DIPHOSPHONATE DERIVATIVES OF THERAPEUTIC AGENTS

Abstract: Novel chemotherapeutic agents having utility in treating infectious diseases such as periodontal disease, certain urinary tract infections, infectious urinary tract stones, and bone cancer, are obtained by combining chemically a diphosphonate compound with a therapeutic agent effective against the foregoing diseases.

Description: D1PH0SPH0NATE DERIVATIVES OF THERAPEUTIC AGENTS Osteomyelitis is a painful and debilitating condition caused by a variety of micro-organisms, mainly Staphylococcus nureuε. This disease occurs more commonly in children. Within the adult population, diabetics and kidney dialysis patients also are vulnerable. The acute form of the disease is treatable with antibiotics, but requires a lengthy period of daily therapy. It can, however, revert to a recurrent or chronic form requiring repeated hospital stays and treatment regimens. The remarks of Waldvogel et al. in their 1980 review continue to be relevant today: "The high success rate observed with antibiotic therapy in most bacterial diseases contrasts with the substantial failure rate in the treatment of bone infections." (1980) New Eno. J. Med. 303:360. Urinary catheters are the most common source of nosocomial infections. The bacteriuria which may result from the catheterization is serious because it is a predisposing factor to Gram-negative septicemia, a disease with a high rate of mortality. Kunin stated the consequences of this infectious nidus succinctly: "Systemic antimicrobial therapy is ineffective in eradicating catheter-associated infections other than temporarily." (1987) Detection. Prevention and Management of U -tqary Trac»_Jj>.tec,t.lp.Qs. t Chapt. 5, pp. .247-297. Urinary calculi can develop anywhere in the urinary tract. They are hard, mineralized substances producing pain, obstructions and secondary infections. Basically there are two types of urinary stones: metabolic, originating through metabolic dysfunctions, and infectious, associated with bacterial infections. Infection persists in 40% of patients treated with antibiotics, and a full 60% of those develop recurring stones. Left untreated, infected calculi can result in kidney loss and even death in 25% of such cases. Some metabolic stones become contaminated and bacteria are entrapped within the interstices during its crystallization. Such infected stones are notoriously resistant to eradication. Current treatment of infectious urinary calculi involves suigical removal with concomitant administration of antimici obia agents. βroadly speaking, there are two categories of periodontal disease gingivitis and periodontitis, both generated by micro-organisms i dental plaque on the tooth surface. Both conditions are characterize by an inflammation of the gingiva, the gurn tissue at the base of th teeth. Periodonti is also involves bone erosion and loss of dentitio over a long period of time. Burt (1992) Clin. Geriat. Med. 3:447. Osteosarco a is an exceedingly malignant tumor that usually occur in children and young adults. The type and extent of the tumo determines the type of treatment which ranges from variously administered chemotherapeutic agents to limb amputation in conjunctio with chemotherapy. DETAILED.D.ES RIPTION The novel pharmaceutically active therapeutic chemical agents o the present invention are diphosphonate (also called bisphosphonate derivatives of therapeutic agents effective in treating infectiou diseases such as osteomyelitis, periodontal disease, certain urinar tract infections, infectious urinary tract stones, and bone cancer. Th diphosphonate groups cause the therapeutic agent to be attracted to, an to concentrate on, the surfaces of various salt crystals and the mor complex forms of such crystals, 'such as hydroxyapatite, a majo constituent of bone and the surface of dentition. Bacteria associate with these crystals are thereby exposed to an elevated concentration o the therapeutic agent, relative to the surrounding milieu. Organism harbored in bone (osteomyelitis), at the gum-dentition interfac ( periodontal disease), on the surface of salt-encrusted indwellin urinary catheters and in infectious urinary calculi, are targeted by th therapeutic agents. Because of the relative inaccessibility of micro-organisms in thi p rotected environment, there is a dangerous tendency on the part o attending physicians to treat these infections through indiscriminat use of antibiotics. This often leads to the development of resistan forms, a frequent occurrence, for example, in urinary tract infections When treated according to the present invention, however, not only ar the free-floating, planktonic organisms neutralized by the therapeuti agents disclosed herein but, more importantly, the source of th infection, namely the sessile forms adhering to the catheter ar attacked. Chemotherapy of ostβosarcoma is another area in which th therapeutic agents of the present invention provide a two-par therapeutic advantage over agents not containing diphosphonate groups Diphosphonate derivatives of anti-neoplastic drugs like methotrexate an adriamycin concentrate in bone tissue, thereby allowing lower effectiv doses to be employed, thus attenuating their toxicity and reducing sid effects. Diphosphonic acid compounds useful as intermediates in the prese invention have the general formula V-R-Z (1) wherein V * is halogen preferably Cl, Br and I, OH, SH, NR'R", COOR' , CO-X wherein X i halogen or azido, 0-CO-X wherein X is halogen, O-CO-OR' , CO-SR * , CO-X, NR'-CO-X, NR'-NHR", NR'-CN, NR*-C(=NH)-NH-CN, or metal (covalently bound or ibnic) , .for exampl Li, Na or Mg, wherein R, R' and R * ' are independently hydrogen or organic group and Z is I -C-OH I PO j R 2 wherein each R 3 is independently H, alkyl or substituted alk of from 1 to about 10 carbons that may be linear or branched, saturat or unsaturated; cycloalkyl or substituted cycloalkyl of from 3 to abo 10 carbons that may be saturated or unsaturated; monocyclic polycyclic aryl such as, for example phenyl or naphthyl, optionall substitued by halogen, trifluoromethyl, alkyl of 1 to about 4 carbon nitro, amino, hydroxy or carboxyl; aralkyl or substituted aralkyl, th is to say alkyl carrying an aryl substituent wherein the alkyl group h from 1 to about 10 carbons that may be linear or branched, saturated unsaturated; or a saturated 5- or 6-membered heterocyclic such as, f example, piperidine, orpholine and piperazine, or 5- or 6-member unsaturated heterocyclic such as, for example pyridine, fura thiophene, pyrazine, pyri idine, purine and imidazole. If desired or necessary, the OH group of Z may be protected by techniques established and known in the art. Pharmaceutically active chemical entities useful in the present invention have the general formula A-V wherein A is the residue of a pharmaceutically active cnemical entity and V has the meaning given above. The compounds of the present invention have the general formula and A-(V) B -(R) n -Z (2) wherein m and n are independently O or 1, A, R, and Z have the meanings given above and V is one of, but not limited to, O, S, NR*. CONR', CO-O, O-CO, O-CO-0, CO-S, S-CO, S-CO-S, NR * -CO, O-CO-NR', NR'-CO-O, NR'-CO-NR", CO-NR'-NR", NR'-NR"-CO, NR'-C(=NH)- NR", NR'-C(=NH)-NH-C(=NH)-NR" or another acyclic or cyclic aliphatic or heteroorganic connecting structural unit; R, R*, R", and Z arc as defined above, and R" is' hydrogen or an organic group that can be the same as R' or can be different from R*. Compounds of the foregoing formula wherein either n or m is 1, or wherein both n and *m are 1 are obtained by reacting various compounds of fdrmula (1) with a pharmaceutically active chemical entity of formula A-V carrying a functional group or substituent appropriate for the formation of the connecting structural unit by the chemical reaction. Thus, when the pharmaceutically active chemical entity contains a halogen atom, it can be reacted with a diphosphonate compound of formula V'-R-Z (1) wherein V is primary or secondary amino to eliminate hydrogen halide and yield a compound of the formula A-NR'-R-Z (3), which corresponds to formula (2) with n and = 1, and V = NR' wherein R' is H or an organic group; it can also be reacted with a reactant containing two primary or secondary amino groups in an acyclic or cyclic 'structure and with a compound of formula (1) or (la) wherein Y is halogen, to give a compound of formula (2) wherein n = 1 and V is a connecting group attached by nitrogen atoms (-NR'-) to both A and R. Compounds of formula (3) can, however, be obtained as well by reacting a pharmaceutically active chemically entity compound containing a primary or secondary amino group with a compound of formula (1) containing a halogen atom. Alternatively, when the pharmaceutically active chemical entit contains a carboxylic group, or a reactive carboxyl group derivativ { e. g, acyl halide ester or azide), it can be reacted with a compound of formula (1) wherein V * is a primary or secondary amino group t eliminate water or another molecule as results from the correspondin condensation reaction and form a compound of the formula A-CO-NR'-R-Z I (13), which corresponds to (2) with m = 1, and n = 1 and V = CONPft, bu also with a compound of formula (1) wherein V can be, but is no limited to, for example, OH or SH, to give A-CO-V-R-Z (14), wherein A, R and Z have the previously stated meanings whereas V can be S, 0 o another atom or group which can connect CO to R by chemical bonds. Likewise, a compound of formula (1) wherein V * is COOH or a reactiv derivative thereof ( e.g. acyl halide, ester or azide) can be reacte with a pharmaceutically active chemical entity containipg a primary o secondary amino group (A-NHR * ), to give compounds of the formula A-NR * - CO-R-Z (15) or, conversely, to give a compound of the formula A-CO- NR * -R-Z (16), wherein A, R, and Z have the previously stated meanings. The combination of groups, precursors, reactions and reaction condition are easily understood by those skilled in the art in light of th discussions above. When one of the reactants or both contain othe reactive groups than those needed to establish, the chemical connectio between A and R-Z, the interfering groups are protected by technique established and known in the art. The condensation reactions of the foregoing synthetic procedure are conventional in the art and are carried out under standar condensation conditions that are well known to those skilled in the art. In addition, as mentioned previously, when the pharmaceuticall active chemical entity contains a carboxylic group, it can be reacte directly with P(OH) 3 and PCl j as described below to yield a compound of formula A-Z (12) wherein A and Z have the previously stated meanings. Diphosphonic acid compounds of formula V'-R-Z (1) can b synthesized by any of various methods. Treating the carboxylic group o an organic acid with phosphorous acid, P(0H)., and phosphorou trichloride, PCl j , according to the method of US patent 4,621,07 converts the carboxylic acid group to Z. In another method [Worms al. (1976) In: Kosolapoff GM, Maier L (eds) Organic phosphor compounds, vol. 7. Wiley, New York, p 1] an organic carboxylic acid formula RCOOH, wherein R is an organic group, typically the residue an aliphatic or aromatic carboxylic acid, optionally substituted by su groups as amino and halogen, is reacted with a mixture of water a phosphorus trichloride according to the following (equation: I (I) RCOOH + Hf + PCl j - R-C-OH (or R-Z) I The products obtained under these anhydrous conditions are condensate i.e., two or more molecules of the diphosphonate condensed via remov of a molecule of water. These condensates can then be converted to t compounds of formula R-Z by heating in water or in 6 rt HC1. Tetraalkyl esters of ≤re/»-diphosphonic acids (R-Z, wherein R and have the previously stated meaning and and R J withih Z is alkyl) can prepared by the reaction of a carboxylic acid chloride with tr ialkylphosphite. The resultant acylphosphonatβ reacts under slight basic conditions with a dialkylphosphite to yield a diphosphona tetraalkyl ester, which then is hydrolyzed with acid or base to t corresponding free acid. For sensitive compounds, which include mo antibiotics, reaction with trimethylbromosilane inchlorofor of CCl^ preferred, followed by reaction with water (no catylst). The l-amino-l,l-diphosphonates are made [Worms et al. (1979), Λnorg Allg Chem 457:209-213] by reacting a nitrile or an amide wi ii-PO. and a phosphorus trihalide and hydrolyzing the product with water or by carrying out the reaction directly in the presence of water. Substituting a haloacid of the formula X-(CH 2 )-C00H (13), where X is Cl, Br, or I and is an integer from 1 to 10, for RCOOH equation (I) yields the product of formula X-(CH 2 ) § -Z (14), i.e. 1, " (CH j ), which is an intermediate for preparing compounds of the prese invention. Reacting a compound of formula (14) with a derivative ammonia of the formula R I H-M-N-H I R 2 (15) wherein M is N or C, and R l and R 2 are independently: hydrogen; alkyl, preferably C^lkyl; alkyl, preferably C.. 6 alkyl, substituted with one or more of OH, SH, COOH halogen or primary or secondary amine, provided that at leas one of R l and R 2 is always substituted alkyl, preferabl substituted C^alkyl, or R l and R 2 , taken together with th atom to which they are each attached, form a ring such as piperazine or i idazolidine, yields the compound of the formula R l I H-M - N-(CH 2 ) B -Z I R 2 (16). Compounds of formula (16) wherein at least one o R l and R contains a reactive group, such as a primary or secondary amin group, a halogen atom, COOH, OH, or SH, are intermediates for use i preparing the novel pharmaceutically active chemical entities of th present invention by reaction with a pharmaceutically active compoun containing a functional group which can react with the compound o formula (16). NH ∑ Compounds of the formula I R-CH-Z (17) are prepared by using a σ-amino acid as the compound of formula RCOOH in equation (I) Compounds of the formula NH j I R-CH-CH--Z (18) are prepared by using a .iπiino acid as the compound of formula RCOOH in equation (I). Compoun uf the formula NH. I R-CH-(CH 2 ) B -Z (19) wherein n is from 2 to 7 ar prepared by using the corresponding amino acid (for R=H this is referre to as an omega-amino acid) as the compound of formula RCOOH in equatio (I). An alternative method for preparing a compound of formula (1 wherein X is l-piperazyl is to react the corresponding compound wherei X is NH 2 , (for example (17), (18) or (19), with bis(2-chloroethyl)amine. Examples of some specific acids that can be converted t diphosphonates of formula R-Z according to any. of the foregoin procedures are the following: m-aminobenzoic acid, p-aminobenzoic acid, 3-chloro-4- aminobenzoi acid, 2-chloro-4-aminobenzoic acid, 2-chloro-5-aminobenzoic acid, and 3- chloro-5-aminobenzoic acid, compounds of formula (13) wherein X is Cl , Br, or I, and n ■ 1-10. α-amino acids, e.g. . alanine, aminobutyric acid, arginine, asparagine, aspartic acid, canavanine, citrulline, cysteine, cystine, dibromotyrosine, dihydroxyphenylalanine, diiodotyrosine, 'glutamic acid, glutamine, glycine, histidine, hydroxylysine, hydroxyproline, isoleucine, leucine, lysine, methionine, norieucine, norvaline, omithine, phenylalanine, proline, serine, thiolhistidine, threonine, thyroxine, tryptophane. tyrosine, and valine, β-ami o acids of formula RCH(NH«)CH,C00H wherein R is H or alky optionally substituted by OH, SH, and halogen, ga ma-amino acids of formula RCH^H j HCH j ^CH j COOH wherein n is 1 10, and R is H or alkyl optionally substituted by OH, SH, and halogen. Specific diphosphonates of formula (1) usable according to th present invention include the following: 1,2-dihydr oxyethane-1, 1-diphosphonic acid, dichloromcthanenediphosphonic acid (Cl j MBP), difluoromethanenediphosphonic acid (F.M8P), 3-amino-l-hydι oxypropane-1,1-diphosphonic acid (AHPrBP), 4-amino-1-hydroxybutane-1,1-diphosphonic acid (AHBuBP), 5- amino- 1-hydroxypentane-l, 1-diphosphonic acid (AHPeBP), t-a ino-1-hydι υxyhexane-1, 1 -diphosphonic acid (AHHexβP), 3-aminophenyl-hydroxymethanediphosphonic acid, 4-aminophenyl-hydroxymethanediphosphonic acid, 2-chloro-4-aminophenyl-hydroxymethanedipliosphonic acid, 3-chloro-4-ami ophβnyl-hydroxymethanediphόsphonic acid, 2-chloro-5-aminophenyl-hydroxymethanediphosphonic acid, 3-chloro-5-aminophenyl-hydroxymethanediphosphonic acid, 2--(4--aminophenyl)-l-hydroxyethane- 1. I-diphosphonic acid, 3-(2-chloro-4-aminopheny1-1-hydroxypropane-1,1- diphosphonic acid, 4-(2-chloro-5-aminophenyl)-1-hydroxybυtane-1,1- diphosphonic acid, 5-(3-chloro-5-aminophenyl)-1-hydroxypentane-1 ,^- diphosphonic acid, 2-bromo-l-hydroxy-1,1-ethanediphosphonic acid, 3-fluoro-1-hydroxy-1,1-propanediphosphonic acid, 4 -chloro-1-hydroxy-l, 1-butanediphosphonic, acid, 5-bromo-l-hydroxy-l,l-pentanediphosphonic acid, 6-fluoro-1-hydroxy-1,1-hexanediphosphonic acid, 7-chloro-l-hydroxy-l,1-heptanediphosphonic acid, 8-bromo-l-hydroxy-1, 1-octanediphosphonic acid, 9-fluoro-l-hydroxy-1, 1-nonanediphosphonic acid, 10-chloro-l-hydroxy-1,1-decanediphosphonic acid, 2-a no-1-hydroxy-1,1-ethanediphosphonic aci , 3-ami o-1-hydroxy-1,1-propanediphosphonic acid, 4-amino-l-hydroxy-l,1-butanediphosphonic acid, 5-amino-l-hydroxy-l,1-pentanediphqsphonic acid, 6-amino-l-hydroxy-l,1-hexanediphosphonic acid, 7-amino-l-hydroxy-l,1-heptanediphosphonic acid, 8-amino- l-hydroxy-1,1-octanediphosphonic acid, ?-amino-1-hydroxy-1,l-nonanediphosphonic acid, 10-amino-l-hydroxy-1,1-dβcanediphosphonic acid, (l-piperazyl)-hydroxymethanediphosphonic acid. ?. - ( 1- piperaiyl )- 1-hydr oxy- 1.1 ethanediphosphonic acid, 3 (l-piperazyl) 1 -hydroxy- 1 , 1 pi opanediphosphonic acid, 4-( l-piperazyl)-l-hydroxy-1 ,1-butanediphosphonic acid, or 5-( l-pipera∑yl)-l-hydroxy-l.l-pentanediphosphonic acid. Also usable accoi ding to the present invention are the e-teis of the diphosphonic acids listed above. R Reaction of a compound of formula Z-P. NH, or | H-A - N-( CH 2 ) n -Z I R 2 (16) With halogen-containing pharmaceutically active chemical entity results in the formation of hydrogen halide and bonding of e 7. containing moiety to the chemical entity. Pharmaceutically active chemical entities containing groups capable of reacting with the V * -substituent of the diphosphonates of formula (1), namely, carboxyl group or derivative thereof { e. g. , acyl halide, ester , azide), primary and secondary amino group, hydroxyl, and halogen (Cl, Br- and I) are useful according to the present invention. Coir.-.tiqucntly, examples of useful pharmaceutically active chemical entities include, without intending to be limiting thereto, an aminoglycoside such as amikacin (US patent 3,781,268), apramyciri (US patent 3,691,279), arbekacin (US patent 4,107,424). ba bermyciri (US patent 3,674,866), butirosin (US p a t e n t 3,541,078), dibekacin (German patent 2,135,191) , dihydrostrepto ycin (US patent 2,498,574), fortimycin A (US patent 3,976,768) and fortimycin B (Japan Kokai 75 145,588), gentamicin (US patents 3,091,572 and 3,136,704), isepamicin (Belgian patent 818,431), kanamycin (US patent 2,931,798), icr onomicin (German patent 2,326,781), neσmycin (2, 79*9,620) , neomycin undecylenate (US patent 3,022,286), netil icin (German patent 2,437,160), paromomycin (US patent 2.916,485), ribostamycin (German patent 1,814,735), si^omicin (US patent 3,832,286), spectinomycin (US patent 3.234,092), streptomycin (US patent 2,868,779), 71 1 1 sLieptonicozid (Pennington et al . . J. Am . Chem. Soc. 75, 2261 (1953) and tobramycin (Stark et al . . Higgenε, astner; Thompson, Presti; Wick. Welles, Antinicrυb. A Chemother. , 1967. 