - R I7 and R 18 are -H, and pharmaceutically acceptable salts thereof. Also disclosed are Phosphonophosphinate esters of formula (XVIII) R 14 -X-(CW) ml -CR 15 R 16 -CH 2 -CM[P(0)(OR 4 )(OR 5 )][P(0)(OR 4 )(R 19 )] (XVIII) where m, is O or 1; where M is -H, -Cl or -CH 3 ; where R 4 is -Q alkyl; where R 5 is C r C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; R 14 is (1) -φ optionally substituted with 1 or 2 -φ or with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r Cι 0 alkyl, C 3 -C, cycloalkyl, -OH, C,-C 4 alkoxy, -SH, -NH 2 , -0-CO-R 14 . ] where R 14 ., is C r C J0 alkyl, -C, cycloalkyl, pyridine, where n, is 1 thru 3 and R 14 . 2 is -H, C,- alkyl, - . -CH 2 -φ, -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, -C, cycloalkyl, -OH, C,-C 4 alkoxy, -O-φ, C C Λ alkylthio, -N- CO-R ]4 _ 3 where R 14 _ 3 is C,-C 10 alkyl, -C, cycloalkyl, pyridine, -(CH^-COO-R,^, where n, is 1 thru 3 and R 14 . 9 is -H, C,-C 6 alkyl, -Φ. -CH 2 -φ, -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,-Cι o alkyl, - cycloalkyl, -OH, C r C Λ alkoxy, -O-φ, C r C 4 alkylthio, -0-S(0) 2 -R 14- where R J<W is C,-C 10 alkyl, -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,-C 10 alkyl, - cycloalkyl, -OH, C,-C 4 alkoxy, -O-φ, C,-C 4 alkylthio, -N-CO-R 2 . 3 where R 2 . 3 is as defined above, naphthalene optionally substituted with 1 or 2 -φ, naphthalene optionally substituted with 1-7 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,-C 10 alkyl, - cycloalkyl, -OH, C r C 4 alkoxy, -O-φ, C r C 4 alkylthio or -N(CH 3 ) 2 , -N(R 14 . 5 )(R 1 < ) where R 14 . 5 and R^ are the same or different and are -H, C r C 6 alkyl, -C, cycloalkyl, -φ, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and where R 2 . 5 and R w are taken together with the attached nitrogen atom to form a heterocyclic ring containing 4 thru 6 carbon atoms, a 1-morpholine and 1-piperidine ring, -N(R 14 . 7 )-CO-R 14 _, where R 14 . 7 is H, C,-C 6 alkyl, C 3 -C, cycloalkyl, -φ, 2- pyridinyl, 3-pyridinyl, 4-pyridinyl, and where R 14 . j is as defined above, -N(R 14 . 5 )-CO-0-R 14 . 8 where R 14 . 8 is -H, C r C 6 alkyl, - cycloalkyl, -φ and -CH 2 -φ, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 14 ^) where R 14 . 5 , R 14 ^ and R 14 _ 7 are as defined above, -N(R 14 . 7 )-S0 2 -R 1<M where R 14J , and R 14 . 7 are as defined above, (2) 2- and 3-furanyl optionally substituted with 1 or 2 -φ, or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,-C 10 alkyl, -C, cycloalkyl, -OH, -SH, -NH 2 , -O-CO-R^, where R 14 _, is as defined above, -0-S(0) 2 -R 14 ^ where R 14J , is as defined above, -N(R 14 _ 5 )(R 14 ^) where R ]4 . 5 and R 1<w are as defined above, -N(R 14 . 7 )-CO-R 14 ., where R 14 ., and R 14 . 7 are as defined above, -N(R 14 _ 5 )-CO-0-R 14 _ 8 where R 14 . 5 and R 14 _ 8 are as defined above, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 14 . 6 ) where R 14 . 5 , R 14 ^ and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -Rι 4^1 where R 1 and R 14 . 7 are as defined above, (3) 2-, 4- and 5-pyrimidinyl optionally substituted with 1 or 2 -φ, or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, -C, cycloalkyl, -OH, -SH, -NH 2 , -0-CO-R 14 ., where R ]4 _, is as defined above, -0-S(0) 2 -R 14J4 where R 1M is as defined above, -N(R 14 . 5 )(R 14 ^) where R 14 _ 5 and R 14 . 6 are as defined above, -N(R 14 . 7 )-CO-R )4 ., where R 14 ., and R 14 . 7 are as defined above, -N(R 14.5 )-CO-0-R 14 _ 8 where R 14 _ 5 and R 14 _ 8 are as defined above, -N(R, 4 . 7 )-CO-N(R 14 . 5 )(Rj 4 _ 6 ) where R 14 . 5 , R 14 ^ and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R liW! where R 1<ω and R 14 . 7 are as defined above, (4) 2-, 3- and 4-pyridinyl optionally substituted with 1 or 2 -φ. or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, C j -C, cycloalkyl, -OH, -SH, -NH 2 , -0-CO-R 14 ., where R 14 ., is as defined above, -0-S(0) 2 -R 14 ^ where R 14J) is as defined above, -N(R 14 . 5 )(R 14 -^ where R 14 . 5 and R 14 ^ are as defined above, -N(R 14 . 7 )-CO-R 14 .] where R 14 ., and R 14 . 7 are as defined above, -N(R 14 . 5 )-CO-0-R 14 _ 8 where R 14 . 5 and R 14 _ 8 are as defined above, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 14 ^) where R 14 . 5 , R M and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R 1 where R 1 4 and R 14 . 7 are as defined above, (5) 2- and 3-thiophenyl optionally substituted with 1 or 2 -φ, or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C i0 alkyl, Q-C, cycloalkyl, -OH, -SH, -NH 2 , -0-C0-R 14 ., where R,^ is as defined above, -0-S(0) 2 -R )<M where R 1 4 is as defined above, -N(R 14 . 5 )(R 14 ^) where R 14 _ 5 and R 14 ^ are as defined above, -N(R 14 . 7 )-C0-R 14 ., where R 14 _, and R 14 . 7 are as defined above, where R 14 . s and R 14 _ 8 are as defined above, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 14 ^) where R 14 . 5 , R,^ and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R 14 ^ where R 14Jt and R 14 . are as defined above, (6) 1- and 2-naphthalyl optionally substituted with 1 or 2 -φ, or with 1 thru 7 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,-C 10 alkyl, Q-Q cycloalkyl, -OH, -SH, -NH 2 , -0-CO-R 14 _, where R 14 . j is as defined above, -0-S(0) 2 -R 1 where R li is as defined above, -N(R 14 . 5 )(R 14 ^) where R 14 _ 5 and R 14 _ 6 are as defined above, -N(R 14 . 7 )-CO-R 14 _, where R 14 ., and R ]4 _ 7 are as defined above, -N(R 14 . 5 )-CO-0-R 14 . 8 where R 14 _ 5 and R 14 . 8 are as defined above, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 14 ^) where R 14 . 5 , R 14 ^ and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R 1 - 4 where R 14Jt and R 14 . 7 are as defined above; (7) 2-thiazoIyl optionally substituted with 1 or 2 -F, -Cl, -Br, C r C 4 alkoxy, C,- C 4 alkyl or -φ, (8) 2-benzothiazoyl optionally substituted with 1 thru 4 -OH or C,-C 4 alkoxy, (9) C,-C 4 alkyl, (10) C 3 -C 6 cycloalkyl, (R 15 /R 16 -I) R !5 and R 16 together with the attached carbon atom form a cycloalkyl ring of 3 thru 7 carbon atoms, . (R 15 /R 16 -II) R 15 is -H and R 16 is -H, R ) , -CO-0-R 14 _ 8 , -CO-R 2 , -CN, -CO-NH-R 2 , -NH- CO-R 14 _„ -S-R 14 ., and -CO-NH-thiadiazole optionally substituted with -φ where R 14 , R 14 .„ R 14J) and R 14 _ 8 are as defined above, (R 15 /R I6 -III) R 15 is -H and R 16 is -F, -Cl, -Br or -I, (R 15 R 16 -IV) R 15 and R 16 are the same or different and are - o alkyl; (W,-I) W, is =0, =S, =N-N(R 14 . 7 ) 2 where R,^, is as defined above, (W,-II) W j is W j . j rW j . 2 where W,., and Wj. 2 are the same and are C,-C 4 alkoxy, -O-φ, C r C 4 alkylthio or -S-φ, (W r III) W, is W ! . 3 :W M where W,. 3 and W M are taken together with the attached carbon atom to form a 1,3-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,3-dithiolane or 1,3-oxoathiolane ring system, (W,-IV) W ! is -H.-W j .s where W^ is -OH, -SH, -NH 2 , -S-W w where W w is C,-C 4 alkyl, -0-CO-R 14 . ! where R )4 _, is as defined above, -0-S(0) 2 -R ]4 - 4 where R 14J , is as defined above, -N(R 14 . S ) R U ^ where R 14 _ 5 and R J4 ^ are as defined above, -N(Rι 4 . 7 )-CO-R 14 . 1 where R 14 _ : and R 14 . 7 are as defined above, -N(R 14 _ 5 )-CO-0-R 14 . 8 where R I4 . 5 and R 14 . 8 are as defined above, -N(R I4 . 7 )-CO-N(R 14 . 5 )(R 14 ^) where R 14 . 5 , R 14 ^ and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R 1< where R 14 and R J4 . 7 are as defined above; R 19 is C,-C 4 alkyl; X is where n 2 is 0 thru 5 and n 3 is 0 thru 2, with the proviso that when R 4 is -R 14 , m, is 1 and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION The phosphono compounds (XII) of the present invention are of four types (III, IX, X, and XI). The "benzyl-type" N-phosphono compounds (III) are known to those skilled in the art or can be readily prepared from known starting material by methods known to those skilled in the art. The "benzyl-type" N-phosphono compounds (III) require that there be a methylene group -CR x R y - (n = 1) between the phenyl (indole or naphthyl) group and the carbon atom to which the amino acid nitrogen atom is bonded. The novel "nonphenyl-type" N-phosphono compounds (IX) do not contain a phenyl group attached to the linker -CR-R..