DERIVATIVES OF METHYLENE-BISPHOSPHONIC ACID, PROCESS FOR THEIR PREPARATION AND A PHARMACEUTICAL COMPOSITION

Abstract: Hitherto unknown compounds of formula (I) in which R1 is a straight or branched, saturated or unsaturated aliphatic or alicyclic C1-C10 hydrocarbon radical, an aryl or an aryl-C1-C4-alkyl radical, R1 if desired being unsubstituted or substituted with straight or branched C1-C4-alkyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)-amino, carboxy, C1-C4-alkoxycarbonyl, hydroxy, C1-C4-alkoxy, phenoxy, mercapto, C1-C4-alkylthio, phenylthio, halogen, trifluoromethyl; R2 stands for hydrogen, C1-C8-alkyl, aryl-C1-C4-alkyl or halogen; X is O or S and n is an integer from 0 to 2; with the proviso that R2 cannot be hydrogen or methyl if n=0 and R1 is methyl. The compounds of the invention are valuable in the human and veterinary practice.

Description: Derivatives of methylene-bisphosphonic acid, process for their preparation and a pharmaceutical composition. The present invention relates- to hitherto unknown com¬ pounds useful in the human and veterinary therapy, to pharmaceuti¬ cally acceptable salts and easily hydrolyzable esters thereof, to methods for producing said new compounds, to pharmaceutical com¬ positions containing the new compounds, to dosage units of the compositions, and to methods of treating patients using said composi¬ tions and dosage units. The present compounds have the formula I HO - P - C - P - OH (I) OH 0-(CH 2 -CH 2 -X) n -R 1 in which R- is a straight or branched, saturated or unsaturated ali¬ phatic or alicyclϊc C.-C. Q hydrocarbon radical, an aryl or an aryl- C j -C.-alkyl radical, R- if desired being unsubstituted or substituted with straight or branched C ^ -C.-alkyl, amino, C.-C.-alkylamino, di- (C.-C.-alkyO-amino, carboxy, C.-C 4 -alkoxycarbonyl, hydroxy, C^-C. -alkoxy, phenoxy, mercapto, C.-C.-alkylthio, phenylthio, halogen, trifluoromethyl; R 2 stands for hydrogen, C.-Cg-alkyl, aryi- C 1 ~C 4 -alkyl or halogen; X is O or S, and n is an integer from 0 to 2; with the proviso that R„ cannot be hydrogen or methyl if n=0 and R 1 is methyl. In particular, R- stands for straight or branched C--C β - alkyl, phenyl or benzyl optionally substituted with amino, hydroxy, methyl or halogen, and R ? for hydrogen, straight or branched C j -C.-alkyl, benzyl or halogen; preferably R- is propyl, butyl, aminopropyl, aminobutyl, 2,2,2-trifluoroethyl, phenyl or tolyl, and R 2 is hydrogen, methyl, ethyl or chlorine. As stated above, the invention also relates to salts of the compounds of formula I which are tetrabasic acids and thus form mono-, di-, tri- and tetrabasic salts with bases. As examples of salts formed with pharmaceutically acceptable, non-toxic bases, mention may be made of alkali metal salts and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, and calcium salts, as well as salts with ammonia and suitable non-toxic amines, such as lower alkylamines, e.g. triethylamine, lower alkanolamines, e. g . diethanola ine or trϊethanolamine, procaine, cycloalkylamines, e.g . dicyclohexylamine, benzylamines, e. g . N-methylbenzyiamine, N-ethylbenzylamine, N-benzyl-β-phenethylamine, N , N * -dibenzylethyl- enediamine or dibenzylamine, and heterocyclϊc amines, e.g . morpho- line, N-ethylpiperidine and the like. Being tetrabasic acids, the compounds of formula I can form mono- , di- , tri- or tetraesters . The esters of the present invention are |n_ vivo easily hydrolyzable esters, the ester forming residue being selected from the group consisting of aikanoyloxymeth- yl of three to six carbon atoms, . -(alkanoyloxy)ethyl of four to seven carbon atoms, 1 -methyl-1 -(alkanoyloxy)ethyl of five to eight carbon atoms, al koxycarbonyloxymethyl of three to six carbon atoms, 1 -(al koxycarbonyloxy)ethyI of four to seven carbon atoms, 1 -methyl- -1 -(alkoxycarbonyloxy)ethyi of five to eight carbon atoms, 3-phtha- lidyl , 4-crotonolactonyl , y-butyrolacton-4-yl , (2-oxo-1 ,3-dioxoIen-4- -yl)methyl , (5-methyl-2-oxo-1 ,3-dioxolen-4-yl )methyl , and (5-phen- yl-2-oxo-1 ,3-dioxolen-4-yl )methyl as well as dial kylaminoai kyl , acet- onyl , and methoxymethyl . Especially, preferred are al kanoyloxyal kyl and alkoxycarb- onyloxy al kyl esters, such as pϊvaloyloxymethyl and ethoxycarbonyl- oxyethyl esters . The normal bones are living tissues undergoing constant resorption and redeposition of calcium, with the net effect of main¬ tenance of a constant mineral balance. The dual process is commonly called "bone turnover" . I n normal growing bones , the mineral depo¬ sition exceeds the mineral resorption , whereas in certain pathological conditions, bone resorption exceeds bone deposition resulting in e. g . hypercalcemia, for instance due to malignancy or primary hyperpara- thyroidϊsm, or in osteoporosis. The calcium deposition may also take place in undesirable amounts and areas leading to other pathological conditions, e. g . osteoarthritis, rheumatoid arthritis, atherosclerosis, and Paget's disease which is characterized by a combination of an abnormal high bone resorption followed by an abnormal calcium deposition . Research within other areas affected by calcium deposition and/or resorption , such as the development of detergents for use in areas with hard water, or of tooth-pastes which could provide a pro¬ tection against calcium resorption due to acid dissolution or calcium deposition in the form of dental calculus, has been conducted with compounds forming complexes with calcium . Examples of such complex forming compounds are certain bisphosphonates . It has long been known that such compounds can inhibit not only the crystal growth , but also can delay dissolution of already formed crystals. I n spite of the fact that a great number of bisphosphonic acids are known , only a few have been used clinically. An example is 1 -hydroxyethylϊdene-1 ,1 -bisphosphonic acid (etidronate) which is the only marketed compound of this type. It is not very active and inhibits bone mineralization in doses close to those necessary for the more useful inhibition of bone resorption . Dichloromethylene-bisphosphαnic acid (clodronate) has been shown to inhibit bone resorption without affecting bone mineraliza¬ tion , but has been associated with certain adverse effects . 