314-348: T " "3 chlorampphenicol [Bartz, J. Biol . Chem. 172, 445 (1948)1. chloramphenicol pal itate '(US patent 2,662,906), chloramphenic pantothenate (US patent 3.078,300), florfenicol (US pate 4,235,892) and thiamphenicol [Cutler el al . , J. Am: Chem. So 74, 5475 (1952)]; ΛΠ ansatiiycin such as rifamide (US patent 3,313,804); a ca apene , for example, imipene (US patent 4,194,047); cephalospor in, for example, cefaclor (US p.πte t. 3,925,372 cephadroxil US 3,816,25$),' cefamandole US patent 3,641,021 cefatrizine (US patent '3,970,651), cefazedohe (German pate 2,345,402), 'cefazolin (US patent 3,516,997) . 'cefiκime (US pate 4,409,214), cefmenoxime US ' patent 4,098,888) , " cefodizime ( patent 4,278,793), ce'fonicid (US patent ' ,093,723) . cefoperazo (US patent 4,410,5220, ceforanide (US patent 4,172,196), cefotaκi (US patent ' 4.098,888), cefotiam ' (German patent 2,607,064 cefpimizole (US patent 4,217,450), cefpiramide (Belgian pate 833,063), cefpodoxime proxetil (US patent 4,486,425), cefroxidi (US 4,073,902), cefsulidin, (US 4,065.619), ceftazidi e (US patent 4,258,041), ceftei m (Belgian patent 890,499), ceftozole ( patent 3,516,997), ceftibuten (US 4,634,697), ceftizoxi e ( patent 4,427,674), ceftr'iaxone (US patent' 4,327,210), cefuroxi (US ' patent 3,974,153), cefuzonam (US patent 4,399,132), cephalex (US patent 3,275,62b), cephaloglycin (US patent 3.422,103 cephalor idine (French patent 1,384,197), cephalospor-in C (US pate 3,082,155), cephalothin (French p3tent 1,384,197), cep apir sodium (US patent 3,422,100), cephradine (US patent 3,485,819) a pivecfalexin (German patent 1,951,01?); Λ cepha ycin such, as cefbuperazone (US ' patent . 4,263,292), cefmetazolθ (US patent 4,007,177), cefminox (US pate 4,357,331), cofotctan (US patent 4,263,432) and cefoxi.in ( U patent 4,297,480); a onobactam such as aztreonam (Netherlands patent application 8,100,571, carumonam (US patent 4,572,801), and tigomon-υn (US patent 4 ,<b38,0cl ); an oxacephem such as flomoϊ ' βf (US patent' <1 ,532,233 and mσ y air»r;t f (US patent 4.138,486); a penicillin such as amdinocillin (US patent 3,957,76 , ' mo icillin (U patent 3,192,193) ampicillin (US patenL 2,905,648) , car benici11i (US patent 3,142,673), clometocillin (US patent 3.007,' :» 20) cloxacillin (Doyle et al., J. Chem. Soc. 1963, 5838), cyclacilli (US patent 3,194,802), " dicloxacillin (US patent 3.239,507) epicillin (US patent 3,485,819), floxacillin (US 3,239,507) hetacillin (US patent 3,198,804), lenampicilliή ' (US patent " ' 4,342,693), metampicillin (Belgian patent 661,232). oxacillin (U patent 2,996,501), penicillin V (Brandl bέ al . , Uien. Ne tWochenschr. 1953, 602), piperacillin (US ,• patent , 4,087 ,424) pivampicillin ((US 3,660,575)V propicillin (British paten 877,120), sulbenicillin,.(US patent 3,660,379), and ticarcillin (U patent 3,282,926); a lincosamide .such- as clind^myein (US patent 3,475,407) an lincomycin (US patents 3,086,912 and 3,155,580); a macrolide such, as azi.thnomycin . US patent 4,517,35?), carbomyci (US patent 2,960,438),' clarithromycin (US patent 4,331.803) erythromycin (US patent 2,823,203), josamycin (Japanese patent 6 21,759), leuco ycins (US patent 3,535,309); midecaπiycins (US paten 3,761,588), miokamycin (Japanese Kokai 74124087), oleandomycin (U patents 2,757,123 and 2,842,481), primycin (US patent 3,498,884) rokita ycin (German patent 2,918,954), josaramicin (S. African patent 71 00.402), rόxithromycin (US patent 4,359,545) ,' spiramyci (US patent 2,943,023), and troleandomycin (British paten 877,730); polypeptide such as bacitracin (US 2,915,432), capi eomycin (U patent 3,143,468), colistin (Japanese patent 57 4898) enduracidin (British patent 1,163,270), envio ycin (US patent 3,892,732), gramicidin (US patent 2,534,541), mikamyci (French patent 1,349,946), polymyxin (US patent 2,565,057) polymyxin B-methanesulfonic acid (US patent 3,044,934) pristinamycin (US patent 3,154,475), ristocetin (US pate 2,990,329), teicoplanin (US patent 4,239,751), thiostrepton (U patents 2,982,689 and 2,982,698), tuberact^nomycin (US paten 3,639,580), tyrocidine (US patent 3,265,572), tyrothricin vancomycin (US patent 3,067,099), viomycin (US patent 2,633,445) virginiamycin, and zinc bacitracin (US patent 2,803,584); a tetracycline such as apicycline (Netherlands patent application 6,515,688), chlortetracycline (US patent 2,482,055), clomocyclin (Belgian patent 628,142), de eclocycline (US patent 2,878,289) doxycycline (US patent 3,200,149), guamecycline (British paten 1,042,207), ly ecycline (US patent 3,043,716), meclocycli 2,984,686), mathacycline (US patent 3,026,354), minocycline ( patents 3,148,212 and 3,226,436), , oxytetracycline (US pate 2,516,080), penimepicycline (British patent 897,826), pipacycli (British patent 888,968), rolitetetracycline (US patent 3,104,240), sancycline (US patent 3,019,260), senociclin (US patent 3,218,335), and tetracycline (US patent 2,699,054); a cycloserine (US patent 2,773,878), doxorϋbicin (US paten 3,590,028), and upirocin (US patent 3,977,943); a 2,4-diaminopyrimidine such as brodimoprim (US patent 4,024,145) tetroxoprim (US patent 3,992,379), and trimethopri (US patent 3,049,544); a nitrofuran such as furazoliu chloride (US patent 3,169,970), nifuradene (US patent 2,746,960), nifurprazine (British patent 966,832), nifurtoinol (US patent 3,446,802), and nitrofurantoin (US patent 2,610,181); a quinolone or quinolone analog such as amifloxacin (US paten 4,499,091), cinoxacin (US patent 3,669,965), ciprofloxacin (U patent 4,670,444), difloxacin (US patent 4,730,000), enoxaci (US patent 4,359,578), fleroxacin (US patent 4,398,029) flumequine (US patent 3,896,131), lomefloxacin (US patent 4.528,287), iloxacin (US patent 3,799,930), nalidixic acid (US patent 3,149,104), norfloxacin (US patent 4,146,719), ofloxacin (US patent 4,382,892), oxolinic acid (US patent 3,287,458), pefloxacin (US patent 4,292,317), pipemidic acid (US patent 3,887,557), piromidic acid (British patent 1,12^,358), rosoxacin (US patent 3,753,993), sparfloxacin (βntijnicrobial_ gents & Chemotherapy 1989, $3., 1167-1173) and tosufloxacin (US patent 4,704,459); sulfonamide such as acetyl sulfamethoxypyrazine (US patent 3,098,069), acetyl sulfisoxazole (US patent 2,721,200), azosulfamide (US patents 2,123,634 and 2,148.910), benzylsulfamide, chloramine-B, chloramine-T, dichloramine T (US patent 2,495,489), formosulfathizale [Druey et al . , Helv. Chim. Acta 31, 2184 (1948)], N 2 -formylsulfisomidine (German patents 1,122,511 and 1,126,857), N 4 -β-D-glucosylsulfanϊlamide [Kuhn et al . , Ber. 71, 621 (1938)], mafenide (US patent 2,288,531), 4'-methyl- -sulfamoyl)sulfanilanilide (French patent 817,034), p-nitro- sulfathiazole (US patent 2.443,742), norprylsulfamide (US patent 2,262,544), phthalylsulfacβtamide [(Basu, J. Indian Chem. Soc. 26, 130 (1949)], phthalylsulfathiazole (US patents 2.324,013 and 2,324,015), salazosulfadimidine [Korkuczanski, Przem. Chem. 37, 162 (1958)], succinylsulfathiazole (US patents 2,324,013 and 2,324,014), sulfabenzamide (US patent 2,240,496), sulfacetamide (US patent 2,411,495, sulfachlorpyridazine (US patent 2,790,798), sulfachrysoidine [Gley et ), . , Compt. Rend. Soc. Biol. 125, 1027 (1937)], sulfacytine (US patent 3,375,247), sulfadiazine (US patent 2,407,966), sulfadicramide (US patent 2,417,005), sulfadi ethoxine (US patent 2,703,800) , sulfadoxine (US patent 3,132,139), sulf ethidole [Wojahn βt al . . Arch. Pharm. , 284, 53 (1951)], sulf guanidine (US patents 2,218,490, 2,229,784 and 2,233,569), sulf guanole (US patent 3,562,258), sulfalenβ ( U S patent 3,098,069), sulfaloxic acid (German patent 960,190), sulfamerazine (US patent 2,407,966), sulfametor (US patent 3,214,335), sulfamethazine (US patent 2.407,966), sulfamethizole (US patent 2.447,702), sulfamethomidine (German patent 926,131), sulf methoxazole (US patent 2,888,455), sulfamethoxypyridazine (US patent 2,712,012), sulfametrole (US patent 3,247,193), and sulfa idochrysoidine (US patent 2,085,037); a sulfone such as acedapsone [Fromm et al. , Ber, 41, 2270 (1908)], acediasulfone [Jackson, J. Am. Chem. Soc. 70, 680 (1948)], acetosulfone sodium (US patent 2,358,365), dapsone (French patent 829,926), diathymosulfone (British patent 758,744), glucosulfone sodium (Swiss patent 234,108), solasulfone (British patent 491,265), succisulfone (US patent 2,268,754), sulfonilic acid, p- sulfanilylbenzylaminβ (Dewing, J. Chem. Soc. 1946, 466), p,p' ~ sulfonyldianiline-/V, V'-digalactoside, sulfoxone sodium (US patent 2,256,575), and thiazolsulfone (2,389,126); others such as clofoctol (US patent 3,830,852), hexedine (US patent 3,357,886), nitroxoline [Kostanecki, Ber. 24, 154 (1891)], xibornol (British patent 1,206,774); hydnocarpic acid [Diaper et al., Biochem J. 42, 581 (1948)], p-amino-salicylic acid (US patent 427,564), p-aminosalicylic acid hydrazide (Spanish patent 206,645), benzoylpas (British patent 676,363), 5-bromosalicylhydroxamic acid (Urbanski et al. , Nature 170, 753 (1952), capreomycin (US patent 3,143.468). clofazimine (Barry et al . . Nature 179, 1013 (1957), cyacetacide (US patent 2,849,369), dihydrostreptomycin (US patent 2,498,574), enviomycin (US patent 3,892,732), ethambutol [Wilkinson et al., J. Am. Chem. Soc. 83, 2212 (1961)], ethionamide (British patent 800,250), 4 * -formylsuccinanilic acid (German patent 852,086), furonazide [Miyatake et al . J. Pharm. Soc. Japan 75, 1066, (1955)], glyconiazide (US patent 2,940,899), isobutol (US patent 3,718,655), isonizid (US patent 2,830,994), isoniazid ethanesulfonate (US patent 2,759,944), morphazinz ide (German patent 1,129,492). opiniazide [Pershin et al., CA. 51. 10/47e (1957)], pasiniazide (Swiss patent 303,085), phenyl aminosalicylate (US patent 2,604,488). protionamide (British patent 800,250), pyrazinamide (German patent 632,257), rifampin (US patent 3,342.810), salinizid [Hart et al.. Antibiot . & Cha other. 