WO1987003598A1 - Novel bisphosphonic derivatives, a method for their production and a pharmaceutical composition - Google Patents

Novel bisphosphonic derivatives, a method for their production and a pharmaceutical composition Download PDF

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Publication number
WO1987003598A1
WO1987003598A1 PCT/DK1986/000132 DK8600132W WO8703598A1 WO 1987003598 A1 WO1987003598 A1 WO 1987003598A1 DK 8600132 W DK8600132 W DK 8600132W WO 8703598 A1 WO8703598 A1 WO 8703598A1
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Prior art keywords
formula
compound
methyl
thiomorpholinylmethylene
formyl
Prior art date
Application number
PCT/DK1986/000132
Other languages
French (fr)
Inventor
Ernst Torndal Binderup
Sven Liisberg
Original Assignee
Leo Pharmaceutical Products Ltd. A/S
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Publication date
Application filed by Leo Pharmaceutical Products Ltd. A/S filed Critical Leo Pharmaceutical Products Ltd. A/S
Priority to DE8787900075T priority Critical patent/DE3670639D1/en
Publication of WO1987003598A1 publication Critical patent/WO1987003598A1/en
Priority to DK406987A priority patent/DK169678B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6544—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms

Definitions

  • Novel bisphosphonic derivatives a method for their production and a pharmaceutical composition.
  • the present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutically acceptable salts and easily hydrolyzable esters thereof, to methods for producing said new compounds, to pharmaceutical compositions containing the new compounds, to dosage units of the compositions, and to methods of treat ⁇ ing patients using said compositions and dosage units.
  • R..-R.... can be the same or different and stand for hydrogen, a straight or branched aliphatic or alicyclic C 1 ⁇ C 10 n y drocarDo ⁇ radical, an aryl or an ary1-C, -C. -alkyl radical; n is zero or one, and m is zero, one or two.
  • R lagoon and R. when taken together can form a saturated aliphatic 5-, 6- or 7-membered ring which may be substituted ith one or more C,-C. -alkyl radicals.
  • R -R_ - stand for hydrogen, C- -C 5 -alky1 , or phenyl .
  • the invention comprises all possible stereoisomeric forms of compounds of formula I as well as mixtures thereof.
  • the invention also relates to salts of the compounds of formula I which are acids and thus form salts with bases.
  • alkali metal salts and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts
  • suitable non-toxic amines such as lower alkylamines, e.g. triethylamine , lower alkan- olamines, e.g. diethanolamine or triethanolamine, procaine, 5 cycloalkylamines, e.g. dicyclohexylamine, benzylamines, e.g.
  • esters of the present compounds are i ⁇ vivo eas ⁇ ily hydrolyzable .
  • ester forming residues are alkanoyloxy ethyl of three to six carbon atoms, l-(alk- anoyloxy)ethyl of four to seven carbon atoms, 1-methyl-l- (alkanoyloxy)ethyl of five to eight carbon atoms, alkoxy-
  • the normal bones are living tissues undergoing con ⁇ stant resorption and r ⁇ deposition of calcium, with the net effect of aintenance of a constant mineral balance.
  • bone turnover In normal grow-, ing bones, the mineral deposition exceeds the mineral re ⁇ sorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition resulting in e.g. hyper- calcemia, for instance due to malignancy or primary hyper- 0 parathyroidism, or in osteoporosis. In other pathological conditions the calcium deposition may take place in undesir ⁇ able amounts and areas leading to e.g. osteoarthritis , rheu ⁇ matoid arthritis, kidney or bladder stones, atherosclerosis, and Paget's disease which is a combination of an abnormal
  • the compounds of the present invention like known bisphosphonates (e.g. 1-hydroxyethy1idene-1 ,1-bisphosphonic acid (etidronate) and 3-amino-1-hydroxypropylidene-1 , 1-bisphosphonic acid (APD)) reduce bone resorption as shown by their inhibition of the urinary excretion of hydroxyproline , but in contrast to these known compounds which also inhibit bone alkaline phosphatase, the new compounds of this invention surpris ⁇ ingly stimulate bone alkaline phosphatase, indicating a stimulation of the bone forming cells - the osteoblasts - and a substantial increase in bone mass is actually observed during treatment with the present compounds.
  • known bisphosphonates e.g. 1-hydroxyethy1idene-1 ,1-bisphosphonic acid (etidronate) and 3-amino-1-hydroxypropylidene-1 , 1-bisphosphonic acid (APD)
  • etidronate 1-hydroxyethy1idene-1
  • R--R,- and m have the meanings mentioned above.
  • the compounds of formula II are either known or may be prepared in analogy with the known compounds. They are transformed into acid amide chlorides of formula III by treatment with e.g. phosgene or oxalyl chloride
  • R--R,, and m have the meanings defined above and R,_ is a C.-C. -alkyl radical, preferably methyl or ethyl, or a benzyl or a substituted benzyl radical.
  • esters may also be cleaved by an alternative method described in Jour. f. prakt. Chemie 320 , 344 (1978). Treatment with bromotrimethylsilane at room temperature or moderately elevated temperature leads to a tetra-tri- methylsilyl ester which is easily cleaved with water or alcohol to yield the free acid of formula I.
  • Easily hydrolyzable esters of the compounds of formula I may be prepared by reacting a salt, e.g. a silver salt or a quaternary ammonium salt, of a compound of formula I with a reactive halide corresponding to the desired ester.
  • a salt e.g. a silver salt or a quaternary ammonium salt
  • Tetra-esters may be cleaved by reaction with an iodide, e.g. sodium iodide, to form di-esters of the com- pounds of formula I.
  • an iodide e.g. sodium iodide
  • the present compounds are as mentioned above in ⁇ tended for use in pharmaceutical compositions which are useful in the treatment of osteoporosis, rheumatoid ar ⁇ thritis and other arthritic disorders, atherosclerosis, hypercalcemia due to malignancies or primary hyperpara- thyroidism, Paget's disease, and other conditions with an abnormal calcium balance.
  • the present compounds may also be used in tooth ⁇ pastes in order to prevent calcium deposition in the form of dental calculus or in order to protect against calcium resorption due to acid dissolution.