3-Amino-1 -hydroxypropylϊdene-1 ,1 -diphosphonic acid (APD) is more active on a weight basis than the two aforementioned com¬ pounds, but has also undesirable effects . A common drawback of the three abovementioned compounds is their very poor oral absorbability (about 2-6%) . The ideal compound for the purpose is one which is select¬ ive, i .e. a compound which only influences one of the processes in the mineral balance, either the resorption or the deposition depend¬ ing upon the pathological condition treated , and furthermore the ideal compound should be absorbed to a great extent when given orally and should be devoid of side effects . It has now surprisingly turned out that the present com¬ pounds have these desired characteristics . Compared with the com¬ pounds known to have a systemic activity, they show a high degree of selectivity combined with a good oral absorbability and a low toxi- city. The activity in inhibiting bone resorption is determined as follows. Female rats (140 - 160 g) were placed in metabolic cages and urine was collected for 2 days . The compound to be tested was solu- bϊlized in a 2% bicarbonate buffer and administered daily subcutan- eously at 16 μmoi/kg for 7 days . Urine was collected daily, and the urinary content of hydroxyproiine which is an indication of bone resorption , confer P . H . Reitsma et al , Calcif . Tissue I nt. 32, 145-157 (1980)) , was determined by the method of Prockop and Udenfriend (Anal . Biochem . , 228-239, 1960) . I nhibition of bone resorption was expressed as % change in hydroxyproline excretion after 7 days of treatment, each rat serving as its own control . Results of the testing of four compounds of formula I (n=0) together with 3 reference compounds at a dose of 16 μmol/- kg/day to groups of 5 rats are given in Table I . Table I The compound of the present invention with R ? = H may be prepared from a dichloromethyl ether of formula I I according to the following reaction scheme R.., X, and n have the meanings mentioned above and Alk stands for C 1 -C 8 -alkyl. Some of the dichloromethyl ethers of formula II are known. These as well as the unknown can be prepared as described in Chem. Ber. 94, 548 (1961) or in Recueil Des Travaux Chϊmiques Des Pay-Bas 90, 556 (1971). As shown in the reaction scheme these dichloromethyl ethers can be converted into tetraalkyl esters of formula IV either directly or through intermediates of formula III. The intermediates of formula 111 and IV are unknown and are thus part of the invention. Cleavage of the tetraalkyl esters, e.g. with boiling hydro¬ chloric acid leads to the compounds of the invention with R ? = H. Tetraalkyl esters may also be cleaved by an alternative and milder method described in Jour. f. prakt. Chemie 320, 344 (1978). Treatment with bromo-trimethylsilane at room temperature or moderately elevated temperature leads to a tetra-trimethylsilyl ester which is easily cleaved with water to yield the free acid of formula I (R 2 = H). The compounds of the invention in which R ? is an al kyl or aral kyl radical may be prepared by alkyiatϊon of compounds of for¬ mula IV, e. g . by treatment with sodium hydride followed by an alkyl or aralkyl halide. The reaction is performed in a suitable solvent, such as dimethylformamide or tetrahydrofuran . Cleavage of the tetraal kyl esters results in the compounds of the invention with R p = al kyl or aral kyl . The compounds of the invention in which R ? = halogen may be prepared by halogenation of compounds of formula IV , e. g . sodium hypochlorite followed by cleavage of the tetraethyl ester. The present compounds are as mentioned above intended for use in pharmaceutical compositions which are useful in the treat¬ ment of osteoporosis, rheumatoid arthritis and other arthritic disor¬ ders, atherosclerosis, hypercalcemia due to malignancies or primary hyperparathyroϊdism, Paget's disease, and other conditions with an abnormal calcium balance. The compounds of the invention may also be used in the prevention of dental calculus, e.g . as an ingredient in tooth-paste. The amount required of a compound of formula ( I ) (here- inafter referred to as the active ingredient) for therapeutic effect will , of course, vary both with the particular compound , the route of administration and the mammal under treatment. A suitable dose of a compound of formula ( I ) for a mammal suffering from e. g . a hy- percalcemic condition as defined hereinbefore Is 0.01 to 25 mg per kilogram bodyweight, the most preferred dosage being 0.02 to 10 mg/kg of bodyweight, for example 0.05 to 5 mg/kg ; administered once or more times daily. I n the case of profylactic treatment of e. g . postmenopausal osteoporosis, a suitable daily dose of a compound of formula ( I ) is 0.01 to 10 mg per kilogram bodyweight, the most preferred dosage being 0.02 to 5 mg/kg of bodyweight. While it is possible to administer an active compound as such , it is sometimes preferable to present it as a pharmaceutical formulation . Conveniently, the active ingredient comprises from 0.1% to 99.9% by weight of the formulation. Conveniently, dosage units of a formulation contain . between 1 mg and 1 g of the active ingredient. For topical administration, the active ingredient preferably comprises from 1% to 2% by weight of the formulation but the active ingredient may comprise as much as 10% w/w. By the term "dosage unit" is meant a unitary, i . e. a sing¬ le dose which is capable of being administered to a patient, and which may be readily handled and packed , remaining as a physically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers . The formulations, both for veterinary and for human medi¬ cal use, of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier and optionally other therapeutic ingredient(s) . The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof . The formulations include those in a form suitable for oral , rectal , parenteral (including subcutaneous, intramuscular and intra- venous) , or topical administration . The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients . I n general , the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both , and then , if necessary, shaping the product into the de¬ sired formulation . Formulations of the present invention suitable for oral ad¬ ministration may be in the form of discrete units as capsules, sa¬ chets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules ; in the form of a solution or a suspension in an aqueous liquid or non-aque- ous liquid ; or in the form of an oil-ϊn-water emulsion or a water-ϊn- -oil emulsion . The active ingredient may also be in the form of a bolus, electuary or paste. Formulations for rectal aministration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema . Formulations suitable for parenteral administration conveni¬ ently comprise a sterile aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Form lations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingre¬ dient which may be in microcrystallϊne form, for example, in the form of an aqueous microcrystalline suspension . Liposomal formula- tions or biodegradable polymer systems may also be used to present the active ingredient for intra-articular administration . Formulations suitable for topical administration include li¬ quid or semi-liquid preparations such as liniments, lotions, applica¬ tions; oil-in-water or water-in-oil emulsions such as creams, oint- ments or pastes, including tooth-pastes; or solutions or suspensions such as drops . In additon to the aforementioned ingredients, the formula¬ tions of this Invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e. g . methyl hydroxy- benzoate (including anti-oxidants) , emulsifying agents and the like. The compositions may further contain other therapeutϊcally active compounds usually applied in the treatment of the above men¬ tioned pathological conditions, for instance vitamin D ? and D- and hydroxylated derivatives, e. g . 