CA1305166C - 1-hydroxy-3-(n-methyl-n-proplylamino)propane-1,1- diphosphonic acid, pharmaceutical compositions and methods of use - Google Patents
1-hydroxy-3-(n-methyl-n-proplylamino)propane-1,1- diphosphonic acid, pharmaceutical compositions and methods of useInfo
- Publication number
- CA1305166C CA1305166C CA000541756A CA541756A CA1305166C CA 1305166 C CA1305166 C CA 1305166C CA 000541756 A CA000541756 A CA 000541756A CA 541756 A CA541756 A CA 541756A CA 1305166 C CA1305166 C CA 1305166C
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- Prior art keywords
- formula
- acid
- methyl
- pharmaceutically acceptable
- propane
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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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
Abstract
ABSTRACT
1-Hydroxy-3-(N-methyl-N-propylamino)propane-1,1-diphosphonic acid of formula
1-Hydroxy-3-(N-methyl-N-propylamino)propane-1,1-diphosphonic acid of formula
Description
L3U~lbtj The pr~sent lnvention relates to l-Hydroxy-3-(N methyl-N-propylamino)propane~ dlphosphonic acid, processes for the preparation thereo~ and pharmaceutical compositions contalning it.
Federal Republic o~ Germany Patent Specification No. 18 13 659 describ~ diphosphonic acid derivativeq, o~ which l-Hydroxyethane-l,l~diphosphonic acid has achiev~d importance as an agent for the treatment of Paget's disease. Federal Republic of Germany Patent Specification No. 29 43 498 and No. 27 02 631, European Patent Specification No. 96-931-A and Z. Anorg. Allg. Chem. 457, 214 (1979) describe 1-Hydroxy-3-(N,N-dialkylamino)propane~
diphosphonic acid~ as good calcium complex formers which can also be used for the treatment of increased bone resorption.
Federal Republic of Germany Patent Specification No. 25 3~ 391 claimed l-Hydroxy-3-(N-methyl-N-propylamino)propane~
diphosphonic acid in the general formula, but it is not desoribed as an example or as a preferred compound.
Compared with the described substances in this patent we now found that this compound which is unsymmetrically dialkylated at the nitrogen atom can also be used as a good calcium complex former, but it is much more e~fective for the broader treatment of calcium metabolism disturbances and of good tolerance. In particular, it can be well used where tha bone formation and breakdown is disturbed, i. e. it can be used for the treatmPnt of disea~es of the skeletal system, for example osteoporosis, Paget's disease, Bechterew's diseases and ths like.
~owever, on the basis of these properties, it can also be used for ths therapy of bone metastases, urolithiasis and for the prevention of heterotopic ossifications. Due to its influence on calcium metabolism, it also forms a basis ~or thQ treatment of rheumatoid arthritis, osteoarthrltis and degenerative arthrosis.
~3~
Thus, accordiny to the present invention, ther~ is provided l-Hydroxy-3-~N-methyl-N-propyl.amino)propane-l,l-diphosphonic acid of the formula:
H3C-c~ C 2 ~ ~ 2 N-cH2-cH2-c-oH ~I~
~3C 03P (OH)2 and the pharmacologically compatible pharmaceutically acceptable salts thereof.
The compound of formula (I) according to the present invention can be preferably prepared by known processes. The compound may also be produced as the cprresponding di- or tetraesters, preferably methyl, ethyl or isobutyl esters, and such esters can be saponified or hydrolysed to the free acid (I), a) a carboxylic acid of the formula:
H C-CH -CH
3 2 2> N-CH2-CH2-COOH (II~
is reacted with a mixture of phosphorous acid or phosphoric acid and a phosphorus halide or a phosphorus halide oxide and subsequently saponified to a free diphosphonic acid of formula (I), wherein R
is hydrogen; or b) a carboxylic acid chloride of the formula:
H3C CH2 CH2~
/ N-CH2-CH~-COCl (III) ~ .
5~
i~ reacted with a trlalkyl phosphite of the general formula:
P(ORI~3 (I~) wherein ~' i9 an alkyl radical contalning up to 4 carbon atoms, preferably a methyl, ethyl or isobutyl radical, to give an acyl phosphonate o~ tha ~ormula:
H3C CH2-CH2 o o ~ N_CH2-CH2-C-P(O~ )2 (V);
wh~r~$n R' ha~ thQ above-givan meaning, which i8 ~ub~equently reacted with a dialkyl pho phita o~ the general formula:
~-P(OR')2 (VI), wherein R' has the above-given meaning, to giv~ a diphosphona~e of th~ formula:
H3C-CH2-CH2 O=P(OR')2 ~ N-CH2 CH2-C-OH (VII), H3C o=P(OR )2 wherein R' has the above-giv n meaning, and the resultant tetraester is optionally ~aponified to the corresponding diester or ~ree l-Rydroxy-3-(N-methyl-N-propylamino)propane-l,l-diphosphonic acld of ~ormula (I); or c) a compound o~ the general formul :
O=P(OR')2 3C CH2-CH2-NH-c~2-cH2-c-oH (VIII), O=P(OR')2 wherein R' ha3 the above-gi~en meaning, is m~thylatsd and the resultant tetraester is optionally saponified to the corresponding diester or fre~ l-Hydroxy-3-~N methyl-N-~L3(~S3L~6 propylamino)propane~ diphosphonic acid o~ formula (I) and,if desired, the compound thu~ prepared is converted into its pharmacologically compatible~p~aceutically acceptable sal-ts.