- which can be from 1 thru 4 units (m = 1-4). The novel "phenyl-type" N-phosphono compounds (X) contain a phenyl group but do not contain any linker -CR-.R y -, (n would be 0). The novel "phenylethylene-type" N-phosphono compounds (XI) contain a phenyl group attached to the linker -CR x R y - which can be from 2 thru 4 units (p = 2-4). The novel "nonphenyl-type" N-phosphono compounds (IX), "phenyl-type" N-phosphono compounds (X) and "phenylethylene-type" N-phosphono compounds (XI) are all made by methods know to those skilled in the art from known amino acids. In general the novel N-phosphono compounds are prepared in a two step process. First esterification following known processes, for example those of E. Fisher, Berichte 38, 4186 (1905) or Boissonnas, et al, Helv. Chim. Acta, 41 1875 (1958) followed by phosphorylation again following known processes, for example that of J Am. Chem. Soc. 74, 5759 (1952). CHART A discloses a general method for the production of the phosphono compounds (Xn), of which the "benzyl-type" N-phosphono compounds (HI) is one-type. Following the this procedure the amino acid esters (II) are made from available amino acids (I). This is in either racemic or optically active form and by methods known to those skilled in the art, see Fisher esterification [E. Fisher, Berichte 38, 4186 (1905)] or using thionyl chloride [Boissonnas, et al, Helv. Chim. Acta, 41 1875 (1958)]. In one case the amino acids have no substitution on the nitrogen atom (I-NH) or are substituted with an alkyl group (I-NR)- In the final product both - H and alkyl are included in the definition of the variable substituent R 2 . The N-phosphoamino acid esters (III-NH and III-NR) are prepared from the corresponding amino acid ester (II) also by known methods, see . Am. Chem. Soc. 74, 5759 (1952). This method uses a dialkylchlorophosphate in the presence of a base preferably triethylamine or pyridine. After extraction of the reaction mixture, the crude product is purified by known means, preferably chromatography over silica gel. The N-phosphoamino acid ester (III-NH) can readily be converted to the corresponding N-alkylated-N-phosphoamino acid ester (III-NR) by deprotonation and alkylation with an alkyl halide or dialkyl sulfate or similar alkylating agent, see Modern Synthetic Reactions, H. O. House, 2nd Edition, p 510. Preferably excess base is used, more preferably a 2-3 fold excess is used. Preferably a strong base {Modern Synthetic Reactions, p 547) is used, most preferably sodium hydride is used. Suitable solvents for strong bases are known, see Modern Synthetic Reactions, p 547, more preferably dimethylformamide is used. CHART B discloses that the pyrimidinylhomoalanine ester (VIII) starting material is produced as follows. The 2,3-Dimethyl-6-phenylpyrimidin-4-one (IV) is heated with at least an equivalent of dimethylformamide dialkyl acetal, more preferably with at least 2 equivalents or most preferably in neat dimethylformamide dialkylacetal. The preferred dimethylformamide dialkylacetal is dimethylformamide di-t-butyl acetal. The reaction temperature is preferred to be 50-100° and usual reaction time is from 2-48 hr, more preferably about 95° for about 5-6 hr. Extractive workup or preferably the reaction mixture is diluted with ether and the solid dimethylaminoethylidinepyrimidone (V) is collected. The dimethylaminoethylidinepyrimidone (V) is reduced using sodium cyanoborohydride under typical conditions [Lane, Aldrichimica Acta, 8(1), 3 (1975)] in an acidic medium, preferably acidic to methyl orange using excess sodium cyanoborohydride, preferably an excess of 62 mole %. The reaction can be performed from about -10 to about 50°, preferably at about 20-25°. Alcoholic solvents or aqueous alcohol mixtures are suitable, preferably methanol is used. Acids described by Lane are suitable, preferably aqueous hydrochloric acid. Workup is performed by extraction with organic solvents, preferably halocarbon solvents such a methylene chloride or chloroform from aqueous reaction medium after addition of base to raise the pH above pH 12. Crystallization, preferably from ethyl acetate and hexane gives the desired dimethylaminoethylpyrimidinone (VI) in suitable pure form. Dimethylaminoethylpyrimidinone (VI) is used to alkylate diethylformamido malonate under conditions similar to those which have been used for other Mannich Bases [see Modern Synthetic Reactions, p 655] to produce the corresponding formamidomalonoethylpyrimidinone (VII). Following the method of House, Modern Synthetic Reactions, p 602, dimethylaminoethylpyrimidinone (VI) is quatemized with an alkylating agent, preferably a volatile agent so the excess can be evaporated, more preferably with methyl iodide. The resulting quaternary salt is treated with formamidomalonate in the presence of a base which is capable of both deprotonating the formamidomalonate and converting the quaternary Mannich Base derived from dimethylaminoethylpyrimidinone (VI), to a reactive ethylene derivative so it will react with the deprotonated formamidomalonate. A variety of bases such as metal alkoxides or tertiary amine bases can be used. It is preferable to use the tertiary a ine bases so that the reactive ethylene intermediate is formed slowly and in low concentration so that it has a chance to react with the deprotonated formamidomalonate rather than having it formed rapidly and in high concentration under which conditions it is destroyed by polymerization. Preferably DBU is used as the base. The reaction can be performed from about -20 to about 50°, with a reaction time of about 4 hr to 4 weeks; more preferably at about 20-25° for about 4 days. Suitable solvents for Michael reaction are described in Modern Synthetic Reactions, Chapter 10, which include alcohols and ethers, more preferably THF. After concentration of the reaction mixture it is diluted with water and aqueous hydrochloric acid to a pH of 1-3 and extracted with an organic solvent, preferably a halocarbon, more preferably chloroform. Treatment of a concentrate with ethyl acetate gives a solid form of the formamidomalonoethylpyrimidinone (VII). The formamidomalonoethylpyrimidinone (VII) is converted to the corresponding pyrimidinylhomoalanine ester (VDI) by complete hydrolysis of the ester and formamide groups to give a amino malonic acid. The amino malonic acid intermediate is not isolated but decarboxylates to an amino acid salt which also is preferably not isolated but is concentrated by removal of water and the acid used for hydrolysis. For this reason volatile acids preferably 6 N hydrochloric acid are preferred. The reaction temperature should be about 60 to about 100° to perform the reaction in about 10 hr to 10 days. Preferably one uses about 100° for about 24 hr. After concentration usual esterification methods for esterification of amino acids are used. The Fisher method or thionyl chloride method discussed above are preferred. The Fisher process is preferred over the thionyl chloride process. It should be realized that the pyrimidinylhomoalanine ester (VIII) is one particular amino acid ester (ϋ) where R, is the 2,3- dimethyl-4-phenylpyrimidinylethyl side chain. The N,N'-diphosphonodiamine esters (XV) are prepared according to known methods as disclosed in CHART D. The coupling of a diamine (XIII) and a halophosphate ester (XIV) is well known, see for example, J. Chem. Soc, 3614 (1971) which discloses that diamines can be diphosphorylated with diphenylphosphite or diphenyl phosphorochloridothionate to produce diphosphorylated diamines and J. Med. Chem., 27, 654 (1984) which discloses how to prepare diphosphorylated diamine phenyl esters. It is preferred that the diamine (Xm) be coupled with the halophosphate ester (XIV) Cl-P(0)(OR 3 )(OR 4 ). The preferred solvents are chloroform and methylene chloride. It is preferred to add a base to scavange the acid produced; preferred bases include DBU, pyridine and triethylamine. The phosphonophosphinate esters (XVIII) are prepared by known methods, the Michael Reaction. The phosphonophosphinate esters (XVIII) are prepared by contacting an electron deficient olefin, the ethylene phosphate esters (XVI) with a nucleophile (XVII) in the presence of a base. This reaction is so well known when the electron withdrawing group is a carbonyl group that it is termed the Michael Reaction, Michael Addition or 1 ,4-addition. For a review of this reaction see H. O. House, Modern Synthetic Reactions, Second Edition, W. A. Benjamin, Inc., Menlo Park, CA (1972), p 595-623. However, when phosphorous is the electron withdrawing group, see WO 88/06158. The ethylene phosphate esters (XVI) are known to those skilled in the art, see J. Organomet. Chem., 312, 283 (1986) or can readily be prepared by methods known to those skilled in the art. The nucleophiles (XVII) are known, see International Publication WO92/03451. Suitable bases include methoxide, ethoxide, DBU, DBN, butyl lithium, methyl lithium, carbonate, bicarbonate, lithium hema ethyldisilazane (in THF or pyridine), hydride, lithium