1α-hydroxy-vitamin D„, 1α-hydroxy- -vϊtamin Dp, 1α,25-dihydroxy-vϊtamin D~ , 1α,25-dihydroxy-vitamin D ? / calcitonin (human , porcine or salmon) , mϊtramycϊn , sodium fluoride, estrogens, and non-steroid antiinflammatory drugs , e. g . acetylsalicylic acid , indomethacin, naprosyn , and timegadϊne. According to the invention, the present compounds are administered to a patient suffering from one of the above mentioned pathological conditions in a daily dose (for adults) from 0.7 mg to 1750 mg, preferably from 1 , 5 - 1000 mg , and in the veterinary practice correspondingly in daily doses from 0.01 to 25 mg/kg body- weight. The invention will now be further described in the follow¬ ing non-limiting Examples : (Except where otherwise specified , NMR- spectra have been recorded with tetramethylsilane as internal refer¬ ence. ) Example 1 Diethyl α-chloro-α-(n-butoxy) -methyl hosphonate A mixture of dichloromethyl butyl ether (13.5 g) , triethyl phosphite (16.1 ml) and anhydrous zinc chloride (70 mg) was heated at 100°C for 1 hour. Distillation n vacuo gave the title compound as a colourless oil. B.p. 93-95°C (0.15 mm Hg). NMR (CDCI 3 ): δ = 0.93 (t, 3H), 1.37 (t, 6H), 1.3-1.8 ( , 4H), 3.4-3.6 (m, 1H), 3.8-4,1 (m, 1H), 4.1-4.5 (m, 4H), and 5.65 (d, 1H) ppm. Example 2 By following the procedure described in Example 1 and by using the appropriate dichloromethyl alkyl ethers the following com- pounds were prepared: Diethyl α-chloro-c.-(n-propoxy)-methylphosphonate B.p. 95-100°C (0.75 mm Hg). NMR (CDCI 3 ): δ = 0.96 (t, 3H), 1.37 (t, 6H), 1.65 (m, 2H), 3.4-3.7 (m, 1H), 3.8-4.1 (m, 1H), 4.1-4.5 (m, 4H), and 5.66 (d, 1H) ppm. Diethyl α-chloro-α-(n-pentyloxy)-methylphosphonate B.p. 108-117°C (0.1 mm Hg). NMR (CDCI 3 ): δ = 0.90 (t, 3H), 1.37 (t, 6H), 1.3-1.8 (m, 6H), 3.4-3.6 (m, 1H), 3.8-4.1 (m, 1H), 4.2-4.5 (m, 4H), and 5.66 (d, 1H) ppm. Diethyl α-chloro-α-(isobutoxy)-methylphosphonate B.p. 100°C (0.5 mm Hg). NMR (CDCI 3 ): δ = 0.95 (d, 6H), 1.37 (t, 6H), 1.96 (m, 1H), 3.2-3.4 ( , 1H), 3.7-3.9 (m, 1H), 4.1-4.5 (m, 4H), and 5.65 (d, 1H) ppm. Diethyl α-chloro-α-(n-decyloxy)-methylphosphonate B.p. 171-175°C (0.8 mm Hg). NMR (CDCI 3 ): δ = 0.88 (t, 3H), 1.27 (bs, 14H), 1.37 (t, 6H), 1.6 (m, 2H), 3.4-3.7 (m, 1H), 3.8-4.1 ( , 1H), 4.1-4.5 (m, 4H), and 5.65 (d, 1H) ppm. Example 3 Tetraethyl (n-butoxymethylene)-bisphosphonate Diethyl phosphite (11.6 mi) was added dropwise at 20°C to a stirred suspension of 55% sodium hydride (3.45 g) in dry tetrahy¬ drofuran (65 ml). After stirring for a further 15 minutes, the mix- ture was cooled to 0°C, and diethyl α-chloro-α-(n-butoxy)-methyl- phosphonate (16.5 g) was added during 10 minutes. The mixture was stirred at room temperature for 1 hour, diluted with saturated aqueous sodium chloride and extracted with chloroform. The organic phase was dried and evaporated to leave an oil which was purified by chromatography on silica gel (eluent: ether-acetone 1:1). The pure title compound was isolated as a colourless oil. NMR (CDCI 3 ): δ = 0.92 (t, 3H), 1.35 (t, 12H), 1.2-1.8 (m, 4H), 3.75 (t, 2H), 3.91 (t, 1H), and 4.0-4.4 ( , 8H) ppm. Example 4 By following the procedure described in Example 3 and using the compounds described in Example 2 instead of diethyl α-chloro-c.-(n-butoxy)-methylphosphonate, the following compounds were prepared: Tetraethyl (n-propoxymethylene)-bisphosphonate NMR (CDCI 3 ): δ = 0.94 (t, 3H), 1.36 (t, 12H), 1.65 (m, 2H), 3.72 (t, 2H), 3.92 (t, 1H), and 4.1-4.5 (m, 8H) ppm. Tetraethyl (n-pentyloxymethylene)-bisphosphonate NMR (CDCi 3 ): δ = 0.89 (t, 3H), 1.35 (t, 12H), 1.2-1.8 (m, 6H), 3.73 (t, 2H), 3.90 (t, 1H), and 4.0-4.4 (m, 8H) ppm. Tetraethyl (isobutoxymethylene)-bisphosphonate NMR (CDC! 3 ): δ = 0.93 (d, 6H), 1.35 (t, 12H), 1.90 (m, 1H), 3.53 (d, 2H), 3.90 (t, ' 1H), and 4.0-4.4 (m, 8H) ppm. Tetraethyl (n-decyloxymethylene)-bisphosphonate Microanalysis: Calculated: C: 51.34 H: 9.53 Found: C: 51.47 H: 9.64 Example 5 (n-Butoxymethylene)-bisphosphonic acid, tris-benzylamine salt A mixture of tetraethyl (n-butoxymethylene)-bisphosphon- ate (10.0 g) and 6 N hydrochloric acid (60 ml) was refluxed over¬ night. The resulting solution was evaporated to dryness |n_ vacuo. Residual hydrochloric acid was removed by repeated evaporation with abs. ethanol. The crude product was redϊssolved in abs. ethanol (100 ml), and benzylamine (12.2 ml) was added with stirring. The crystalline salt was isolated by filtration and dried in_ vacuo. NMR (CD 3 OD): δ = 0.86 (t, 3H), 1.1-1.8 (m, 4H), 3.70 (t, 1H), 3.80 (t, 2H), 4.04 (s, 6H), and 7.3-7.7 (m, 15H) ppm. Example 6 By following the procedure of Example 5 and using the compounds described in Example 4 instead of tetraethyl (n-butoxy- methylene)-bisphosphonate the following compounds were obtained: (n-Propoxymethylene)-bisphosphonic acid, tris-benzylamine salt NMR (CD 3 OD): 6 = 0.88 (t, 3H), 1.60 (m, 2H), 3.70 (t, 1H), 3.76 (t, 2H), 4.04 (s, 6H), and 7.3-7.7 ( , 15H) ppm. (n-Pentyloxymethylene)-bisphosphonlc acid This compound was isolated as the free acid in crystalline form. NMR ((CD 3 ) 2 SO): δ = 0.95 (t, 3H), 1.1-1.8 (m, 6H), 3.70 (t, 2H), and 3.71 (t, 1H) ppm. The tris-benzylamine salt was also prepared. NMR (D ? 0): δ = 0.70 (t, 3H), 1.0-1.7 (m, 6H), 3.47 (t, 1H), 3.56 (t, 2H), 4.01 (s, 6H), and 7.31 (s, 15H) ppm. HDO = 4.66 ppm was used as internal reference. (Isobutoxymethylene)-bisphosphonic acid, tris-benzylamine salt NMR (CD 3 OD): δ = 0.90 (d, 6H), 1.88 (m, 1H), 3.59 (d, 2H), 3.71 (t, 1H), 4.04 (s, 6H), and 7.3-7.7 (m, 15H) ppm. (n-Decyloxymethylene)-bisphosphonic acid, tris-benzylamine salt NMR (CD 3 OD): δ = 0.87 (t, 3H), 1.23 (s, 14H), 1.4-1.7 (m, 2H), 3.70 (t, 1H), 3.79 (t, 2H), 4.04 (s, 6H), and 7.3-7.6 (m, 15H) ppm. Example 7 By substituting dichloromethyl 3-chloropropyl ether, di¬ chloromethyl 2-ethoxyethyl ether or dichloromethyl 2,2,2-trifluoro- ethyl ether for dichloromethyl butyl ether in Example 1 and by following the procedures described in Examples 1, 3 and 5 the fol- lowing compounds are prepared: (3-chloropropoxymethylene)-bisphosphonic acid, tris-benzyl amine salt [2-(ethoxy)-ethoxymethylene] -bisphosphonic acid, tris-benzyl amine salt (2,2,2-trifluoroethoxymethylene)-bisphosphonic acid, tris-benzylamine salt. NMR (CD 3 OD): δ = 3.84 (t, J=15 Hz, 1H), 4.04 (s, 6H), 4.31 (q, J=9 Hz, 2H) and 7.4 (m, 15 