4. 803 (1954)], subathizone [bernstcin at al . . J. Am. Chem. Soc. 73, 906 (1951), sulfoniazidc (US patent 2,727,041), thiacetazone [Domagk et al . . Naturlmiss 33. 315 (1946)], tiocarlide (US patent 2,703,815), tuberactlino ycin (US patent 3,639,580), tubercidin [Anzai et al . , J. Antiobot. 10A, 201 (1957)], tuberin (Japanese patent 647399). verazide [Fox et al . , J. Org. Chem. 18, 983 (1953), viomycin (US patent 2,633,445), and viomycin pantothenate (German patents 954,874 and 1,011,800). Synthesis of..Intermediates 2-Amino-l-hydroxyalkane-l ,i-diphosphonic acids can be prepared following the procedure of Example 1 of US patent 4,621,077 except substituting for the 5-aminovaleric acid of that example an equivalent amount of another amino acid such as, for example: glycine, alanine, β - alanine, 5-aminopentanoic acid, and 6-aminocaproic acid. (Aminophenyl)-hydroxymethanediphosphonic acids are prepared by employing in the foregoing procedure an aminobenzoic acid such as, for example: 2-aminobenzoic acid. 3-aminobenzoic acid, 4-aminobenzoic acid, 2-fluoro-3-aminobenzoic acid, 2-fluoro-4- a inobenzoic acid, 2-fluoro-5-aminobenzoic acid, 3-fluoro-4-aminobenzoic acid, 3-fluoro-5-aminobenzoic acid, 2-chloro-3-aminobenzoic acid, (2- chloro-4-aminobenxoic acid, 2-chloro-5-aminobenzoic acid, 2-amino-3- chlorobenzoic acid, 3-chloro-4-aminobenzoic acid, 3-chloro-5- aminobenzoic acid, 2-trifluoro-methyl-3-amino-benzoic acid, 2- trifluoromethyl-4-aminobenzoic acid, 2-trifluoromethyl-5-aminobenzoic acid, 3-trifluoromethyl-4-aminobenzoic acid and » -trifluoromethyl-5- a inobenzoic acid. The compounds of the present invention are intended for treatment of a member of a mammalian species, e.g. , dogs,- mice, primates and humans, and normally are administered orally but also can be administered by other routes, for example, parenterally or by injection. For oral administration, the compounds can be used at a dosage amount that is in the range of from about 10% to about 1000%, preferably from about 25% to about 750%, and most preferably from about 50% to about 500% that at which the pharmaceutically active component itself is used. In general, the compounds of the present invention frequently can b used at a dosage level that is less than that at which th pharmaceutically active component itself is employed. The compounds o the present invention are used in the form of various pharmaceutica preparations such as tablets, capsules, powders, granules, syrups an the like which are well known in the art, and which can be prepared b methods known per se using suitable diluents, bindings, disintegrators coating agents and the like. Other preparations suitable for injectio or parenteral use can also be prepared by techniques known in the art The following examples illustrate the presen invention without, however, limiting the same thereto. EXAMPLE. X 9-Fluoro-3-methyl-10-{4-[4-hydroxy-4,4-bis(dimethoxy- phosphono)-l-butyl]-l-piperazyl3-7-OXO-2,3-dihydro-7H- pyrido[l.2.3-delCl.41 benzoxazine-6-carboxylic acid 4-Chloro-l-hydroxy-l,l-butanediphosphonic acid is prepared by treating 4-chlorobutanoic acid either with phosphorous acid and phosphorus trichloride as described in US patent 4,621,077, or by treatment with phosphorus trichloride and methanesulfonic acid, as described in US patent 4,922,007. The acid is converted to the tetramethyl ester by reaction with trimethyl orthoformate (Nicholson et al. , J. Org. Chem. 1970, 35, 3149) and the ester is then reacted with piperazine to yield 4-(l-piperazyl)-l-hydroxy 5 -!,1- butanediphosphonic acid tetramethyl ester. (An alternative synthesis is to react 4-amino-i-hydroxy-l,1-butanediphosphonic acid tetramethyl ester with bis-(2-chloroethyl)amine. ) 9,10-Difluoro-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylic acid is prepared following the procedure of example 2 of US Patent 4,382,892. The 6-carboxylic acid is then subjected to the procedure of example 3 of US patent 4,382,892 except substituting for N-methylpiperazine an equivalent amount of 4-(l-piperazyl)-l-hydroxy-4,4i-butane-diphosphoni acid tetramethyl ester. The crude product gives after extraction, solvent evaporation and recrystallization 9-fluoro-3 ιnethyl-10-{4-[4- hydroxy-4,4-bis(dimβthoxyphosphono)-1-buty1]-l-piperazyl)-7-oxo-2,3- dihydro-7H-pyrido[1,2,3-de] [1,4)benzoxazine-6-carboxy1ic acid. EXAMPLE 2 9-Fluoro-10-(4-[3-hydroxy-3,3-bis(dimethoxyphosphono)-l- propyl]-l-piperazyl)-7-oxo-2,3-dihydro-7H-pyrido-[1,2,3- e] [1,4] enz κazi . ne 6-carboxylic aci,d The tetramethyl ester of 3-chloro-l-hydroxy-l,I- propanediphosphonic acid is reacted with sodium azide and forms tetramethyl 3-azido-l-hydroxypropane-i,l-diphosphqnate, which is hydrogenated over Pt at room temperature under 1 bar of hydrogen to tetramethyl 3-amino-1-hydroxy-1, 1-propanediphosphonate. 9,10- Difluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de] [1,4]- benzoxazine-6- carboxylic acid is prepared according to the procedure of example 1 of US patent 4,382,892. The acid is then employed in the procedure of example 7 of the cited patent except substituting for methyl hydrazine an equivalent amount of 3-(l-piperazyl)-l-hydroxy-l,1- propanediphosphonic acid tetramethyl ester, prepared by reaction of 3- amino-i-hydroxy-1,1-propanediphosphonic acid tetramethyl ester with bis-(2-chloroethyl)-amine, to yield 9-fluoro-10-(4-[3-hydroxy-3,3- bis(dimethoxyphosphono)-1-propyl]-l-piperazyl}-7-oxo-2,3-dihydro-7H- pyrido-[l,2,3-de] [1,4] benzoxazine-6-carboxylic acid. Capsules suitable for oral administration are prepared from the following formulation in known manner: 9-fluoro-10-[4-(3-hydroxy-3,3- diphosphono-1-propy1)-l-piperazyl]-7-oxo- 2,3-dihydro-7H-pyrido[l,2,3-de][l,4)- benzoxazine-6-carboxylic acid 100.0 mg CMC calcium 23.0 mg Corn starch 22.5 mg Magnesium stearate 1.5 mg EXAMPLE_.3 9r-Chloro-3-methyl-10-f4-C2-hvdroxy-2.2-bis(dimethoxy- Phosphpno)ethyl]-l-pjperazyl -7-oxo-2.3-dihvdro-7H- Plϋ-idoCl. Z.3-del n.4l-benzoxazine-6-carboχylic acid 9-Chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3- de][l,4]b β nzoxazine-6-carboxylic acid is prepared according to the procedure of example 8 of US patent 4,382,892. The acid then is employed in the procedure of example 3 of the cited patent except substituting for N-methylpiperazine an equivalent amount of l-[2- hydroxy-2,2-bis(dimethoxyphosphono)ethyl]-piperazine to yield 9- . chloro-3-methyl-1 0 -(4-[2-hydroxy-2,2-bis(dimethoxyphosphono)ethyl]- piperazyl)-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]- benzoxazine- carboxylic acid. EXAMPLE_ 4 9-Fiuoro-3-methyl-10-(4-[2-hydroxy-2,2- bis(dimethoxyphosphono)ethyl)-l-piperazyl}-7-oxo-2,3- dihydro-7H-pyrido[l,2,3-de] [1,4]benzoxazine-6-carboxylic The procedure of example 3 of US patent 4,382,892 is repeated except substituting for N-methylpiperazine an equivalent amount of tetramethyl 2-(l-piperazyl)-l-hydroxy-1,1-ethanediphosphonate, prepared by the reaction of C1-(CH 2 )-Z (2-chloro-l-hydroxy-l,l-ethan diphosphonic acid, tetramethyl ester) and piperazine, to yield the title compound. EXAMPLES 9-Fluoro-3-methyl-10-[3-hydroxy-3,3-bis(dimethoxyphosphono)- l-propylamino]-7-oxo-2,3-dihydro-7H-pyrido[1-2,3- deJL l -A3 eπz_-pxazine-6.r_carbpxy1ic acid 9,10-Difluoro-3-mβthyl-7-oxo-2,3-dihydro-7H-|>yrido[1,2,3- de] [l,4]benzoxazine-6-carboxylic acid, prepared according to the procedure of example 1 of US patent 4,382,892, is reacted with 3- hydroxy-3,3-bis(dimethoxyphosphono)-l-propylamine and a quantity of base sufficient to neutralize the acid groups of both reactants and the acid formed in the reaction, thus yielding 9-fluoro-3-methyl-10 [3-hydroxy-3,3-bis(dimethoxyphosphono)-l-propylamino]-7-oxo-2,3- dihydro-7H-pyrido[l,2,3-de] [l,4]benzoxazine-6-carboxylic acid. EXAMPLE 6 9-Fluoro-3-[hydroxy-bis(diethoxyphosphono)mβthyl]-10-(4- methyl-1- piperazyl)-7-oκo-2,3-dihydro-7H-pyrido[l,2,3- deJI1.4]benzoxazine-6-carboxylic acid 3.9 g of 2,3-difluoro-6-nitrophenol and 3.0.g of chloropyruvic acid are reacted as described for chloroacetone in Example 8 of US patent 4,382,892, to yield (2,3-difluoro-6-nitrophenoxy)-pyruvic ac Catalytic hydrogenation (Pd/C or Raney Ni, room temperature) of th product yields in one step 7,8-difluoro-[l,4]benzoxazine-3-carboxyl acid, which is converted to its acid chloride and then is reacted first with triethylphosphite and next with diethylphosphite and a base, to form 7,8-difluoro-3-[hydroxy-bis(diethoxyphosphono)methyl]- [1,4]benzoxazine. Condensation of the latter with diethyl ethoxymethylidenemalonate, as in the above-mentioned patent, cyclization, and ester hydrolysis gives ", 10-difluoro-3- [hydroxy- bis(diethoxyphosphono)methyD-7-oxo-2,3-d hydro-7H-pyrido[1,2,3- de] [l,4]benzoxazine-6-carboxylic acid, which is finally reacted with 1-methylpiperazine to yield 9-fluoro-3-[hydroκy- bis(diethoxyphosphono)methyl]-10-(4-methyl-l-piper azyl)-7-oxo-2,3- dihydro-7H-pyrido[l,2,3-de] [1,4]benzoxazine-6-carboxylic acid. EXAMPL£_7 9-Fluoro-3-methyl-6-[hydroxy-bis(diethoxyphosphono)methyl]- 10-(4-methy1-l-piperazyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3- de] [1,4]-benz xazjlne 9-Fluoro-3-methy1-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro- 7H-pyrido[l,2,3-de] [1,4]benzoxazine-6-carboxylic acid, which is prepared according to the procedure of example 3 of US patent 4,382,892, is reacted with phosphorous acid and phosphorous trichloride as shown in Example 6, supra, and gives 9-fluoro-3-methyl- 6-(hydroxydiphosphono-methyl)-10-(4-methyl-l-piperazyl)-7-oxo-2,3- dihydro-7H-pyrido[l,2,3-de] [1,4]benzoxa∑ine. EXAMEkE_8 6-Chloro-l-ethyl-7-{4-[3-hydroxy-3,3- bis(dimethoxyphosphono)-l-propyl]-l-piperazyl)-4-oxo-l,4- 9-JL y.drpg inoline-3-carboxylic acid 6,7-Dichloro-l-ethyl-(4-oxo-l,4-dihydroquinoline-3-carboxylic acid is prepared according to the procedure of US patent 4,292,317. The acid is then employed in