diisopropylamide. It is preferred that the base be DBU, lithium hexamethyldisilazane or carbonate depending on the nature of the particular starting materials. In the case where one of R i5 or R 16 is not -H, then the reaction is practiced by refluxing the ethylene phosphate ester (XVI), nucleophile (XVII) and base for about 0.5 to about 24 hours. After refluxing the mixture is diluted with water, extracted with an organic solvent such as methylene chloride, dried and concentrated under reduced pressure. The concentrate is preferably purified by (column) chromatography, distillation or crystallization as is known to those skilled in the art. When R 15 and R 16 are both -H the nucleophile (XVII) is first cooled to about 0 to about -78°, contacted slowly with a reagent such as lithium hexamethyldisilazane, and stirred a short period of about 15 minutes to about 1 hr. The ethylene phosphate ester (XVI) is then added to the reaction mixture stirred cold (about 0°) for a short period (about 30 min) and then permitted to warm (about 20-25°) and stirred for another short period (about 30 min). For the phosphonophosphinate esters (XVIII) it is preferred that M is -H. It is preferred that R 4 and R 5 is C,-C 4 alkyl, more preferrably ethyl. It is preferred that R 14 is 2-pyridinyl, 3- pyridinyl, 2-fiιranyl, 2-thienyl or -φ optionally substituted with 1 thru 2 -F, -Cl, -N(R 14 . 7 )-CO- R 14 _, where R 14 . 7 is -H and R 14 ., is C, alkyl, alkyl or -φ. It is even more preferred that R 14 be (substituted) -φ or 2-pyridinyl. It is preferred that n 2 and n 3 are 0 (that X is not present), that W is =0, that m, is 1. It is preferred that R ]5 is -H and that R 16 is -H, R 14 _ 4 , -CO-0-R 14 . 8 , -CO-R 14 , -CN and -CO-NH-R 14 . When it is desired that W is -H:W j . s where l 5 is -OH, those compounds can readily be prepared from compounds where W is =0 by reduction of the ketone carbonyl to the corresponding alcohol by reaction with a mild reducing agent such as sodium borohydride. This type of reduction is well known to those skilled in the art. The use of stronger reducing agents (lithium aluminum hydride) results in reduction of the phosphonate groups. When M is -CH 3 , these compounds can be obtained by deprotonating the starting material under kinetic conditions with a strong base such as lithium hexamethyldisilzane or lithium diisopropyl amide and trapping the resulting anion with an appropriate electrophile. When R 15 and R 16 are not the same, the bisphosphonates have an asymmetric center at the carbon to which R 15 and R 16 are attached. The enantiomers can be separated as discussed below. The amino acid (I), amino acid ester (II) and N-phosphono compounds (III) contain an asymmetric center and therefore produce two enantiomers one "S" and the other "R", either of which can be (+/d) and the other (-/l). Both enantiomers (+) and (-) may be useful in the same way as the optically impure (racemic, +) mixture. In this case, they may be utilized in the racemic form without separating them. However, if it is desired to utilize the more potent enantiomer, the optically impure mixture can be resolved by means known to those skilled in the art. Also, many amino acids are available in optically pure form. It is possible to resolve the racemic mixture at the stage of the amino acid or amino ester (I or II) using methods known to those skilled in the art, see for example, Optical Resolution Procedures for Chemical Compounds, Vol 1,: Amines and Related Compounds, Paul Newman, Optical Resolution Information Center, Manhattan College, Riverdale, NY, 10471, 1978. For example, treatment of the racemic mixture (II) with an optically active acid such as (-f-)-tartaric acid or alternatively with (-)-tartaric acid, would yield a mixture of diastereomeric salts, which can be separated most conveniently by fractional crystal- lization to give a salt containing only one enantiomer of the racemic mixture. Other suitable optically active acids include, (-) dibenzoyltartaric acid, (+)-camphoric acid, (+)- and (-)-malic acid and (+)-camphor-10-sulfonic acid. By reacting the diastereomeric salt with a base one obtains the desired enantiomer as the free amino compound (II). These optically pure compounds are then used in the same way as the racemic mixture. When used in this patent application the term N-phosphoamino acid ester includes both enantiomers as well as optically impure forms thereof, the most common of which is a racemic mixture (+, dl). For convenience regarding the utility of the compounds of the present invention, the term phosphono compounds (XH will be used to designate and is meant to include the "benzyl- type" N-phosphono compounds (HI), the "nonphenyl-type" N-phosphono compounds (IX), the "phenyl-type" N-phosphono compounds (X), the "phenylethylene-type" N-phosphono compounds (XI), the N,N'diphosphonodiamine esters (XV) and the phosphonophosphinate esters (XVIII). Generally, for the phosphono compounds (XII) it is preferred that R 3 is C r C 4 alkyl, it is more preferred that R 3 is C, or C alkyl. It is preferred that R 4 is C C Λ alkyl, it is more preferred that R 4 is C-, alkyl. It is preferred that R s is C,-C 4 alkyl, it is more preferred that R 5 is C- 2 alkyl. It is preferred that R 4 and R 5 are the same. For the "benzyl-type" N-phosphono compounds (III), it is preferred that R, is φ-CH 2 - optionally substituted with 1 -OH, it is more preferred that R, is φ-CH 2 -. It is preferred that R 2 is -H or -CH 3 , it is more preferred that R 2 is -H. For the "nonphenyl-type" N-phosphono compounds (IX), it is preferred that R^ is thienyl and thienyl substituted with a -F, -Cl or -Br atom, it is more preferred that Rg is thienyl. It is preferred that R 7 is -H or -CH 3 , it is more preferred that R 7 is -H. For the "phenyl-type" N-phosphono compounds (X), it is preferred that R 8 is -φ optionally substituted with 1 or 2 -OH or -F, it is more preferred that R 8 is -φ. It is preferred that R 9 is -H or -CH 3 , it is more preferred that R 9 is -H. For the "phenylethylene-type" N-phosphono compounds (XI), it is preferred that R 10 is - CH 2 -CH 2 -φ and -CH 2 -CH 2 -φ-OH, it is more preferred that R 10 is -CH 2 -CH 2 -φ. It is preferred that R j , is -H or -CH 3 , it is more preferred that R u is -H. The preferred compounds are those of EXAMPLES 10, 13 and 16. The phosphono compounds (XII) are useful as antiinflammatory and antiarthritic agents. The phosphono compounds (XII) are useful in treating human inflammatory, granulomatous, calcemic artherosclerotic and hypertensive disease. Particulary preferred utilities are for the treatment of inflammation and arthritis. The phosphono compounds (XII) can be administered orally, rectally, buccally, parenterally (intravenous, subcataneous, intramuscularly), topically or by aerosol by suitable pharmaceutical compositions. The phosphono compounds (XII) are preferrably administered orally at from about 2 to about 100 mg, administered from about 1 to about 6 times a day. The preferred dose is from about 0.01 to about 10 μg/kg/min when administered by intravenous infusion and when given intravenously from about 0.5 to about 10 mg. The preferred daily dose is about 0.03 to about 85 mg/kg of body weight. The phosphono compounds (Xϋ) of the present invention can also be used in combination with antiarthritic and antiinflammatory agensts such as phenylbutazone, indomethacin, gold sodium thiomulate, dexamethasone, penicillamine, sodoxicam, ibuprofen and naproxea The exact dosage and frequency of administration depends on the particular phosphono compounds (XII) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the phosphono compounds (XII) in the patient's blood and/or the patient's response to the particular condition being treated. DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims. I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Z 1 or "Rj" where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z x would represent a bivalent variable if attached to the formula CH 3 -C(=Z,)H. Groups Rj and R, would represent monovalent variable substituents if attached to the formula CH 3 -CH 2 -C(Rj)(R j )-H. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both Rj and R, are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as C,, where "i" is the integer corresponding to the carbon atom number. For example, C 6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term "R^" represents a variable substituent (either monovalent or bivalent) at the C 6 position. Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" in general represents a bond between two atoms in the chain. Thus CH 3 -0-CH 2 -CH(Rj)-CH 3 represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol "=" represents a double bond, e.g., CH 2 =C(R j )-0-CH 3 , and the symbol "≡" represents a triple bond, e.g., HC-≡C-CH(Rj)-CH 2 -CH 3 . Carbonyl groups are represented in either one of two ways: -CO- or -C(=0)-, with the former being preferred for simplicity. Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear fashion by N * =C(CH 3 )-CH=CC1-CH=C * H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-l-piperazinyl can be represented by -N * - (CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C * H 2 . A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, -C(X,)(X 2 )- the two substituents may be in either an axial or e- quatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X,) which is "below" another substituent (X-) will be identified as being in the alpha (α) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol " " or "...". The corresponding substituent attached "above" (X 2 ) the other (X,) is identified as being in the beta (β) configura¬ tion and is indicated by an unbroken line attachment to the carbon atom. When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable Rj attached to a carbon atom as -C(=Rj)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (- CO-) or as two separately attached monovalent variable substituents α-Rj. j and β-R,_ k . When a bivalent variable, Rj, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α-R,..:β-R 1 . t " or some variant thereof. In such a case both α-R,.. and β-R,. t are attached to the carbon atom to give -C(α-R H j )(β-Rj. k )-. For example, when the bivalent variable 1^, -C(=R^)- is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are α-R^B-R^- etc, giving -C(α-R 6 . 1 )(β-R 6 . 2 )- -C(α-R 6 . 9 )(β-R 6 . 10 )-, etc. Likewise, for the • bivalent variable R u , For a ring substituent for which separate α and β orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the α and β designations are omitted. Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -C 1 (Rj)H-C 2 (R j )H- ( and define arbitrarily a first and second carbon atom, respectively) R, and R j may be defined to be taken together to form (1) a second bond between and or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide. When Rj and R, are taken together to form a more complex entity, such as the group -X-Y-, then the orientation of the entity is such that C, in the above formula is bonded to X and is bonded to Y. Thus, by convention the designa¬ tion "... Rj and R j are taken together to form -CH 2 -CH 2 -0-CO- ..." means a lactone in which the carbonyl is bonded to . However, when designated "... R j and Rj are taken together to form - C0-0-CH 2 -CH 2 -the convention means a lactone in which the carbonyl is bonded to C,. The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "C,-C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C,-C 4 alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus (-VQ alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -0-CO- where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the "C r C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional conven- tion (Ci-C,)alkoxycarbonyl has the same meaning as C alkoxycarbonyl because the "Ci- " refers only to the carbon atom content of the alkoxy group. Similarly while both Q- alkoxyalkyl and (C 1 -C 3 )alkoxy(C,-C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms. When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent. II. DEFINITIONS All temperatures are in degrees Centigrade. TLC refers to thin-layer chromatography. THF refers to tetrahydrofuran. Saline refers to an aqueous saturated sodium chloride solution. IR refers to infrared spectroscopy. FTIR refers to Fourier transform infrared spectroscopy. ATR refers to attenuated total reflectance. CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfϊeld from TMS. NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane. TMS refers to trimethylsilyl. -φ refers to phenyl ( H 5 ). [αJ t , 25 refers to the angle of rotation of plant polarized light (specific optical rotation) at 25° with the sodium D line (5893A). MS refers to mass spectrometry expressed as m/e or mass/charge unit. [M + H] + refers to the positive ion of a parent plus a hydrogen atom. El refers to electron impact Cl refers to chemical ionization. FAB refers to fast atom bombardment. Ether refers to diethyl ether. Pharmaceutically acceptable refers to those properties and or substances which are acceptable to the patient from a pharmacologicalΛoxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. When solvent pairs are used, the ratios of solvents used are volume/volume (v/v). EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. PREPARATION 1 0,0,0 -Triethylmethylmethylenephosphonophosphinate Anhydrous THF (100 ml) is cooled in a dry ice/acetone bath and n-butyllithium (1.6M, 100 ml) in hexane is added. When the addtion is complete diethylmethylphosphonate (23.5 ml, 24.5 g, 0.16 mol) is added. The reaction is heated at -78° for 40 min and then at 20-25° for 1 hr. The reaction is then quenched with hydrochloric acid (2N, 800 ml) and the tetrahydrofuran is removed under reduced pressure. The residue is extracted with chloroform. The extracts are washed with saline and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure affords a liquid which is distilled to give the title compound, bp = 148-150° at 2.5mm of Hg; NMR(CDC1 3 ) 4.16, 2.41, 1.6 and 1.34 δ. PREPARATION 2 l-[(Ethoxymethylphosphinyl)]-l-ethenyl phosphonic acid, diethyl ester (XVI) A mixture of 0,0,0-triethylmethylmethylenephosphonophosphinate (11.4 g, 44.15 mmol), of paraformaldehyde (6.9 g, 0.23 mol) and of triethylamine (5.02 g, 48.57 mmol) is refluxed under nitrogen for 5 days. During the course of the reaction, additional paraformaldehyde (8.4 g, 0.30 mol) is added. The reaction is monitored by GC. The solvent is removed under reduced pressure and the residue is taken up in toluene (500 ml). A trace of p- toluensulfonic acid is added and the solution is refluxed for 48 hr. The solvent is removed under reduced pressure and the residue chromatographed on silica gel (300 g, slurry-packed in chloroform). The column is eluted with methanol/chloroform (1 99, 2 1), methanol/chloroform (2/98, 2 1) and methanol/chloroform (3/97, 1 1). Pure fractions were found by TLC analysis, combined and concentrated to give the title compound as a liquid, NMR (CDCI 3 ) 7.03, 4.23- 3.90, and 1.71 δ; FTIR (ATR deposited from CHC1 3 ) 3469, 2984, 2935, 2908, 1654, 1589, 1779, 1445, 1392, 1303, 1249, 1228, 1164, 1098, 1020, 969, 897, 840, 795, 766, 624 and 617 cm '1 ; MS (El, m/e) 270 (m + ), 255, 243, 215, 169, 133, 107, 79, and 65. EXAMPLE 1 DL-3-Fluorophenylalanine methyl ester (I-NHj) DL-3-Fluorophenylalanine (I, 21.86 mmole) is dissolved in absolute methanol (150 ml) and concentrated sulfuric acid (5.00 ml) is added with stirring. The solution is heated at 55° for 48 hrs and then held under nitrogen for 3 days. The solution is concentrated to 40 ml, poured on ethyl acetate (150 ml) plus saturated aqueous sodium carbonate (100 ml). The phases are separated, the organic phase is washed with water (30 ml), dried over sodium sulfate and concentrated to give the title compound, NMR (CDC1 3 ) 2.92, 3.72, 3.74, 6.93, and 6.28 δ. EXAMPLE 2 N-diethylphosphoryl-3-fluorophenylalanine methyl ester (III-NHj) DL-3-fluorophenylalanine methyl ester (H-NH 2 , Example 1, 17.7 mmole) is dissolved in methylene chloride (40 ml) and pyridine (30 mmole) and diethylchlorophosphate (14.47 mmole) are added. After stirring at 20-25° under nitrogen for 19.5 hrs the solution is diluted with chloroform (60 ml) and washed with 10% potassium bisulfate (60 ml). The aqueous phase is washed again with chloroform (45 ml) and then the organic extracts are washed, in sequence, with dilute sodium bicarbonate (45 ml). The extracts are dried over sodium sulfate and concentrated. The residue is concentrated and crystallized from ethyl acetate to give the title compound, mp 82-83.5°; NMR (CDC1 3 ) 1.26, 3.01, 3.15, 3.71, 3.84, 3.96, 4.13, 6.93 and 6.24 δ. EXAMPLE 3 N-(DiethyIphosphoryl)-N-methyl-phenylalanine ethyl ester (III-NR) Under an atmosphere of nitrogen N-(diethylphosphoryl)-phenylalanine ethyl ester (III-NH 2 , Example 2, 1 mmol) and 8 mmol of methyl iodide in anhydrous tetrahydrofuran (3 ml) are combined. The mixture is cooled in an ice bath and treated with 3 mmol of sodium hydride as a 60% dispersion in mineral oil. The reaction is stirred at 0° for two hours at which