The carhoxyllc acid of formula (II) used in process a) is reacted with 1 to 5 and preferably 2 to 3 mol phosphorus acid or phosphoric ac~d and 1 to 5 and preferably 2 to 3 mole phosphorus trihalide or phosphorus trihalide oxide at a temperature of 80 to 130 ~ and pre~erably of 80 to 100 C.
The reaction can also be carried out in the presence of diluents, for example halsgenated hydrocarbons, espec$ally chlorobenæene or tetrachloroethane, or also dioxan. The subseguent hydrolysis takes place by boiling with water but preferably with semiconcentrated hydrochloric or hydrobromic acid.
As phosphorus trihalides in the above-mentioned processes, there can be used, for example, phosphorus trichloride or phosphorus tribromide, as phosphorus trihalide oxide can be taken phosphorus trichloride oxide.
In the case of process b), the acid chloride of formula (III) is reacted with the trial~yl phosphite of formula (IV) at a temperature of 0 to 60 C and preferably of 20 to 40 C. The reaction can be carried out without a solvent or also in the presence o~ inert solvents, for example diethyl ether, tetrahydrofuran, dioxan or also halogenated hydrocarbons, for example methylene chloride. The acyl phosphonate o~ general formula (V) formed as intermediate can be isolated or further reacted directly. The subsequent reaction is carried out in the presence of a weak base, preferably of a secondary amine, for example dibutylamine, at a temperature of 0 to 60 C and preferably o~ 10 ~o 30 C.
In the ca3e of the reductive alXyla~ion according to process c), a mixture of secondary amlne o~ general formula (VIII) and ~ormaldehyde or of the acetal thereo~ reated in ~he presence o~ a hydrogenat~on catalyst, ~or example palladium on ~3~
charcoal or nickel, with hydrogen at atmospherlc or increased pressure or with the use of formic acid as reducing agent.
In addition, methylation oP the secondary amine of general formula (VIII) can be carried out especially advantageously according to the phase tran~fer process with dimekhyl-sulphats.
The tetraalkyl esters possibly obtained in the processes b) andc) can be saponified to the corresponding diesters or to the free l-Hydroxy-3(N-methyl-~-propylamino)propane~
diphosphonic acid. The saponification to diesters usually takes place by treating the tetraalkyl esters with an alkali metal halide, preferably sodium iodide, in an appropriate solvent, for example acetone, at ambient temperature. There ls hereby obtained the symmetrical diester/disodium salt which, if desired, can be converted into the diester/diacid by means of an acidic ion exchanger. The saponification to the ~ree dipho phonic acids usually takes place by boiling with hydrochloric or hydrobromic acid. However, a cleavage with a trimethylsilyl halide, preferably the bromide or iodide, can also be carried out. on the other hand, the free diphosphonic acid can be converted again into the tetraalkyl esters~by boiling with orthoformic acid alkyl esters. The free l-Hydroxy-3-(N-methyl-N-propylamino)propane~ diphosphonic acid of formula (I) can be isolated as the free acid or in the form of its mono- or dialkali metal salt. The alkali metal salt can usually be readily purified by reprecipitation from water/methanol or from water/acetone.
As pharmacologically compatible pharmaceutically acceptable salts,-there-are preferably used the alkali metal or ammonium salts which can be prepared in the usual way, for example by titration of the compounds with inorganic or organic bases, for example sodiu~ or potassium hydrogen carbonates, aqueous solutions of sodium or pota~sium hydroxide or aqueous solutions of ammonia or of amines, for example trimethyl or triethylamine.
6~
In the speciflcation it will be understood that the qualification that the salts be "pharmaceutically acceptable" means that the salts have the necessary physical characteristics, for example, stability, to render them suitable for formulation into pharma-ceutical compositions. The qualification that the salts be "pharmacologically compatible" is to be under-stood, as extending to salts of non-toxic inorganic or organic cations or base components which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies.
Salts of compounds of formula (I) which are not pharmaceutically acceptable and pharmacologically compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, by conventional means, to different salts having the required physical and chemical characteristics to make them suitable for administration in pharma-ceutical compositions to living bodies.
~3~5~
The compound o~ ~ormula (I) according to the present invention and khe salts thereo* can be administered enterally or paxenterally in liquid or solid form. For this purpose, there can be used all convenkional form~ o~ administration, for example tablets/ capsules, dragees, syrups, solutions, suspens~ons and tho like. As injection medium, it i~ pre~erred to use water which contain~ the additives usual in th~ case of injection solution~, for example stabilising agents, solubilising agents and bu~fers. Additives o~ thig Xind include, for example, tartrate and citrate buf~ers, ethanol, complex formers (such as ethylenediaminetetraacetic acid and the non-toxic salts thereof) and high molecular weight poylmers (such as liquid polyethylene oxide) for viscosity regu:Lation.
Liquid carrier materials for injection solutions must be starile and are preferably placed in ampoules. Solid carrier material~ include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycol). Compositions suitable for oral administration can, i~ desired, also contain flavouring and sweetening agents.