H) ppm. Example 8 Tetraethyl (phenoxymethylene)-bisphosphonate Diethylphosph-ite (20.6 ml) was added dropwϊse at 20°C to a stirred suspension of 55% sodium hydride (6.24 g) in dimethylform- amide (90 ml). After stirring for a further 15 minutes, the mixture was cooled to 0°C, and dichloromethyl phenyl ether (9.27 g) was ad- ded dropwise. Stirring was continued overnight at 45 C , and the mixture was cooled in Ice, diluted with water, neutralized and ex¬ tracted with ethyl acetate. The organic phase was washed repeatedly with water, dried and evaporated ϊn_ vacuo to yield an oil which was purified by chromatography on silica gel . Eluent: ether-acetone 85: 15. The pure title compound was obtained as a colourless oil . NMR (CDCI 3 ) : δ = 1 .22 (t, 6H) , 1 .25 (t, 6H) , 4.1 -4.5 (m, 8H ), 4.87 (t, 1 H) , and 6.9-7.5 (m, 5H) ppm. Example 9 Tetraethyl (m-chlorophenoxymethylene)-bϊsphosphonate This compound was obtained as described in Example 8 by substituting dichloromethyl m-chlorophenyl ether for dichloromethyl phenyl ether. NMR (CDCI 3 ) : δ = 1 .25 (t, 6H ) , 1 .27 (t, 6H) , 4.1 -4.4 (m, 8H ) , 4.81 (t, 1 H) and 6.9-7.3 (m, 4H) ppm . Example 10 (Phenoxymethylene)-bisphosphonic acid , tris-benzylamine salt This compound was prepared as described in Example 5 by substituting tetraethyl (phenoxymethylene)-bisphosphonate for tetra- ethyl (n-butoxymethylene)-bisphosphonate. Colourless crystalline salt. NMR (D 2 0) : δ = 4.07 (s, 6H), 4.52 (t, 1 H), 6.8-7.4 (m, 5H ) , and 7.40 (s, 15H) ppm . HDO = 4.66 ppm was used as internal reference. Example 11 (m-Chlorophenoxymethylene)-bisphosphonic acid , tris-benzylamine salt This compound was obtained from tetraethyl (m-chloro- phenoxymethylene)-bisphosphonate by following the procedure de¬ scribed in Example 5. NMR (D 2 0) : δ = 4.07 (s , 6H) , 4.48 (t, 1 H) , 6.8-7.3 (m, 4H) , and 7.38 (s, 15H) ppm. .HDO = 4.66 ppm was used as internal reference. Example 12 2-(p-Chlorophenoxy)-ethyl formate p-Chlorophenol (112 g) was added to a solution of sodium hydroxide (40 g) in water (100 ml) . The mixture was heated to reflux, and 2-chloroethanol (80 g) was added dropwise with stirring . After cooling to room temperature, the mixture was extracted with ether. The organic phase was dried and evaporated to leave a resi- due which was refluxed with formic acid (150 ml ) for 1 hour followed by distillation ij vacuo. The product had boiling point 138-40°C/I mm Hg . Example 13 Dichloromethyl 2-(p-chlorophenoxy)-ethyl ether Phosphorus pentachlσride (104 g) was added in portions with stirring at 75°C to 2-(p-chlorophenoxy)-ethyl formate (94.2 g) . The mixture was left overnight at room temperature, and phosphorus oxychloride was removed ]rι vacuo. Distillation of the residue gave the title compound with boiling point 130°C/I mm Hg . Example 14 Tetraethyl [2-(p-chlorophenoxy)-ethoxymethylene] -bisphosphonate Anhydrous zinc chloride (10 g) was added at 150°C to a mixture of dichloromethyl 2-(p-chlorophenoxy)-ethyl ether (5.1 g) and triethyl phosphite (6.9 ml) . When the evolution of ethyl chloride ceased, the mixture was cooled, taken up in ether (250 ml), washed with aqueous sodium bicarbonate, dried and evaporated . Unreacted triethyl phosphite was removed [n vacuo, and the crude product was used in the next step without further purification . Example 15 Disodium [2-(p-chlorophenoxy)-ethoxymethylene3 -bisphosphonate Tetraethyl [2-(p-chlorophenoxy)-ethoxymethylene] -bisphos¬ phonate (5 g) was refluxed with concentrated hydrochloric acid (50 ml ) for 3 hours . The hydrochloric acid was removed completely in_ vacuo, and the residue was taken up in ethanol . The disodium salt was precipitated by the addition of sodium 2-ethylhexanoate in ethan¬ ol and isolated by filtration in crystalline form . NMR ((CD 3 ) 2 SO/D 2 0): δ = 3.7 (t, 1 H ), 4.0-4.2 (m, 4H), 6.95 (d , 2H ) , and 7.35 (d, 2H ) ppm. Example 16 Disodium [2-(phenoxy)-ethoxymethylene] -bisphosphonate This compound is prepared by substituting phenol for p- chlorophenol in Example 12 and following the procedures described in Examples 12-15. Example 17 Disodium [2-(phenylth?o)-ethoxymethylene] -bisphosphonate The title compound is prepared as described in Example 16 by substituting thiophenol for phenol . Example 18 (Phenoxymethylene)-bisphosphonic acid A mixture of tetraethyl (phenoxymethylene)-bisphosphonate (20 g) and 6 N hydrochlorϊd acid (150 ml) was refluxed overnight and the resulting solution was evaporated to dryness ]n_ vacuo. Resi¬ dual hydrochloric acid was removed by repeated evaporation with ab¬ solute ethanol. The residue was taken up in acetone (7 ml) and ether (200 ml) was added. The crystalline product was filtered, washed with ether and dried iri vacuo. M.p. 187-188°C. NMR ((CD 3 ) 2 SO): δ = 4.66 (t, J=17 Hz, 1H) and 6.8-7.4 (m, 5H) ppm. Example 19 Disodium (phenoxymethylene) -bisphosphonate A solution of (phenoxymethylene)-bϊsphosphonic acid (53 g) in water (300 ml) was titrated with 2N sodium hydroxide to pH = 5.5. The title compound was precipitated by the addition of acetone (1500 ml). The crystalline salt was filtered and washed with acetone. Drying n vacuo over potassium hydroxide at room temperature gave the title compound in the form of a tetrahydrate. Microanalysis: Calculated: C: 21.89, H: 4.20, H 2 0: 18.7 Found: C: 21.80, H: 4.09, H 2 0: 18.3 Drying in_ vacuo at 60 C gave a monohydrate. Microanalysis: Calculated: C: 25.47, H: 3.05, H 2 0: 5.4 Found: C: 25.54, H: 3.15, H 2 0: 5.1 Example 20 By following the procedure described in Recueil Des Travaux Chimique Des Pays-Bas 84, 1251 (1965), the following formates were prepared: 4-Chlorophenyl formate: B.p. 52°C/0.5 mmHg 4-Bromophenyl formate: B.p. 110 C/15 mmHg 4- Fluorophenyl formate: B.p. 70°C/15 mmHg 2,4-Dich!orophenyl formate: B.p. 60°C/0.1 mmHg 4-tolyl formate: B.p. 80°C/ 5 mmHg 4-Tert-butylphenyl formate: B.p. 110°C/15 mmHg 1-Naphthyl formate: B.p. 100°C/0.4 mmHg 2-Naphthyl formate: B.p. 110°C/0.1 mmHg 4-NItrophenyl formate: M.p. 71-72°C 4-Methoxyphenyl formate: B.p. 115°C/15 mmHg 3-(Trifluoromethyl)-phenyl formate: B.p. 70°C/15 mmHg Example 21 The following dichloromethyl ethers were prepared accord- ing to the procedure described in Recueil Des Travaux Chimiques Des Pays-Bas 90, 556-561 (1971): Dichloromethyl 4-chlorophenyl ether: B.p. 68°C/0.2 mmHg Dichloromethyl 4-bromophenyl ether: B.p. 135 C/15 mmHg Dichloromethyl 4-fluorophenyI ether: B.p. 90°C/15 mmHg Dichloromethyl 2,4-dichlorophenyl ether: B.p. 82°C/0.15 mmHg Dichloromethyl 4-tolyi ether: B.p. 48°C/0.04 mmHg Dichloromethyl 4-tert-buty I phenyl ether: B.p. 140°C/15 mmHg Dichloromethyl -naphthyl ether: B.p. 125°C/0.25 mmHg Dichloromethyl 2-naphthyl ether: B.p. 130°C/0.35 mmHg Dichloromethyl 4-nitrophenyl ether: B.p. 130°C/0.1 mmHg Dichloromethyl 4-methoxyphenyl ether: B.p. 80°C/0.1 mmHg Dichloromethyl 3-(trifIuoromethyl)-phenyl ether: B.p. 90°C/15 mmHg Example 22 By following the procedure described in. Example 8 and substituting the dichloromethyl ethers of Example 21 for dichloro¬ methyl phenyl ether, the following compounds were prepared: Tetraethyl (4-chlorophenoxymethylene) -bisphosphonate NMR (CDCI 3 ): δ = 1.2-1.6 (m, 12H), 4.0-4.5 ( , 8H), 4.75 (t, J=17 Hz, 1H) and 6.95-7.45 (m, 4H) ppm. Tetraethyl (4-bromophenoxymethylene) -bisphosphonate NMR (CDCI 3 ): δ = 1.31 (t, 6H), 1.33 (t, 6H), 4.20 (m, 8H), 4.77 (t, 1H), 7.00 (m, 2H), and 7.37 (m, 2H) ppm. Tetraethyl (4-fluorophenoxymethylene)-bisphosphonate NMR (CDCI 3 ): δ - 1.32 (t, 6H), 1.34 (t, 6H), 4.20 (m, 8H), 4.72 (t, 1H) and 7.00 (m, 4H) ppm. Tetraethyl (2,4-dichlorophenoxymethylene)-bϊsphosphonate NMR (CDCI 3 ): δ = 1.2-1.4 (m, 12H), 4.1-4.5 (m, 8H), 4.88 (t, J=17 Hz, 1H) and 7.0-7.4 ( , 3H) ppm. Tetraethyl (4-tolyloxymethylene) -bisphosphonate NMR (CDCI 3 ): δ = 1.15-1.50 (m, 12H), 2.28 (s, 3H), 3.9-4.5 (m, 8H), 4.77 (t, J=17 Hz, 1H) and 7.00. (m, 4H) ppm. Tetraethyl (4-tert-butylphenoxymethylene)-bisphosphonate NMR (CDCI 3 ): δ = 1.28 (s, 9H), 1.29 (m, 12H), 4.20 (m, 8H), 4.85 (t, 1H), 7.00 (m, 2H), and 7.30 (m, 2H) ppm. Tetraethyl (1 -naphthyloxymethylene)-bisphosphonate NMR (CDCI 3 ): δ = 1.05-1.50 (m, 12H), 3.9-4.5 (m, 8H), 5.12 (t, J=17 Hz, 1H), 7.0-8.0 (m, 6H), and 8.2-8.5 (m, 1H) ppm. Tetraethyl (2-naphthyloxymethylene) -bisphosphonate NMR (CDCI 3 ): δ = 1.2-1.4 (m, 12H), 4.0-4.5 (m, 8H), 5.04 (t, J=17 Hz, 1H), 7.20-7.55 (m, 4H), and 7.60-7.85 (m, 3H) ppm. Tetraethyl (4-nitrophenoxymethylene)-b?sphosphonate In this case the reaction mixture was stirred overnight at room temperature instead of 45 C. NMR (CDCI 3 ): δ = 1.2-1.5 (m, 12H), 4.0-4.55 (m, 8H), 4.92 (t, J=16 Hz, 1H), 7.18 (d, J=9 Hz, 2H), and 8.22 (d, J=9 Hz, 2H) ppm. Tetraethyl (4-methoxyphenoxymethylene)-bϊsphosphonate NMR (CDCI 3 ): δ = 1.31 (t, 6H), 1.34 (t, 6H), 3.76 (s, 3H), 4.20 (m, 8H), 4.71 (t, 1H), 6.80 (m, 2H), and 7.02 (m, 2H) ppm. Tetraethyl (3- (trifluoromethyl )-phenoxymethylene)-bisphosphonate NMR (CDCI 3 ): δ = 1.32 (t, 6H), 1.33 (t, 6H), 4.25 (m, 8H), 4.85 (t, 1H), and 7.33 (m, 4H) ppm. Example 23 (4-Tolyloxymethylene)-b?sphosphonic acid Tetraethyl (4-tolyloxymethylene)-bIsphosphonate was hy- drolyzed with 6N hydrochloric acid as described in Example 18. The crude acid crystallized from acetone-ether to yield a colourless crystalline compound with m.p. 186-189 C. NMR ((CD 3 ) 2 SO): δ = 2.22 (s, 3H), 4.59 (t, J=17 Hz, 1H), and 7.0 (m, 4H) ppm. Example 24 (2,4-Dichlorophenoxymethylene)-bisphosphonic acid Trimethyi bromosilane (17.3 ml) was added to a stirred so- lution of tetraethyl (2,4-dichIorophenoxymethylene)-bϊsphosphonate (5.0 g) in methylene chloride (18 ml). After 3 hours at room tempe¬ rature, the mixture was evaporated iri vacuo, and residual trimethyi bromosilane was removed by repeated evaporation with methylene chloride. The residue was stirred overnight in ethanol and evaporat- ed iin vacuo. Crystallization from ether gave the title compound as colourless crystals. NMR ((CD 3 ) 2 SO): δ = 4.82 (t, J=17 Hz, 1H), 7.3 (m, 2H), and 7.51 (bs, 1H) ppm. Example 25 (1 -Naphthyloxymethylene)-bisphosphonic acid This compound was prepared from tetraethyl (1 -naphthyi- oxymethylene)-bϊsphosphonate according to the procedure described in Example 24. Colourless crystals with m . p . 244°C (dec ) . NMR ((CD 3 ) 2 S0) : δ = 4.97 (t,. J=17 Hz, 1 H), 7.0-7.6 (m, 5H), 7.8 (m, 1 H) , and 8.3 (m, 1H) ppm. Example 26 Disodium (2-naphthyloxymethylene)-bisphosphonate By following the procedure described in Example 24 tetra¬ ethyl (2-naphthyloxymethylene)-bisphosphonate was transformed into the title compound in the form of the free acid which was dissolved in absolute ethanol and treated with an excess of benzylamine to form a crystalline tris-benzylamine salt. The free acid was liberated from the tris-benzylamine salt in water by treatment with an excess of Dowex 50 W (H -form) . The ion exchange resin was filtered , and the filtrate was titrated with 2N sodium hydroxide to pH=5.5. Con¬ centration in_ vacuo and addition of acetone gave a colourless crystal¬ line disodium salt which was isolated by filtration and dried πn vacuo . NMR (D 2 0) : δ = 4.78 (t, J=16 Hz, 1 H ) , 7.2-7.6 (m, 4H ), and 7.7- 7.9 (m , 3H ) ppm . HDO = 4.66 ppm was used as internal reference. Example 27 Tetraethyl (4-aminophenoxymethylene) -bisphosphonate A solution of tetraethyl (4-nϊtrophenoxymethylene)-bis- phosphonate (11 g) in methanol (120 ml ) in a nitrogen atmosphere was cooled in ice and treated with hydrazine hydrate (5.3 ml ) and 10% palladium on carbon (2.4 g) . Stirring was continued for 3 hours at room temperature, and the catalyst was removed by filtration . The filtrate was evaporated in_ vacuo, and the crude product was purified by column chromatography on silica gel to give a colourless oil . NMR (CDCI 3 ) : δ = 1 .23-1 .40 (m, 12H) , 4.0-4.4 (m, 8H) , 4.66 (t, J=17 Hz, 1 H) , 6.59 (d, J=9 Hz, 2H ) , and 6.94 (d , J=9 Hz, 2H ) ppm . Example 28 (4- Amϊnophenoxymethylene) -bisphosphonic acid This compound was prepared from tetraethyl (4-aminophen- oxymethylene)-bisphosphonate by following the procedure of Example 18. NMR (D 2 0 + NaOD) : δ = 4.17 (t, J=15 Hz, 1 H) , 6.61 (d , J=9 Hz, 2H), and 6.85 (d , J=9 Hz, 2H ) ppm. HDO = 4.66 ppm was used as internal reference. Example 29 3-(Phthalim?do)-propyl formate A mixture of 3-(phthalimido)-propanol (20.5 g) and formic acid (33 ml) was refluxed overnight and evaporated mi vacuo to leave a yellow oil which crystallized from absolute ethanol to give colour¬ less crystals with m . p . 68-70 C . Example 30 Dichloromethyl 3-(phthalinTido)-propyl ether A mixture of 3-(phthalimido)-propyl formate (17 g) , phos¬ phorus pentachloride (15.2 g) and alcoholfree chloroform was heated for 1 hour on the steam bath . After cooling and addition of ether, the crystalline product was Isolated by filtration . M . p . 101 -103 C . Example 31 Dichloromethyl 2-methoxyethyl ether A mixture of formic acid (22.6 ml) and 2-methoxyethanol (23.8 ml) was refluxed overnight. After cooling, water and solid so- dium bicarbonate in excess was added . The mixture was extracted twice with ether, and the organic phases were dried . Ether was re¬ moved by distillation at atmospheric pressure, and 2-methoxyethyl formate was then distilled iin vacuo. B . p . 50°C/20 mmHg . A mixture of 2-methoxyethyl formate (10.4 g) and phos- phorus pentachloride (20.8 g) was stirred until a clear solution was formed . Fractionation iin vacuo gave the title compound with b . p . 