time, the reaction is quenched with saturated aqueous ammonium chloride. The solution is concentrated and extracted with chloroform. The extracts are washed with saline and aqueous sodium iodide. After drying over anhydrous sodium sulfate, removal of the solvent under reduced pressure affords an oil which is purified by chromatography on silica gel eluting with an ethyl acetate hexane gradient The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDC1 3 ) 7.22, 4.73, 4.15, 3.95, 3.45, 3.33, 2.98, 2.93, 2.63, 1.24, and 1.01 δ; [α] D = -6° (c 0.7122 in chloroform); MS (El) m/e 343 (m + ), 270, 252, 242, 224, 214, 196, 91 and 42. EXAMPLE 4 l,2,3,4-TetrahydroisoquinoIine-3-carboxylic acid, methyl ester hydrochloride (II- NR) In 150 ml of methanol is suspended 11.29 mmol of L-l,2,3,4-tetrahydroisoquinoline-2- carboxylic acid [I-NR, J. Amer. Chem. Soc, 70, 180 (1948)]. The suspension is cooled in an ice salt bath and is treated with 22.57 mmol of thionyl chloride. The mixture is then heated at 40° for 18 hrs. An additional 11.27 mmol of thionyl chloride is then added and the reaction is completed after 5 hrs of reflux. The reaction is concentrated under reduced pressure and the solid residue is recrvstallized from methanol/ether to give the title compound, mp 161° (dec), NMR (MeOD) 7.29, 4.50, 3.90, 3.43, and 3.23 δ; [α] D = -104° (c 0.845 in methanol). EXAMPLE 5 N-(Diethylphosphoryl)-L-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester (iπ-NR) In 10 ml of methylene chloride under a nitrogen atmosphere are combined 4.44 mmol of L-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester (II-NR, Example 4) and 5.33 mmol of 1.8-diazabicyclo[5.4.0]undec-7-ene. The mixture is cooled in an ice bath and treated with 5.33 mmol of diethyl chlorophosphate. The reaction is stirred overnight slowly coming to 20-25°. The reaction is washed with IN aqueous hydrochloric acid and then saline. After drying over anhydrous sodium sulfate removal of the solvent under reduced pressure gives an oil. Chromatography on silica gel eluting with a methanol/chloroform gradient, pooling and concentrating of the appropriate fractions gives the title compound, NMR (CDC1 3 ) 7.15, 7.04, 4.78, 4.36, 4.16, 4.05, 3.90, 3.64, 3.18, 1.37, and 1.24 δ; [α] D = +3° (c 0.32775 in methanol); MS (El) m e 327 (m + ), 298, 282, 268, 190 and 130. EXAMPLE 6 Dimethylaminoethylidinepyrimidinone (V) 2,3-Dimethyl-6-phenylpyrimidin-4-one (TV, 99.5 mmole) and DMF of t-butyl acetal (50 ml, Fluka) are heated at 90-95° under nitrogen with stirring. After 5-1/2 hrs the solution is cooled, diluted with ether. The crystals are filtered, washed with ether and dried, mp 164-165°; NMR (CDC1 3 ) 88.11, 7.97, 7.43, 6.48, 4.90, 3.53, 3.05 δ; CMR (CDC1 3 ) 168.0, 160.0, 159.1, 151.8, 138.2, 129.7, 128.4, 126.8, 100.9, 85.6, 29.4 δ; IR (mull) 2925.0, 1652.0, 1626.0, 1496.8, 1490.0, 1415.7, 1403.2, 1293.3; MS 255 (M + ), 240, 213, 212, 211, 110, and 68. EXAMPLE 7 Dimethylaminoethylpyrimidinone (VI) A solution of dimethylaminoethylidinepyrimidinone (V, Example 6) (11.72 mmole) and methyl orange (5 mg) in methanol (120 ml) is brought to a red color with 6NHC1 and sodium cyanoborohydride (1.20 g, 19.1 mmole) is added slowly and in portions while the red color is maintained with 6 N hydrochloric acid. After completion, the solution is stirred 10 min and checked by TLC (CH 2 0H CHC1 3 , 1/9) to show clean conversion to a polar material. The solution is diluted with water (20 ml) and sodium hydroxide and extracted with chloroform (200 ml). After washing the extracts with water (20 ml) the extracts are dried over sodium sulfate and concentrated to an oil. Dilution with ethyl acetate (5 ml) and hexane (15 ml) gives the title compound which is filtered and dried, mp 109-110°; NMR (CDC1 3 ) 7.47, 7.44, 6.79, 3.57, 2.93, 2.36 δ; CMR (CDCy 163.1, 159.8, 158.9, 136.2, 130.2, 128.5, 126.7, 106.5, 55.8, 45.4, 33.4, 29.9 δ; IR (mull) 1670.4, 1664.6, 1572.9, 1550.8, 1417.7, 1027.3, 782.1, 669.2; MS 257 (M + ), 242, 213, 212, 211, 201, 58. EXAMPLE 8 Foπnamidomalonoethylpyrimidinone (VII) A solution of dimethylaminoethylpyrimidinone (VI, Example 7) (4 mmole) is dissolved in methylene chloride (25 ml) and methyl iodide (0.76 ml, 12 mmole) is added. After stirring under nitrogen for 2 hrs the mixture is concentrated under reduced pressure. The residue is diluted with dry THF. Diethylformamidomalonate (4 mmole) and DBU (0.5 ml) are added and the reaction is stirred under nitrogen for four days at which time TLC (methanol/chloroform, 5/95) and (acetonitrile/chloroform, 1/4) show clean conversion. The mixture is concentrated under reduced pressure with heat diluted with chloroform (15 ml) which is washed with water (60 ml) and 6N hydrochloric acid (20 ml). The aqueous phases are backwashed in sequence with chloroform (40 ml). The two organic extracts are finally washed, in sequence, with water (40 ml) dried over sodium sulfate and concentrated. The concentrate is diluted with ethyl acetate (40 ml) to give the title compound, mp 153-155°; NMR (CDC1 3 ) 8.24, 7.95, 7.45, 7.02, 6.79, 4.24, 3.56, 2.89, and 1.26 δ; CMR (CDC1 3 ) 167.2, 163.0, 159.9, 159.7, 158.9, 135.9, 130.3, 128.5, 126.7, 106.6, 64.8, 62.9, 29.9, 29.7, 29.6, 13.7 δ; IR (mull) 3361, 1740, 1722, 1677, 1662, 1485, 1467, 1454, 1377, 1296, 1291, 1251, 781, 704; MS 415 (M + ), 370, 342, 314, 268, 213, 200, 158, and 146. EXAMPLE 9 Pyrimidinylhomoalanine ester (VIII) A mixture of formamidomalonoethylpyrimidinone (VII, EXAMPLE 8, 9.71 mmoles) in 6 N hydrochloric acid is heated at 100° for 24 hrs. The mixture is cooled and concentrated under reduced pressure. The residue is mixed with toluene (2 x 500 ml) and concentrated twice to azeotrope away remaining water. The solid is then taken up in absolute ethanol (400 ml) and ethanol (40 ml) which had been saturated with hydrogen chloride gas at 0° is added. After four days at reflux, the mixture is cooled and then concentrated to about 200 ml. The mixture is diluted with saturated aqueous sodium carbonate (500 ml) and chloroform (400 ml). The lower phase is washed with water (50 ml). Aqueous extracts are washed in sequence with chloroform (200 ml), and the organic extracts are dried over sodium sulfate, filtered and concentrated. This material is crystallized from ethyl acetate (20 ml) and hexane (5 ml) to give the title compound, mp 87-89°; NMR (CDC1 3 ) 8.00, 7.45, 6.81, 4.20, 3.64, 3.58, 3.00, 2.45, 2.08 and 1.30 δ; CMR (CDC1 3 ) 177.0, 163.4, 160.4, 150.0, 137.0, 130.4, 128.6, 126.8, 106.5, 61.0, 53.4, 30.9, 30.6, 29.9 and 14.2 δ; MS 315 (M + ), 242, 275, 213, 200, 171, 146,, 130 and 97. EXAMPLES 10-23 Following the general procedure of CHART A and EXAMPLES 1-5 and utilizing the esterification process of E. Fisher, Berichte 38, 4186 (1905) or Boissonnas, et al, Helv. Chim. Acta, 41 1875 (1958) and the phosphorlation process of J Am. Chem. Soc. 74, 5759 (1952) and making non-critical variations and using the amino acid starting material of Column A, the N- phosphono compounds of Column B are obtained: EXM Column A Column B 10 L-phenylalanine N-(diethylphosphoryl)-L-phenylalanine methyl ester, mp 65-67° 11 L-tryptophane N-(diethylphosphoιyl)-L-tryptophane methyl ester, mp 124-125° 12 L-phenylalanine N-(diethylphosphoryl)-L-phenylalanine ethyl ester, mp 80-81° 13 1 ,2,3,4-tetrahydro- N-(diethylphosphoryI)- 1 ,2,3,4-tetrahydroisoquinoline- isoquinoline-3- carboxylic acid methyl ester, [α] D = +3° carboxylic acid 14 L-serine N-(diethylphosphoryl)-L-serine methyl ester, [α] D -1° 15 L-methionine N-(diethylphosphoryl)-L-methionine methyl ester, [α] D +3° 16 D-phenylglycine N-(diethylphosphoryl)-D-phenylglycine methyl ester, mp 66-67° 17 4-[2-(3-methyl-6- N-(diethylphosphoryl)-4-[2-(3-methyl-6-phenylpyrimidin- phenylpyrimidin- 4-on)-yl]-DL-homoalanine ethyl ester, mp 130-132° 4-on)-yI]-DL- homoalanine 18 3-(2-thienyl)-D L- N-(diethylphosphoryl)-3-(2-thienyI)-DJ-.