the procedure of example 31 of the cited patent except substituting for 1-methyl hydrazine an equivalent amoun of l-[3-hydroxy-3,3-bis(dimβthoxyphosphono)-l-propyl]-piperazine to yield 6-chloro-l-ethyl-7-C4-[3-hydroxy-3,3-bis(dimethoxyphosphono)-l- propyl]-l-piperazyl}-4-oxo-l,4-dihydroquinoline-3-carboxylic acid. For oral administration, suitable forms of administration are, for example, compressed tablets, capsules, pills and suspensions. The solid forms preferably contain at least 100 mg of 6-chloro-l-ethyl-7- (4-[3-hydroκy-3,3-bis(dimethoxyphosphono)-l-pr opyl]-l-piper zyl)] -4- oxo-1 ,4- dihydroquinoline-3-carboxylic acid. Suitable carriers for such solid forms are, for example, lactose, starch, talc, gelatin and magnesium stearate. Aqueous forms preferably contain at least 20 g of the active compound per ml. Water soluble high, molecular weight compounds such as, for example, cellulose esters and polyethylene glycols, may be included in such suspensions as stabilizers. Sweetening agents, aromatising agents and/or colorants also may be added. EXAMPLE.9 6-Fluoro-l-methyl-7- [4-hydroxy-4,4-bis(dimethoxyphosphono)- l-j3uty . lairi . ipo)r4-oxjDr . l Λ 4rdi . hydjoquii?pl . ine-3j:cajbo>y_lic. acid„ 7-Chloro-6-fluoro-l-methyl-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid is prepared according to the procedure of US patent 4,292,317. The acid is then employed in the procedure of example 32 of the cited patent except substituting for piperazine an equivalent amount of H2N-(CH-) ~Z (4-amino-l-hydroxy-butanβ-l,1-diphosphonic acid, tetramethyl ester) to yield 6-fluoro-l-methyl-7-[4-hydroxy-4,4- bis(dimethoxyphosphono)-l-butylamino]-4-oxo-l,4-dihydroquincline-3- carboxylic acid. Injectable compositions preferably comprise solutions containing at least 200 mg of the active compound per 5 or 10 ml of final solution. If desired the solution may contain the necessary amount of NaCl to render the solution isotonic. The solutions can be presented in 5 or 10 ml ampoules which are sterilized in an autoclave Equally, after sterile filtration, 5 or 10 ml of the solution can be filled into the appropriate sized sterile ampoules and then subjected to lyophilization. EXAHPLE_10 6-Chloro-l-ethyl-3-(hydroxy-diphosphonomethyl)-7-(4- mβthyl-l-piperazyl)-4-oxo-l,4-dihydroquinoline and its tSJtraethyJ._es . te: 6-Chloro-l-ethyl-7-(4-methyl-l-piperazyl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid is prepared according to the procedure of US patent 4,292,317. The acid then is reacted with P(0H) j and PCl j as shown in Example 1, supra, to afford 6-chloro-l- ethy1-3-(hydroxy-diphosphono ethy1)-7-(4-methyl-l-piperazyl)-4-oxo- 1 ,4-dihydroquinoline. Alternatively, the carboxylic acid group rs ^ converted to the acid chloride and then is reacted first with triethylphosphite and next with diethylphosphite and a base, to form the tetraethyl ester of the title compound. EXAMPLE ^ .11 6-Chloro-7-[6-hydroxy-6,6-bis(dimethoxyphosphono)-l- hexylamino]-l-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylic 6,7-Dichloro-l-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid is prepared according to the procedure of US patent 4,292,317. The acid is then employed in the procedure of example 17 of the cited patent except substituting for piperazine an equivalent amount of H^I-(CH 2 ) 5 -Z (tetramethyl 6-amino-l- hydroxy-l,l-hexanediphosphonate) to yield 6-fluoro-7-(6-hydroκy-6,6- bis(dimethoxyphosphono)-l-hexylamino]-l-methyl-4-oxo-l,4- dihydroquinoline-3-carboxylic acid. EX MPLE_JL2. 6- luoro-1-(3-hydroκy-3,3-diphosphσno-1-propyl)-7-(-4- methyl-l-pipβrazyl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acAd 7-Chloro-3-ethoxycarbonyl-6-fluoro-4-oxo-l,4-dihydroquinoline is reacted with Cl^CH j ^-Z (3-chloro-l-hydroxy-l,l-propanediphosphonic acid, tetramethyl ester) following the procedure αf US patent 4,292,317 and gives 7-chloro-3-ethoxycarbonyl-6-fluoro-l-[3-hydroxy- 3,3-bis(dimethoxyphosphono)-l-propyl]-4-oxo-l,4-dihydroquinoline which, in turn, is treated with 1-methylpiperazinβ to yield 3- ethoxycarbonyl-6-fluoro-l-[3-hydroxy-3,3-bis(dimethoxyphosphono)- 1-propyl]-7-(4-methyl-l-pipβrazyl)-4-oκo-l » 4-dihydroquinoline. Hydrolysis of carboxylate and phosphonate ester groups of this compound yields the title compound. In an alternative synthesis of the title compound, ethyl 2-(2,4- dichloro-5-fluoro-benzoyl)-3-ethoxyacrylate is reacted with (tetramethyl 3-amino-l-hydroxy-1,1-propanediphosphonate) in a solvent, as described in US patent 4,292,007 for the analogous case of cyclopropylamine. Cyclization of the resulting substituted α-benzoyl- β -alkylamino acrylate as described in the same patent gives ethyl 7- chloro-6-fluoro-l-[3-hydι oκy-3,3-bis(dimethoxyphosphono)-l-propyl]-4 oxo-1 ,4- dihydroquinoline-3-carboxylate. The latter is reacted with 1 ethylpiperazine as described for the analogous reaction in Example 1 t.o give the ethyl ester at the car boxylate group and tetramethyl esLo at the phosphonate groups of the title compound. EXAMPLE 13 l-Cyclopropyl-7-(4- [3-hydroκy-3,3-biε(dimethoκyphosphono) l-propyl]-l-piperazyl}-4-oxo -1 ,4-dihydro-l,6-,naphthyι idine- 3_r.carbo.xy.lic. acid 7-Chloro-i-cyclopropyl-4-oxo-l ,4-dihydro-l ,6-"-naphthyridine-3- carboxylic acid is prepared following the procedure of example 20(e) of US patent 4,670,444. The acid then is employed in the procedure o example 1 of the cited patent except substituting for N- methylpiperazine an equivalent amount of 3-(l-piperazyl )-l-hydroxy- 1,1-propanediphosphonic acid, tetramethyl ester, to yield 1- cyclopropyl-7-C4-[3-hydroxy-3,3-bis(dimethoxyphosphono)-1- propyl]-l-piperazyl}-4-oxo-l,4-dihydro-l,6-naphthyridine-3-car boxylie acid. A tablet formulation is prepared from the following formulation: l-cyclopropyl-7-{4-[3-hydroxy-3,3- bis(dimethoxyphosphono)-l-propyl]-l- piperazyl}-4-oxo-l,4-dihydro-l,6- naphthyridine-3-carboxylic acid 290.0 mg Avicel 47.0 mg Moist corn starch 13.5 mg Pregelatinized starch 6.0 mg Magnesium stearate 3.5 mg Fi1m.jco_atirjg HPM cellulose 3.0 mg Polyethylene glycol 4000 1.0 mg Titanium dioxide 1.0 mg EXAMPLE. 14 7-(4-Methylpiperazino)-1-cyclopropy1-4-oxo-1,4- dihydro-l,6-naphthyridine-3-{N-[5-hydroxy-5,5- bis (jd jme tJh tt Y Ph P sphonp )ρentyl] -carboxamide'H 7- ( 4-Mβthylpiperaz ino)- l-cyclopropyl-4-oxo- l ,4-dihydro- l ,6- naphthyridine-3-carboxylic acid , which is prepared as descr ibed in US patent .4,670,444 , is converted to its acid chloride and reacted with H^^CH j ^-Z (tetramethyl 5-amino-l-hydroxy-l , 1-pentanediphosphonate) and an excess of triethyla ine to give, after product purification, 7- (4-methylpipβrazino)-l-cyclopropyl-4-oxo-l ,4-dihydro -1 ,6- naphthyridine-3-CN-[5-hydroxy-5,5-bis(dimethoxyphosphono)pentyl]- carboxamide] . EXAMPLE„i§ l-Cyclopropyl-6-fluoro-7-{4-[3-hydro y-3,3-bis dimethoxy- phosphono)-l-propyl]-l-piperazyl}-l,4-dihydro-4-oxo- quΛoQ1ine-3-carboxylie,.ac.i.d,. 7-Chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-quinoline-3- carboxylic acid is prepared according to the procedure of columns 7-8 of US patent 4,670,444. The acid is then employed in the procedure of example 23 of the cited patent except substituting for piperazine an equivalent amount of 3-(l-piperazyl)-l-hydroxy-1, 1-propanediphosphonic acid, tetramethyl ester to yield l-cyclopropyl-6-fluoro-7-(4- [3- hydroxy-3,3-bis(dimethoxyphosphono)-1-propyl]-l-piperazyl}-1,4- dihydro-4-oxo-quinoline-3-carboxylic acid. EXAMPLJE__16. 6-C2-Ethoxy-5-[3-hydroxy-3,3-bis(dimethoxyphosphono)-1- propylamino]naphthoy1}]-amino-3,3-dimethyl-7-oxo-4-thia-1- azabicycIo r ,3.2.Q]heptane-2-carboxvlic acid and isomers A mixture of 5-amino-2-ethoxy-l-naphthoic acid and 3-chloro-l- hydroxy-1 , 1-propanediphosphonic acid, tetramethyl ester) are heated in an alcohol solution containing 2 equivalents of base. Isolation and purification yield 2-ethoxy-5- [3-hydroxy-3,3-bis(dimethoxyphosphono)~ l-propyl]-amino-l-naphthoic acid. The latter is condensed by the procedure disclosed in US patent 3,132,136 with am nopenicilianatβ to afford 6-(2-ethoxy-5-[3-hydroxy-3,3-bis(dimethoκyphosphono)-l- propylamino]naphthoy1}-amino-3,3-dimethyl-7-oxo-4-,thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid. Substituting 3-amino-2-ethoxy-l-naphthoic acid for 5-amino-2- ethoxy-1-naphthoic acid in the foregoing procedure yields 6-{2-ethoxy- 3-[3-hydroxy-3,3-bis(dimethoxyphosphono)-l-propylamino]-naphthoyl}- amino-3,3-dim β thyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2- carboxylic acid. Substituting 4-amino-2-ethoxy-l-naphthoic acid for 5-amino-2- nthoxy-1-naphthoic acid in the foregoing procedure yields 6-[2-ethoxy- 4-[3-hydroxy-3,3-bis(dimethoxyphosphono)-1-propylamino)-naphthoyl))- amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2- carboxylic acid. Substituting 6-amino-2-ethoxy-l-naphthoic acid for 5-amino-2- ethoκy-1-naphthoic acid in the foregoing procedure yields 6-(2-ethoxy 6 -[ 3 -hy d roxy-3,3-bis(dimethoxyphosphono)-1-propylamino]-naphthoyl} - amino-3.3-dimethy1-7-OXO-4-thia-l-azabicyclo[3.2.0]heptane-2- carboxylic acid. Substituting 7-amino-2-ethoxy-l- naphthoic acid for 5-amino-2- ethoxy-1-naphthoic acid in the foregoing procedure yields 6-{2-ethoxy- 7-[3-hydroxy-3,3-bis(dimethoxyphosphono)-1-propylamino]-naphthoy1}- amino-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2- carboxylic acid. EXAMPLE._17 7B-[α-(Z-Methoxyimino)- (2-aminothiazol-4-yl)acetamido]-3- (1-methyl-l.2,3-triazol-5-ylthiomethyl)-3-cephem-4-{N-[5- by^lroxy-5.5-bis(dimethoxyphosphono)-1-pentyl]-parboxyamidel 7B-[α-(Z-Methoxyimino)- (2- tert- njtoxycarbonylaminothiazol-4-yl) ■ acetamido]-3-[(1-methyl-l,2,3-triazol-5-yl)thiomethy1]-3-cephem-4- carboxylic acid is treated with thionyl chloride in anhydrous methylene chloride, with cooling. After evaporation of the excess of thionyl chloride, the residue is treated with tetramethyl 5-amino-l- hydroxy-1,1-pentanediphosphonate and base. Removal of the tert- bu oxycarbony1 protecting group with cold trifluoroacetic acid and anisole, isolation of product, and purification yield 7β-[α-( - methoxyimino)-α-(2-aminothiazol-4-yl)-acetamido]-3-[(1-methyl-l,2,3- triazol-5-yl)-thiomethyl]-3-cephem-4-{N-[5-hydroxy-5,5- bis(dimethoxyphosphono)-l-pentyl])-carboxamide}. EXAMPLE_18 7β-[α-(Z-Methoxyimino)-α-(2-aminothiazol-4-yl)-acetamido]-3- C[4-hydroxy-4,4-bis(dimethoxyphosphono-1-butylcarbamoyl]- Pχymethyl}-3-cephem-4-carbox lic acjd 7β-[α-(Z-Methoxyimino)-α-(2- tert-butoxycarbonylaminothiazol-4- yl)-acetamido]-3-hydroκymethyl-3-cephem-4-carboxylic acid- tert- butyl ester is reacted with phosgene (toluene solution) in the presence of pyridine. The resulting chlorocarbonate is reacted without purification with tetramethyl 4-amino- l-hydroxy-1 , 1- butanediphosphonate in the presence of one equivalent of base, to give 7β-[ -( /-methoxyimino)-α-(2- tert-bx toxycarbonylaminothiazol-4-yl )- acetamido]-3-{[4-hydroxy-4,4-bis(dimethoxyphosphono)-l- butylcarbamoyl]-oxymethyl}-3-cephem-4-carboxylic acid- ter £-butyl ester-. Deprotection with trifluoroacetic acid and anisole gives 7 β - [ -(Z-methoxyimino)-u-(2-aminothiazol-4-yl )-acetamido]-3- ( [(4- ydroxy - 4,4-bis(dimethoxyphosphono)-l-butylcarbamoyl]-oxymethyl}-3-cephem-4- carboxylic acid. EXAMPL.E_19 7β- [α-(Z-Methoκyimino)~α-(2-aminothiazol-4-yl)-acetamido]-3- C[4-hydroxy-4,4-bis(diethoxyphosphono)-butanoyloxy]-methyl}- 3r.cephe.mr4.