  • a suitable dose of a compound of formula I for a mammal suffering from ' e.g. a hypercalcemic condition as defined hereinbefore is 0.001 to 25 mg per kilogram body ⁇ weight, the most preferred dosage being 0.002 to 10 mg/kg of mammal bodyweight, for example 0.005 to 5 mg/kg; admini ⁇ stered once or more times daily.
  • a suitable dose of a compound of for mula (I) is 0.001 to 10 mg per kilogram bodyweight, the most preferred dosage being 0.002 to 5 mg/kg of mammal bodyweight.
  • an active ingredient comprises from 0.1? ⁇ to 99.9.0 by weight of the formulation.
  • dosage units of a formulation contain between 0.1 mg and 1 g of the active ingredient.
  • 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.
  • dosage unit is meant a unitary) i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, re- maining 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 medical use, of the present invention comprise an active ingredient in association with a pharmaceutically accept ⁇ able 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, intra ⁇ muscular and intravenous), 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. In 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 desired formulation.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, 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-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • the active ingredient may also be in the form of bolus, electuary or paste.
  • Formulations for rectal administration may be in the form of a suppository incorporating the active ingre- 5 histone, or in the form of an enema.
  • Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active ingredient which is preferably isoto ⁇ ic with the - ⁇ - blood of the recipient.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations such as lini ⁇ ments, lotions, applications; oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, including 15 tooth-pastes; or solutions or suspensions such as drops.
  • the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavour ⁇ ing agents, binders, surface active agents, thickeners, 0 lubricants, preservatives, e.g. methylhydroxybenzoate (in ⁇ cluding anti-oxidants) , emulsifying agents and the like.
  • additional ingredients such as diluents, buffers, flavour ⁇ ing agents, binders, surface active agents, thickeners, 0 lubricants, preservatives, e.g. methylhydroxybenzoate (in ⁇ cluding anti-oxidants) , emulsifying agents and the like.
  • compositions may further contain other thera-Guinically active compounds usually applied in the treat ⁇ ment of the above mentioned pathological ' conditions , for 5 instance vitamin D floss and D, and hydroxylated derivatives, e.g. l ⁇ -hydroxy-vitamin D,, l ⁇ -hydroxy-vitamin D ⁇ , l ⁇ .,25- -dihydroxy-vitamin D,, l ⁇ , 25-dihydroxy-vitamin D combat , calci- tonin (human, porcine or salmon), mitramycin, sodium fluor ⁇ ide, estrogens, and non-steroid antiinflammatory drugs, 0 e.g. acetylsalicylic acid, indomethacin , naprosyn, and timegadine .
  • other thera-Guilated derivatives e.g. l ⁇ -hydroxy-vitamin D, l ⁇ -hydroxy-vitamin D ⁇ , l ⁇ .,25- -dihydroxy-vitamin D,, l ⁇ , 25-
  • the present compounds are administered to a patient suffering from one of the above mentioned pathological conditions in a daily dose 5 (for adults) from 0.07 mg to 1750 mg, preferably from 0.15 - 1000 mg, and in the veterinary practice correspondingly in daily doses from 0.001 to 25 mg/kg bodyweight.
  • This compound was prepared as described in Prepara- tion 2 by substituting 2 , 5 , 5-tri ethy1-3-thiomorpholinone for 5,5-dimethyl-3-thiomorpholinone. Boiling point: 76 - 77°C/15 mmHg.
  • N-Formyl-3,3-dimethyl-thiomorpholine B.p.: 155-156°C/15mmHg
  • N-Formyl-2,5,5-trimethyl-thiomorpholine B.p. : 154-155°C/15 mmHg
  • N-Formyl-2-(1-butyl)-thiomorpholine B.p. : 160-162°C/15 mmHg
  • N-Formyl-2-phenyl-thiomorpholine B . .p. : 148-150 ⁇ C/l mmHg
  • N-Formyl-2-isobutyl-3-methyl-thiomorpholine B.p. : 115-116°C/1 mmHg
  • N-Formy l - perhydro- l , 4-benz oth iaz i ne
  • N-Formyl-2-isobutyl-thiomorpholine B.p. : 150-155°C/15 mmHg
  • N-Formyl-2,5-dimethyl-thiomorpholine B.p. : 142-143°C/15 mmHg
  • This compound was prepared as described in Prepara ⁇ tion 10 by using bromomethyl tert-butyl ketone instead of ⁇ -bromo-diethyl ketone and by omitting the treatment with chloral.
  • the title compound was distilled in vacuo, b.p. : 73-74°C/l mmHg.
  • This compound was prepared by following the proce- dure of Preparation 19, but substituting ethyl 2-mercapto- propionate for ethyl thiogiycolate .
  • 2-Methy1-tetrahydro- -l,4-thiaz ⁇ pin-3-one with m.p. 192-193°C was isolated as an intermediate.
  • the title compound was a colourless oil with b.p. 104-105°C/1 mmHg.
  • Oxalyl chloride (16.6 ml) was added dropwise at 0°C to a stirred solution of N-formyl-thiomorpholine (26.2 g) in methylene chloride (200 ml). The mixture was stirred at room temperature until the gas evolution ceased (about 5 hours later). Triethyl phosphite (66 ml) was then added during 1.5 hours at room temperature. Unreacted triethyl phosphite was removed i_n_ vacuo , and the residue was refluxed with 20 °a' hydrochloric acid (150 ml) for 3 hours. The mixture was evaporated to dryness in_ vacuo , and the residue was stirred with acetone. The crystalline product was filtered and recrystallized from water. M.p.: >250°C (dec). Microanalysis :
  • Example 2 By following the procedure described in Example 1 and substituting the appropriate N-formyl-derivatives de ⁇ scribed in Preparations 8, 9, 10, 11 and 12 for N-formyl- -thiomorpholine, the following compounds were prepared:
  • Oxalyl chloride (0.85 ml) was added dropwise at -10°C to a stirred solution of N-formyl-thiomorpholine (1.31 g) in tetrahydrofuran (10 ml), arid the mixture was stirred at -10°C for 1 hour.
  • Example 6 The procedure of Example 1 is repeated, except that N-formyl-thiomorpholine is replaced by the appropriate N- -formyl derivatives described in Preparation 13. This af ⁇ fords :
  • Example 8 The procedure of Example 7 was repeated, except that N-formyl-3-isobuty1-thiomorpholi ⁇ e was replaced by the appropriate N-formyl-derivative described in Preparation 13, 17 and 18. In this way the following compounds were prepared
  • This compound was prepared from tetra-acetoxym ⁇ thy1 ( -thiomorpholinylmethyl ⁇ ne )-bisphosphonate by following the procedure of Example 14.