The dosage can depend upon various factors, such as the mode of administration, species, age and/or individual condition. The dosages to be administered daily are about 1 to 1000 mg in the case of humans preferably 10 to 200 mg and can be given once or several times per day.
The following examples illustrate some of the process variants which can be used for the synthesis of the compound a~cording to the pres~nt invention. The ~tructure of this compound was veri~ied by lH- and 3lp_NMR ~pectroscopy and the purity by means of 31p_NMR spectroscopy, thin layer electrophoresis (cellulose, oxalate bu~fer of pH 4.0) and by means of C, H, N, P and Na analyses. For the characterisation of the compound, th~re is given the Mrel value (relative mobility) re~erred to pyrophosphate (Mr~l- 1.0).
~3~i~ ~
Exam~
l-Hydroxy-3-(N-methyl-N~propylaminoLe~ ne~ diphosphonic acid.
18 g 3-(N-methyl-N propylamino)prooionic acid are kept ~or 12 hours at 100 C. with 15 g. phosphorus acid and 32 ml.
phosphorus trichloride in 90 ml. chlorobenzene. The solvent is then decanted o~f and the residue i3 stirred under reflux with ~50 mlO 6N hydrochIoric acid ~or 2 hours. Insoluble material is filtered of~ and tha ~iltrate i~ concentrated and applied to a column o~ Amberlite IR 120 (H+ ~orm). The elution with water i~
monitored electrophoretically. The de~ired ~ractions are combined, evaporated and stirred up with acetone/me~hanol and the crystals obtalned ar~ isolated. Thore are thus obtalned 14.1 g. o~ crude product. A~ter recrystallisation ~rom water/methanol, there are obtalned 9.8 (27 % o~ theory) o~
analytically pure pxoduct in the ~orm of the sesquihydrate;
Mrel ~ 0.4; m. p. 96 - 102~ C, 108 C. (decomp.).
The starting material is obtained as follows:
N-methyl-N-propylamine (J.A.C,S., 79 4720/1957) is reacted with methyl acrylate in toluene in th~ molar ratio 1 : 3 and the ester obtained in a yield o~ 84 % o~ theory is, without distilIation, saponi~ied with lN aqueous sodium hydroxide solution. The oily acid i~ thus obtained in a yield o~ 92 % o~
theory and is used without further puri~ication.
~, 5~
9 _ Exa~ple 2 10 g 3-(N-mathyl-N-propylamino)propionic acid are heated to ~0 C. with 11.4 g. phosphorus acid. The melt i~ mixed with 12 ml. phosphorus trichloride and kept at tha same temperature ror 16 hour~.
Excess phosphorus trichloride i3 distilled off, 140 ml. 6N
hydrochloric acid ara added thereto and the reaction mixture is stirred ~or 3 hours at 100 C. It is then ~iltered, the filtrate is concentrated in vacuum and the oil obtained is puri~ied by ion exchanger chromatography in the manner described in Example 1. Yield 6.95 g. ~35 % of theory~ as sesquihYdrate7 Mrel = 04;
m. p. 96 - 102 C., 108 C. (decomp.).
Example 3 In a manner analogous to that describe~ in Example 2, 15 g.
3-(N-methyl-N-propylamino)propionic acid are heated to 80 C.
with 17 g. phosphorus acid and 19 ml. phosphoru~ trichloride oxide. After 18 hours at 80 C the excess phosphorus trichloride oxide i~ distilled off and the residue is saponi~ied by heating it with 210 ml 6N hydrochloric acid for 2 hours. The crude product was purified by ion exchanger chromotography in the manner described in Example 1 (Amberllte*
IR 120, H~ form). Mrel 8 o,4, Yield 16,2 g (54 % o~ theory) as ~esquihydrate after recrystallisation from water/methanol;
m. p. 96 - 102 C, 108 C ~decomp.~.
* Trade Mark - 10 - 3~3~
Method~
Male Wistar rat~ weighing about 160 g. were thyroparathyroidectomized on day 1. On day 5, the success of the operation was controlled by measuring calcemia after a night fasting. ~rom that day on, all the animal~ were group-fed, that means all of them ate the same guantity o~ food.
Furthermore, the animals received then daily for 3 days 2 subcutaneous in~ections, one containing 25 /ug of ethyl p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8 tetramethyl-~-naphthyl)-l~
propenyl]benzoat, a synthetic retinoid the oth~r one the bisphosphonate to be tested. Addltionally, all animals were given 2 /ug of thyroxine the ~irst and last day o~ txeatment.
24 h after the last in;ection of the retinoid and the bisphosphonate and a~ter one night ~asting, blood was tak~n by retroorbital puncture under ether anesthesia. Plasma calcium wa~ then analyzed by means of atomic absorption.
The bisphonsphonates were given first at a dose o~ 0.1 mg P/kg in a volume o~ 2ml/kg. In a second time, the active compounds were injected at 0.01 and 0.001 mg P/kg.
During all these experiments, the animals received water ad libitum. The diet given was Kliba 331, which contains 1.0 g~
Ca/100 g., 0.8 g. Pi/100 ~., and to which 800 I. U. of vitamin D3/kg. was added. Each group consisted of two or more animals.
mg P/kg ~. c.
