IE54135B1 - Diphosphonic acid derivatives, and pharmaceutical preparations containing them - Google Patents

Diphosphonic acid derivatives, and pharmaceutical preparations containing them

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Publication number
IE54135B1
IE54135B1 IE147/83A IE14783A IE54135B1 IE 54135 B1 IE54135 B1 IE 54135B1 IE 147/83 A IE147/83 A IE 147/83A IE 14783 A IE14783 A IE 14783A IE 54135 B1 IE54135 B1 IE 54135B1
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Ireland
Prior art keywords
hydroxyethane
dimethyl ester
bis
chlorophenyl
acid
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IE147/83A
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IE830147L (en
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Schering Ag
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Priority claimed from DE19823203308 external-priority patent/DE3203308A1/en
Priority claimed from DE19823225468 external-priority patent/DE3225468A1/en
Application filed by Schering Ag filed Critical Schering Ag
Publication of IE830147L publication Critical patent/IE830147L/en
Publication of IE54135B1 publication Critical patent/IE54135B1/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 Table
    • 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3882—Arylalkanephosphonic acids
    • 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 Table
    • 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • 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 Table
    • 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or 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
    • C07F9/404—Esters of poly(thio)phosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • 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 Table
    • 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
    • C07F9/65527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Diphosphonic acid derivatives of the general formula in which n is 0, 1 or 2, R<1> is hydrogen or (C1-4) alkyl, R<2> is hydrogen or (C1-4) alkyl, and Ar is optionally substituted phenyl, biphenyl, naphthyl or thienyl, processes for their preparation and their use as anti-inflammatory and anti-arthritic agents.