Abstract

Novel compounds of formula (I), in which R1?-R11? can be the same or different and stand for hydrogen, a straight or branched aliphatic or alicyclic C1?-C10? hydrocarbon radical, an aryl or an aryl-C1?-C4?-alkyl radical; n is zero or one, and m is zero, one or two; or R2? and R4? when taken together form a saturated aliphatic 5-, 6- or 7-membered ring which may be substituted with one or more C1?-C4?-alkyl radicals; and pharmaceutically acceptable salts and easily hydrolyzable esters thereof, methods for producing said new compounds, pharmaceutical compositions containing the new compounds, dosage units of the compositions, and methods of treating patients using said compositions and dosage units. The present compounds are valuable in the human and veterinary practice by reducing bone resorption and surprisingly also stimulating bone alkaline phosphatase. A substantial increase in bone mass is actually observed during treatment with the present compounds.

Description

Novel bisphosphonic derivatives, a method for their production and a pharmaceutical composition.
The present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutically acceptable salts and easily hydrolyzable esters thereof, to methods for producing said new compounds, to pharmaceutical compositions containing the new compounds, to dosage units of the compositions, and to methods of treat¬ ing patients using said compositions and dosage units.
The present compounds have the formula I
Figure imgf000003_0001
in which R..-R.... can be the same or different and stand for hydrogen, a straight or branched aliphatic or alicyclic C1~C10 nydrocarDoπ radical, an aryl or an ary1-C, -C. -alkyl radical; n is zero or one, and m is zero, one or two.
In addition R„ and R. when taken together can form a saturated aliphatic 5-, 6- or 7-membered ring which may be substituted ith one or more C,-C. -alkyl radicals.
In particular, R -R_ - stand for hydrogen, C- -C5-alky1 , or phenyl .
The invention comprises all possible stereoisomeric forms of compounds of formula I as well as mixtures thereof.
As stated above, the invention also relates to salts of the compounds of formula I which are acids and thus form salts with bases. As examples of salts formed with pharma¬ ceutically acceptable, non-toxic ' bases , mention may be made of alkali metal salts and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts, as well as salts with ammonia and suitable non-toxic amines, such as lower alkylamines, e.g. triethylamine , lower alkan- olamines, e.g. diethanolamine or triethanolamine, procaine, 5 cycloalkylamines, e.g. dicyclohexylamine, benzylamines, e.g. N-methylbenzylamine, N-ethylbenzylamine , N-benzyl-β-phen- ethyla'mine, N,N ' -dibenzylethylenediamine or dibenzylamine , and heterocyclic amines, e.g. morpholine, N-ethylpiperidine and the like.
10 The esters of the present compounds are i ~ vivo eas¬ ily hydrolyzable . Examples of such ester forming residues are alkanoyloxy ethyl of three to six carbon atoms, l-(alk- anoyloxy)ethyl of four to seven carbon atoms, 1-methyl-l- (alkanoyloxy)ethyl of five to eight carbon atoms, alkoxy-
15 carbonyloxymethyl of three to six carbon atoms, l-(alkoxy- carbonyloxy )ethyl of four to seven carbon atoms, 1-methyl-l- -(alkoxycarbonyloxy )ethyl of five to eight carbon atoms, 3- -phthalidyl, 4-crotonolactonyl , y*-butyrolacton-4-yl , (2-oxo- -1 ,3-dioxόlen-4-yl )methyl , (5-methyl-2-oxo-l, -dioxolen-4-
20 -yl)methyl, and (5-phenyl-2-oxo-l ,3-dioxolen-4-yl)methyl as well as dialkylaminoalkyl , acetonyl, and methoxymethyl .
The normal bones are living tissues undergoing con¬ stant resorption and rεdeposition of calcium, with the net effect of aintenance of a constant mineral balance. The dual
25 process is commonly called "bone turnover". In normal grow-, ing bones, the mineral deposition exceeds the mineral re¬ sorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition resulting in e.g. hyper- calcemia, for instance due to malignancy or primary hyper- 0 parathyroidism, or in osteoporosis. In other pathological conditions the calcium deposition may take place in undesir¬ able amounts and areas leading to e.g. osteoarthritis , rheu¬ matoid arthritis, kidney or bladder stones, atherosclerosis, and Paget's disease which is a combination of an abnormal
^ high bone resorption followed by an abnormal calcium depo¬ sition.
Most of the currently available therapeutic agents for the treatment of osteoporosis, e.g. estrogens and cal- citonin, act by reducing bone resorption in the osteoporotic patient. Since bone fracture is a severe problem in osteopo¬ rosis, the ideal therapeutic agent should be able to in¬ crease bone mass to a level which exceeds the fracture thres¬ hold.
Experiments in rats have shown that the compounds of the present invention like known bisphosphonates (e.g. 1-hydroxyethy1idene-1 ,1-bisphosphonic acid (etidronate) and 3-amino-1-hydroxypropylidene-1 , 1-bisphosphonic acid (APD)) reduce bone resorption as shown by their inhibition of the urinary excretion of hydroxyproline , but in contrast to these known compounds which also inhibit bone alkaline phosphatase, the new compounds of this invention surpris¬ ingly stimulate bone alkaline phosphatase, indicating a stimulation of the bone forming cells - the osteoblasts - and a substantial increase in bone mass is actually observed during treatment with the present compounds.''
The compounds of the present invention (n = 0) may be prepared from a compound of formula II
Figure imgf000005_0001
where R--R,- and m have the meanings mentioned above. The compounds of formula II are either known or may be prepared in analogy with the known compounds. They are transformed into acid amide chlorides of formula III by treatment with e.g. phosgene or oxalyl chloride
Figure imgf000006_0001
(R,-R,, and m as defined above). Reaction of compounds of formula III with trialkyl- phosphites leads to tetraalkyl esters of formula IV
Figure imgf000006_0002
where R--R,, and m have the meanings defined above and R,_ is a C.-C. -alkyl radical, preferably methyl or ethyl, or a benzyl or a substituted benzyl radical.
Cleavage of the esters of formula IV by hydrolysis, e.g. with boiling hydrochloric acid, or by hydrogenolysis , leads to the compounds of formula I (n = 0).
The esters may also be cleaved by an alternative method described in Jour. f. prakt. Chemie 320 , 344 (1978). Treatment with bromotrimethylsilane at room temperature or moderately elevated temperature leads to a tetra-tri- methylsilyl ester which is easily cleaved with water or alcohol to yield the free acid of formula I.
Alternatively, compounds of formula I (n = 0) may be prepared by reacting compounds of formula II with phos¬ phorous acid and phosphorus trichloride followed by hydro¬ lysis of the reaction mixture.
Compounds of formula I in which n = 1 may be prepared by oxidation of compounds of formula I or IV (n = 0) with the well known reagents for the preparation of sulfoxides from sulfides, e.g. 3-chloroperbenzoic acid or hydrogen peroxide, optionally followed by ester cleavage.