-alanine methyl ester, CMR α-carbon at 52.15 Δ N-(diethylphosphoryl)-L-homophenylalanine methyl ester, CMR α-carbon at 52.24 Δ N-(diethylphosphoryl)-D,L-o-fluorophenylalanine methyl ester, mp 60-61.5° N-(diethylphosphoryl)-L-tyrosine methyl ester, [α] D = -18° N-(diethylphosphoryl)-D,L-m-fluorophenylalanine methyl ester, mp 82-83.5° N-(diethylphosphoryI)-N-methyl-L-phenylalanine ethyl ester, [α] D = -6° ,N'-diethoxyphosphoryl-l,2-benzenediamine (XV) 1,2-phenylenediamine (XIII, 1.08 g, 10 mmol) and pyridine (3.88 ml, 48 mmol) are combined in methylene chloride (20 ml). The mixture is cooled in an ice bath and diethyl chlorophosphate (XIV, 3.03 ml, 21 mmol) is added dropwize. The reaction is stirred for 24 hr, slowly coming to 20-25°. The reaction is then washed with IN aqueous hydrochloric acid, water, then saturated aqueous sodium bicarbonate. After drying over anhydrous sodium sulfate, removal of the solvent under reduced pressure give the title compound, mp 89-91°; NMR (CDC1 3 ) 7.26, 6.93, 4.23, and 1.30 δ; IR (ATR, deposited from CHC1 3 ) 3273, 2983, 2934, 2906, 1603, 1515, 1479, 1421, 1393, 1370, 1290, 1254, 1226, 1165, 1099, 1029, 967, 802, 750, 623 and 614 cm "1 ; MS (El, m/e) 380 (m + ), 335, 244, 198, 170, and 108; Exact mass calcd for C 14 H 26 N 2 0 6 P 2 = 380.126, found = 380.1269. EXAMPLE 25 (2S)-N,N'-Diethoxyphosphoryl-3-phenyI-l,2-propanediamine (XV) (2S)-l,2-propanediamine (XIII, 189 mg, 1.25 mmol) is dissolved in dichloromethane (10 ml). The mixture is cooled to 0° and is treated with DBU (0.70 ml, 4.71 mmol) followed by diethyl chlorophosphate (XIV, 0.68 ml, 4.71 mmol). The reaction is stirred for 3 hr, coming to 20-25°. Work up as described in EXAMPLE 24 affords a white solid. The solid is chromatographed on silica (35 g), eluting with methanol/chloroform (2/98), pooling and concentration of the appropriate franctions gives the title compound, mp 112-114°; NMR (CDC1 3 ) 7.27, 4.10-3.90, 3.66, 3.45, 3.05, 2.93-2.81 and 1.29 δ; IR (ATR deposited from CHC1 3 ) 3186, 2980, 2930, 2905,1474, 1395, 1369, 1241, 1220, 1166, 1119, 1035, 966, 870, 801, 747 and 703 cm" 1 ; Specific Rotation [α] D 25 -14°(c 1.00, methanol); MS (FAB) (m+H) + 423; EXAMPLE 26 ±-trα/w-N,N'-diethoxyphosphoryl-l,2-cyclohexanediamine (XV) ±-trα/w-l,2-cyclohexanediamine (XIII, 1.01 g, 8.84 mmol) and DBU (2.78 ml, 18.57 mmol) are combined in methylene chloride (20 ml). The mixture is cooled in an ice bath and was treated with diethyl chlorophosphate (XIV, 2.68 ml), a vigorous exotheπn is observed. The resulting solution is stirred at 0°, slowly coming to 20-25° overnight. The reaction is washed with IN hydrochloric acid and then saline. After drying over anhydrous sodium sulfate, the solvent is removed under reduced pressure to afford a white crystalline product The product is recrystallized from ethyl acetate/hexane to give the title compound, mp 137-138°; NMR (CDC1 3 ) 4.08, 3.04, 2.78, 2.13, 1.67, 1.31 and 1.23 δ; IR (ATR deposited from CHC1 3 ) 3178, 2980, 2919, 2854, 1470, 1445, 1394, 1368, 1221, 1162, 1139, 1121, 1099, 1055, 1034, 1009, 964, 916, 845, 801, 768, 657 and 615 cm "1 ; MS (El, m/e) 386 (m + ), 341, 249, 233, 220, 204, 192, 178, 166, 154, 137, 126, 110, 96, and 81; EXAMPLES 27-30 Following the general procedure of EXAMPLES 24-26 and making noncritical _ variations and using diethyl chlorophosphate (XIV) but starting with different diamines (XH3) the corresponding N,N'-diphosphonodiamine esters (XV) are obtained: EXAMPLE N,N'-diphosphonodiamine ester (XV) 27 N,N'-diethoxyphosphoryl-l,3-benzenediamine, mp 196-212°(dec) 28 N,N'-diethoxyphosphoryl-2,3-naphthalenediamine, mp 106-109° 29 (2R)-N,N'-diethoxyphosphoryl-3-phenyl-l,2-propanediamine, mp 111-112° 30 (2S)-N,N'-dietøoxyphosphoryl-3-(3-indoIyl)-l,2-propanediamine, NMR (CDCl j ) 8.68, 7.60, 7.36, 7.10, 4.04, 3.76, 3.53, 3.19, 2.97 and 1.25 δ EXAMPLE 31 l-[(Ethoxymethylphosphinyl)]- -(3-fluorophenyl)-4-oxo-butane phosphonic acid diethyl ester (XVTfl) 3-Flouroacetophenone (XVII, 123 μl, 138 mg, 1.1 mmol) and anhydrous tetrahydrofuran (5 ml) are cooled in a dry ice/acetone bath and litium bis(trimethylsilyl)amide in hexanes (1 M, 1.2 ml) is added. The reaction is stirred at -78° for 30 min and l-[(ethoxymethylphosphinyl)]-l- ethenyl phosphonic acid, diethyl ester (XVI, PREPARATION 2, 270 mg, 1.0 mmol) in tetrahydrofuran (1 ml) is added. The reaction is stirred at -78° for 1.5 hr and then at 0° for 1 hr. After quenching the reaction with saturated ammonium chloride, the reaction is concentrated under reduced pressure and the residue extracted with chloroform. The extracts are washed with saline and dried over sodium sulfate. Removal of the solvent under reduced pressure affords an oil which is taken up in chloroform and chromatographed on 45g of silica, slurry-packed in chloroform. The column is eluted with methanol/chloroform (1 99, 1 1) followed by methanol/chloroform (2%, 2 1). Pure fractions are found by TLC analysis and combined. Removal of the solvent under reduced pressure gives the title compound, NMR (CDC1 3 ) 7.75, 7.64, 7.43, 7.26, 4.16, 3.41, 2.49-2.30, 1.70 and 1.33 δ; IR (ATR deposited from CHC1 3 ) 3435, 2985, 2910, 1688, 1589, 1484, 1445, 1414, 1393, 1370, 1304, 1245, 1163, 1098, 1024, 969, 895, 841, 794, 759, 684, and 619 cm '1 ; MS (El, m/e) 408 (m + ), 380, 363, 301, 285, 271, 258, 123 and 95; EXAMPLE 32 l-[(EthoxymethylphosphinyI)]^-(3-fluorophenyl)-4-oxo-butane phosphonic acid diethyl ester, disodium salt (XVHI) l-[(Ethoxymethylphosphinyl)]-4-(3-fluorophenyl)-4-oxo-butane phosphonic acid diethyl ester (XVIII, EXAMPLE 31, 118 mg, 0.289 mmol) is dissolved in concentrated hydrochloric acid (2 ml). The solution is refluxed for 24 hr and concentrated. The product is taken up in water and neutralized to pH = 7 with IN sodium hydroxide. The solution is frozen and lyophilized to give the title compound, H NMR (D 2 0) 7.86, 7.76, 5.56, 7.42, 2.17, 1.92 and 1.38 δ: FTIR (ATR deposited from MeOH) 3072, 1686, 1589, 1485, 1444, 1296, 1250, 1156, 1083, 876, 753, 683, 631 and 618 cm "1 ; MS (FAB) Exact mass calcd for C„H 13 FNa 2 0 6 P 2 (m + + H) = 369.1566, found: 369.0110. EXAMPLE 33 l-[(Ethoxymethylphosphinyl)]-4-(3-pyridyl)-4-oxo-butane phosphonic acid diethyl ester (XVm) Following the general procedure of EXAMPLE 31 and making non-critical variations but using 3-acetylpyridine (XVTJ, 241 μl, 266 mg, 2.2 mmol) the title compound is obtained, NMR (CDC1 3 ) 9.21, 8.82, 8.34, 7.52, 4.16, 3.46, 2.39, 1.71 and 1.35 δ; FTIR (ATR deposited from CHC1 3 ) 3459, 2983, 2908, 1689, 1586, 1479, 1445, 1419, 1392, 1372, 1302, 1230, 1163, 1097, 1028, 967, 894, 794, 706, 665 and 616 cm '1 ; MS (El) 391 (m + ), 346, 284, 271, 258, 254, 106, and 78. CHART A For convenience the term phosphono compounds (XII) will be used to designate and is meant to include the "benzyl-type" N-phosphono compounds of formula (III) R,-CH[NR 2 -PO(OR 4 )(OR 5 )]COOR 3 (III) the "nonphenyl-type" N-phosphono compounds of formula (IX) R 6 -CH[NR 7 -PO(OR 4 )(OR 5 )]COOR 3 (IX) the "phenyl-type" N-phosphono compounds of foπnula (X) R 8 -CH[NR 5 -PO(OR 4 )(OR 5 )]COOR 3 (X) and the "phenylethylene-type" N-phosphono compounds of formula (XI) R 10 -CH[NR H -PO(OR 4 )(OR 5 )]COOR 3 (XI) R,-CH(NH 2 )COOH (I-NH j ) I I 4 R r CH(NH 2 )COOR 3 (U-NH 2 ) I I I R,-CH[NH-PO(OR 4 )(OR 5 )]COOR 3 (EQ-NH) I I I R,-CH[NR-PO(OR 4 )(OR 5 )]COOR 3 (HI-NR) T I I R,-CH(NHR)COOR 3 (D-NR) T I R,-CH(NHR)COOH (I-NR) CHARTB (IV) 10 t t 50 CHART C The notation [N-PO(OR 4 )(OR 5 )] refers to the molecular fragment I -N-P(0)-OR 4 I 0R 5 The notation R,-CH[NR 2 -PO(OR 4 )(OR 5 )]COOR 3 (ID) refers to the following structural formula R r CH-CO-OR 3 (HI) I R 2 -N-P(0)(OR 4 )(OR 5 ) CHART D R 12 -CH[NH 2 ( χπi) I R I3 -CH[NH 2 Cl-P(0)(OR 3 )(OR 4 ) (XIV) 10 i 15 R 12 -CH[NH-PO(OR 4 )(OR 5 )] (XV) I R 13 -CH[NH-PO(OR 4 )(OR 5 )] CHART E CH 2 =C[P(0)(0R 4 )(0R 5 )][P(0)(0R 4 )(R 17 )] (XVI) R 14 -X-(CW) ml -R 15 R 16 -H (XVII) M I I I 4 R I4 -X-(CW) m] -CR 15 R 16 -CH 2 -CM[P(0)(OR 4 )(OR 5 )][P(0)(OR 4 )(R I7 )] (XVIII)