Description

The invention relates to diphosphonic acid derivatives of the general formula 1 R1 P0(0R2), I I Ar-(CH2) -CH-C-OH (I).
PO(ORZ)Z in which n is the number 0, 1 or 2, R^ represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R represents a hydrogen atom or an alkali metal atom, an alkaline earth metal atom, or an alkyl group having from 1 to 4 carbon atoms, and, Ar represents a fluorine- or chlorine-substituted phenyl group, a naphthyl group, abiphenylyl group or a thienyl group.
The invention also relates to pharmaceutical preparation containing these compounds.
Diphosphonic acid derivatives with an anti-atherogenic activity are already known from the European Patent Ho. 0015370. 5413 -3In contrast to the carboxylic acids of the general formula (IV) R1 I Ar-(CH2)n-CHc°0H (IV), (in this formula the substituents are defined as above) compounds according to the present invention have a marked anti-inflammatory and anti-arthritic activity.
In addition, they are also distinguished by being capable, inter alia, of influencing the synthesising and degradation activity of the bone cells (osteoblasts/osteoclasts) in such a manner that curative effects can be clearly detected in rats with induced arthritis.
This anti-arthritic activity of the compounds according to the invention constitutes the basis for a therapy for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and other related disorders especially those of the collagen and of the skeletal system (osteoporosis, Paget's disease). In addition, as good complex formers for calcium the phosphonates may be used in a therapeutically effective manner wherever a disturbed calcium-metabolism has been found to be the cause of a disorder, for example in the case of cardiovascular disorders, ectopic calcifications, etc..
S413S -4The compounds may be employed in the form of their esters or semi-esters, but are preferably employed in the form of the free phosphonic acids or of their physiologically tolerable salts with, for example, alkali metal hydroxides or alkaline earth metal hydroxides or tolerable organic bases, like for example sodium hydroxide, potassium hydroxide, calcium hydroxide, piperazine, or methyl glucamine.
Suitable galenical formulations are capsules, tablets, dragees and suppositories, also injection and infusion solutions and dermal preparations. Local application for treating dermal or systemic disorders is possible also.
The preparation of a compound of the invention may be effected by methods well known to a person skilled in the art (Houben-Weyl, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 4th edition, 1963 Volume XII/ 1,453 ff), for example as shown in the following reaction scheme. -6Examples which may be mentioned of bases that are suitable for carrying out a process according to the invention are secondary amines, for example diethylamine, dipropylamine, di isopropyl amine, morpholine and piperidine. The reaction may be carried out in an inert organic solvent, e.g. ether (for example diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran) and chlorinated hydrocarbon (for example dichloromethane, tetrachloroethane, chloroform or carbon tetrachloride).
The optional subsequent hydrolysis of an ester may be carried out using a mineral acid (for example semiconcentrated hydrochloric acid or sulphuric acid).
The cleavage may be achieved especially gently in an inert solvent (for example one of the above-mentioned chlorinated hydrocarbons) with trimethylsilyl iodide.
In order to form a salt, a free acid may be reacted in customary manner with a corresponding base.