62°C/20 mmHg . Example 32 Dichloromethyl cyclohexyl ether Cyclohexyl formate (12.8 g) and phosphorus pentachloride (20.8 g) were stirred until a clear solution was formed . Phosphorus oxychloride was removed iri vacuo at room temperature, and the crude product was used in the next step without purification . Example 33 Dichloromethyl benzyl ether This compound was prepared from benzyl formate and phosphorus pentachloride as described in Example 32. Example 34 Tetraethyl (2-methoxyethoxymethylene) -bisphosphonate Diethyl phosphite (18.0 mi) was added dropwise at 20°C to a stirred suspension of 55% sodium hydride (5.45 g) in dry tetrahy- drofuran (100 ml). After stirring for a further 15 minutes, the mix¬ ture was cooled in ice, and dichloromethyl 2-methoxyethyl ether > (7.15 g) was added during 15 minutes. The mixture was stirred at room temperature for 1 hour, diluted with saturated aqueous sodium chloride and extracted with chloroform. The organic phase was dried and evaporated to leave an oil which was purified by chromatography on silica gel. The pure title compound was isolated as a colourless oil. NMR (CDCI 3 ): δ = 1.25-1.43 (m, 12H), 3.36 (s, 3H), 3.6 (m, 2H), 3.9 (m, 2H), and 3.9-4.4 (m, 9H) ppm. Example 35 By following the procedure described in Example 34 and by substituting the dichloromethyl ethers of Examples 32, 33 and 30 for dichloromethyl 2-methoxyethyl ether, the following three compounds were prepared as colourless oils: Tetraethyl (cyclohexyloxymethylene) -bisphosphonate NMR (CDCI 3 ): δ = 1.28-1.42 (m, 12H), 1.0-2.1 (m, 10H), 3.5-3.8 (m, 1H), 4.11 (t, J=17 Hz, 1H), and 4.1-4.4 (m, 8H) ppm. Tetraethyl (benzyloxymethylene) -bisphosphonate NMR (CDCI 3 ): δ = 1.25-1.41 (m, 12H), 4.06 (t, J=17 Hz, 1H), 4.0-4.4 (m, 8H), 4.84 (s, 2H), and 7.35 (m, 5H) ppm. Tetraethyl (3-(phthalimido)-propoxymethylene) -bisphosphonate NMR (CDCI 3 ): δ = 1.2-1.6 (m, 12H), 2.0 (m, 2H), 3.65-4.5 (m, 13H), and 7.6-7.9 (m, 4H) ppm. Example 36 (2-Methoxyethoxymethylene)-bisphosphonic acid, tris-benzylamine salt A solution of tetraethyl (2-methoxyethoxymethylene)-bis- phosphonate (4.0 g) in methylene chloride (16 ml) was cooled in ice and treated with trimethyi bromosilane (16.2 ml). The mixture was stirred at room temperature for 2 hours and evaporated |n vacuo. The residue was stirred with absolute ethanol overnight at room temperature and evaporated n vacuo to leave the crude acid which was taken up in absolute ethanol (30 ml) and treated with benzyl¬ amine (4.5 ml). The colourless crystalline title compound was isolated by filtration . NMR (D 2 0) : δ = 3.09 (s, 3H ) , 3.4-3.55 (m, 2H), 3.48 (t, J=15 Hz, 1 H), 3.62-3.75 (m, 2H), 3.99 (s, 6H) and 7.30 (s, 15H ) ppm. HDO = 4.66 ppm was used as internal reference. Example 37 By following the procedure of Example 36 and by substitut¬ ing tetraethyl (cyclohexyloxymethylene) -bisphosphonate or tetraethyl (benzyloxymethylene)-bisphosphonate for tetraethyl (2-methoxyeth- oxymethylene)-bϊsphosphonate, the following two compounds were prepared : (Cyclohexyloxymethylene)-bisphosphonic acid, tris-benzylamine salt NMR (D 2 0) : δ = 0.8-2.0 (m, 10H ) , 3.3-3.6 (m, 1 H) , 3.71 (t, J=16 Hz, 1 H), 4.03 (s, 6H) , and 7.3 (s, 15H ) ppm. HDO = 4.66 ppm was used as internal reference. (Benzyloxymethylene)-bisphosphonic acid , tris-benzylamine salt NMR (D £ 0) : δ = 3.72 (t, J=15 Hz, 1 H) , 4.71 (s, 2H) , and 7.3 (s, 5H ) ppm. HDO = 4.66 ppm was used as internal reference. Example 38 (2-Hydroxyethoxymethylene)-bisphosphonic acid , tris-benzylamine salt A mixture of tetraethyl (2-methoxyethoxymethylene)-bis- phosphonate (2 g) and 6N hydrochloric acid (40 ml) was refluxed overnight and evaporated to dryness in_ vacuo. Traces of hydro¬ chloric acid were removed by repeated evaporation with absolute ethanol . The crude product was dissolved in absolute ethanol , and benzylamine in excess was added . The crystalline salt was isolated by filtration and dried n vacuo. NMR (D 2 0) : δ = 3.50 (t, J=16 Hz, 1 H) , 3.5-3.75 (m, 4H ) , 4.03 (s, 6H), and 7.33 (m, 15H) ppm. HDO = 4.66 ppm was used as internal reference. Example 39 (3- Aminopropoxymethylene) -bisphosphonic acid A mixture of tetraethyl (3-(phthaiϊmido)-propoxymethyl- ene)-bisphosphonate (4.4 g) and 6N hydrochloric acid (25 ml) was refluxed overnight. After cooling, the mixture was diluted with water and extracted twice with ether. The aqueous phase was eva¬ porated to dryness, and the residue was stirred with absolute ethan¬ ol . The title compound was isolated by filtration and dried iri vacuo. NMR (D 2 0 + NaOD): δ = 1.65-2.0 (m, 2H), 3.09 (t, 2H), 3.55 (t, J=16 Hz, 1H) and 3.81 (t, 2H) ppm. HDO = 4.66 ppm was used as in¬ ternal reference. Example 40 Disodium (4-chlorophenoxymethylene)-bisphosphonate This compound was prepared from tetraethyl (4-chloro- phenoxymethylene)-bisphosphonate by following the procedure de¬ scribed in Example 26. NMR (D 2 O): δ = 4.55 (t, J=16 Hz, 1H), 7.01 (d, J=9 Hz, 2H), and 7.26 (d, J=9 Hz, 2H) ppm. HDO = 4.66 ppm was used as internal reference.. Example 41 By following the procedure of Example 18, the following compounds were prepared: (4-Bromophenoxymethylene)-bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 4.66 (t, 1H), 7.00 (d, 2H), 7.40 (d, 2H), and 9.80 (s, 4H) ppm. (4- Fluorophenoxymethylene) -bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 4.59 (t, 1H), 7.05 (m, 4H), and 9.90 (s, 4H) ppm. (3- (Trifluoromethyl )-phenoxymethylene)-bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 4.65 (t, 1H), 7.30 (m, 4H), and 9.60 (s, 4H) ppm. (4-Nitrophenoxymethylene) -bisphosphonic acid NMR (CD 3 OD + DCI): δ = 5.13 (t, J=16 Hz, 1H), 7.31 (d, J=9 Hz, 2H), and 8.23 (d, J=9 Hz, 2H) ppm. Example 42 Disodium (4-tert-butylphenoxymethylene) -bisphosphonate Tetraethyl (4-tert-butylphenoxymethylene)-bisphosphonate was transformed into the title compound as described in Example 26. NMR (D 2 0): δ = 1.23 (s, 9H), 4.57 (t, J=16 Hz, 1H), 7.04 (d, J=9 Hz, 2H), and 7.38 (d, J=9 Hz, 2H) ppm. HDO = 4.66 ppm was used as internal reference. Example 43 (4-Methoxyphenoxymethylene) -bisphosphonic acid Tetraethyl (4-methoxyphenoxymethylene)-bisphosphonate (4 g) was dissolved in trimethyi bromosilane (16.4 ml). After 3 hours at room temperature, the mixture was evaporated ]n_ vacuo. The re- maining oil was heated with absolute ethanol (30 ml) on the steam bath for 2 hours. Evaporation jn_ vacuo and crystallization from ether gave the title compound as colourless crystals. NMR ((CD 3 ) 2 SO): δ = 3.68 (t, 3H), 4.51 (t, 1H), 6.80 (d, 2H), 7.00 (d, 2H), and 9.10 (s, 4H) ppm. Example 44 (4-Hydroxyphenoxymethylene)-bisphosphoπ?c acid Tetraethyl (4-methoxyphenoxymethyiene)-bisphosphonate (2 g) and concentrated hydrochloric acid (20 ml) were refluxed over- night. Evaporation to dryness iri vacuo gave the title compound as an oil which crystallized. NMR ((CD 3 ) 2 SO): δ = 4.40 (t, 1H), 6.6 (m, 2H), 6.9 ( , 2H), and 7.8 (m, 5H) ppm. Example 45 Tetraethyl (1 -phenoxypropylidene)-bIsphosphonate Tetraethyl (phenoxymethylene)-bϊsphosphonate (1.14 g) was added to a suspension of 55% sodium hydride (0.15 g) in dimeth- ylformamide (10 ml). After 