Easily hydrolyzable esters of the compounds of formula I may be prepared by reacting a salt, e.g. a silver salt or a quaternary ammonium salt, of a compound of formula I with a reactive halide corresponding to the desired ester.
Tetra-esters may be cleaved by reaction with an iodide, e.g. sodium iodide, to form di-esters of the com- pounds of formula I.
The present compounds are as mentioned above in¬ tended for use in pharmaceutical compositions which are useful in the treatment of osteoporosis, rheumatoid ar¬ thritis and other arthritic disorders, atherosclerosis, hypercalcemia due to malignancies or primary hyperpara- thyroidism, Paget's disease, and other conditions with an abnormal calcium balance.
The present compounds may also be used in tooth¬ pastes in order to prevent calcium deposition in the form of dental calculus or in order to protect against calcium resorption due to acid dissolution.
The amount required of a compound of formula I (here¬ inafter referred to as the active ingredient) for thera¬ peutic 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 hypercalcemic condition as defined hereinbefore is 0.001 to 25 mg per kilogram body¬ weight, the most preferred dosage being 0.002 to 10 mg/kg of mammal bodyweight, for example 0.005 to 5 mg/kg; admini¬ stered once or more times daily.
In the case of the profylactic treatment of e.g. post- memopausal osteoporosis, a suitable dose of a compound of for mula (I) is 0.001 to 10 mg per kilogram bodyweight, the most preferred dosage being 0.002 to 5 mg/kg of mammal bodyweight. While it is possible for an active ingredient to be administered alone as the pure compound, it is prefer¬ able to present it as a pharmaceutical formulation. Conve¬ niently, the active ingredient comprises from 0.1?≤ to 99.9.0 by weight of the formulation. Conveniently., dosage units of a formulation contain between 0.1 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 single dose which is capable of being administered to a patient, and which may be readily handled and packed, re- maining 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 medical use, of the present invention comprise an active ingredient in association with a pharmaceutically accept¬ able 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, intra¬ muscular and intravenous), 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. In 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 desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, 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-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be in the form of bolus, electuary or paste.
Formulations for rectal administration may be in the form of a suppository incorporating the active ingre- 5 dient and a carrier such as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active ingredient which is preferably isotoπic with the -■ - blood of the recipient.
Formulations suitable for topical administration include liquid or semi-liquid preparations such as lini¬ ments, lotions, applications; oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, including 15 tooth-pastes; or solutions or suspensions such as drops.
In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavour¬ ing agents, binders, surface active agents, thickeners, 0 lubricants, preservatives, e.g. methylhydroxybenzoate (in¬ cluding anti-oxidants) , emulsifying agents and the like.
The compositions may further contain other thera- peutically active compounds usually applied in the treat¬ ment of the above mentioned pathological ' conditions , for 5 instance vitamin D„ and D, and hydroxylated derivatives, e.g. lα-hydroxy-vitamin D,, lα-hydroxy-vitamin D~ , lα.,25- -dihydroxy-vitamin D,, lα, 25-dihydroxy-vitamin D„ , calci- tonin (human, porcine or salmon), mitramycin, sodium fluor¬ ide, estrogens, and non-steroid antiinflammatory drugs, 0 e.g. acetylsalicylic acid, indomethacin , naprosyn, and timegadine .
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 5 (for adults) from 0.07 mg to 1750 mg, preferably from 0.15 - 1000 mg, and in the veterinary practice correspondingly in daily doses from 0.001 to 25 mg/kg bodyweight.
The invention will now be further described in the following non-limiting Preparations and Examples: Preparation 1 5,5-Dimethyl-3-thiomorpholinone
2 , 2-Dimethylaziridine (35.5 g) was added dropwise with stirring at 100°C to methyl mercaptoacetate (53 g) during 1.5 hours. After a further 2 hours at 100QC, the mixture -was cooled and crystallized from ethyl acetate. Melting point: 151 - 152°C.
Preparation 2 ,3-Dimethyl-thiomorpholine
5 , 5-Dimethyl-3-thiomorpholinone (50 g) was added in portions to a stirred suspension of lithium aluminium hydride (25 g) in tetrahydrofuran (1000 ml). After 20 hours reflux, unreacted lithium aluminium hydride was destroyed by the addition of sodium sulfate decahydrate. The mixture was filtered, and the filtrate was evaporated _i_n vacuo. Distillation ii vacuo gave the title compound with boiling point 71-72°C/15 mmHg.
Preparation 3
2,5,5-Trimethyl-3-thiomorpholinnne
This compound was obtained from 2 , 2-dimethylaziridine and methyl-2-mercaptopropionate as described in Preparation
1. Melting point: 137 - 138°C.
Preparation 4 2,5 ,5-Trimethyl-thiomorpholine
This compound was prepared as described in Prepara- tion 2 by substituting 2 , 5 , 5-tri ethy1-3-thiomorpholinone for 5,5-dimethyl-3-thiomorpholinone. Boiling point: 76 - 77°C/15 mmHg.
Preparation • 5 2-(l-Butyl)-3-thiomorpholinone
Potassium hydroxide (56 g) was added to a suspension of cysteamine, hydrochloride (56.5 g) in absolute ethanol (300 ml) followed by dropwise addition of ethyl 2-bromo- hexanoate (111.5 g). When the exothermic reaction ceased, the mixture was refluxed for 3 hours and filtered. Concen¬ tration of the filtrate .L_n vacuo gave the title compound as a viscous oil which was used in the next step without purification.
Preparation 6 2-(l-Butyl)-thiomorpholine, hydrochloride This compound was prepared as described in Prepara¬ tion 2 by substituting 2-( 1-butyl )-3-thiomorpholinone for 5,5-dimethyl-3-thiomorpholinone.
A solution of the crude 2-( 1-butyl ) -thiomorpholine in ether was treated with an excess of hydrogen chloride in ether to yield a crystalline hydrochloride with melting point 104°C. Microanalysis :
Calculated: C: 49.08 H: 9.27 N: 7.16 S: 16.38 Cl: 18.11 Found: . ' C: 49.12 H: 9".34 N: 7.09 S: 16.19 Cl: 18.00
Preparation 7 N-Formyl-thiomorpholine
Chloral (10 ml) was added dropwise to a solution of thiomorpholine (10 g) in tetrachloromethane (50 ml), and the resulting mixture was refluxed for 1 hour. Distil¬ lation i_π vacuo gave N-farmy1-thiomorpholine with boiling point 140°C/15 mmHg. When kept at room temperature, the pure product formed low melting crystals.
Preparation 8