The starting materials of the general formula II required for the process according to the invention may be obtained from a corresponding acid chlorides of the general formula V by reaction with a di-alkyl phosphites of the general formula P(OR2)3, The ways of synthesis shown in the reaction scheme are illustrated in the following typical and representative Examples. -75 413 3 Example I A solution of 6.9 g of trimethyl phosphite in 20 ml of diethyl ether is added dropwise while stirring at 0°C to a soluiton of 9.5 g of 4-chlorophenylacetic acid chloride in 50 ml of diethyl ether. Stirring is continued for 90 minutes, the precipitate is suctionfiltered and 9.3 g (71%) of 2-(4-chlorophenyl)-1hydroxyethene-l-phosphonic acid dimethyl ester having a melting point of 89-92°C are obtained.
A solution of 3.95 g of 2-(4-chlorophenyl)-1hydroxyethenephosphonic acid dimethyl ester in 10 ml of dichloromethane and 15 ml of diethyl ether is added dropwise at 0°C to a solution of 1.5 g of dimethyl phosphite and 0,114 g of diethylamine in 50 ml of diethyl ether. Stirring is continued for 60 hours at 0°C , the product which has separated is suction-filtered and washed with diethyl ether, and 4.0 g (71.6%) of 2-(4-chlorophenyl)-l-hydroxyethane-l,1-bis(phosphonic acid dimethyl ester) having a melting point of 123°C are obtained.
Example 2 8.7 g of iodotrimethylsilane are added dropwise at 0°C under a nitrogen atmosphere to a suspension of 3.35 g of 2-(4-chlorophenyl)-l-hydroxyethane-l,1-bis (phosphonic acid dimethyl ester) in 30 ml of carbon tetrachloride. -8The mixture is allowed to stand for 4 hours and is concentrated and the residue is hydrolysed using acetone/ water and reerystallised form acetonitrile/diethyl ether. 2.45 g of 2-{4-chlorophenyl)-l-hydroxyethane-l,1-diphos5 phonic acid having a melting point of 219°C are obtained.
Example 3 3.35 g of 2-(4-chlorophenyl)-l-hydroxyethane-l,1-bis (phosphonic acid dimethyl ester) are heated in 20 ml of concentrated hydrochloric acid for 2 hours on a steam bath. The mixture is then allowed to cool and is diluted with water, and the product which has separated is suction-filtered, dried and reerystallised from acetonitrile/diethyl ether. 2.21 g (78%) of 2-(4-chlorophenyl)-l-hydroxyethane-l,1-diphosphonic acid haivng a melting point of 219°C are obtained.
Example 4 4- Biphenylylacetic acid chloride is reacted as described in Example 1 and 2-(4-biphenylyl)-l-hydroxyethene-lphosphonic acid dimethyl ester having a melting point of 156 - 157°C is obtained (from toluene).
The resulting product is reacted as described in Example 1, and 2-(4-biphenylyl)-1-hydroxyethane-1,1 bis(phosphonic aied dimethyl ester) having a melting -9point of 147 - 149°C is obtained (from carbon tetrachloride) .
Example 5 4-Fluorophenylacetic acid chloride is reacted as 5 described in Example 1, and 2-(4-fluorophenyl)-1hydroxyethene-l-phosphonic acid dimethyl ester having a melting point of 63°C is obtained (from hexane/diisopropyl ether).
The resulting product is reacted as described in Example 1, and 2-(4-fluorophenyl)-l-hydroxyethane-l ,1 bis(phosphonic acid dimethyl ester) having a melting point of 129°C is obtained (from diethyl ether).
Example 6 2-(4-F1uorophenyl)-l-hydroxyethane-1,1-bis(phos15 phonic acid dimethyl ester) is reacted as described in Example 2, and 2-(4-fluorophenyl)-l-hydroxyethane-l ,1diphosphonic acid having a melting point of 211-213°C is obtained (from isopropanol).
Example 7 2-Fluorophenylacetic acid chloride is reacted as described in Example 1, and 2-(2-fluorophenyl)-1-hydroxyethene-lphosphonic acid dimethyl ester having a melting point of 5413 5 -1071-73°C is obtained (from carbon tetrachloride/hexane).