O. 001 O. 01 0 1 _ _. ______ __ _ ._ ___ _ _ _ . _. . ~ . _._ __~ . ~_T
A O
B + ~+~
C - + ~+~ ~+~
.. _ .....
o = degradation of hypercalcemia from -0.99 to ~ 0.99 mg %
l.o ~o }.99 mg %
2.0 to 2.99 mg %
~+ = ~ 3-0 to 3.99 mg %
+++ = I~ " ll " ~.o to 4.99 mg %
++++ , - ~ > 5.0 A ~ l-Hydroxy-3(N,N-dimethylamino)propane-l,l-diphosphonic acid B = 3-(N,N-diethylamino)-l-hydroxypropane~ diphosphonic acid C - l-Hydroxy-3-(N-methyl-N-propy~amino)propane l,l-diphosphonic acid .
A and B are compound~ o~ DE-PS 25 34 391 ,: ....
N is to be understood ~t in this specificatiorl references to sap~ificatiQn ar~ ~o be un~erst~od as ~hracing hydrolysis ~ses.
Federal Republic o~ Germany Patent Specification No. 18 13 659 describ~ diphosphonic acid derivativeq, o~ which l-Hydroxyethane-l,l~diphosphonic acid has achiev~d importance as an agent for the treatment of Paget's disease. Federal Republic of Germany Patent Specification No. 29 43 498 and No. 27 02 631, European Patent Specification No. 96-931-A and Z. Anorg. Allg. Chem. 457, 214 (1979) describe 1-Hydroxy-3-(N,N-dialkylamino)propane~
diphosphonic acid~ as good calcium complex formers which can also be used for the treatment of increased bone resorption.
Federal Republic of Germany Patent Specification No. 25 3~ 391 claimed l-Hydroxy-3-(N-methyl-N-propylamino)propane~
diphosphonic acid in the general formula, but it is not desoribed as an example or as a preferred compound.
Compared with the described substances in this patent we now found that this compound which is unsymmetrically dialkylated at the nitrogen atom can also be used as a good calcium complex former, but it is much more e~fective for the broader treatment of calcium metabolism disturbances and of good tolerance. In particular, it can be well used where tha bone formation and breakdown is disturbed, i. e. it can be used for the treatmPnt of disea~es of the skeletal system, for example osteoporosis, Paget's disease, Bechterew's diseases and ths like.
~owever, on the basis of these properties, it can also be used for ths therapy of bone metastases, urolithiasis and for the prevention of heterotopic ossifications. Due to its influence on calcium metabolism, it also forms a basis ~or thQ treatment of rheumatoid arthritis, osteoarthrltis and degenerative arthrosis.
~3~
Thus, accordiny to the present invention, ther~ is provided l-Hydroxy-3-~N-methyl-N-propyl.amino)propane-l,l-diphosphonic acid of the formula:
H3C-c~ C 2 ~ ~ 2 N-cH2-cH2-c-oH ~I~
~3C 03P (OH)2 and the pharmacologically compatible pharmaceutically acceptable salts thereof.
The compound of formula (I) according to the present invention can be preferably prepared by known processes. The compound may also be produced as the cprresponding di- or tetraesters, preferably methyl, ethyl or isobutyl esters, and such esters can be saponified or hydrolysed to the free acid (I), a) a carboxylic acid of the formula:
H C-CH -CH
3 2 2> N-CH2-CH2-COOH (II~
is reacted with a mixture of phosphorous acid or phosphoric acid and a phosphorus halide or a phosphorus halide oxide and subsequently saponified to a free diphosphonic acid of formula (I), wherein R
is hydrogen; or b) a carboxylic acid chloride of the formula:
H3C CH2 CH2~
/ N-CH2-CH~-COCl (III) ~ .
5~
i~ reacted with a trlalkyl phosphite of the general formula:
P(ORI~3 (I~) wherein ~' i9 an alkyl radical contalning up to 4 carbon atoms, preferably a methyl, ethyl or isobutyl radical, to give an acyl phosphonate o~ tha ~ormula:
H3C CH2-CH2 o o ~ N_CH2-CH2-C-P(O~ )2 (V);
wh~r~$n R' ha~ thQ above-givan meaning, which i8 ~ub~equently reacted with a dialkyl pho phita o~ the general formula:
~-P(OR')2 (VI), wherein R' has the above-given meaning, to giv~ a diphosphona~e of th~ formula:
H3C-CH2-CH2 O=P(OR')2 ~ N-CH2 CH2-C-OH (VII), H3C o=P(OR )2 wherein R' has the above-giv n meaning, and the resultant tetraester is optionally ~aponified to the corresponding diester or ~ree l-Rydroxy-3-(N-methyl-N-propylamino)propane-l,l-diphosphonic acld of ~ormula (I); or c) a compound o~ the general formul :
O=P(OR')2 3C CH2-CH2-NH-c~2-cH2-c-oH (VIII), O=P(OR')2 wherein R' ha3 the above-gi~en meaning, is m~thylatsd and the resultant tetraester is optionally saponified to the corresponding diester or fre~ l-Hydroxy-3-~N methyl-N-~L3(~S3L~6 propylamino)propane~ diphosphonic acid o~ formula (I) and,if desired, the compound thu~ prepared is converted into its pharmacologically compatible~p~aceutically acceptable sal-ts.