45 minutes at room temperature, ethyl iodide (0.49. ml) was added, and the mixture was left overnight at room temperature, diluted with ethyl acetate and washed with 40% aqueous calcium chloride. The organic phase was dried and evaporat¬ ed to leave an oil which was purified by chromatography on silica gel. The title compound was isolated as a colourless oil. NMR (CDCI 3 ): δ = 1.06 (t, 3H), 1.35 (t, 12H), 2.12 (m, 2H), 4.30 (m, 8H), and 7.0-7.4 (m, 5H) ppm. Example 46 By following the procedure of Example 45 and by substi¬ tuting methyl iodide, butyl bromide or benzyl bromide, respectively, for ethyl iodide, the following compounds were prepared: Tetraethyl (1 -phenoxyethylidene)-bisphosphonate NMR (CDCI 3 ): δ = 1.38 (t, 12H), 1.56 (t, 3H), 4.25 (m, 8H), and 7.0-7.4 (m, 5H) ppm. Tetraethyl (1 -phenoxypentylidene)-bisphosphonate NMR (CDCI 3 ): δ = 0.75 (t, 3H), 1.0-1.5 (m, 4H), 1.34 (t, 6H), 1.36 (t, 6H), 2.0 (m, 2H), 4.25 (m, 8H), and 7.0-7.4 (m, 5H) ppm. Tetraethyl (1 -phenoxy-2-phenylethylidene)-bisphosphonate Colourless crystalline compound with m.p.: 90-92 C. NMR (CDCI 3 ): δ = 1.12 (t, 6H), 1.24 (t, 6H), 3.46 (t, 2H), 4.10 (m, 8H), and 7.0-7.5 (m, 10H) ppm. Example 47 Tetraethyl (1 -n-butoxypentylidene)-bisphosphonate Tetraethyl (n-butoxymethylene)-bisphosphonate (1.2 g) was added to a stirred solution of potassium tert-butoxide (0.37 g) in tert-butanol (5 ml). After 30 minutes at room temperature, butyl bromide (0.36 ml) was added and the mixture was refluxed for 8 hours. After cooling, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried and evaporated to give an oil which was purified by chromatography to yield the title compound. NMR (CDCI 3 ): δ = 0.92 (t, 6H), 1.5 (m, 8H), 1.34 (t, 12H), 2.10 (m, 2H), 3.75 (t, 2H), and 4.20 (m, 8H) ppm. Example 48 By following the procedure described in Example 47, and substituting ethyl Iodide, octyl bromide, benzyl chloride or 3-phεn- yl-propyl bromide, respectively, for butyl bromide, the following compounds were prepared: Tetraethyl (1 -n-butoxypropyl?dene)-b?sphosphonate NMR (CDCI 3 ): δ = 0.92 (t, 3H), 1.09 (t, 3H), 1.2-1.6 (m, 4H), 1.33 (t, 12H), 2.15 (m, 2H), 3.75 (m, 2H), and 4.20 (m, 8H) ppm. Tetraethyl (1 -n-butoxynonylidene)-b?sphosphonate NMR (CDCI 3 ): δ = 0.88 (t, 3H), 0.92 (t, 3H), 1.2-1.4 (m, 4H), 1.26 (bs, 12H), 1.34 (t, 12H), 2.0 (m, 2H), 3.75 (m, 2H), and 4.20 (m, 8H) ppm. Tetraethyl (1 -n-butoxy-2-phenylethylidene)-bisphosphonate Tetraethyl (1-n-butoxy-4-phenylbutylidene) -bisphosphonate Example 49 (1 -Phenoxypropylidene)-bisphosphonic acid A solution of tetraethyl (l-phenoxypropylidene)-bisphos- phonate (2.1 g) in trimethyi bromosilane (8 ml) was kept at room temperature overnight, followed by evaporation ]n_ vacuo. The resi¬ due was stirred overnight in absolute ethanol. Evaporation n vacuo gave the desired compound. NMR ((CD 3 ) 2 SO): δ = 0.92 (t, 3H), 2.00 (m, 2H), 7.0-7.4 (m, 5H), and 8.4 (s, 4H) ppm. Example 50 By following the procedure described in Example 49, and substituting the tetraethyl esters of Examples 46, 47, 'and 48 for te¬ traethyl (l-phenoxypropylidene)-bisphosphonate, the following com¬ pounds were prepared: (1 -Phenoxyethy!idene)-bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 1.37 (t, 3H), 7.0-7.4 (m, 5H) and 7.8 (s, 4H) ppm. (l-Phenoxypentylidene)-bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 0.66 (t, 3H), 0.8 (m, 2H), 1.35 (m, 2H), 1.90 (m, 2H), 6.9-7.4 (m, 5H), and 8.05 (s, 4H) ppm. (1 -Phenoxy-2-phenylethylidene)-b?sphosphonic acid NMR ((CD 3 ) 2 SO): δ = 3.14 (t, 2H), 7.0-7.5 ( , 10H), and 8.2 (s, 4H) ppm. (1 -n-Butoxypentyl?dene)-bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 0.87 (t, 6H), 1.35 (m, 8H), 1.90 (m, 2H), 3.75 (m, 2H), and 7.30 (s, 4H) ppm. (1-n-Butoxypropylidene) -bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 0.87 (m, 3H), 0.99 (t, 3H), 1.1-1.6 (m, 4H), 2.0 (m, 2H), 3.77 (m, 2H), and 8.9 (s, 4H) ppm. (1 -n-Butoxynonylidene)-bisphosphonic acid NMR ((CD 3 ) 2 SO): δ = 0.86 (m, 6H), 1.24 (bs, 12H), 1.1-2.1 (m, 6H), 3.73 (m, 2H), and 7.40 (bs, 4H) ppm. (1 -n-Butoxy-2-phenylethylidene)-bisphosphonic acid (1-n-Butoxy-4-phenylbutylidene)-bisphosphonic acid Example 51 Tetra-(pivaloy loxymethyl ) (phenoxymethylene)-bisphosphonate A solution of (phenoxymethylene)-bisphosphonic acid (8.04 g) in absolute ethanol (50 ml) was added to a stirred solution of silver trifluoroacetate (33.15 g) in absolute ethanol (200 ml). The mixture was cooled In ice and filtered. Drying i vacuo gave tetra- silver (phenoxymethylene)-bisphosphonate as a beige powder (17.9 g) which was suspended in acεtonitrlle (360 ml) and treated with Iodomethyl pivalate (31.1 g). After stirring for 30 minutes at room temperature, the mixture was filtered, and the filtrate was evaporat¬ ed ui vacuo to leave a crude oil which was purified by chromatogra- phy on silica gel to give the title compound as a colourless oil. NMR (CDC1 3 ): δ = 1.16 (s, 18H), 1:19 (s, 18H), 5.01 (t, 1H), 5.75 (m, 8H), and 7.15 (m, 5H) ppm. Example 52 Tetra-(acetoxymethyl ) (n-butoxymethylene)-bisphosphonate This compound was prepared as described in Example 51 by substituting (n-butoxymethylene)-bisphosphonic acid for (phen- oxymethylεne)-bisphosphonic acid and by substituting iodomethyl acetate for iodomethyl pivalate. NMR (CDCI 3 ) : δ = 0.92 (m, 3H) , 1 .3-1 .6 (m, 4H) , 2.15 (s, 12H ) , 3.74 (bt, 2H), 4.10 (t, 1 H), and 5.80 ( , 8H) ppm. Examples 53-77 By starting from the appropriately substituted phenols and by following the procedures described in Examples 20, 21 , 8, 18, 27, and 44, the compounds of formula V are prepared Table I I : 0 H H ° || HO - P - C - P - OH V I i I OH O OH I R Example 78 For the preparation of tablets , the following composition was made: Disodium (phenoxymethylene)-bisphosphonate 1000 g Corn starch 700 g Hydroxypropylcellulose 15 g Sodium carboxymethyl starch 65 g Magnesium stearate 20 g Disodium (phenoxymethylenε)-bisphosphonate was mixed with corn starch and granulated with a 5% ethanolic solution of hydroxypropylcεllulose. The granules were dried at 50 C , sifted through a 0.7 mm sieve, mixed with sodium carboxymethyl starch and magnesium stearate and pressed to 8 mm circular plane tablets, each weighing 180 mg . Example 79 For the preparation of a sterile solution for injection , the fol lowing composition was prepared : Disodium (phenoxymethylene)-bisphosphonate 50 g Sodium chloride 60 g Sodium acetate 20 g Acetic acid q . s . Water for injection to 10.000 ml Disodium (phenoxymethylene)-bisphosphonate, sodium chloride and sodium acetate werε dissolvεd in water for Injection , and the pH was adjusted to 5.2 by the addition of acetic acid . The solution was diluted to 10 liters with water for inject¬ ion and sterile filtered through a 0.2 μm membranε filter. The solu¬ tion was- filled aseptically in ampoules , each containing 1 ml .