By following the procedure described in Preparation 7 and substituting the appropriately substituted thiomorph¬ oline for thiomorpholine itself, the following compounds were prepared: N-Formyl-2-methyl-thiomorpholine: B.p. : 141-142°C/15 mmHg N-Formyl-3-methyl-thiomorpholine: B.p. : 146-147°C/15 mmHg
N-Formyl-3,3-dimethyl-thiomorpholine: B.p.: 155-156°C/15mmHg N-Formyl-2,5,5-trimethyl-thiomorpholine: B.p. : 154-155°C/15 mmHg
N-Formyl-2-ethyl-thiomorpholine: B.p. : 75°C/1.5 mmHg
N-Formyl-2,2-dimethyl-thiomorpholine: B.p. : 75-76°C/l mmHg
N-Formyl-3-ethyl-thiomorpholine: B.p. : 145-146°C/15 mmHg
N-Formyl-2-(1-butyl)-thiomorpholine: B.p. : 160-162°C/15 mmHg N-Formyl-2-phenyl-thiomorpholine: B..p. : 148-150αC/l mmHg
Preparation 9 N-Formyl-2,6-dimethyl-thiomorpholine
Piperidine (10 ml) and 10 ml of a 40?ό solution of benzyltrimethylammoniumhydroxide in methanol were added to a solution of N-formyl-diallylamine (55 g) in methanol (200 ml). Hydrogen sulfide (50 g) was introduced into the resulting solution, and unreacted hydrogen sulfide was kept at reflux for 7 hours by means of a "cold finger". The mixture was left at room temperature for 48 hours, flushed with nitrogen, diluted with ether, and washed with water. The organic phase was dried, and the solvent evaporated JL--B. vacuo . Distillation of the residue gave the title com¬ pound with boiling point 145°C/15 mmHg. Preparation 10 N-Formyl-3-ethyl-2-methyl-thiomorpholine
Cystea ine, hydrochloride (68.2 g, 0.6 mole) was added to an ice-cold stirred solution of sodium (27.6 g, 1.2 mole) in ethanol (1000 ml). -Bromo-diethyl ketone (99 g, 0.6 mole) was then added slowly in a nitrogen atmosphere while the temperature was kept below 25°C.
After stirring for 2 hours, the mixture as filtered, and the filtrate evaporated ij vacuo to leave an oil which was taken up in water (300 ml) and extracted with ether (2 x 500 ml). The organic phase was separated, dried and evaporated to give an oil which was distilled ijn vacuo . The distillate (b.p. 70°C/1 mmHg) was heated to 140°C with stirring, and formic acid (100 ml) was added at such a rate that the temperature was kept at 135-140°C without external heating. After standing overnight at room temperature, the stirred mixture was slowly treated with 40?ό potassium hydr¬ oxide (200 ml) and extracted with ether'(2 x 500 ml). The organic phase was dried and concentrated to about 500 ml. Chloral (80 ml) was added, and the mixture was refluxed for 1 hour, cooled and evaporated to leave an oil which was distilled jjτ_ vacuo to give the title compound with b.p.: 102 - 104°C/1 mmHg.
Preparation 11 By following the procedure described in Preparation
10 and substituting the appropriate α-bromo ketones for α-bromo-diethy1 ketone, the following compounds were pre¬ pared :
N-Formyl-2,3-dimethyl-thiomorpholine: B.p. : 88-90°C/l mmHg
N-Formyl-2-isopropyl-3-methyl-thiomorpholine: B.p. : 125-126°C/1 mmHg
N-Formyl-2-isobutyl-3-methyl-thiomorpholine: B.p. : 115-116°C/1 mmHg N-Formy l - perhydro- l , 4-benz oth iaz i ne :
M . p . : 70- 71 ° C .
B.p. : 128-130°C/1 mmHg
N-Formyl-7-methyl-perhydro-l,4-benzothiazine: M.p.: 135-136°C
N-Formyl-3-isobutyl-thiomorpholine: B.p. : 110-114°C/1 mmHg
Preparation 12 By using the appropriate starting materials and fol¬ lowing the procedures described in Preparations 1,2 and 7, the following compounds were prepared.
N-Formyl-2-isobutyl-thiomorpholine: B.p. : 150-155°C/15 mmHg N-Formyl-2,5-dimethyl-thiomorpholine: B.p. : 142-143°C/15 mmHg
Preparation 13 By repeating the procedure of Preparation 10 and replacing α-bromo-diethyl ketone by the appropriate α-bromo ketones, the following compounds were prepared.
N-Formyl-3-(n-propyl) -thiomorpholine
N-Formyl-3-isopropyl-thiomorpholiπe B.p. : 95-96°C/l mmHg N-Formyl-3-phenyl-thiomorpholine
N-Formyl-2-ethyl-3-methyl-thiomorpholine
N-Formyl-3-(n-butyl) -thiomorpholine
N-Formyl-2-ethyl-3-propyl-thiomorpholine B.p. : 122-123°C/1 mmHg N-Formyl-2-isopropyl-3-isobutyl-thiomorpholine B.p. : 122-123°C/1 mmHg
N-Formyl-2,2-dimethyl-3-isopropyl-thiomorpholine B.p. : 116-117DC/1 mmHg N-Formyl-3-cyclopropyl-thiomorpholine B.p. : 109-110°C/1 mmHg
N-Formyl-3-nonyl-thiomorpholine B.p. : 147-148°C/1 mmHg N-Formyl-3-tert-butyl-thiomorpholine B.p. : 113-114°C/1 mmHg
N-Formyl-2,2-dimethyl-3-phenyl-thiomorpholine
N-Formyl-5-methyl-2-phenyl-thiomorpholine
N-Formyl-3-isopentyl-thiomorpholine N-Formyl-3-cyclohexyl-thiomorpholine
N-Formyl-2-phenyl-3-benzyl-thiomorpholine
N-Formyl-2-pentyl-3-hexyl-thiomorpholine
Preparation 14 3-t&rt-Butyl-thiomorpholine
This compound was prepared as described in Prepara¬ tion 10 by using bromomethyl tert-butyl ketone instead of α-bromo-diethyl ketone and by omitting the treatment with chloral. The title compound was distilled in vacuo, b.p. : 73-74°C/l mmHg.
Preparation 15 (+)-3-tert-Butyl-thiomorpholine
3-tert-Buty1-thiomorpholine (159 g, racemic form des- cribed in Preparation 14) was added to a hot solution of (+)-tartaric acid (150 g) in water (100 ml). The mixture was left overnight and filtered. The crystalline salt
20 which showed [α.]n = +20° (c=l, H_0) was recrystallized repeatedly from water until [α], 2-.0 = +32° (c=l, H„0). The free base was liberated with an excess of 30 % potassium hydroxide and taken up in ether. The solution was dried and evaporated to leave the title compound as an oil with
[ ]p° = +36.1° (c=l, EtOH) . Preparation 16 (-)-3-tert-Butyl-thiomorpholine
3-tert-Butyl-thiomorpholine - liberated from the combined filtrates obtained in Preparation 15 during the preparation of the tartrate - was treated with (-) tartaric acid in water. The resulting tartrate was recrystallized - until [ctlr 2j0 = -31.4° (c=l, H_0). The free base showed
[α]p° = -36.0° (c=l, EtOH).
Preparation 17
The compounds prepared in Preparations 15 and 16 were formylated with chloral as described in Preparation 7 to yield
(+)-N-formyl-3-tert-butylthiomorpholine [α]p° = +108° (c=l, EtOH) and
(-)-N-formyl-3-tert-butylt-hiomorpholine [α]p° = -107° (c=l, EtOH).
Preparation 18
By following the procedures described in Examples 15, 16 and 17 other substituted thiomorpholines may be resolved into the enantiomers and subsequently formylated to form e.g. (+)-N-formyl-3-isobutylthiomorpholine
(-)-N-formyl-3-isobutylthiomorpholine
Preparation 19 N-Formyl-tetrahydro-l,4-thiazepin-3-one To a solution of sodium (23 g) in absolute ethanol
(1 1) was added ethyl thioglycolate (60.1 g) and 3-bromoprop- ylamine, hydrobromide (109.5 g). After reflux for 12 hours, the mixture was cooled and filtered. The filtrate was evapo¬ rated in vacuo, and the residue was crystallized from ethanol to yield tetrahydro-1 ,4-thiazepin-3-one with m.p. 145-148°C. 60 g of this product was added in portions to a stirred suspension of lithium aluminium hydride (25 g) in tetra- hydrofuran (2.5 1). The mixture was kept at 45-50°C for 2 hours followed by reflux for a further 2 hours. After cooling a mixture of water (62 ml) and tetrahydrofuran (250 ml) was added dropwise with stirring. Filtration and evaporation of the filtrate gave a residue which was dis¬ solved in ether (250 ml), dried over magnesium sulfate, filtered and treated dropwise with chloral (40 ml). After reflux for 1 hour the solvent was evaporated, and the residue distilled in vacuo to yield the title compound with b.p. 158-159°C/18 mmHg.