The carhoxyllc acid of formula (II) used in process a) is reacted with 1 to 5 and preferably 2 to 3 mol phosphorus acid or phosphoric ac~d and 1 to 5 and preferably 2 to 3 mole phosphorus trihalide or phosphorus trihalide oxide at a temperature of 80 to 130 ~ and pre~erably of 80 to 100 C.
The reaction can also be carried out in the presence of diluents, for example halsgenated hydrocarbons, espec$ally chlorobenæene or tetrachloroethane, or also dioxan. The subseguent hydrolysis takes place by boiling with water but preferably with semiconcentrated hydrochloric or hydrobromic acid.
As phosphorus trihalides in the above-mentioned processes, there can be used, for example, phosphorus trichloride or phosphorus tribromide, as phosphorus trihalide oxide can be taken phosphorus trichloride oxide.
In the case of process b), the acid chloride of formula (III) is reacted with the trial~yl phosphite of formula (IV) at a temperature of 0 to 60 C and preferably of 20 to 40 C. The reaction can be carried out without a solvent or also in the presence o~ inert solvents, for example diethyl ether, tetrahydrofuran, dioxan or also halogenated hydrocarbons, for example methylene chloride. The acyl phosphonate o~ general formula (V) formed as intermediate can be isolated or further reacted directly. The subsequent reaction is carried out in the presence of a weak base, preferably of a secondary amine, for example dibutylamine, at a temperature of 0 to 60 C and preferably o~ 10 ~o 30 C.
In the ca3e of the reductive alXyla~ion according to process c), a mixture of secondary amlne o~ general formula (VIII) and ~ormaldehyde or of the acetal thereo~ reated in ~he presence o~ a hydrogenat~on catalyst, ~or example palladium on ~3~
charcoal or nickel, with hydrogen at atmospherlc or increased pressure or with the use of formic acid as reducing agent.
In addition, methylation oP the secondary amine of general formula (VIII) can be carried out especially advantageously according to the phase tran~fer process with dimekhyl-sulphats.
The tetraalkyl esters possibly obtained in the processes b) andc) can be saponified to the corresponding diesters or to the free l-Hydroxy-3(N-methyl-~-propylamino)propane~
diphosphonic acid. The saponification to diesters usually takes place by treating the tetraalkyl esters with an alkali metal halide, preferably sodium iodide, in an appropriate solvent, for example acetone, at ambient temperature. There ls hereby obtained the symmetrical diester/disodium salt which, if desired, can be converted into the diester/diacid by means of an acidic ion exchanger. The saponification to the ~ree dipho phonic acids usually takes place by boiling with hydrochloric or hydrobromic acid. However, a cleavage with a trimethylsilyl halide, preferably the bromide or iodide, can also be carried out. on the other hand, the free diphosphonic acid can be converted again into the tetraalkyl esters~by boiling with orthoformic acid alkyl esters. The free l-Hydroxy-3-(N-methyl-N-propylamino)propane~ diphosphonic acid of formula (I) can be isolated as the free acid or in the form of its mono- or dialkali metal salt. The alkali metal salt can usually be readily purified by reprecipitation from water/methanol or from water/acetone.
As pharmacologically compatible pharmaceutically acceptable salts,-there-are preferably used the alkali metal or ammonium salts which can be prepared in the usual way, for example by titration of the compounds with inorganic or organic bases, for example sodiu~ or potassium hydrogen carbonates, aqueous solutions of sodium or pota~sium hydroxide or aqueous solutions of ammonia or of amines, for example trimethyl or triethylamine.
6~
In the speciflcation it will be understood that the qualification that the salts be "pharmaceutically acceptable" means that the salts have the necessary physical characteristics, for example, stability, to render them suitable for formulation into pharma-ceutical compositions. The qualification that the salts be "pharmacologically compatible" is to be under-stood, as extending to salts of non-toxic inorganic or organic cations or base components which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies.
Salts of compounds of formula (I) which are not pharmaceutically acceptable and pharmacologically compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, by conventional means, to different salts having the required physical and chemical characteristics to make them suitable for administration in pharma-ceutical compositions to living bodies.
~3~5~
The compound o~ ~ormula (I) according to the present invention and khe salts thereo* can be administered enterally or paxenterally in liquid or solid form. For this purpose, there can be used all convenkional form~ o~ administration, for example tablets/ capsules, dragees, syrups, solutions, suspens~ons and tho like. As injection medium, it i~ pre~erred to use water which contain~ the additives usual in th~ case of injection solution~, for example stabilising agents, solubilising agents and bu~fers. Additives o~ thig Xind include, for example, tartrate and citrate buf~ers, ethanol, complex formers (such as ethylenediaminetetraacetic acid and the non-toxic salts thereof) and high molecular weight poylmers (such as liquid polyethylene oxide) for viscosity regu:Lation.
Liquid carrier materials for injection solutions must be starile and are preferably placed in ampoules. Solid carrier material~ include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycol). Compositions suitable for oral administration can, i~ desired, also contain flavouring and sweetening agents.
The dosage can depend upon various factors, such as the mode of administration, species, age and/or individual condition. The dosages to be administered daily are about 1 to 1000 mg in the case of humans preferably 10 to 200 mg and can be given once or several times per day.