The resulting product is reacted as described in Example 1, and 2-(2-fluorophenyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) having a melting point of 146-148°C is obtained (from carbon tetrachloride/ diisopropyl ether).
Example 8 2-(2-Fluorophenyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) is reacted as described in Example 2, and 2-(2-fluorophenyl)-l-hydroxyethane-l ,1-diphosphonic acid having a melting point of 218-220°C is obtained (from isopropanol).
Example 9 2,6-Dichlorophenylacetic acid chloride is reacted as described in Example 1 to give 2-(2,6-dichlorophenyl)-lhydroxyethene-l-phosphonic acid dimethyl ester.
The resulting product is reacted as described in Example 1, and 2-(2,6-dichlorophenyl)-l-hydroxyethane-l,1-bis (phosphonic acid dimethyl ester) having a melting point of 130-132°C is obtained (from toluene). -ΠExample 10 2-(2,6-Dichlorophenyl )-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) is reacted as described in Example 2, and 2-(2,6-dichlorophenyl)-15 hydroxyethane-1,1-diphosphonic acid having a melting point of 226-228°C is obtained (from isopropanol).
Example 11 2-Thienylacetic acid chloride is reacted as described in Example 1, and 2-(2-thienyl)-l-hydroxyethene-l10 phosphonic acid dimethyl ester having a melting point of 148°C is obtained.
The resulting product is reacted under the conditions described in Example 1 to give 2-(2-thienyl)-l-hydroxyethane-1,l-bis(phosphonic acid dimethyl ester).
Example 12 2-(2-Thienyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) is reacted as described in Example 2 to give 2 -(2-thienyl)-1-hydroxyethane-1,1-disphosphonic acid. -12Example 13 2-Naphthylacetic acid chloride is reacted as described in Example 1 to gi ve 2-(2-naphthyl )-l-hydroxyethene—1phosphonic acid dimethyl ester having a melting point of 120°C.
The resulting product is reacted as described in Example 1, and 2-(2-naphthyl)-l-hydroxyethane-T,l-bis-(phosphonic acid dimethyl ester) having a melting point of 119°C is obtained.
Example 14 2-(2-Naphthyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) is reacted as described in Example 3, and 2-{2-naphthyl)-l-hydroxyethane-l,1-diphosphonic acid having a melting point of 257°C is obtained.
Example 15 1-Naphthylacetic acid chloride is reacted as described in Example 1 to give 2-(l-naphthyl)-l-hydroxyethene-lphosphonic acid dimethyl ester having a melting point of 118°C.
The resulting product is reacted as described in Example to give 2-(l-naphthyl)-l-hydroxyethane-l,1-bis(phosphonic acid dimethyl ester) having amelting point of 145°C. -13Example 16 2-(1-Naphthyl )-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) is reacted as described in Example 3 to give 2-(l-naphthyl)-l-hydroxyethane-l,1-diphos5 phonic acid.
Example 17 2-{4-Chloropheny1)-propionic acid chloride is reacted as described in Example 1 to give 2-{4-chlorophenyl)-1hydroxypropene-l-phosphonic acid dimethyl ester.
The resulting product is reacted to give 2-(4-chlorophenyl)-l-hydroxypropane-l,l-bis(phosphonic acid dimethyl ester).
Example 18 2- (4-Chlorophenyl)-1-hydroxypropane-1,1-bis-(phosphonic acid dimethyl ester) is reacted as described in Example to give 2-(4-chlorophenyl)-l-hydroxypropane-l,1-diphos phonic acid.
Example 19 3- Chlorophenylacetic acid chloride is reacted under the conditions described in Example 1, and 2-(3-chlorophenyl)-l-hydroxyethene-l-phosphonic acid dimethyl ester 413 5 -14having a melting point of 136-138°C is obtained (from diethyl ether).
The resulting product is reacted as described in Example 1 and 2-(3-chlorophenyl)-l-hydroxyethane-l,1-bis (phosphonic acid dimethyl ester) having a melting point of 115-116°C is obtained (from hexane/diethyl ether).