Preparation 20 N-Formyl-2-methyl-tetrahydro-l,4-thiazepin-3-one
This compound was prepared by following the proce- dure of Preparation 19, but substituting ethyl 2-mercapto- propionate for ethyl thiogiycolate . 2-Methy1-tetrahydro- -l,4-thiazεpin-3-one with m.p. 192-193°C was isolated as an intermediate. The title compound was a colourless oil with b.p. 104-105°C/1 mmHg.
Example ' 1 (4-Thiomorpholinylmethylene)-bisphosphonic acid
Oxalyl chloride (16.6 ml) was added dropwise at 0°C to a stirred solution of N-formyl-thiomorpholine (26.2 g) in methylene chloride (200 ml). The mixture was stirred at room temperature until the gas evolution ceased (about 5 hours later). Triethyl phosphite (66 ml) was then added during 1.5 hours at room temperature. Unreacted triethyl phosphite was removed i_n_ vacuo , and the residue was refluxed with 20 °a' hydrochloric acid (150 ml) for 3 hours. The mixture was evaporated to dryness in_ vacuo , and the residue was stirred with acetone. The crystalline product was filtered and recrystallized from water. M.p.: >250°C (dec). Microanalysis :
Calculated: C: 21.67 H: 4.73 N: 5.05 S: 11.57 Found:. C: 21.56 H: 4.77 N: 4.95 .S: 11.35 NMR (NaOD, TMS = 0.0 ppm as reference): S = 2.8-3.1 (lit, 4H); 3.21 (t, J=18 Hz, 1H) and 3.7-4.0 (m, 4H) ppm.
Example 2 By following the procedure described in Example 1 and substituting the appropriate N-formyl-derivatives de¬ scribed in Preparations 8, 9, 10, 11 and 12 for N-formyl- -thiomorpholine, the following compounds were prepared:
(2-Methyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: >250°C (dec).
NMR (NaOD, HD0 = 4.66 ppm as reference) : & - 1.20 (d, J=6.8 Hz, 3H) and 2.7-3.8 (m,8H) ppm. (2-(l-Butyl)-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 226-227°C.
NMR (NaOD, HD0 = 4.66 ppm as reference): £> = 0.78 (t, 3H); 1.28 (bs, 6H) and 2.4-3.6 (m, 8H) ppm.
(2-Ethyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 237-238°C.
NMR (NaOD, HD0 = 4.66 ppm as reference): ^ 0.85 (m, 3H); 1.40 (m, 2H) and 2.4-3.4 (m, 8H) ppm. (3,3-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid
NMR (NaOD, HDO = 4.66 ppm as reference): 6 = 1.52 (bs, 6H);
2.91 (bs, 2H) and 2.8-4.0 (m, 5H) ppm. (2,5,5-Trimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid
M.p.: 200°C (dec).
NMR (NaOD, HDO = 4.66 ppm as reference): 6 = 1.20 (d, J=7 Hz, 3H); 1.48 (s, 3H); 1.58 (s, 3H) and 2.6-4.0 (m, 6H) ppm, (2-Phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 250°C (dec).
NMR (NaOD, HDO = 4.66 ppm as reference): 6 - 2.4-3.6 (m, 7H); 4.0 (m, 1H) and 7.25 (m, 5H) ppm.
(2,2-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid
M.p.: 246-247°C.
NMR (NaOD, HDO = 4.66 ppm as reference): 6 = 1.37 (s, 6H); 3.00 (bt, 2H); 3.41 (t, J=18.5 Hz, 1H); 3.61 (bs, 2H) and 3.75 (bt, 2H) ppm. (3-Methyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 221-222°C.
NMR (NaOD, HDO = 4.66 ppm as reference): 6 - 1.46 (d, J=6.5 Hz, 3H); 2.4-3.2 (m, 4H) and 3.5-4.3 (m, 4H) ppm.
(3-Ethyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 226-227°C.
NMR (NaOD, TMS = 0.0 ppm as reference): S = 1.01 (t, 3H); 2.00 (m, 2H); 2.9-3.2 (m, 4H); 3.5 (t, 1H) and 3.7-4.3 (m, 3H) ppm .
(2,6-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid
M.p.: 245°C (dec).
NMR (NaOD, TMS = 0.0 ppm as reference): 0 - 1.4 (m, 6H) and
3.1-4.0 (m, 7H) ppm. (2,5-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid, monohydrate M.p.: 219-220°C.
NMR (NaOD, TMS = 0.0 ppm as reference): i = 1.4-1.8 (m, 6H), 3.2 (d, 2H) and 3-4.5 (m, 5H) ppm.
(2,3-Dimethyl-4-thiomorpho Iin-y'lme hylene)- bisphosphonic acid
M.p.: 200-202°C.
NMR (D O, HDO = 4.66 ppm as reference): 6 = 1.18 (m, 3H), 1.43 (m, 3H) and 2.5-4.3 (m, 7H) ppm.
(2-Isobutyl-4-thiomorphάlinylmethylene)-bisphosphonic acid M.p.: 238°C (dec).
NMR (NaOD, HDO = 4.66 ppm as reference): 6= 0.83 (d, 6H); 1.35 (t, 2H); 1.7 (m, IH) and 2.75-4.0 (m, 8H) ppm. (2-Isobutyl-3-methyl-4-thiomorpholinylmethylene)-bisphos¬ phonic acid, disodium salt
NMR (D O, TMS =.0.0 ppm as- reference): & = 0.93 (m, 6H); 1.1-2 (m, 6H) and 2.9-4.3 (m, 7H) ppm.
(3-Ethyl-2-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid
NMR (NaOD, HDO = 4.66 ppm as reference): 6 - 0.83 (t, 3H), 1.17 (m, 3H); 1.8-2.1 (m, 2H) and 2.5-4.25 ( , 7H) ppm.
(2-Isopropyl-3-methyl-4-thiomorpholinylmethylene)-bisphos¬ phonic acid M.p.: 214-216°C.
NMR (NaOD, HDO = 4.66 ppm as reference): & - 0.95 (m, 6H); 1.47 (d, 3H); 1.55 (m,lH); 3.46 (t, J=16 Hz, IH) and 2.6-4.7 (m, 6H) ppm .
[(7-Methyl-perhydro-l,4-benzothiazin-4-yl)-methylene]-bis- phosphonic acid M.p.: 256-257°C.
NMR (NaOD, HDO = 4.66 ppm as reference): 8 = 0.80 (d, 3H), 0.9-2.0 (m, 6H), 2.2-2.5 (m, IH) and 2.6-4.3 (m, 7H) ppm. [(Perhydro-l,4-benzothiazin-4-yl)-methylene]-bisphosphonic acid
M.p.: 257-258°C.
NMR (NaOD, HDO = 4.66 ppm as reference): <£ = 0.9-2.0 (m,
7H); 2.2-3.8 (m, 7H) and 4.15 (bd, IH) ppm. (3-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 237-238°C (dec).
NMR (NaOD, TMS = 0.0 ppm as reference): o = 0.97 (bm, 6H); 1.4-2.0 (m, 3H); 2.5-3.2 (m, 4H) and 3.3-4.0 (m, 4H) ppm.
Example 3
[l-(4-Thiomorpholiny1) -ethylidene]-bisphosphonic acid, bis-
-benzylamine salt
A mixture of N-acety1-thiomorpholine (14.5 g) and phosphorous acid (24.6 g) was heated at 100°C for 3 hours. Phosphorus trichloride (41.1 g) was added dropwise with stirring and after reflux for 3 hours, water (80 ml) was added slowly, and the mixture was kept at 100°C for 3 hours.
Filtration and evaporation of the filtrate ga.ve an oil which was taken up in ethanol. The title compound was precipitated by the addition of ether. The crude product was transformed into a bis-benzylamine salt with m.p. : 223-224°C.
NMR (D O, HDO = 4.66 ppm as reference): 6 = 1.51 (t, 0=13
Hz, 3H); 2.95 (t, 4H); 3.85 (m, 4H); 4.07 (s, 4H) and 7.36
(s , 10H) ppm .
Example 4 Tetrabenzyl (4-thiomorpholinylmethylene) -bisphosphonate sulf- oxide
Oxalyl chloride (0.85 ml) was added dropwise at -10°C to a stirred solution of N-formyl-thiomorpholine (1.31 g) in tetrahydrofuran (10 ml), arid the mixture was stirred at -10°C for 1 hour.
A solution of sodium dibenzylphosphite in tetrahydro- furan (20 ml) ^prepared from dibenzylphosphite (8.4 g) and 55?ό NaH (1.08 g)) was added, and after stirring for 1 hour the solvent was evaporated and the remaining oil distributed between water and ethylene chloride. The organic phase was dried and evaporated to leave an oil which was purified by flash chromatography on silica gel (ether :acetone 90:10 as elαent) to yield tetrabenzyl (4-thiomorpholinylmethyl- ene)-bisphosphonate (1.27 g) which was taken up in alcohol- free chloroform (15 ml). This solution was cooled in ice and treated dropwise with a solution of 90% 3-chloroper- benzoic acid (0.38 g) in alcoholfree chloroform (5 ml). The ice bath was removed, and after stirring for a further 90 minutes the solvent was removed ijn vacuo , and the residue was purified by chromatography on silica gel to give the title compound as a colourless oil.