The following examples illustrate some of the process variants which can be used for the synthesis of the compound a~cording to the pres~nt invention. The ~tructure of this compound was veri~ied by lH- and 3lp_NMR ~pectroscopy and the purity by means of 31p_NMR spectroscopy, thin layer electrophoresis (cellulose, oxalate bu~fer of pH 4.0) and by means of C, H, N, P and Na analyses. For the characterisation of the compound, th~re is given the Mrel value (relative mobility) re~erred to pyrophosphate (Mr~l- 1.0).
~3~i~ ~
Exam~
l-Hydroxy-3-(N-methyl-N~propylaminoLe~ ne~ diphosphonic acid.
18 g 3-(N-methyl-N propylamino)prooionic acid are kept ~or 12 hours at 100 C. with 15 g. phosphorus acid and 32 ml.
phosphorus trichloride in 90 ml. chlorobenzene. The solvent is then decanted o~f and the residue i3 stirred under reflux with ~50 mlO 6N hydrochIoric acid ~or 2 hours. Insoluble material is filtered of~ and tha ~iltrate i~ concentrated and applied to a column o~ Amberlite IR 120 (H+ ~orm). The elution with water i~
monitored electrophoretically. The de~ired ~ractions are combined, evaporated and stirred up with acetone/me~hanol and the crystals obtalned ar~ isolated. Thore are thus obtalned 14.1 g. o~ crude product. A~ter recrystallisation ~rom water/methanol, there are obtalned 9.8 (27 % o~ theory) o~
analytically pure pxoduct in the ~orm of the sesquihydrate;
Mrel ~ 0.4; m. p. 96 - 102~ C, 108 C. (decomp.).
The starting material is obtained as follows:
N-methyl-N-propylamine (J.A.C,S., 79 4720/1957) is reacted with methyl acrylate in toluene in th~ molar ratio 1 : 3 and the ester obtained in a yield o~ 84 % o~ theory is, without distilIation, saponi~ied with lN aqueous sodium hydroxide solution. The oily acid i~ thus obtained in a yield o~ 92 % o~
theory and is used without further puri~ication.
~, 5~
9 _ Exa~ple 2 10 g 3-(N-mathyl-N-propylamino)propionic acid are heated to ~0 C. with 11.4 g. phosphorus acid. The melt i~ mixed with 12 ml. phosphorus trichloride and kept at tha same temperature ror 16 hour~.
Excess phosphorus trichloride i3 distilled off, 140 ml. 6N
hydrochloric acid ara added thereto and the reaction mixture is stirred ~or 3 hours at 100 C. It is then ~iltered, the filtrate is concentrated in vacuum and the oil obtained is puri~ied by ion exchanger chromatography in the manner described in Example 1. Yield 6.95 g. ~35 % of theory~ as sesquihYdrate7 Mrel = 04;
m. p. 96 - 102 C., 108 C. (decomp.).
Example 3 In a manner analogous to that describe~ in Example 2, 15 g.
3-(N-methyl-N-propylamino)propionic acid are heated to 80 C.
with 17 g. phosphorus acid and 19 ml. phosphoru~ trichloride oxide. After 18 hours at 80 C the excess phosphorus trichloride oxide i~ distilled off and the residue is saponi~ied by heating it with 210 ml 6N hydrochloric acid for 2 hours. The crude product was purified by ion exchanger chromotography in the manner described in Example 1 (Amberllte*
IR 120, H~ form). Mrel 8 o,4, Yield 16,2 g (54 % o~ theory) as ~esquihydrate after recrystallisation from water/methanol;
m. p. 96 - 102 C, 108 C ~decomp.~.
* Trade Mark - 10 - 3~3~
Method~
Male Wistar rat~ weighing about 160 g. were thyroparathyroidectomized on day 1. On day 5, the success of the operation was controlled by measuring calcemia after a night fasting. ~rom that day on, all the animal~ were group-fed, that means all of them ate the same guantity o~ food.
Furthermore, the animals received then daily for 3 days 2 subcutaneous in~ections, one containing 25 /ug of ethyl p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8 tetramethyl-~-naphthyl)-l~
propenyl]benzoat, a synthetic retinoid the oth~r one the bisphosphonate to be tested. Addltionally, all animals were given 2 /ug of thyroxine the ~irst and last day o~ txeatment.
24 h after the last in;ection of the retinoid and the bisphosphonate and a~ter one night ~asting, blood was tak~n by retroorbital puncture under ether anesthesia. Plasma calcium wa~ then analyzed by means of atomic absorption.
The bisphonsphonates were given first at a dose o~ 0.1 mg P/kg in a volume o~ 2ml/kg. In a second time, the active compounds were injected at 0.01 and 0.001 mg P/kg.
During all these experiments, the animals received water ad libitum. The diet given was Kliba 331, which contains 1.0 g~
Ca/100 g., 0.8 g. Pi/100 ~., and to which 800 I. U. of vitamin D3/kg. was added. Each group consisted of two or more animals.
mg P/kg ~. c.