Example 20 2-{3-Chlorophenyl)-1-hydroxyethane-1,1-bis-(phosphonic acid dimethyl ester) is reacted as described in Example 2, and 2-(3-chlorophenyl)-l-hydroxyethane-l,1-diphosphonic acid having a melting point of 198-200°C is obtained (from isopropanol).
Example 21 A solution of 1.23 g of calcium acetate in 10 ml of water is added to a solution of 2.1 g of 2-(2-fluorophenyl)-1hydroxyethane-1,1-diphosphonic acid in 30 ml of water and the whole is stirred for one hour at room temperature. The percipitate is then suction-filtered, boiled with ethanol and dried, and 2.28 g (96.3%) of the calcium salt of 2-(2-fluorophenyl)-l-hydroxyethane-1,1-diphosphonic acid having a melting point of more than 350°C are obtained. -15Example 22 2- (4-Biphenylyl)-1-bydroxyethane-1,1-bis(phosphonic acid dimethyl ester) is reacted with iodotrimethylsilane and worked up as described in Example 2. 2-(4-Biphenylyl)-l-hydroxyethane-l,1-diphosphonic acid having a melting point of 218-219°C is obtained (from isopropanol).
Example 23 3- (4-Chlorophenyl)-T-oxoprdpane-l-phosphonic acid 1° dimethyl ester a) A solution of 3.6 g of trimethyl phosphite in 10 ml of diethyl ether is added dropwise at 0°C to a solution of 5.1 g of 3-(4-chlorophenyl) propionic acid chloride in 25 ml of diethyl ether. The whole is stirred first for 2.5 hours at 0°C and then for a further 2 hours at room temperature. After the solution has been concentrated, the residue is distilled using a bulb tube at 200-205°C and under a pressure fo 0.02mm (2.7 Pa), 5.2 g (74%) of 3-(4-chlorophenyl-l-oxopropane-l-phosphonic acid dimethyl ester are obtained. 3-(4-Chlorophenyl)-l-hydrioxypropane-l,lTbis(phosphonic acid dimethyl ester) b) A solution of 4.7 g of 3-(4-chlorophenyl)-1-oxopropane-l-phosphonic acid dimethyl ether in 15 ml of 413 5 -16diethyl ether is added dropwise while stirring at 0°C to a solution of 2.1 g of dimethyl phosphite and 0.1 g of diethylamine in 15 ml of diethyl ether. Stirring is continued for 30 minutes, the precipitate is suc5 tion-filtered and washed with diethyl ether. 5.6 g (84%) of 3-(4-chlorophenyl)-l-hydroxypropane-l,1-bis(phosphonic acid dimethyl ester) having a melting point of 112°C are obtained.
Example 24 3-(4-Chlorophenyl)-l-hydroxypropane-l,1-diphosphonic acid ml of concentrated hydrochloric acid are added to 2.7 g of 3-(4-chlorophenyl)-l-hydroxypropane-l,1-bis (phosphonic acid dimethyl ester) and the whole is heated at 100°C for 3 hours. After cooling, the crystallisation product is suction-filtered and recrystallised from isopropanol, 1.62g (70%) of 3(4-chlorophenyl)-1-hydroxypropane-1,1-diphosphonic acid having a melting point of 201°C are obtained.
The following are manufactured in a manner analogous to that described in Example 23. -17Example 25 a) 3-(3,4-Dichlorophenyl )-1-oxopropane-1-phosphonic acid dimethyl ester (distilled in a bulb tube at 0.03 mm (4 Pa), 235-40°C 5 oven temperature) and from it b) 3 - (4 - d i c h 1 o r ο p h eny 1)-T-hydro xyp ro pa ne -1,1 - b i s (phosphonic acid dimethyl ester) Melting point 120°C (hexane/diethyl ether).
Example 26 10 a) 4-(4-Chlorophenyl)-T-oxobutane-l-phosphonic acid dimethyl ester (distilled in a bulb tube at 0.02 mm (2.7 Pa), 225°C oven temperature) and from it b) 4-(4-chIorophenyT)-T-hydroxybutane-I,1-bis(phos15 phonic acid dimethyl ester) Melting point 75°C (hexane/diethyl ether).
The following are manufactured in a manner analogous to that described in Example 2.
Example 27 3-(3,4-PichloropheriyT)-T-hydroXypropane-1,1diphosphonic acid Melting point 187°C (isopropanol). 413 3 -18Example 28 4-(4-Chlorophenyl)-l-hydroxybutane-l,1-diphosphonic acid Melting point 181°C (isopropanoi).