Claims: CLAIMS 1. Use of a "benzyl-type" N-phosphono compounds of formula (III) R r CH[NR 2 -PO(OR 4 )(OR 5 )]COOR 3 (HI) where Rj is R I . 3 -(CR 1 . 1 R 1 . 2 ) n - where R,., and Rj. 2 are the same or different and are -H or C,-C 4 alkyl, where n = 1 and where R^ is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR M where R M is C, - alkyl or -CO-C r C 4 alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR M where R is as defined above, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR where R M is as defined above, or combinations thereof; where R 2 is -H or C,-C 4 alkyl; where R 3 is -H or C r C 4 alkyl; where R 4 is -H or C r C 6 alkyl; where R 5 is -H or C r C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms and pharmaceutically acceptable salts thereof to prepare a medicament to treat a human who has arthritis or an inflammatory disease. 2. Use according to claim 1 where Rj is φ-CH 2 - optionally substituted with 1 -OH. 3. Use according to claim 1 where R 2 is -H or -CH 3 . 4. Use according to claim 1 where R 3 is C r C 4 alkyl. 5. Use according to claim 1 where R 4 is C r C 4 alkyl and where R 5 is C C 4 alkyl. 6. Use according to claim 1 where the "benzyl-type" N-phosphono compound (III) is selected from the group consisting of N-diethylphosphoryl-3-fluorophenylalanine methyl ester, N-(diethylphosphoryl)-L-phenylalanine methyl ester, N-(diethylphosphoryl)-L-tryptophane methyl ester, N-(diethylphosphoryl)-L-phenylalanine ethyl ester, N-(diethylphosphoryl)-D,L-o-fluorophenylalanine methyl ester, N-(diethylphosphoryl)-L-tyrosine methyl ester, N-(diethylphosphoryl)-N-methyl-L-phenylalanine ethyl ester. 7. "Nonphenyl-type" N-phosphono compounds of formula (IX) R 6 -CH[NR 7 -PO(OR 4 )(OR 5 )]COOR 3 (DQ where R 3 is -H or C,-C 4 alkyl; where R 4 is -H or C,-C 6 alkyl; where R 5 is -H or C,-C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; where Rg is R 6 . 3 -(CR 6 . 1 R 6 . 2 ) m - where R^ and R^ are the same or different and are -H or C,-C 4 alkyl, where m = 1-4 and where R^ is ortho-(-CH 2 -R fr4 )-phenyl- where R^ and R 7 are taken together to form a ring selected from the group consisting of 5 thru 9 atoms, 2- or 3-thienyl optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OR^ where R^ is -C, alkyl or -CO- -Q alkyl or combinations thereof and where R 7 is -H or C,-C 4 alkyl, 2-, 3- and 4-pyridinyl optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OR < ^ where R^ is as defined above, or combination thereof and where R 7 is -H or -C 4 alkyl, 3-methyI-6-phenyl-pyrimidin-4-one-2-yl where the phenyl portion is optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OR^ where R^ is as defined above and where R 7 is -H or Cj- alkyl, 2- or 4-quinolinyl optionally substituted with 1 thru 6 -F, -Cl, -Br, -OH, -OR^ where R^ is as defined above, or combinations thereof and where R 7 is -H or C,-C 4 alkyl, 2-triazinyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR^ where R^ is as defined above, or combinations thereof and where R 7 is -H or C,-C 4 alkyl; -OH and -O-R^ where R^ is - alkyl; -SH and where is as defined above; and pharmaceutically acceptable salts thereof. 8. "Nonphenyl-type" N-phosphono compounds of formula (IX) according to claim 7 where R f , is thienyl and thienyl substituted with a -F, -Cl or -Br atom. 9. "Nonphenyl-type" N-phosphono compounds of formula (IX) according to claim 7 where R 7 is is -H or -CH 3 . 10. "Nonphenyl-type" N-phosphono compounds of formula (IX) according to claim 7 where R 3 is C,-C 4 alkyl. 1 1. "Nonphenyl-type" N-phosphono compounds of formula (IX) according to claim 7 where R 4 is C C Λ alkyl and where R 5 is C,-C 4 alkyl. 12. "Nonphenyl-type" N-phosphono compounds of formula (IX) according to claim 7 where the "nonphenyl-type" N-phosphono compound is selected from the group consisting of N-(diethylphosphoryl)-l,2,3,4-tetrahydroisoquinolinecarboxylic acid methyl ester, N-(diethylphosphoryl)-L-serine methyl ester, N-(diethylphosphoryl)-L-methionine methyl ester, N-(diethylphosphoιyl)-4-[2-(3-methyl-6-phenylpyrimidin-4-on)-yl]-DL-homoaIanine ethyl ester, N-(diethylphosphoryl)-3-(2-tl-ienyl)-D -alanine methyl ester. 13. "Phenyl-type" N-phosphono compounds of formula (X) R 8 -CH[NR,-PO(OR 4 )(OR 5 )]COOR 3 (X) where R 3 is -H or C r C 4 alkyl; where R 4 is -H or - alkyl; where R j is -H or C,-C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; where R 8 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR M where R w is -C, alkyl or -CO- - alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR w where R M is C, - alkyl or -CO- - alkyl, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR w where R f , is as defined above, or combinations thereof; where R 9 is -H or C r C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms and pharmaceutically acceptable salts thereof. 14. "Phenyl-type" N-phosphono compounds of formula (X) according to claim 13 where R 8 is -φ optionally substituted with 1 or 2 -OH or -F. 15. "Phenyl-type" N-phosphono compounds of formula (X) according to claim 13 where R 9 is is -H or -CH 3 . 16. "Phenyl-type" N-phosphono compounds of formula (X) according to claim 13 where R 3 is C,-C 4 alkyl. 17. "Phenyl-type" N-phosphono compounds of formula (X) according to claim 13 where R 4 is C r C 4 alkyl and R 5 is C r C 4 alkyl. 18. "Phenyl-type" N-phosphono compounds of formula (X) according to claim 13 where the "phenyl-type" N-phosphono compound is selected from the group consisting of N-(diethylphosphoryl)-D-phenylglycine methyl ester. 19. "Phenylethylene-type" N-phosphono compounds of formula (XI) R 10 -CH[NR, ,-PO(OR 4 )(OR 5 )]COOR 3 (XI) where R 3 is -H or C r C 4 alkyl; where R 4 is -H or C r C 6 alkyl; where R 5 is -H or C,-C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; where Rj 0 is Rιo. 3 -(CR 1(M ιo- 2 ) p - where R^ and R^ are the same or different and are - H or C C 4 alkyl, where p = 2-4 and where R 10 . 3 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR 1{M where R 1CM is C, -C 3 alkyl or -CO-Cj-C 4 alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR 1(M where R 1(M is C, -C, alkyl or -CO- - alkyl, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR ltM where R 1(M is as defined above, or combinations thereof; 2-[3-methyl-6-phenylpyrimidin-4-one]yl; where Rn is -H or C r C 4 alkyl and pharmaceutically acceptable salts thereof. 20. "Phenylethylene-type" N-phosphono compounds of formula (XI) according to claim 19 where R 10 is -CH 2 -CH 2 -φ and -CH 2 -CH 2 -φ-OH. 21. "Phenylethylene-type" N-phosphono compounds of formula (XI) according to claim 19 where R n is is -H or -CH 3 . 22. "Phenylethylene-type" N-phosphono compounds of formula (XI) according to claim 19 where R 3 is C r C 4 alkyl. 23. "Phenylethylene-type" N-phosphono compounds of formula (X) according to claim 19 where R 4 is C,-C 4 alkyl and where R 5 is C r C 4 alkyl. 24. "Phenylethylene-type" N-phosphono compounds of formula (XI) according to claim 19 where the "phenylethylene-type" N-phosphono compound is selected from the group consisting of N-(diethylphosphoryl)-L-homophenylalanine methyl ester. 25. N,N'-diphosphonodiamine esters of formula (XV) R 12 -CR π [NH-PO(OR 4 )(OR 5 )] (XV) I R 13 -CR 18 [NH-PO(OR 4 )(OR 5 )] where R 4 is -H or - alkyl; R 5 is -H or Cj- alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; C,-C 4 alkyl, Cς-Cη cycloalkyl, i 2 - 3 -( i 2 -i i 2 - 2 n _ where and R 12 . 2 are the same or different and are -H or Cj-C 4 alkyl, where n = 0 or 1 and where R 12 . 3 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR 12jJ where R l2 ^ is C, -C 3 alkyl or -CO- - alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR,^ where R IW is as defined above, or combinations thereof, 2- or 3-indoIyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR IM where R 12-4 is as defined above, or combinations thereof; R 13 is C r C 4 alkyl, ς-Cη cycloalkyl, R 13 . 3 -(CRj 3 . 1 R 13 . 2 ) n - where R 13 ., and R 13 . 2 are the same or different and are -H or C,-C 4 alkyl, where n = 0 or 1 and where R 13 . 3 is -φ optionally substituted with 1 thru 5 -F, -Cl, -Br, -OH, -OR 1M where R 1W is C, -C 3 alkyl or -CO-C,-C 4 alkyl, or combinations thereof, 1- or 2-naphthyl optionally substituted with 1 thru 7 -F, -Cl, -Br, -OH, -OR 13Jt where R ]W is as defined above, or combinations thereof, 2- or 3-indolyl optionally substituted with 1 or 2 -F, -Cl, -Br, -OH, -OR 1M where R 13 ^ is as defined above, or combinations thereof and where R, 2 and R 13 are taken together with the attached carbon atoms to form (1) a phenyl ring - R 17 and R 18 are taken together to form a double bond. (2) a 2,2'-naphthyl ring - R, 7 and R 18 are taken together to form a double bond, or (3) a cycloalkyl ring of C 5 -C 8 - R 17 and Rι 8 are -H, and pharmaceutically acceptable salts thereof. 26. N,N'-diphosphonodiamine esters of formula (XV) according to claim 25 where R 4 is C r C 4 alkyl and where R 5 is C,-C 4 alkyl. 27. N,N'-diphosphonodiamine esters of formula (XV) according to claim 25 where R 12 is -CH 2 -φ and -CH 2 -[3-indolyl], where R 13 is -H and where R 12 and R 13 are taken together to foim a phenyl ring, a 2,2'-naphthyl ring and a cycloalky ring of six atoms. 28. N,N'-diphosphonodiamine esters of formula (XV) according to claim 25 which are selected from the group consisting of N,N '-diethoxyphosphoryl- 1 ,2-benzenediamine, (2S)-N,N'-diethoxyphosphoryl-3-phenyI- 1 ,2-propanediamine, ±-trατw-N,N'-diethoxyphosphoιyl-l,2-cyclohexanediamine, N,N'-diethoxyphosphoryl-2,3-naphthalenediamine, (2R)-N,N'-diethoxyphosphoryl-3-phenyl- 1 ,2-propanediamine, (2S)-N,N '-diethoxyphosphoryl-3-(3-indolyl)- 1 ,2-propanediamine. 