^carboxyl.i^._aci-d. Tetraethyl l-hydroxy-4-pentene-l , 1-diphosphonate, prepared from 1 prntenoyl chloride as dosci ibed for- tha analogous compound in r.".ample 1 is subjected to an ozonolysis -oxid tionprotccol to give the 4 hydr o> y-4 ,4- bis( i thoκyphosphone)-butanoic acid. The hydroxyl gι oup of the latter is protected as £er£-butoxycarbonate ester, aftei which the 4-( Let t- butoxycarbonyloxy)-4,4-bis(diethoxyphosphono)- butanoyl chloride is prepared by reaction with oxaloyl chloride. The eaction of benzhydryl 7β-[α-(Z-methoxyimino)-α- [2- tert- butoxycarbonylamino)-thiazol-4-yl]-acetamido}-3-hydroxymethy1-3- ephem-4-carboxylate with the 4-( £er£-butoxycarbonyloxy)-4,4- bis(diethoxyphosphono)-butanoyl chloride in the presence of pyridine leads to the benzhydryl ester of the 7β-(α-( -methoxyimino)-α- [2- tert- butoxycarbonyl-amino)-thiazy1-4-yl]-acetamido}-3-thiazol-4-yl]- acetamido}-3-([4-( £er£-butoxycarbonyloxy)-4,4-bis(diethoxyphosphono)- butanoyloxy]methyl}-3-cephem-4-carboxylic acid. Deprotection by reaction with cold trifluoroacetic acid and anisole yields 7β-[α-(Z- methoκyimino)-α-(2-aminothiazol-4-yl)-acetamido]-3-{[(4-hydroxy-4,4- bis(diethoxyphosphono)-butanoyloxy]-methyl}-3-cephem-4-carboxylie acid. EXAMPLE 20 7 β -{α-(Z-Methoxyimino)-α-[2-(3-hydroxy-3,3- bis(dimethoxyphosphono)-l-propylamino-thiazol-4-yl]- acetarnido}-3-acetoκymethyl.τ3-cephem-4,rcarboxylic acid Reaction of Cl^CH j ^-* (3-chloro-l-hydroxy-l,1- propanediphosphonic acid, tetramethyl ester) with 7β-[α-(Z- methoκyimino)-α (2-aminothiazol-4-yl )-acetamido]-3-acetoxy ethy1-3- cephem-4-carboxylic acid in the presence of sodium carbonate yields 7β-{α-(/-methoxyimino)-α- [2-(3-hydroxy-3,3-bis(dimethoxyphosphono)- 1- propylamino-thiazolyl-4-yl]-acetamido}-3-acetoxymethy1-3-cephem- - carboxylic acid. EXAMe. ξ_21 7β-{α-(Z-Methoκyimino)-α-[2-(6-hydroκy-6,6- bis(diethoxyphosphono)-hexanoylamino)-thiazol-4-yl]- ac_θ.tamido}-3.-acet.oxyme_thy1ι3^cep_hem-4_^_carboxylic_acid 6-Hydroxy-6,6-diphosphonohexanoic acid, tetramethyl ester is treated with £er£-butoκycarbonyl chloride, and the 6- tert- butoxycarbonyloκy)-6,6-diphosphonoheκanoic acid, tetramethyl ester thus formed is converted to the corresponding acid chloride with oxalyl chloride and pyridine. The acid chloride is condensed with 7β- tα-( -mβthoxyimino)-α-(2-aminothiazol-4-yl )-acetamido]-3- acetoxymethyl-3-cephem-4-carboxylic acid and, again in the presence of pyridine, and forms 7β-{α-(Z-methoκyimino)-α[2-(6- tert- butoxycarbonyloxy)-6,6-bis(diethoxyphosphono)hexanoyl-amino)-thiazol- 4-yl]-acetamido}-3-acetoxymethyl-3-cephem-4-carbox iic acid. Deprotection with trifluoroacetic acid and anisole yields the title compound. EXAMPLE_22 7β-Ci-(Z-Methoκyimino)-α-[2-(3-hydroκy-3,3- bis(diethoxyphosphono)-propanoylamino)-thiazol-4-yl]- acetamido)-3-acetoxymethy1-3-cephem-4-carboκyi.i.c_.acid 3-Hydroxy-3.3-diphosphonopropanoic acid, tetramethyl ester is converted to 3-( tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)- propionic acid and then to 3-( ter£-butoxycarbonyloxy)-3,3- bis(diethoxyphosphono)propanoyl chloride. The acid chloride is then added to α-(Z-methoxyimino)-α-(2-aminothiazol-4-yl)-acetic acid and pyridine to form α-(Z-methoxyimino)-α-{2-[3-( Her£-butoxycarbonyloxy)- 3,3-bis(diethoxyphosphono)-propanoyl-amino)-thiazol-4-yl}-acetic acid. The latter is reacted with oxaloyl chloride to form the acid chloride. 28 ( Z-methoxyimino)-α-(2-[3-( £er£-butoxycarbonyloκy)-3,3-bis(diethoxy phosphono)-propanoyl-amino)-thiazol-4-yl]-acetyl chloride. This .aci chloride is reacted with 7β-amino-3-acetoκymethyl-3-cephem-4 carboxylic acid and pyridine and gives 7β-(α-(Z-methoxyimino)-α-[2-( tert-bistoxycarbonyloxy)-3,3-bis(diethoxyphosphono)propanoy1-amino)- thiazol-4-yl]-acetamido}-3-acetoxymethyl-3-cephem-4-carboxylie acid. Deprotection with trifluoroacetic acid and anisole yields the title compound. EXAMPLE 23 6?,7 -7[α-(Z-Methoκyimino)-α-(2-amino-thiazol-4-y1- acetamido)-3-{[2,5-dihydro-6-(4-hydroκy-4,4-bis(dimethoκy- phosphono)-l-butylaminocarbonyloκy)-2-methyl-5-oκo-as- triazin-3-yllthio-methvll-3-cephem-4-carboxylic acid. 6Λ,7Λ-7{ -(Z-Methoxyimino)- -[2-( terc-butoxycarbonylamino)- thiazol-4-yl)acθtamido}-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oκo-as- triazin-3-yl)thio-methyl]-3-cephem-4-carboκylic acid benzhydryl este is reacted as described in Example 18, first with;phosgene and then with tetramethyl 4-amino-l-hydroxy-l,l-butanediphosphonoate, to form (6?,7?)-7{α-(Z-methoxyimino)-α-[2-( tert-butoxycarbonylamino)-thiazol 4-yl]acetamido}-3-[(2,5-dihydro-6-(4-hydroxy-4,4-bis(dimethoxy- phosphono)-l-butylaminocarbonyloxy)-2-methyl-5-oxo-as-triazin-3- yl]thio-methyl}-3-cephem-4-carboκylic acid benzhhydryl ester. Deprotection with trifluoroacetic acid and anisole yields the title compound. EXAMPLE 24 (6/?,7/?)-7-[α-(Z-Methoκyimino)-α-[2-(2-hydroxy-2,2- bis(dimethoxyphosphono)-l-ethylamino)-thiazol-4-yl]- acetamido}-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as- t.riazin-3-yl)-thio-methyl]-3-cephem-4-carboxvlic acid Reaction of Cl-CH j -Z (2-chloro-i-hydroxy-l,1-ethanediphosphonic acid, tetramethyl ester) as described in Example 20 with 6R,7Λ)-7-[α- (Z-methoxyimino)-α-(aminothiazol-4-yl)-acetamido]-3-[2,5-dihydro-6- hydroxy-2-methyl-5-oxo- as-triazin-3-yl)-thio-methyl]-3-cephem-4- carboxylic acid gives the title compound. E^A E E_25. 7 β -[5-Hydroxy-5,5-bis(dimethoxyphosphono)-l- pentylaminocarbonylamino)-7-methoxy-3-ca bamoyloxymethy1 3 cephem-4-carboxylic acid 7β- A mino-7-methoxy-3-carbamoyloxymethyl-3-cephem-4 car boxylic acid is reacted with an excess of phosgene (in toluene solution) in the presence of pyridine. The 7-chlorocarbamoyl derivative thus formed is reacted with tetramethyl 5-amino- 1-hydroκy-1,1 - pentanediphosphonate and one equivalent of base, to yield the title compound. EXAMPLE.26 7β-[6-Hydroκy-6,6- bis(dimethoκyphosphono)-hexanoylamino] 7- me . thoxy-3-Qarbamoyloxymethyl-3-cephemr4-carboxylic . acid 6-( £er£-butoxycarbony1)-6,6-diphosphonoheκanoyl chlor ide , prepared as in Example 21, is reacted with 7β-amino-7-metho>cy-3- carbamoyloxymethyl-3-cephem-4-carboκylic acid in the presence of pyridine. Deprotection with trifluoroacetic acid and anisole yields the title compound. EXAMPLE. . 27 7β-(2-Thienylacetarnido)-7-methoκy-3-{[3-hydroκy-3,3- bis(dimethoxyphosphono)-l-propylcarbamoyl]-oκyme hy1}-3- cephem-4-carboχyljc acid The benzhydryl ester of 7β-(2-thienylacetamido)-7-methoxy- 3-hydroxymethyl-3-cephem-4-carboxylic acid is reacted first with phosgene and then with tetramethyl 3-amino-l-hydroxy-1,1-propane diphosphonate, by the procedure described in Eκample 18. Cleavage of the ester with trifluoroacetic acid yields 7β-(2-thienylacetamido)-7- ethoκy-3-[[3-hydroxy-3,3-bis(dimethoxyphosphono)-l-propylcarba oyl]- oxymethyl}-3-cephem-4-carboκylic acid. EXAMPL . E_.28 7β-(5-[3-Hydroxy-3,3-bis(dimethoxyphosphono)-l-propylamino]- 2-thienylacetamido}-7-methoxy-3-carbamoyloκymethy1-3-cephem- 4-carboκylic_ac_id 5-(2,2,2-trichloroethoxycarbonylamino)-2-thienylacetic acid is reacted with the benzhydryl ester of 7β-amino-7-methoxy-3- carbamoyloκymethyl-3-cephem-4-carboκylic acid in the presence of dicycloheκyl-carbodiimide. The reaction product, benzhydryl 7β- [5- (2,2,2-trichloroethoxycarbonylamino)-2-thienylacetamido]-7-methoκy-3- carbamoyloκymethyl-3-cephem-4-carboxylate, is treated with zinc dust in 90% formic acid and forms benzhydryl 7β-[5-amino-2-thienyl¬ acetamido]-7-methoxy-3-carbamoyloκymethy1-3-cephem-4-carboxylate. Reaction with 2-chlor o-1-hydroκy-i , 1-ethanediphosphonic acid tetramethyl ester as described in Example 24, followed by cleavage of the benzhydryl ester as described in Eκample 27, yields 7β-{5-[3- hydroκy-3,3-bis(dimethoκyphosphono)-1-propylamino]-2-thienyl¬ acetamido}-7-methoxy-3-carbamoyloxymethy1-3-cephem-4-carboκylie acid. E><AMPLE_29 7β-{[5-(3-Hydroκy-3,3-bis(dimethoκyphosphono)-l- propylaminocarbonyl-amino)-2-thienyl)-acetamido}-7-methoκy- 3-carbamoy_lpxymethyl-3-cephem-4-car-boκylic acjd The benzhydryl ester of 7β- [5-amino-2-thienylacetamido]-7- methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid is reacted with phosgene and pyridine. The benzhydryl 7β-[5-(chlorocarbonyl- amino)-2-thienylacetamido)-7-methoxy-3-carbamoyloκymethyl-3-cephem-4- carboxylate thus formed is treated with tetramethyl 3-amino-l-hydroκy- 1,1-propanediphosphonate, as described in Eκample 25, and gives benzhydryl 