Claims (1)

1.CLAIMS 1. Diphosphonic acid derivatives of the general formula I R 1 P0(0R Z )_ ι ι 5 Ar-{CH z ) n -CH-C-OH P0(0» 2 ) 2 (i)> wherein n represents the number 0, 1 or 2 and wherein r1 is a hydrogen atom or an alkyl group of 1 to 10 4 carbon atoms ρ R is a hydrogen atom, an alkali-metal atom, an alkaline earth metal atom or an alkyl group of 1 to 4 carbon atoms and Ar is a fluorine- or chlorine-substituted phenyl 15 group, a naphthyl group, a biphenylyl group or a thienyl group. 3. -( 4. -Chlorophenyl)-l-hydroxypropane-l,1-bis (phosphonic acid dimethyl ester) and 3-(4-chlorophenyl)-l-hydroxypropane-l,1-diphos20 phonic acid. -203. 3-(3,4-Dichlorophenyl)-l-hydroxpropane-l,1-bis (phosphonic acid dimethyl ester) and 3-(3,4-dichiorophenyl)-l-hydroxypropane-l,1diphosphonic acid. 5. 4. 4-(4-Chlorophenyl)-l-hydroxybutane-l,1-bis (phosphonic acid dimethyl ester) and 4-(4-chlorophenyl)-1-hydroxybutane-1,1 disphosphonic acid. 5. 2-(4-Chlorophenyl)-1-hydroxyethane-1,1-bis 10 (phosphonic acid dimethyl ester) and 2-(4-chlorophenyl)-1-hydroxyethane-1,1-diphosphonic acid. 6. 2-(4-Biphenylyl)-l-hydroxyethane-l,l-bis(phosphonic acid dimethyl ester) 15 and 2-(4-Biphenylyl)-l-hydroxyethane-l,l-di$phosphonic acid. 7. 2-(4-Fluorophenyl)-l-hydroxyethane-l,1-bis (phosphonic acid dimethyl ester), 2-(4-fluorophenyl)-1-hydroxyethane-1,1-diphosphonic acid 20 and its calcium salts. 8. 2-(2-Flourophenyl)-1-hydroxyethane-1,1-bis(phosphonic.acid dimethyl ester) and 2-(2-fluorophenyl)-l-hydroxyethane-l,1-diphosphonic acid. -219. 2-(2,6-Dichlorophenyl)-l-hydroxyethane-l ,1bis (phosphonic acid dimethyl ester) and 2-(2,6-dichlorophenyl)-1-hydroxyethane-1,1diphosphonic acid. 9. 10. 2-(2-Thieny1)-1 -hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) and 2-(2-thienyl)-l-hydroxyethane-l,1-diphosphonic acid. 10. 11. 2-(2-Naphthyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) and 2-(2-naphthyl)-l-hydroxyethane-l,1-diphosphonic acid. 11. 12. 2-(1-Naphthyl )-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) and 2-(1-naphthyl)-l-hydroxyethane-l,1-diphosphonic acid. 12. 13. 2-(4-Chlorophenyl)-1-hydroxypropane-1,1-bis(phosphonic 15 acid dimethyl ester) and 2-{4-chlorophenyl)-l-hydroxypropane-l,1-diphosphonic acid. 13. 14. 2-(3-Chlorophenyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) 20 and 2-(3-chlorophenyl)-l-hydroxypropane-l,1-diphosphonic acid. 5 413 5 -2215. Pharmaceutical preparations fcharacterised by a content of a diphosphonic acid derivative according to claims 1 to 14. 16. Process for the preparation of diphosphonic acid 5 derivatives of the general formula I according to claim 1, characterised in that an acylphosphonate of the general formula II. Ar-(CH 2 ) n -CHR 1 -C0-P0(0R 2 ) 2 1 2 wherein Ar, n, R and R have the meanings given in 10 claim 1 is reacted in the presence of a base with a dialkylphosphite of the general formula III HP0(0R Z ) 2 (HI). wherein R has the meaning given in claim 1, the formed ester is optionally saponified and the acids 14. 15 are optionally converted into their salts. 15. 17. A compound of Formula I substantially as hereinbefore described with reference to the Examples. 16. 18. A process for the preparation of compound of Formula I substantially as hereinbefore described 17. 20 with reference to the Examples.
IE147/83A 1982-01-27 1983-01-26 Diphosphonic acid derivatives, and pharmaceutical preparations containing them IE54135B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19823203308 DE3203308A1 (en) 1982-01-27 1982-01-27 DIPHOSPHONIC ACID DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
DE19823225468 DE3225468A1 (en) 1982-07-05 1982-07-05 Diphosphonic acid derivatives and pharmaceutical preparations containing them

Publications (2)

Publication Number Publication Date
IE830147L IE830147L (en) 1983-07-27
IE54135B1 true IE54135B1 (en) 1989-06-21

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IE147/83A IE54135B1 (en) 1982-01-27 1983-01-26 Diphosphonic acid derivatives, and pharmaceutical preparations containing them

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GB (1) GB2113688A (en)
IE (1) IE54135B1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3425812A1 (en) * 1984-07-13 1986-01-16 Deutsches Krebsforschungszentrum, 6900 Heidelberg NEW 1-HYDROXY-1,1-DIPHOSPHONIC ACID COMPOUNDS, PROCESS FOR THEIR PRODUCTION AND PHARMACOLOGICAL PREPARATIONS, IN PARTICULAR FOR THE TREATMENT OF BONE TUMORS
ATE455121T1 (en) * 2001-07-16 2010-01-15 Univ Paris 13 PROCESS FOR PRODUCTION OF DERIVATIVES OF BISPHOSPHONATES

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GB2113688A (en) 1983-08-10
GB8302177D0 (en) 1983-03-02
IE830147L (en) 1983-07-27

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