29. Phosphonophosphinate esters of formula (XVTII) R 14 -X-(CW) πιl -CR 15 R 16 -CH 2 -CM[P(0)(OR 4 )(OR 5 )][P(0)(OR 4 )(R I9 )] (XvTJI) where m, is 0 or 1; where M is -H, -Cl or -CH 3 ; where R 4 is C r C 6 alkyl; where R 5 is C j -C 6 alkyl and where R 4 and R 5 are taken together to form a heterocyclic ring consisting of 5 thru 7 atoms; R 14 is (1) -φ optionally substituted with 1 or 2 -φ or with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, C 3 -C, cycloalkyl, -OH, C,-C 4 alkoxy, -SH, -NH 2 , where R 14 _ι is C,-C 10 alkyl, C j - cycloalkyl, pyridine, -(CH^-COO-R,^ where n, is 1 thru 3 and R 14 . 2 is -H, C,-Q alkyl. -Φ. -CH 2 -φ, -φ optionally substi ted with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, - cycloalkyl, -OH, C,-C 4 alkoxy, -O-φ, C C Λ alkylthio, -N- CO-R 14 . 3 where R J4 . 3 is C r C 10 alkyl, C J -C J cycloalkyl, pyridine, -(CH-^-COO-R^s where n* is 1 thru 3 and R 14 _ 9 is -H, - alkyl, -φ, -CH 2 -φ, -φ optionally substimted with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, -C, cycloalkyl, -OH, C,-C 4 alkoxy, -O-φ, C,-C 4 alkylthio, -0-S(0) 2 -R 14 ^ where R llM is C r C 10 alkyl, -φ optionally substimted with 1 thru 5 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, - cycloalkyl, -OH, C,-C 4 alkoxy, -O-φ, C,-C 4 alkylthio, -N-CO-R 2 . 3 where R 2 . 3 is as defined above, naphthalene optionally substimted with 1 or 2 -φ, naphthalene optionally substimted with 1-7 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, - cycloalkyl, -OH, C,-C 4 alkoxy, -O-φ, C,-C 4 alkylthio or -N(CH 3 ) 2 , -N(R 14 . S )(R 14 ^) where R 14 . 5 and R 14 ^ are the same or different and are -H, Cj-C 6 alkyl, - cycloalkyl, -φ, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and where R 2 . 5 and R 2 ^ are taken together with the attached nitrogen atom to form a heterocyclic ring containing 4 thru 6 carbon atoms, a 1-morpholine and 1-piperidine ring, -N(R 14 . 7 )-CO-R 14 _, where R ]4 . 7 is H, C C 6 alkyl, -C, cycloalkyl, -φ, 2- pyridinyl, 3-pyridinyl, 4-pyridinyl, and where R 14 . j is as defined above, -N(R 14 . 5 )-CO-0-R 14 . 8 where R 14 . 8 is -H, C r C 6 alkyl. -C, cycloalkyl, -φ and -CH 2 -φ.. -N(R J4 . 7 )-CO-N(R 14 . 5 )(R 14 ^) where R 14 . 5 , R 14 ^ and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R (4Jl where R ]4Jl and R 14 _ 7 are as defined above, (2) 2- and 3-furanyl optionally substimted with 1 or 2 -φ, or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,- 0 alkyl, - cycloalkyl, -OH, -SH, -NH 2 , -0-CO-R 14 ., where R 14 _, is as defined above, -0-S(0) 2 -R ) where R J4 is as defined above, -N(R 14 . 5 )(R 14 ^) where R^ and R 14 ^ are as defined above, -N(R 14 . 7 )-CO-R, 4 . j where R 14 ., and R 14 . 7 are as defined above, -N(R 14 . 5 )-CO-0-R 14 ^ where R 14 . s and R 14 _ 8 are as defined above, -N(_Rι_ -ι)-CO-N(]R 14 _. 5 )φ. lA ^ where R 14 _ 5 , R 14 ^ and R 14 . 7 are as defined above, are as defined above, (3) 2-, 4- and 5-pyrimidinyl optionally substimted with 1 or 2 -φ, or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C r C 10 alkyl, -C, cycloalkyl, -OH, -SH, -NH 2 , -0-CO-R 14 . ! where R 14 ., is as defined above, -0-S(0) 2 -Rι 44 where R J<M is as defined above, -N(R 14 . 5 )(R 14 ^) where R 14 . 5 and R liWi are as defined above, -N(R 14 . 7 )-CO-R 14 _ι where R 14 . ] and R 14 . 7 are as defined above, where R 14 . 5 and R 14 _ 8 are as defined above, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 1 - 6 ) where R J4 . 5 , R^ and R 14 . 7 are as defined above, -N(R I4 _ 7 )-S0 2 -R 14 - 4 where R 14^ , and R ]4 . 7 are as defined above, (4) 2-, 3- and 4-pyridinyl optionally substimted with 1 or 2 -φ, or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,-C 10 alkyl, - cycloalkyl, -OH, -SH, -NH 2 , -0-C0-R 14 . j where R iΛ . t is as defined above, -0-S(0) 2 -R 14Jt where R l 4 is as defined above, -N(R 14 . 5 )(R 14 ^) where R 14 . 5 and R 1-w are as defined above, -N(R 14 . 7 )-CO-R 14 -. ! where R 14 _, and R I4 . 7 are as defined above, -N(R 14 . 5 )-CO-0-R 14 . 8 where R 14 . 5 and are as defined above, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 14 where R^, R liU> and R 14 , 7 are as defined above, -N(R 14 . 7 )-S0 2 -R,, t - 4 where R 14^ , and R 14 . 7 are as defined above, (5) 2- and 3-thiophenyl optionally substimted with 1 or 2 -φ, or with 1 thru 3 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , -C 10 alkyl, C j -C, cycloalkyl, -OH, -SH, -NH 2 , -0-CO-R ]4 ., where R 14 . ] is as defined above, -0-S(0) 2 -R 14 ^ where R 1<M is as defined above, -N(R 14 . 5 )(R 14 ^) where R 14 . 5 and R 14 ^ are as defined above, -N(R 14 _ 7 )-CO-R 14 _, where R 14 _, and R 14 . 7 are as defined above, -N(R 14 _ 5 )-CO-0-R 14 ^ where R 14 _ 5 and R 14 . 8 are as defined above, -N(R 14 . 7 )-CO-N(R 14 . 5 )(R 14 ^) where R 14 . 5 , R 14 -« and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R 1 4 where R 1J and R 14 7 are as defined above, (6) 1- and 2-naphthalyl optionally substimted with 1 or 2 -φ, or with 1 thru 7 -F, -Cl, -Br, -I, -N0 2 , -CN, -CF 3 , C,-C, 0 alkyl, C j -C, cycloalkyl, -OH, -SH, -NH 2 , -0-CO-R 14 ., where R 14 . ] is as defined above, -0-S(0) 2 -R 1<w where R 1<M is as defined above, are as defined above, -N(R 14 . 7 )-CO-R 14 ., where R^, and R 14 . 7 are as defined above, where R 14 - 5 and R 14 - 8 are as defined above, -N(R 14 . 7 )-CO-N(R 14 _ s )(R JiWj ) where R 14 _ 5 , R 1<w and R 14 _ 7 are as defined above, where R liM and R I4 - 7 are as defined above; (7) 2-thiazoIyl optionally substimted with 1 or 2 -F, -Cl, -Br, C r C 4 alkoxy, C,- C 4 alkyl or -φ, (8) 2-benzothiazoyl optionally substimted with 1 thru 4 -OH or C,-C 4 alkoxy, (9) C,-C 4 alkyl, (10) - cycloalkyl, (R 15 R 16 -I) R JJ and R 16 together with the attached carbon atom form a cycloalkyl ring of 3 thru 7 carbon atoms, (Ri 5 /R j6 -π) R 15 is -H and R 16 is -H, R )4 ^, -CO-0-R 14 ^, -CO-R 2 , -CN, -CO-NH-R 2 , -NH- CO-R 14 .„ -S-Ri,,. ! and -CO-NH-thiadiazole optionally substimted with -φ where R 14 , R 14 _„ R 1<w and R j4 . 8 are as defined above, (R 15 R 16 -III) R ]5 is -H and R 16 is -F, -Cl, -Br or -I, (R, 5 R 16 -IV) R 15 and R 16 are the same or different and are C,-C 10 alkyl; (Wj-I) Wj is =0, =S, =N-N(R 14 . 7 ) 2 where R ]4 . 7 is as defined above, (W r II) W J is W j .,:W,. 2 where W,., and W,^ are the same and are C C 4 alkoxy, -O-φ, C r C 4 alkylthio or -S-φ, (Wj-III) W, is W L3 :W M where W,. 3 and W M are taken together with the attached carbon atom to form a 1,3-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,3-dithiolane or 1,3- oxoathiolane ring system, (W r IV) W, is -H:-W,. 5 where W M is -OH, -SH, -NH 2 , -S-W w where W w is C r C 4 alkyl, -0-CO-R 14 _, where R 14 _, is as defined above, -0-S(0) 2 -R J where R 14 is as defined above, -N(R 14 . 5 )(R 14 ^) where R 14 . 5 and R 14 ^ are as defined above, -N(R 14 . 7 )-CO-R 14 . 1 where R^., and R l4 .η are as defined above, -N(R 14 . 5 )-CO-0-R 14 . 8 where R 14 . 5 and R 14Ji are as defined above, -N(R 14 . 7 )-CO-N(R 14 _ 5 )(R 14 ^) where R 14 _ 5 , R 14 ^ and R 14 . 7 are as defined above, -N(R 14 . 7 )-S0 2 -R J<w where R 144 and R 14 _ 7 are as defined above; R 19 is C r C 4 alkyl; X is -(CHjX - or -(CH=CH) n3 - where i^ is 0 thru 5 and n 3 is 0 thru 2, with the proviso that when R 4 is -R 1 4 , 1 is 1 and pharmaceutically acceptable salts thereof. 30. A phosphonophosphinate esters of formula (XVIII) according to claim 29 where R 4 is C C 4 alkyl and where R 5 is C r C 4 alkyl. 31. A phosphonophosphinate esters of formula (XVUI) according to claim 29 where R 14 is 2- pyridinyl, 3-pyridinyl, 2-fiιranyl, 2-thienyl or -φ optionally substituted with 1 thru 2-F, -Cl, -N(R 14 . 7 )-CO-R 14 . ! where R 14 . 7 is -H and R 14 ., is C, alkyl, alkyl or -φ. 32. A phosphonophosphinate esters of formula (XVUI) according to claim 29 where r^ and n 3 are 0. 33. A phosphonophosphinate esters of formula (XVIII) according to claim 29 where W is =0. 34. A phosphonophosphinate esters of formula (XVUI) according to claim 29 where mj is 1. 35. A phosphonophosphinate esters of formula (XVIII) according to claim 29 where R, 5 is -H and where R 16 is -H, R,^, -CO-0-R 14 _ 8 , -CO-R 14 , -CN and -CO-NH-R 14 . 36. A phosphonophosphinate esters of formula (XVUI) according to claim 29 where M is -H. 37. A phosphonophosphinate esters of formula (XVIII) according to claim 29 where the phosphonophosphinate ester is l-[(ethoxymethylphosphinyl)]-4-(3-fluorophenyl)-4-oxo-butane phosphonic acid diethyl ester, l-[(ethoxymethylphosphinyI)]-4-(3-pyridyI)-4-oxo-butane phosphonic acid diethyl ester.

Inventors: FRITZEN EDWARD LAWRENCE JR, WHITE DAVID RAYMOND, FRITZEN, EDWARD, LAWRENCE, JR., WHITE, DAVID, RAYMOND
Applicants: FRITZEN EDWARD LAWRENCE JR, UPJOHN CO, WHITE DAVID RAYMOND, THE UPJOHN COMPANY
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61P29, C07F9