O. 001 O. 01 0 1 _ _. ______ __ _ ._ ___ _ _ _ . _. . ~ . _._ __~ . ~_T
A O
B + ~+~
C - + ~+~ ~+~
.. _ .....
o = degradation of hypercalcemia from -0.99 to ~ 0.99 mg %
l.o ~o }.99 mg %
2.0 to 2.99 mg %
~+ = ~ 3-0 to 3.99 mg %
+++ = I~ " ll " ~.o to 4.99 mg %
++++ , - ~ > 5.0 A ~ l-Hydroxy-3(N,N-dimethylamino)propane-l,l-diphosphonic acid B = 3-(N,N-diethylamino)-l-hydroxypropane~ diphosphonic acid C - l-Hydroxy-3-(N-methyl-N-propy~amino)propane l,l-diphosphonic acid .
A and B are compound~ o~ DE-PS 25 34 391 ,: ....
N is to be understood ~t in this specificatiorl references to sap~ificatiQn ar~ ~o be un~erst~od as ~hracing hydrolysis ~ses.
3~3~S~6 : - 12 -The Patent SpeciEications referred to herein are more fully identified as follows:
1. DE 1,813,659 Inventors : Francis, Marion David, Cincinnati, Ohio, U.S.A.
Assignee : The Procter and Gamble Co.
U.S.A.
Application Date : July 3, 1969.
Laid Open : December 10, 1986.
Canadian Counterpart : No. 946,290.
2. DE 2,702,631 Inventors : Helmut Blum et al Assignee : Henkel KGaA
Application Date : January 22, 1979.
Laid Open : July 27, 1978.
3. DE 2,534,391 Inventors : Blum, Helmut et al Assignee : Henkel and Cie Gmb~, Dusseldorf, West Germany Application Date : August 1, 19750 Laid Open : February 17, 1977.
U.S. Counterpart : No. 4,054,598 4. EP 96,931 Inventors, : Benedict, James John et al Assignee : Mallinckrodt Inc., St. Louis, U. S. A.
Application Date : June 7, 1933.
Laid Open : December 28, 1983.
1. DE 1,813,659 Inventors : Francis, Marion David, Cincinnati, Ohio, U.S.A.
Assignee : The Procter and Gamble Co.
U.S.A.
Application Date : July 3, 1969.
Laid Open : December 10, 1986.
Canadian Counterpart : No. 946,290.
2. DE 2,702,631 Inventors : Helmut Blum et al Assignee : Henkel KGaA
Application Date : January 22, 1979.
Laid Open : July 27, 1978.
3. DE 2,534,391 Inventors : Blum, Helmut et al Assignee : Henkel and Cie Gmb~, Dusseldorf, West Germany Application Date : August 1, 19750 Laid Open : February 17, 1977.
U.S. Counterpart : No. 4,054,598 4. EP 96,931 Inventors, : Benedict, James John et al Assignee : Mallinckrodt Inc., St. Louis, U. S. A.
Application Date : June 7, 1933.
Laid Open : December 28, 1983.
5. DE 2,943,498 Inventors : Helmut Blum et al Assignee : Henkel KGaA
Filed : October 27, lg79 Published : January 27, 1983.
Filed : October 27, lg79 Published : January 27, 1983.
Claims (11)
1. A diphosphonate compound of the formula:
(I) and the pharmacologically compatible, pharma-ceutically acceptable salts thereof.
(I) and the pharmacologically compatible, pharma-ceutically acceptable salts thereof.
2. A process for the preparation of a diphos-phonate of formula (I):
(I) and the pharmacologically compatible, pharma-ceutically acceptable salts thereof, wherein a) a carboxylic acid of the formula:
(II) is reacted with a mixture of phosphorus acid or phosphoric acid and a phosphorus halide or phosphorus halide oxide and subsequently saponified or hydro-lysed to give a free diphosphonic acid of formula (I); or b) a carboxylic acid chloride of the formula:
(III), is reacted with a trialkyl phosphite of the general formula:
P (OR')3 (IV), wherein R' is an alkyl radical containing up to 4 carbon atoms, to give an acyl phosphonate of the formula:
(V), in which R' has the above-given meaning, which subsequently is reacted with a dialkyl phosphite of the general formula:
H-?(OR')2 (VI), in which R' has the above-given meaning, to give a diphosphonate of the formula:
(VII), in which R' has the above-given meaning, and the tetraester obtained is saponified or hydrolysed to give the corresponding free 1-hydroxy-3-(N-methyl-N-propylamino)propane-1,1 diphosphonic acid of formula (I); or c) a compound of the general formula:
(VIII), in which R' has the above-given meaning, is methy-lated and the tetraester obtained is saponified or hydrolysed to give the corresponding free 1-hydroxy-
(I) and the pharmacologically compatible, pharma-ceutically acceptable salts thereof, wherein a) a carboxylic acid of the formula:
(II) is reacted with a mixture of phosphorus acid or phosphoric acid and a phosphorus halide or phosphorus halide oxide and subsequently saponified or hydro-lysed to give a free diphosphonic acid of formula (I); or b) a carboxylic acid chloride of the formula:
(III), is reacted with a trialkyl phosphite of the general formula:
P (OR')3 (IV), wherein R' is an alkyl radical containing up to 4 carbon atoms, to give an acyl phosphonate of the formula:
(V), in which R' has the above-given meaning, which subsequently is reacted with a dialkyl phosphite of the general formula:
H-?(OR')2 (VI), in which R' has the above-given meaning, to give a diphosphonate of the formula:
(VII), in which R' has the above-given meaning, and the tetraester obtained is saponified or hydrolysed to give the corresponding free 1-hydroxy-3-(N-methyl-N-propylamino)propane-1,1 diphosphonic acid of formula (I); or c) a compound of the general formula:
(VIII), in which R' has the above-given meaning, is methy-lated and the tetraester obtained is saponified or hydrolysed to give the corresponding free 1-hydroxy-
3-(N-methyl-N-propylamino)propane-1,1-diphosphonic acid of formula (I) and the free acid thus obtained is, if desired, converted into a pharmacologically compatible, pharmaceutically acceptable salt.