7β-{[5-(3-hydroκy-3,3-bis(dimethoxyphosphono)-1- propylaminocarbonyl-amino)-2-thienyl]-acetamido}-7-methoκy-3- carbonyloxymethyl-3-cephem-4-carboxylate. Ester cleavage with trifluoroacetic acid yields the title compound. EXAMPLE 30 7-Azido-7-CC(5-hydroxy-5,5-bis(dimethoxyphosphono)-l- pentylamino]-carbonyl}-3-carbamoyloκymethy1-3-cephem-4- carboxylic acid The benzhydryl ester of 7-azido-7-chlorocarbonyl-3-acetoκy- methyl-3-cephem-4-carboκylic acid, prepared as described in eκample 109 of US patent 4,338,437, is reacted with tetramethyl 5-amino-l- hydroκy-1,1-pentanediphosphonate and sodium carbonate to give benzhydryl 7-azido-7-{[5-hydroxy-5,5-bis(dimethoxyphosphono)-l- pentylamino]-carbonyl}-3-acetoxymethyl-3-cephem-4-carboxylate. Selective hydrolysis of the acetate ester with citrus acetyl enzyme, as described by Jeffery et al. , Biochem. J. 1961, Bl, 591, produces benzhydryl 7-azido-7-C[(5-hydroxy-5,5-bis(dimethoκyphosphono)-l- pentylamino]-carbonyl}-3-hydroκymethyl-3-cephem-4-,carboκylate. The latter is reacted with carbamoyl chlor ide in the presence of pyi idinc and gives benzhydryl 7-azido-7-{[5-hydroκy-5,5-bis(dimethoxy- phosphono)-l-pentylamino]-carbonyl}-3-carbamoyloκymethy1- 3- cephem-4- carboκylate. Cleavage of the benzhydryl ester group with trifluoroacetic acid gives 7-azido-7-{[5-hydroκy-5,5-bis(dimethoκy- phosphono)-l-pentylamino]-carbonyl}-3-carbamoyloκymethy1-3-cephem-4- carboκylic acid. EXA.MPLJE„3i. 7-Azido-7-C[5-hydroκy-5,5-bis(dimethoκyphosphono)-l- pentylamino]-carbonyl}-3-acetoκymethyl-3-cephβm-4-carboxylie a&id Cleavage of benzhydryl 7-azido-7~C[5-hydroxy-5,5- bis(dimethoxyphosphono)-l-pentylamino)-carbonyl}-3-acetoxymethy1-3- cephem-4-carboxylate, prepared as described in Example 30, with trifluoroacetic acid gives 7-azido-7-([5-hydroxy-5,5- bis(dimethoxyphosphono)-1-pentylamino]-carbonyl}-3-acetoxymethy1-3- cephem-4-carboxylic acid. EXAMPLE_3.2 7-(2-Thienylacetamido)-7-C5-hydroxy-5,5- bis(dimethoκyphosphono)-l-pentylamino]-carbonyl}-3- carbamoyipxymethyl-3-cephem-4-carboxy1ic acid The 7-azido-7-f.[5-hydroxy-5,5-bis(dimethoκyphosphono)-l- pentylamino]-carbonyl}-3-carbamoyloκymethyl-3-cephem-4-carboxylie acid, obtained as described in Eκample 30, is hydrogen ted at atmospheric pressure with hydrogen in the presence!of platinum oxide as catalyst and gives 7-amino-7-([5-hydroxy-5,5-bis(dimethoxy- phosphono)-l-pentylamino]-carbonyl}-3-carbamoyloκyrnethyl-3-cephem-4- carboxylic acid. Reaction of the latter with 2-thienylacetyl chloride and pyridine yields 7-(2-thienyl-acetamido)-7-{[5-hydroxy-5,5- bis(dimethoκyphosphono)-l-pentylamino]-carbonyl}-3-carbamoyloxymethy1- 3-cephem-4-carboκylic acid. E.XAMP_L_E_33_ 4-Methoxy-6,7,9, 11-tetrahydroxy-9-([5-hydroxy-5,5- bis(dimethoκyphosphono)-l-pentylamino]-acetyl) — 5.7.8.9.10. 2-hexahvdro-tetracβnβ-5.12-dionβ 4-Methoxy-6,7,9,11-tetrahydroκy-9-bromoacety1-5,7,8,9,10,12- hβκahydro-tetracβne-5,12-dione is prepared as described in US patent 3,803,124 and it is reacted with tetramethyl 5-amino-l- hydroκy-l,l-pentanediphosphonate and potassium carbonate to yield 4- methoκy-6,7,9,11-tetrahydroκy-9-{[5-hydroκy-5,5-bis(dimethoxy ¬ phosphono-1-pentylamino]-acetyl}-5,7,8,9,10,12-hexahydro-tetracene- 5,12-dione. EXAMPLE 34 4-Mβthoκy-6,7,9,11-tetrahydroxy-9-{[3-hydroxy-3,3- bis(dimethoxyphosphono)-l-propylaminocarbonyloxy]-acetyl}- 5,.7.,3,.9. t .lj0^12r-heκahy.d.r j.β_tracerje-J5.,.l .-dione.. 4-Methoκy-6,7,9,ll-tetrahydroκy-9-acetyl-5,7,8,9,10,12-heκahydro tetracene-5,12-dione is prepared as described in US patent 3,803,124 and the hydroxyl groups are protected as (2-methoxyethoκy)-methyl ethers by reaction with (2-methoκyethoκy)-methyl chloride, CHJ-O-CHJ- CHJ-O-CHJC . The 4-methoκy-6,7,9,ll-tetra-[(2-methoxyethoxy)- methoκy]-9-acetyl-5,7,8,9,10,12-hexahydro-t©tracene-5,12-dione thus formed is converted to the 9-bromoacstyl derivative by reaction with bromine in methanol solution, and to the 9-hydroxyacetyl derivative b reaction with sodium hydroxide, as described for the non-etherified compounds in US patent 3,803,124. Reaction with phosgene and then with tetramethyl 3-amino-l-hydroκy-l,l-propanediphosphonate affords 4 methoκy-6,7,9,ll-tetra-[(2-methoxyethoκy)-methoκy]-9-(.[3-hydroκy-3,3- bis(dimβthoxyphosphono)-l-propylaminocarbonyloxy]-acetyl}- 5,7,8,9,10, 12-hexahydro-tetracene-5,12-dione. Deprotection is accomplished by reaction with fluoroboric acid, as. described by Ikota et al. , J. Soc. Chem. Co mun. 1978, 869, and yields 4-methoxy- 6,7,9,11-tetrahydroxy-9-{[3-hydroxy-3,3-bis(dimethoxy-phosphono)-l- propyla inocarbonyloxy]-acety1}-5,7,8,9,10,12-heκahydro-tetracene- 5,12-dione. E_XAM.PLE_._3_5 4-Methoxy-6,7,9,ll-tetrahydroxy-9-C[l-hydroxy-l,l- bis(dimethoxyphosphono)-2-propylaminocarbon loxy]-acetyl}- 5.. ^ 8. -10.12-hexahvdro-tetracene-5.12-dione The 4-methoxy-6,7,9,ll-tβtra-[(2-mβthoxyethoxy)-methoxy]-9- bromoacetyl-5,7,8,9,10,12-hexahydro-tetracene-5,12-dione compound whose preparation is described in Example 34 is treated with 2- amino-l-hydroxy-l,l-propanediphosphonic acid tetramethyl ester as descr ibed for the analogous compound in Example 33. Removal of the protecting groups as described in Exampl 30 yields 4-metho y 6,7,9, 11-tetrahydroκy-9-([l-hydroxy- 1,1- bis(dime hoxyphosphono) -2-pr opylamino-c i bonyloxy]-acetyl] 5,7,8,9,10, 12-hexahydro-tetracene-5, 12-dione. EXAMPLE 36 l,6-Bis-£N 1 :N 1 '-[4-chloro-3-(hydroxy- bis(dimethoxyphosphono-methyl)-phenyl]- diguanido N j :N 5 '}-hexane _ 2 Chloro-5-aminobenzoic acid is reacted with phosphorous acid and phosphorus trichloride according to Equation I to fo m u-hydtoxy (1? ch-oro-5-aminophenyl )-methanediphosphonic acid, which is converted Lυ its tetramethyl ester as described in Eκample 1, and then is reacted by the procedure described for an analogous compound in US patent 2,684,924 with heκa ethylene-bis-dicyana ide and yields 1,6-bis- (N j :N j '- [4-chloro-3-(hydroκy-bis(di ethoκyphosphono-methyl)-phenyl)- diguanido-N j :N j * }-heκane.

Claims: What is claimed is: 1. A method for preparing a compound of the formula Λ-(V) -(R) -Z, wherein A is the residue of a pharmaceutically active chemical entity, V is 0, S, NR', CONR * , CO-0, 0-CO, 0-CO-O, C0- S, S-CO, S-CO-S, NR'-CO, OCO-NR * , NR'-CO-O, NR'-CO-NR " , CO-NR * - NR", NR'-NR'-CO, NR'-C( =NH)-NR" or NR * -C(=NH)-NH-C(=NH)-NR "' wherein R, R' and R" are H or an organic or heteroorganic group, and and n are each 1, or one of and n is 0, comprising reacting a pharmaceutically active chemical entity of the formula A-V wherein V is halogen, OH, SH, NR'R " , C00R * , CO-X wherein X is halogen or azido, 0-CO-X wherein X is halogen, O- C0-0R*. CO-SR', S-CO-X, NR'-CO-X, NR'-NHR", NR'-CN, NR'-C(=NH) NH-CN, or metal (covalently bound or ionic), with a diphosphonate compound of the formula V'-R-Z wherein V and R have the previous meanings and Z is P n j H 2 I -C-0H I 0^« 2 , which optionally may be protected, the composition of V * in the pharmaceutically active chemical entity of formula A-V and in the diphosphonate compound of formula V'-R-Z being different and being selected to permit a condensation reaction therebetween. 2. A method for prepa ing a compound of Claim 1 of the formula A-Z, comprising subjecting a compound of formula A-V, wherein A and Z have the same meaning as in claim 1, and V is COOH, to conditions effective to convert the COOH group to Z. 3. A method according to claim 1 wherein V is NH, said compound being formed from a pharmaceutically active chemical entity wherein V is halogen, amino, or a sulfonate ester, and a diphosphonate compound wherein V is amino or halogen. 4. A method according to claim 1 wherein V is a tertiary a ino- containing group, said compound being formed from a pharmaceutically active chemical entity wherein V is halogen, a sulfonate ester or a secondary amino-containing group, and a diphosphonate compound wherein V is a secondary amino-containing group or halogen. 5. A method according to claim 1 wherein V is CONR' , said compound being formed from a pharmaceutically active chemical entity wherein V is carboκyl, and a diphosphonate compound wherein V is primary or secondary amino. 6. A method according to claim 1 wherein V is NR * CO, said compound being formed from a pharmaceutically active chemical entity wherein V is primary or secondary amino, and a diphosphonate compou wherein V is carboxyl. 7. A method according to claim 1 wherein V is CO-0, said compound being formed from a pharmaceutically active chemical entity wherein V is carboxyl or a reactive carboκyl group derivative, and diphosphonate compound wherein V is halogen or hydroxyl. 8. A method according to claim 1 wherein V is 0-CO, said compound being formed from a pharmaceutically active chemical entity wherein V is halogen or hydroxyl, and a diphosphonate compound wherein V is carboxyl. 9. A compound of the formula A-(V) | -(R) B -Z, wherein A, V, R, and Z have the same meaning as in claim 1, and m and n are one of th following conditions: (a) both m and n are 0, (b) both m and n are 1, or (c) one of m and n is 1 and the other is 0. 10. A compound of Claim 9 wherein A is the residue of a pharmaceutically active compound selected fron the group consisting an aminoglycoside, an amphenicol, an ansamycin, a carbapenem, a cephalosporin, a cephamycin, a diaminopyri idine, a lincosamide, a macrolide, a monobactam, a nitrofuran, an oκacepham, a penicillin, a polypeptide, a quinoline, a quinoline analog, a sulfonamide, a sulfo and a tetracycline. 11. A compound of claim 9 wherein V is 0, S, NR' , CONR', CO-0, 0-CO, 0-CO-O, CO-S, S-CO, S-CO-S, NR'-CO, 0C0-NR', NR*- C0-0, NR'-CO-NR", CO-NR'-NR", NR'-NR"-C0, NR'-C(=NH)-NR" or NR C(=NH)-NH-C(=NH)-NR". 12. A compound according to claim 11 wherein V is NR', CONR' 0C0-NR', NR'-CO-NR", CO-NR'-NR", NR-C(=NH)-NR" or NR'-C(sNH)-NH-C(=NH)-NR". 