NMR (CDC1,, TMS = 0.0 ppm as reference): 6 = 2.62 (bt, 4H); 3.0 (b , 2H); 3.36 (t, J=25 Hz, IH); 3.60 (b , 2H); 5.04 (m, 8H) and 7.30 (s, 20H) ppm.
Example 5 (4-Thiomorpholinylmethylene) -bisphosphonic acid sulfoxide
To a solution of tetrabenzyl (4-thiomorpholinylmeth- ylene)-bisphosphonate sulfoxide (1 g) in ethyl acetate (15 ml) were added water (15 ml) and 10?ά palladium on carbon (1 g). The resulting mixture was shaken vigorously in a hydrogen atmosphere until the consumption of hydrogen ceased The catalyst was removed by filtration, and the aqueous phase was separated and freeze-dried to yield the title compound as an amorphous powder.
NMR (NaOD, HDO = 4.66 ppm as reference): 6 = 2.75 (t, J= 22.6 Hz, IH); 2.7-3.25 (m, 6H) and 3.3-3.7 (m, 2H) ppm.
Example 6 The procedure of Example 1 is repeated, except that N-formyl-thiomorpholine is replaced by the appropriate N- -formyl derivatives described in Preparation 13. This af¬ fords :
[3-(n-Propyl)-4-thiomorpholinylmethylene]-bisphosphonic acid (3-Isopropyl-4-thiomorpholinylmethylene) -bisphosphonic acid M.p. : 240-241°C
(3-Phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 257-258°C (d). (2-Ethyl-3-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid
[3-(n-Butyl)-4-thiomorpholinylmethylene]-bisphosphonic acid
Example 7
(3-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid
A mixture of N-formyl-3-isobuty1-thiomorpholine (18.7 g) and phosphorous acid (16.4 g) was heated at 100°C for 2 hours. Phosphorus trichloride (30 ml) was added drop- wise with stirring, and after reflux for 3 hours water (180 ml) was added slowly. The mixture was refluxed for 1 hour and filtered. Evaporation of the filtrate gave a residue which was triturated wi'th ethanol to yield a cry¬ stalline compound which was isolated by filtration. M.p.: 237-238°C (dec).
Example 8 The procedure of Example 7 was repeated, except that N-formyl-3-isobuty1-thiomorpholiπe was replaced by the appropriate N-formyl-derivative described in Preparation 13, 17 and 18. In this way the following compounds were prepared
(3-Phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 257°C (dec).
(2-Ethyl-3-propyl-4-thiomorpholinylmethylene)-bisphosphonic acid
M.p.: 213-215°C.
(3-Isopropyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 240-241°C. (2-Isopropyl-3-isobutyl-4-thiomorpholinylmethylene)-bis- phosphonic acid M.p. : 225°C.
(2,2-Dimethyl-3-isopropyl-4-thiomorpholinylmethylene)-bis- phosphonic acid M.p.: 202-205°C.
(2, 2-Dimethyl-3-phenyl-4-thiomorpholinylmethylene)-bis¬ phosphonic acid M.p.: 242°C. (3-Methyl-2-phenyl-4-thiomorpholinylmethylene)-bisphosphon¬ ic acid M.p.: 251°C. (dec.)
(3-Cyclopropyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 221°C. (dec.)
(3-Nonyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 197-200°C.
(3-Tert.butyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 217°C (dec).
(+)-(3-Tert.butyl-4-thiomorpholinylmethylene)-bisphosphonic acid
M.p.: 216-217°C (dec).
[α]p° = + 33.4° (c=l, IN NaOH). (-)-( 3-Tert.butyl-4-thiomorpholinylmethylene)-bisphosphonic acid
M.p. : 216-217°C (dec. ). [α]p° = -33.8° (c=l, IN NaOH).
(3-Isopentyl-4-thiomorpholinylmethylene)-bisphosphonic acid
(3-Cyclohexyl-4-thiomorpholinylmethylene)-bisphosphonic acid (+)-(3-1sobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid
[α]p° = +54° (c=l, IN NaOH)
(-)-(3-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid o-]p° = -54.3° (c=T, IN NaOH)
(2-Phenyl-3-benzyl-4-thiomorpholinylmethylene)-bisphosphonic acid (2-pentyl-3-hexyl-4-thiomorpholinylmethylene)-bisphosphonic acid
Example 9 Disodium (4-thiomorpholinyImethylene)-bisphosphonate sulf- oxide, monohydrate
30?ό Aqueous hydrogen peroxide (11.1 ml) was added with stirring to a solution of ( -thiomorpholinylmethylene)- -bisphosphonic acid (27.7 g) in 5 M NaOH (40 ml). When the exothermic reaction had ceased the solvent was evapo- rated, and the residue was treated with ethanol and filtered to yield the title compound as colourless crystals. The NMR-spectrum was identical with that described in Example 5.
Example 10
By following the procedure described in Example 9 the following sulfoxides were prepared:
Disodium [3- (tert.butyl )-4-thiomorpholinylmethylene]-bis¬ phosphonate sulfoxide Disodium (3-isobutyl-4-thiomorpholinylmethylene)-bisphos¬ phonate sulfoxide
Disodium (3-cyclopropyl-4-thiomorpholinyImethylene)-bisphos¬ phonate sulfoxide
Example 11
By following the procedure of Example 1, but substi- tuting the N-formyl-derivatives of Preparation 19 and 20 for N-formyl-thiomorpholine the following compounds were prepared :
(Tetrahydro-l,4-thiazepin-4-yl-methylene)-bisphosphonic acid
M.p.: 239-240°C.
(2-Methyl-tetrahydro-l,4-thiazepin-4-yl-methylene)-bis¬ phosphonic acid
M.p.: 241°C.
Example 12 Tetra-pivaloyloxymethyl (4-thiomorpholinylmethylene)-bis¬ phosphonate
A solution of (4-thiomorpholinylmethylene )-bisphos- phonic acid (2.8 g) in water (60 ml) was treated with four equivalents of aqueous te rabutylammonium hydroxide and freeze-dried. Remaining water was removed azeotropically with toluene. The resulting salt was suspended in tetra- hydrofuran (120 ml), and iodomethyl pivalate (9.4 ml) was added with stirring. After stirring for 1 hour at room temperature, the mixture was filtered, and the filtrate evaporated in vacuo. The residue was taken up in ethyl acetate and washed with aqueous sodium bicarbonate, dried and evaporated in vacuo. Chromatography on silica gel (eluent: petroleum ether - ethyl acetate 7:3) gave the pure title compound which crystallized on standing. M.p.: 86-88°C.
NMR (CDC13): & = 1.24 (s, 36H); 2.65 (m, 4H); 3.25 (m, 4H); 3.55 (t, J=26 Hz, IH) and 5.70 (m, 8H) ppm.
Example 13 Tetra-acetoxymetyl (4-thiomorpholinylmethylene)-bisphos- phonate
By following the procedure described in Example 12, but substituting iodomethyl acetate for iodomethyl pivalate, the title compound was obtained as a colourless oil.
NMR (CDC13): 5 = 2.14 (s, 6H); 2.16 (s, 6H); 2.65 (m, 4H);
3.26 (m, 4H); 3.53 (t, J=26 Hz, IH) and 5.70 (m, 8H) ppm.
Example 14 Di-pivaloyloxymetyl (4-thiomorpholinyImethylene) -bisphos¬ phonate disodium salt
A solution of tetra-pivaloyloxymethyl (4-thiomorph- olinyImethylene )-bisphosphonate (0.37 g) and sodium iodide (0.22 g) in acetone (5 ml) was refluxed for 90 minutes, cooled and filtered to yield the title compound as colour¬ less crystals. NMR: (D20): & = 1.16 (s, 18H); 2.65 (m, 4H); 3.05 (t, IH);
3.18 (m, 4H) and 5.52 (m, 4H) ppm
Example 15 Di-acetoxymethyl (4-thiomorpholinylmethylene) -bisphos¬ phonate disodium salt
This compound was prepared from tetra-acetoxymεthy1 ( -thiomorpholinylmethylεne )-bisphosphonate by following the procedure of Example 14.
NMR (D20): 6 - 2.09 (s, 6H); 2.65 (m, 4H); 3.10 (t, IH); 3.25 (m, 4H) and 5.50 (m, 4H) ppm.