3. A process according to claim 2, including converting a free acid (I) obtained to a correspond-ing pharmaceutically acceptable, pharmacologically compatible salt thereof.
3. A process according to claim 2, including converting a free acid (I) obtained to a correspond-ing pharmaceutically acceptable, pharmacologically compatible salt thereof.
4. A diphosphonate of formula (I), as defined in claim 1, or a pharmaceutically acceptable, pharma-cologically compatible salt thereof, whenever pre-pared by a process according to claim 2.
5. A pharmaceutical composition containing a pharmacologically acceptable and effective amount of at least one diphosphonate of formula (I), as defined in claim 1, or a pharmaceutically acceptable, pharmacologically compatible salt thereof, in association with a pharmaceutically and pharmacologically acceptable carrier therefor.
6. The use of a diphosphonate of formula (I), as defined in claim 1, or a pharmaceutically accept-able, pharmacologically compatible salt thereof, for the preparation of a pharmaceutical composition.
7. The use of a diphosphonate of formula (I), as defined in claim 1, or pharmaceutically accept-able, pharmacologically compatible salt thereof, for the treatment of diseases of the calcium metabolism.
8. 1-Hydroxy-3-(N-methyl-N-propylamino)-propane 1,1-diphosphonic acid or a pharmaceutically acceptable, pharmacologically compatible salt thereof for use in the treatment of diseases of the calcium metabolism.
9. A pharmaceutical composition for the treatment of prophylaxis of diseases of the calcium metabolism comprising a pharmacologically acceptable and effective amount of 1-hydroxy-3-(N-methyl-N-propylamino)propane-1,1-diphosphonic acid or a pharmaceutically acceptable, pharmacologically compatible salt thereof in association with a pharmaceutically acceptable carrier therefor.
10. A calcium metabolism disease pharmaceutical composition for the treatment or prophylaxis of diseases of the calcium metabolism comprising a pharmacologically acceptable, therapeutic amount of 1-hydroxy-3-(N-methyl-N-propylamino)propane- 1,1-diphosphonic acid, in association with a pharmaceutically acceptable carrier.
11. A calcium metabolism disease pharmaceutical composition for the treatment or prophylaxis of diseases of the calcium metabolism comprising a pharmacologically acceptable, therapeutic amount of a pharmacologically compatible, pharmaceutically acceptable salt of 1-hydroxy-3-(N-methyl-N-propylamino)propane-1,1-diphosphonic acid, in association with a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863623397 DE3623397A1 (en) | 1986-07-11 | 1986-07-11 | NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DEP3623397.8 | 1986-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1305166C true CA1305166C (en) | 1992-07-14 |
Family
ID=6304949
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000541755A Expired - Lifetime CA1296739C (en) | 1986-07-11 | 1987-07-10 | Diphosphonic acid derivatives, processes for the preparation thereofand pharmaceutical compositions containing them |
| CA000541756A Expired - Lifetime CA1305166C (en) | 1986-07-11 | 1987-07-10 | 1-hydroxy-3-(n-methyl-n-proplylamino)propane-1,1- diphosphonic acid, pharmaceutical compositions and methods of use |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000541755A Expired - Lifetime CA1296739C (en) | 1986-07-11 | 1987-07-10 | Diphosphonic acid derivatives, processes for the preparation thereofand pharmaceutical compositions containing them |
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| Country | Link |
|---|---|
| US (2) | US4927814A (en) |
| EP (2) | EP0252505B1 (en) |
| JP (2) | JP2563954B2 (en) |
| KR (2) | KR950008997B1 (en) |
| AT (2) | ATE80633T1 (en) |
| AU (2) | AU598279B2 (en) |
| BG (1) | BG60839B2 (en) |
| CA (2) | CA1296739C (en) |
| CS (1) | CS265242B2 (en) |
| DD (1) | DD263992A5 (en) |
| DE (4) | DE3623397A1 (en) |
| DK (2) | DK168629B1 (en) |
| ES (2) | ES2036190T3 (en) |
| FI (2) | FI87221C (en) |
| GE (1) | GEP20084347B (en) |
| GR (2) | GR3000616T3 (en) |
| HK (1) | HK87093A (en) |
| HU (2) | HU201950B (en) |
| IE (2) | IE60345B1 (en) |
| IL (2) | IL83149A (en) |
| LU (1) | LU88844I2 (en) |
| MX (1) | MX9203375A (en) |
| NL (1) | NL960032I2 (en) |
| NZ (2) | NZ221027A (en) |
| PT (1) | PT85301B (en) |
| WO (1) | WO1988000590A1 (en) |
| ZA (1) | ZA874877B (en) |
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