13. A compound according to claim 11 wherein V is CO-0 , 0-CO O-CO-O , S-CO , NR ' -CO , NR ' -CO-O , or NR ' -NR' -CO. 14. A compound according to claim 11 wherein V is O, S, CO-S or S-CO-S. 15. A compound of claim 9 having the name 9-fluoro-3-methyl-10-[4-(4-hydroxy-4,4-d phosphono-I-butyl)- l-piperazyl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de]l[l,4]benzoxazine-6- carboxylic acid, 9-fluoro-10-[4-(3-hydroκy-3,3-diphosphono-l-propyl)-l- piperazyl]-7-oxo-2,3-dihydro-7H-pyrido-[l,2,3-de]r^.,4] benzoxazine-6- carboxylic acid, 9-chloro-3-methyl-10-[4-(2-hydroxy-2,2-diphosphono-ethyl)-l- piperazyl]-7-oκo-2,3-dihydro-7H-pyrido[l,2,3-de][1,4]- benzoκazine-6- carboxylic acid, 9-fluoro-3-methyl-10-[4-(2-hydroκy-2,2-diphosphono-l-ethyl)- l-piperazyl]-7-oκo-2,3-dihydro-7H-pyrido[l,2,3-de]tl,4]- benzoκazine-6-carboxylic acid, 9-fluoro-3-methyl-10-(3-hydroκy-3,3-diphosphono-i- propylamino)-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de] 1,4]-benzoxazinβ-6- carboxylic acid, . 9-fluoro-3-(hydroxy-diphosphonomethyl)-10-(4-mβthyl-l- pipβrazyl)-7-oκo-2,3-dihydro-7H-pyrido[l,2,3-de][1^4]benzoκazine-6- carboxylic acid, 9-fluoro-3-methy1-6-(hydroxydiphosphono-methy1)-10-(4- methy1-l-piperazyl)-7-oκo-2,3-dihydro-7H-pyrido[1,2,3- de][1,4]benzoκazine, 6-chloro-l-βthyl-7-[4-(3-hydroxy-3,3-diphosphonopropyl)-i- pipβrazyl]-4-oκo-l,4-dihydroquinoline-3-carboxylic acid, 6-fluoro-l-methyl-7-(4-hydroxy-4,4-diphosphono-l- butylamino)-4-oκo-l,4-dihydroquinoline-3-carboκylic acid, 6-chloro-l-βthyl-3-(hydroxy-diphosphonomethyl)-7-(4-meth l- l-piperazyl)-4-oxo-l,4-dihydro-quinoline, 6-chloro-7-(6-hydroxy-6,6-diphosphono-l-hexylamino)-l- methyl-4-oxo-l,4-dihydroquinoline-3-carboxylic acid, 6-fluoro-i-(3-hydroxy-3,3-diphosphono-l-propyl)-7-(-4- methyl-l-piperazyl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid, l-cyclopropyl-7-[4-(3-hydroxy-3,3-diphosphono-l-propyl)-l- piperazyl]-4-oκo-l,4-dihydro-l,6-naphthyridine-3-carboκylic acid. 6 - f luoro-7-(6-hydroxy-6,6-diphosphono-l-hexylamino)-l- methyl-4-oxo-l,4-dihydroquinoline-3-carboxylic acid, 7-( 4 -mβt h ylpiperazino)-l-cyclopropyl-4-oκo-l,4-dihydro-l,6- naphthyridine-3-[N-(5-hydroκy-5,5-diphosphonopentyl)- carboκamide, l -cyclopropyl-6-fluoro-7-[4-(3-hydroxy-3,3-diphosphono-l- propyl)- l -piperazyl)- l ,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 6-[2-ethoxy-5-(3 hydroκy-3,3-diphosphono-l-propyl)- aminonaphthoyl]-amino-3 3-dimethyl-7-oxo-4-thia-l- azabicyclo[3.2.0]heptane- carboxylic acid, 6 -[2-ethoxy-3-(3-hydroxy-3,3-diphosphono-l-propyl)- aminonaphthoyl]-amino-3,3-dimethyl-7-oκo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[2-ethoκy-4-(3-hydroxy-3,3-diphosphono-l-propyl)- aminonaphthoyl]-amino-3,3-dimethy1-7-OXO-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[2-©thoxy-6-(3-hydroxy-3,3-diphosphono-l-propyl)- aminonaphthoyl]-amino-3,3-diιaethyl-7-oxo-4-thia-l- azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[2-ethoxy-7-(3-hydroxy-3,3-diphosphono-l-propyi)- aminonaphthoyl]-ami o-3,3-dimethyl-7-OXO-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid, 7β-[α-(Z-methoxyimino)-α-(2-aminothiazol-4-yl)-acetamido]-3 [(1-methyl-l,2,3-triazol-5-yl)-thioπjethyl]-3-cephem-4-[N-(5-hydroxy- 5,5-diphosphonopentyl)-carboκamide], 7β-[α-(Z-methoκyimino)- -(2-aminothiazol-4-yl)-acetamido]-3 [(4-hydroxy-4,4-diphosphono-l-butylcarbamoyl)-oxymethyl]-3-cephem-4- caiboxylie acid, 7β-[α-(Z-methoκyimino)- -(2-aminothiazol-4-yl)-acetamido]-3 [(4-hydroxy-4,4-diphosphonobutanoyloκy)-methyl]-3-cephem-4-carboxylic acid, 7β-[α-(Z-methoxyimino)-α-[2-(3-hydroxy-3,3- diphosphonopropylamino)-thiazol-4-y.l]-acetamido}-3-acetoxymethyl-3- cephem-4-carboxylic acid, 7β-[α-(Z-Methoκyimino)-α-[2-(6-hydroκy-6,6-diphosphono- hexanoylamino)-thiazol-4-yl]-acetamido}-3-acetoxymethyl-3-cephem-4- carboxylic acid. 7β-(α-(Z-Methoκyimino)-α-[ 2 -(3-hydroκy-3,3-diphosphono- propanoylamino ) -thiazol- 4 -yl]-acetami d o}-3-acetoκymethyl-3-cephem-4- carboκylic acid, 6 fl,7Λ^7[α-(Z-Methoκyimino)-α-(2-amino-th azol-4-y1- acetamido)-3-{[2,5-dihydro-6-(4-hydroκy-4,4-diphosphono-l- butylaminocarbonyloκy)-2-methy1-5-oκo- as-triazin-3-yl]thio-methyl}-3- cephem-4-carboxylic acid, {6R, 7R)-7-{α-(Z-Methoxyimino)-α-[2-(2-hydroxy-2,2- diphosphono-l-ethylamino)-thiazol-4-yl)-acetamido}-3-[2,5-dihydro-6- hydroκy-2-methyl-5-oκo-as-triazin-3-yl)-thio-methyl]-3-cephem-4- carboκylic acid, 7β-(5-Hydroxy-5,5-diphosphono- l -pentylaminocarbonylamino)-7 methoxy-3-carbamoyloxymethyl-3-cephem-4-carboκylic acid, 7β-(6-Hydroκy-6,6-diphosphono-l-hexanoylamino)-7-methoxy-3- carbamoyloκymethyl-3-cephem-4-carboκylic acid, 7β-(2-thienylacetamido)-7-methoκy-3-[(3-hydroκy-3,3- diphosphono-1-propylcarbamoyl)-oκymethyl]-3-cephemr4-carboκylie acid, 7β-[5-(3-hydroκy-3,3-diphosphono-l-propylamino)-2- thienylacetamido]-7-methoκy-3-carbamoyloκymethyl]-3-cephem-4- carboxylic acid, 7β-C[5-(3-Hydroxy-3,3-diphosphono-l-propylaminocarbonyl- amino)-2-thienyl]-acetamido}-7-methoxy-3-carbamoyloxymethy1-3-cephem- 4-carboκylic acid, 7-azido-7-[(5-hydroxy-5,5-diphosphono-l-pentylamino)- carbonyl]-3-carbamoyloxymethyl-3-cephem-4-carbox lic acid, 7-azido-7-[(5-hydroxy-5,5-diphosphono-l-pentylamino)- carbonyl)-3-acetoκymethyl-3-cephem-4-carboκylic acid, 7-(2-thienyl-acetamido)-7-[(5-hydroxy-5,5-diphosphono-l- pentylamino)-carbonyl)-3-carbamoyloκymethyl-3-cephem-4-carboκylic acid, 4-rrιethoxy-6,7,9,11-tetrahydroxy-9-[(5-hydroκy-5,5- diphosphono-1-pentylamino) -acetyl]-5,7,8,9,10,12-heκahydro-tetracene- 5,12-dione, 4-methoκy-6,7,9,ll-tetrahydroκy-9-[^-hydroκy-S.S- di p hosphono-l-propylaminocarbonyloκy)-acetyl]-5,7,8,9,10,12-heκahydro tβtracene-5 , 12-dione , 4-me thoxy-6 , 7 ,9, 11- tetrahydroκy-9- [l-hydroxy- 1 , 1- diphosphono-2-propylaminocarbonyloκy)-acetyl] -5,7 ,8,9 , 10, 12-heκahydr tetracene-5, 12-dione, or l ,6-bis- (N 1 :N l ' - [4-chloro-3- (hydroxy-diphosphono-methyl )- pheny1]-diguanido-N 5 :N 5 * } hexane, and the pharmaceutically acceptable mono-, di-, tri and tetraesters thereof. 16. An intermediate for a compound of claim 9 having the name 1-(3-hydroκy-3,3-diphosphonopropyl)-piperazine, 4-( l -piperazyl)-l-hydroκy-l,l-butanediphosphonic acid, 1-(2-hydroκy-2,2-diphosphonoethy1)-piperazine, 2-(l-piperazyl)-l-hydroxy-1,1-ethanediphosphonic acid, (2,3-difluoro-6-nitrophenoκy)-pyruvic acid, 7,8-difluoro-[l,4]benzoxazinβ-3-carboκylic acid, 7,8-difluoro-3-(hydroxy-diphosphonomethyl)-[l,43benzoxazine, 9,10-difluoro-3-hydroxydiphosphonomethyl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de][1,4]benzoκazine-6-carboxy1ic acid, 7-chloro-3-ethoxycarbonyl-6-fluoro-l-(3-hydroxy-3,3-diphosphono l-ρropyl)-4-oxo-l,4-dihydroquinoline, 3-ethoxycarbonyl-6-fluoro-l-(3-hydroxy-3,3-diphosphono-l-propyl 7-(4-methyl-l-piperazyl)-4-oxo-l,4-dihydroquinoline, 7-chloro 6-fluoro-l-(3-hydroxy-3,3-diphosphono-propyl)-4-oxo-l,4- dihydroquinoline-3-carboκylate, 2-ethoκy-5-(3-hydroxy-3,3-diphosphono-l-propyl)-amino-l-naphtho acid, 7β- [α- ( Z-methoxyimino)-α- (2- terέ-butoκycarboriylaminothiazol-4- yl )-ace tamido] -3- [(4-hydroκy-4 , 4-diphosphono-l-butylcarbamoyl )- oxymethyl]-3-cephem-4-carboxylic acid- tert-butyl e : ster , 3-cyano- l-hydroκypropane-l , l-diphosphonic acid, 3-( iert-bu toxycarbony loxy )-3,3-diphosphonopropionic acid, 4- ( £βrfc-butoκycarbonyloκy)-4 ,4-diphosphonobutanoic acid, 4- ( ter£-butoκycarbonyloκy)-4 ,4-diphosphono-butanoyl .chloride, 7β- £α- ( Z-methoxy imino )-α- [2- tert-butoxycarbonyl-amino)- thiazol- yl ) -acetamido}-3- [4- ( £eri-butoκycarbonyloxy)-4 ,4-diphosphono- butanoyloκymethyl]-3-cephem-4-carboκylic acid, 7β-[5-(3-hydroxy-3,3-diphosphono-l-propylamino)-2- thienylacetamido]-7-methoκy-3-carbamoyloκymethyl]-3-cephem-4- carboκylic acid, 3-( £βrt-butoκycarbonyloxy)-3,3-diphosphonopropanoyl chloride, -(Z-methoxyimino)- -[2-(3-( ter£-butoκycarbon loxy)-3,3- diphosphonopropanoyl-amino)-thiazol-4-yl]-acetic acid,• α-(Z-methoκyimino)-α-[2-(3-( tβrύ-butoκycarbonyloκy)-3,3- diphosphonopropanoyl-aminothiazol-4-yl]-acetyl chloride, 7β-{α-(Z-methoxyimino)-α-[2-(3- tert-butoκycarbonyloκy)-3,3- diphosphonopropanoyl-amino)-thiazol-4-yl]-acetamido}-3-acetoκymethy1- 3-cephem-4-carboκylic acid, (6/?,7Λ)-7(α-(Z-methoκyimino)-α-[2-( tert-butoxycarbonyl-amino)- thiazol]-4-yl]acetamido}-3-[(2,5-dihydro-6-(4-hydroκy- 4,4-diphosphono-l-butylaminocarbonyloκo)-2-methyl-5-oxo-as-triazin-3- yl]thio-methyl}-3-cephem-4-carboκylic acid benzhhydryl ester, benzhydryl 7β-{[5-(3-hydroxy-3,3-diphosphono-l- propylaminocarbony1-amino)-2-thienyl]-acetamindo}-7-methoxy-3- carbonyloxymethyl-3-cephem-4-carboxylate, benzhydryl 7-azido-7-[(5-hydroxy-5,5-diphosphono-l-pentylamino)- carbonyl]-3-acetoxymethyl-3-cephem-4-carboxylate, benzhydryl 7- azido-7-[(5-hydroxy-5,5-diphosphono-l-pentylamino)-carbonyl]-3- hydroxymethyl-3-cephem-4-carboxylate, 7-azido-7-[(5-hydroκy-5,5- diphosphono-1-pentylamino)-carbonyl]-3-carbamoyloxymethyl-3-cephem-4- carboxylic acid, 7-amino-7-[(5-hydroκy-5,5-diphosphono-l-pentylamino)-carbonyl]-3- carbamoyloκymethyl-3-cephem-4-carboκylic acid, 4-methoκy-6,7,9,ll-tetra-[(2-methoκyethoκy)-methoxy]-9-[(3- hydroxy-3,3-diphosphono-l-propylaminocarbonyloxy)-acetyl]- 5,7,8,9,10,12-hexahydro-tetracene-5,12-dione, 4-methoxy-6,7,9,11-tetrahydroκy-9-[(3-hydroxy-3,3-diphosphono-1- propylaminocarbonyloκy)-acetyl]-5,7,8,9,10,12-hexahydro-tetracene- 5,12-dione, or α-hydroκy-(2-chloro-5-aminophenyl)-methanediphosphonic acid, 17. A composition comprising a pharmaceutically effective amount of a compound of claim 9 and a pharmaceutically acceptable carrier. 18. A method of treating diseases such as osteomyelitis, periodontal disease, certain urinary tract infections, infectious urinary tract stones, and bone cancer, comprising administering a compound of claim 9 in an amount effective to treat said disease.

Inventors: FARCASIU DAN, HARTMANN JOHN F, FARCASIU, DAN, HARTMANN, JOHN, F.
Applicants: ELIZANOR BIOPHARMACEUTICALS IN, ELIZANOR BIOPHARMACEUTICALS, INC.
Application year: 1996
Main classification: A61K31
IPC codes: C07D499, C07D501, C07F9