Claims: [received by the International Bureau on 16 December 1985 (16.12.85); original claim 1 amended; claims 2-9 unchanged; claim 10 new; original claims 10-15 replaced by new claims 11-16 (4 pages)] 1 . A compound of formula I HO - OH ( I ) OH 0-(CH 2 -CH 2 -X) n -R 1 in which R- is a straight or branched, saturated or unsaturated ali¬ phatic or alicyclic C, -C.Q hydrocarbon radical , an aryl or an aryl- C^-C^-aikyl radical, R^ if desired being unsubstituted or substituted with straight or branched C j -C .-aikyl, amino, C j -C .-alkylamino " dϊ-(C 1 -C 4 -alkyl)-amino, carboxy, C j -C^-alkoxycarbonyl , hydroxy, C- j -C^-alkoxy, phenoxy, mercapto, C- -C .-alkylthio, phenylthio, ha¬ logen, trifluoromethyl; R 2 stands for hydrogen, C-'Cg-alkyl, aryl- C j -C 4 -aikyl or halogen; X is O or S, and n is an integer from 0 to 2; with the provisos that R 2 cannot be hydrogen or methyl if n=O and - j is methyl and that Rp cannot be hydrogen if n=O and R- is unsubstituted n-butyl , n-pentyl or π-hexyl ; and pharmaceutically acceptable, non-toxic salts and In the body easily hydrolyzable esters thereof. 2. A compound according to claim 1 , in which Ri, stands for straight or branched C 3 -C 8 -alkyl , phenyl or benzyl optionally substituted with amino, hydroxy, methyl or halogen, and R 2 for hydrogen , straight or branched C- -C . alkyl , benzyl or halogen; preferably R. being propyl , butyl, aminopropyl, aminobutyl , 2,2,2- trifluoroethyl, phenyl , or tolyl, and R 2 being hydrogen, methyl , ethyl or chlorine. 3. A mono-, di-, tri- or tetrabasic salt of a compound of formula I of claim 1 , which is a salt selected from the group consist- ing of alkali metal salts, alkaline earth metal salts, salts with ammo¬ nia, lower alkylamines, lower alkanolamines, procaine, cydoalkyiami- nes, benzylamines, and heterocyclic amines. 4. A mono-, di-, tri- or tetra ester of a compound of formula I of claim 1 , which is an nn vivo easily hydrolyzable ester, the ester forming residue being selected from the group consisting of alkanoyloxymethyl of three to six carbon atoms, 1 -(alkanoyloxy)ethyl of four to seven carbon atoms, 1 -methyl-1-(alkanoyloxy)ethyl of five to eight carbon atoms, alkoxycarbonyloxymethyl of three to six car- bon atoms, 1 -(alkoxycarbonyloxy )ethyl of four to seven carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl of five to eight carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, (2-oxo- 1,3-dioxolεn-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl as well as dϊalkylami- noalkyl, acetonyl - and methoxymethyl . 5. An ester according to claim 4, which is an alkanoyloxy- alkyl or alkoxycarbonyloxy alkyl ester, in particular a pivaloyloxy- methyl or ethoxycarbonyloxyethyl ester. 6. (Phenσxymethyfene)-bisphosphonic acid and its salts and esters. 7. (2,2,2-Trifluoroethoxymethylene)-bisphosphonic acid and its salts and esters. 8. (4-Tolyloxymethylene)-bisphosphonic acid and its salts and esters. 9. (n-Propoxymethylene)-bisphosphonic acid and its salts and esters. 10. (4-Hydroxyphenoxymethyiene)-bisphosphonic acid and its salts and esters. 11. A method for producing a compound of formula I of claim 1, In which a dichloromethyl ether of formula il is used as starting material, and the below reaction sequence is followed: P(OAIk), R 1 -(X-CH 2 CH 2 ) n -O-CH( ) R- , X, and n have the same meanings as in claim 1 and Aik stands for C, -C 8 -alkyl . 12. A composition containing an effective amount of at least one member selected from the group consisting of compounds of the formula I OH 0-(CH 2 -CH 2 "X) n -R 1 in which R- is a straight or branched, saturated or unsaturated ali¬ phatic or alicyclic CH -C-Q hydrocarbon radical, an aryl or an aryl- C- -C . -alkyl radical, - if desired being unsubstituted or substituted with straight or branched C^-C .-alkyl, amino, C j -C .-alkylamino, dϊ-(C, -C 4 -alkyl)-aminα, carboxy, C j -C 4 -alkoxycarbonyl, hydroxy, C--C 4 -alkoxy, phenoxy, mercapto, C--C 4 -alkylthio, phenylthio, ha¬ logen, trifluoromethyl ; R 2 stands for hydrogen, C^Cg-alkyl , aryl- C. -C 4 -alkyl or halogen; X is O or S, and n is an integer from 0 to 2; with the proviso that R 2 cannot be hydrogen or methyl if n=0 and R. is methyl ; and pharmaceutically acceptable, non-toxic salts and in the body easily hydrolyzable esters thereof, together with solid or liquid pharmaceutical carriers and/or auxiliary agents . 13. A composition according to claim 12 containing in addi- tion hereto one or more members selected from the group consisting of vitamin D 2 and D 3 or hydroxylated derivatives thereof, calcitonin , mitramycin, sodium fluoride, estrogens and non-steroid antiinflamma- tory drugs. 14. A method of treating patients suffering from osteoporo- ° sis, rheumatoid arthritis and other arthritic disorders, atheroschle- rosis, hypercalcemia due to malignancies or primary hyperparathy- roidism, Paget's disease, and other conditions with abnormal calcium balance, in which a dose of one or more of the compounds of formula I of claim 12 or their salts or esters as defined in claim 12 is admϊni- stered so that the desired activity is achieved without simultaneous secondary effects. 15. A method as claimed in claim 14, in which the com¬ pounds of formula I of claim 12 are administered one or more times daily in an amount of 0.01 to 25 mg per kilogram bodyweight, pre- ferably from 0.02 to 10 mg per kilogram bodyweight. 16. A method for the prophylactic treatment of postmeno- pausal osteoporosis, in which 0.01 to 10 mg per kilogram bodyweight, preferably 0.02 to 5 mg per kilogram bodyweight is administered daily. STATEMENT UNDER ARTICLE 19 Claim 1 has been restricted by the incorporation of a further pro¬ viso which serves to distinguish the compounds claimed over the disclosure of the citation Soviet Invention Illustrated ( Derwent) , Section Ch : Chemical , abstract No. 84-03505/06 21 March 1985. The new claim 10 is supported by the disclosure of example 44. The subject matter of the remaining claims is substantially identi¬ cal to the subject matter of claims 10- 15 as filed.

Inventors: BINDERUP ERNST TORNDAL, BINDERUP, ERNST, TORNDAL
Applicants: LEO PHARM PROD LTD, LEO PHARMACEUTICAL PRODUCTS LTD. A/S
Application year: 1985
Main classification: C07F9
IPC codes: A61K31, A61P3, A61P43, C07F9