Claims

WHAT WE CLAIM IS:
A compound of the formula I
Figure imgf000028_0001
in which R--R-, can be the same or different and stand for hydrogen, a straight or branched alip atie or alicyclic C.-C,0 hydrocarbon radical, an aryl or an aryl-C, -C.-alkyl radical; n is zero or one, and m is zero, one or two; and salts and in vivo hydrolyzable esters thereof.
2. A compound according to claim 1, in which R„ and - R. in formula I when taken together form a saturated ali¬ phatic ' - , 6- or 7-membered ring which may be substituted with one or more C,-C, -alkyl radicals.
3. A compound according to claim 1, in which R,-R- , being the same or different, stands for hydrogen, C.-C,-- -alkyl or phenyl.
4. A salt according to claim 1, which is a salt of a compound of formula I with a pharmaceutically acceptable non-toxic base, such salt being selected from the group consisting of alkali metal salts, alkaline earth metal salts, or salts with ammonia or suitable non-toxic amines, such as lower alkylamines, lower alkanola ines , procaine, cycloalkylamines, benzylamines, and heterocyclic amines.
5. An ester of a compound of formula I according to claim 1 selectεd from the group consisting of alkanoyloxy- methyl of three to six carbon atoms, 1-(alkanoyloxy )ethyl of four to seven carbon atoms, 1-methyl-l- ( alkanoyloxy )- εthyl of five to eight carbon atoms, alkoxycarbon loxy- methyl of three to six carbon atoms, 1-(alkoxycarbonyloxy )- εthyl of four to seven carbon atoms, 1-methyl-l-(alkoxycarb¬ onyloxy )εthyl of fivε to eight carbon atoms, 3-phthalidy1 , 4-crotonolactony1, y-butyrolacton-4-y1 , (2-oxo-l , 3-dioxolen- -4-yl)methyl, (5-methyl-2-oxo-l,3-dioxolεn-4°-yl)methyl,
(5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl, dialkylaminoalkyl, acεtonyl, and mεthoxymεthyl .
6. A compound of formula I according to claim 1, se- lεctεd from the group consisting of
(4-thiomorpholinyImethylene )-bisphosphonic acid and its salts and esters, and
( 3-isobuty1-4-thiomorpholinylmethylene )-bisphosphonic acid in racemic form or in the form of the singlε enantiomers, and salts and estεrs thereof, and
(3-tert-butyl-4-thiomorpholinylmεthylene)-bisphosphonic acid in racemic form or in the form of the single enantio¬ mers, and salts and esters. thereof, and
(2-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid in racemic form or in the form of the single enantiomers, and salts and esters thereof.
7. A method for producing a compound of formula I of claim 1, in which a compound of formula II
Figure imgf000030_0001
where R--R-- and m have the meanings defined in claim 1, is transf'ormed into an acid amide chloride which is reacted with a trialkylphosphite to form a compound of formula
IV
Figure imgf000030_0002
where R,-R-- and m havε the meanings definεd in claim 1, and R•, ~ is a C.-C. -alkyl radical or a bεnzyl or a substi- tutεd benzyl radical, whereafter the compound of formula IV thus produced is hydrolyzed or hydrogenolyzed to form thε desired compound of formula I (n=0), or the compound of formula IV is optionally oxidized to form a compound in which n=l, followed by a hydrolysis or hydrogenolysis as above to form the desirεd compound of formula I (n=l); thε final compound of formula I bεing recovered as such or as a salt or ester as. defined in claim 1.
8. A method for producing a compound of formula I of claim 1, in which a compound of formula II, where R,-R,- and m have the mεanings dεfinεd in claim 1, is heated with a mixture of phosphorous acid and phosphorus trichloride or phosphorus oxychloride followed by a hydrolysis to form the desired compound of formula I (n=0) optionally followed by an oxidation to form a compound of formula I (n=l), the final compound of formula I being recovered as such or as a salt or ester as defined in claim 1.
9. A pharmaceutical composition, containing an effεctivε amount of onε or more of the compounds of claim 1, together with pharmaceutically acceptablε, non-toxic carriεrs and/or auxiliary agεnts.
10. A method for the treatmεnt of a patiεnt suffεring from ostεoporosis , rhεumatoid arthritis or othεr arthritic disordεr, athεrosclεrosis, hypεrcalcεmia due to malignancies or primary hyperparathyroidism, Pagets diseasε, or othεr condition with an abnormal calcium balancε, in which a composition according to claim 9 is administεrεd to the patient in need of treatment.
PCT/DK1986/000132 1985-12-12 1986-12-10 Novel bisphosphonic derivatives, a method for their production and a pharmaceutical composition WO1987003598A1 (en)

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DE8787900075T DE3670639D1 (en) 1985-12-12 1986-12-10 NEW BIPHOSPHONIC BODIES, THEIR PRODUCTION AND PREPARATION OF MEDICINAL PRODUCTS.
DK406987A DK169678B1 (en) 1985-12-12 1987-08-05 New Bisphosphonic Acid Derivatives, Pharmaceutical Preparations Containing These, and Their Preparation and Use

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EP0416689A2 (en) * 1989-09-06 1991-03-13 Merck & Co. Inc. Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors
WO1992011269A1 (en) * 1990-12-20 1992-07-09 Leiras Oy Novel methylenebisphosphonic acid derivatives
EP0498424A1 (en) * 1991-02-07 1992-08-12 Kaken Pharmaceutical Co., Ltd. Bisphosphonic acid derivatives and bone resorption inhibitors containing them
EP0513760A2 (en) * 1991-05-13 1992-11-19 E.R. SQUIBB &amp; SONS, INC. Use of biphosphonate squalene synthetase inhibitors in pharmaceutical compositions useful in lowering cholesterol
US5227506A (en) * 1989-09-06 1993-07-13 Merck & Co., Inc. Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors
FR2703590A1 (en) * 1993-04-05 1994-10-14 Sanofi Elf Use of bisphosphonic acid derivatives for the preparation of medicaments for promoting bone repair.
US5574024A (en) * 1987-07-06 1996-11-12 Ebetino; Frank H. Methylene phosphonoalkylphosphinates, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
US6692764B2 (en) * 1994-04-29 2004-02-17 Merck & Co., Inc. Wet granulation formulation for bisphosphonic acids

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WO2000028982A2 (en) * 1998-11-19 2000-05-25 The Board Of Trustees For The University Of Arkansas Increasing bone strength with selected bisphosphonates
US7041309B2 (en) * 2002-06-13 2006-05-09 Neuropro Technologies, Inc. Spinal fusion using an HMG-CoA reductase inhibitor
WO2005090370A1 (en) 2004-02-05 2005-09-29 The Regents Of The University Of California Pharmacologically active agents containing esterified phosphonates and methods for use thereof
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5574024A (en) * 1987-07-06 1996-11-12 Ebetino; Frank H. Methylene phosphonoalkylphosphinates, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
EP0416689A2 (en) * 1989-09-06 1991-03-13 Merck & Co. Inc. Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors
EP0416689A3 (en) * 1989-09-06 1991-06-26 Merck & Co. Inc. Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors
US5227506A (en) * 1989-09-06 1993-07-13 Merck & Co., Inc. Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors
WO1992011269A1 (en) * 1990-12-20 1992-07-09 Leiras Oy Novel methylenebisphosphonic acid derivatives
EP0498424A1 (en) * 1991-02-07 1992-08-12 Kaken Pharmaceutical Co., Ltd. Bisphosphonic acid derivatives and bone resorption inhibitors containing them
US5350743A (en) * 1991-02-07 1994-09-27 Kaken Pharmaceutical Co., Ltd. Bisphosphonic acid derivatives, as bone resorption inhibitors
EP0513760A2 (en) * 1991-05-13 1992-11-19 E.R. SQUIBB &amp; SONS, INC. Use of biphosphonate squalene synthetase inhibitors in pharmaceutical compositions useful in lowering cholesterol
EP0513760A3 (en) * 1991-05-13 1992-12-23 E.R. Squibb & Sons, Inc. Use of biphosphonate squalene synthetase inhibitors in pharmaceutical compositions useful in lowering cholesterol
FR2703590A1 (en) * 1993-04-05 1994-10-14 Sanofi Elf Use of bisphosphonic acid derivatives for the preparation of medicaments for promoting bone repair.
US5488041A (en) * 1993-04-05 1996-01-30 Sanofi Method of promoting bone repair using tiludronic disodium salt
US6692764B2 (en) * 1994-04-29 2004-02-17 Merck & Co., Inc. Wet granulation formulation for bisphosphonic acids

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EP0248854A1 (en) 1987-12-16
DK169678B1 (en) 1995-01-09
DE3670639D1 (en) 1990-05-31
US4870063A (en) 1989-09-26
GB8530603D0 (en) 1986-01-22
DK406987A (en) 1987-08-05
EP0248854B1 (en) 1990-04-25

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