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WO1995011249A1 - 2,4-diphosphonoglutaric acid derivatives, methods of preparing them and drugs containing them - Google Patents

2,4-diphosphonoglutaric acid derivatives, methods of preparing them and drugs containing them Download PDF

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Publication number
WO1995011249A1
WO1995011249A1 PCT/EP1994/003434 EP9403434W WO9511249A1 WO 1995011249 A1 WO1995011249 A1 WO 1995011249A1 EP 9403434 W EP9403434 W EP 9403434W WO 9511249 A1 WO9511249 A1 WO 9511249A1
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WIPO (PCT)
Prior art keywords
diphosphono
glutaric acid
cycloalkyl
lower alkyl
hydrogen
Prior art date
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Ceased
Application number
PCT/EP1994/003434
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German (de)
French (fr)
Inventor
Angelika Esswein
Christos Tsaklakidis
Gerd Zimmermann
Frieder Bauss
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Roche Diagnostics GmbH
Original Assignee
Boehringer Mannheim GmbH
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Priority to AU78567/94A priority Critical patent/AU7856794A/en
Publication of WO1995011249A1 publication Critical patent/WO1995011249A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07F9/3839—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)
    • 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)]
    • C07F9/3804—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
    • C07F9/3869—Polyphosphonic acids containing carboxylic acid or carboxylic acid derivative substituents
    • 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
    • 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
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine 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 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
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine 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 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
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • 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
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/6533—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 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
    • C07F9/65515—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 five-membered ring
    • 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
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring

Definitions

  • the present invention relates to new 2,4-diphosphonoglutaric acid derivatives, processes for their preparation and medicaments which contain these substances.
  • R hydrogen, lower alkyl, which may be replaced by hydroxy, alkoxy,
  • Amino, dialkylamino, alkylmercapto, alkylsulfinyl, alkanesulfonyl, cycloalkyl, aryl or a heterocyclic ring may be substituted, lower alkenyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic ring,
  • R ⁇ and R2 can each independently be hydrogen, lower alkyl, cycloalkyl or arylmethyl,
  • Lower alkyl should in all cases be a straight-chain or branched Ci-Cö-alkyl group, such as. B. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, isopropyl, butyl and hexyl.
  • Lower alkenyl means unsaturated residues with 3 - 6 carbon atoms, such as. B. allyl, but-2-enyl, hexa-2,4-dienyl, but especially allyl.
  • Cycloalkyl means a 3- to 7-membered ring, such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring, preferably the cyclopentyl and cyclohexyl ring.
  • Cycloalkenyl is said to be an unsaturated 5-7 ring, such as the cyclopentenyl, cyclohexenyl and cycloheptenyl ring.
  • Alkoxy is understood to be radicals such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy or pentoxy radical, in particular the methoxy, ethoxy, isopropoxy and butoxy radical.
  • Dialkylamino is said to be an amino group with two identical or different C1-C5 alkyl radicals, such as. B. dimethylamino, methylpropylamino, methylpenlylamino, diethylamino or dipropylamino, especially dimethylamino, methylpropylamino and methylpentylamino.
  • Alkyl mercapto, alkylsulfinyl or alkanesulfonyl are preferably methyl mercapto, methylsulfinyl or methanesulfonyl.
  • Aryl means the phenyl or naphthyl radical, which may be mono- or polysubstituted by lower alkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, alkyl mercapto, alkylsulfinyl, alkanesulfonyl, carboxamido, which may be mono- or disubstituted by lower alkyl, Carboxyl, Alkoxycarbonvl or Cyano can be substituted.
  • a heterocyclic ring is a 5- to 7-membered, saturated or unsaturated ring, such as. B. the pyrrolidine, piperidine, azepine, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, furan, thiophene, pyridine, pyrazole, imidazole, thiazole, oxazole, pyrimidine or Pyrazine ring, preferably the pyrrolidine, piperidine, morpholine, furan, thiophene, pyridine and imidazole ring to understand, where the ring system can be substituted one or more times by halogen, lower alkyl or alkoxy.
  • Halogen is said to represent fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine.
  • R has the meaning given above and R ⁇ - R-5 are independently lower alkyl, cycloalkyl or arylmethyl, saponified to the corresponding acids of the general formula I, or
  • R ⁇ and R2 are lower alkyl, cycloalkyl or arylmethyl, a hexaester of the general formula II
  • R has the meaning given above and Rj - R5 is lower alkyl, cycloalkyl or arylmethyl, partially saponified to give diphosphonic acid dicarboxylic acid esters of the general formula I,
  • the complete saponification of the phosphonic and carboxylic acid esters described in process a can be carried out by boiling with hydrohalic acid, preferably with semi-concentrated hydrochloric acid.
  • the partial saponification of the phosphonic esters described in process b in the presence of the carbonic ester gauges is generally carried out without a solvent or in an inert solvent such as methylene chloride using a trimethylsilyl halide such as Trimethylsilyl bromide or iodide, at a temperature between - 50 ° C and room temperature, preferably at 0 ° C.
  • benzyl esters present in compounds of the general formula II can be hydrogenolytically in the presence of z.
  • B. convert palladium / carbon into the corresponding phosphonic or carboxylic acids.
  • salts especially mono- or dialkali or ammonium salts are used, which in the usual way, for. B. by titration of the connections with inorganic bases, such as. B. sodium or potassium hydrogen carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous Ammomak or amines, such as. B. trimethyl or triethylamine.
  • inorganic bases such as. B. sodium or potassium hydrogen carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous Ammomak or amines, such as. B. trimethyl or triethylamine.
  • the salts are usually cleaned by falling over from water / acetone.
  • calcium, magnesium or zinc salts can also be used, which are usually poorly soluble in water, but are sometimes also slightly soluble.
  • These salts can be prepared by adding a calcium, zinc or magnesium salt, such as. B. calcium carbonate, calcium hydrogen carbonate, calcium hydroxide, calcium chloride, zinc carbonate, zinc hydrogen carbonate, zinc hydroxide, zinc chloride, magnesium carbonate, magnesium hydrogen carbonate, magnesium hydroxide or magnesium chloride as an aqueous solution or suspension in a ratio of 1: 1 or 2: 1 with an aqueous solution or suspension of 2,4-diphosphonoglutaric acid Allows to stir 20 - 120 ° C, then the precipitate is suctioned off or the aqueous solution is then concentrated.
  • novel substances of formula I and their salts according to the invention can be in any liquid or solid form suitable for achieving an effective dose, e.g. B. orally, rectally, topically, parenterally, subcutaneously, ocular, nasally, buccally, intravenously and transdermally. All the usual forms of application are possible here, for example tablets, capsules, dragees, syrups, solutions, suspensions, plasters, etc. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers. Such additives are e.g. B.
  • Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are e.g. B.
  • Preparations suitable for oral administration can optionally contain flavorings and sweeteners.
  • the dosage can depend on various factors, such as the mode of administration, species, age and / or individual condition.
  • the doses to be administered daily are approximately 10-1000 mg / person, preferably 100-500 mg / person and can be taken in one or more times distributed.
  • a pharmaceutical formulation of these 2,4-diphosphonoglutaric acids can also be administered intermittently.
  • Phosphonoacetic acid triethyl ester (2.0 ml, 10 mmol) is added to a suspension of sodium hydride (240 mg, 10 mmol) in 30 ml of methanol. After stirring for 30 min at room temperature, a solution of 10 mmol of ⁇ -phosphonoacrylate in 10 ml of methanol is slowly added dropwise. After 24 hours at room temperature, the mixture is concentrated, saturated ammonium chloride solution (20 ml) is added and the mixture is extracted with ethyl acetate (2 ⁇ 50 ml). The combined organic phases are dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • the presentation follows the general working instruction A.
  • rats are injected twice a week with increasing amounts of a solution of 3.7 x 10 5 Bq / ml (10 ⁇ Ci / ml) [7- H] tetracycline ([ 3 H] TC); New England Nuclear, Boston, MA) specific activity 679 mCi / mmol.
  • the volume per injection is increased from 50 ⁇ l / week to 250 ⁇ l in the fifth week and maintained for a further week.
  • the total amount of [ 3 H] TC applied was 20 ⁇ Ci per rat. Rats 51 days old are put into individual metabolism cages and fed a group with food containing 0.5% Ca and 0.35% P.
  • This feed was produced by adding appropriate amounts of calcium glucagonate and neutral sodium phosphate from feed with a low calcium and phosphate content (SODI 2134, Klingenthal mill).
  • SODI 2134 calcium and phosphate content
  • the animals received aqua dest. ad libitum.
  • the collection of the 24-hour urine was started after 61 days.
  • the urine was collected daily at 11 a.m. at that time the animals were also fed.
  • On the sixth day after the start of urine collection the animals received two sc injections with substance (at 8 a.m. and 5 p.m., respectively).
  • the inhibition of bone resorption is reduced by the [H] - Tetracycline excretion indicated on day 8 after the start of urine collection.
  • the 3 H-TC in the urine was determined by liquid scintillation by adding 10 ml of the scintillator Pico-Fluor 30 (packard International, Zurich, Switzerland) to 1 ml urine.
  • Example compound 2 20 2 x 6 mg / kg mg / kg

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concerns compounds of formula (I) in which R is hydrogen, lower alkyl (which may be substituted by hydroxy, alkoxy, amino, dialkylamino, alkylmercapto, alkylsulphinyl, alkansulphonyl, cycloalkyl, aryl or a heterocyclic ring), lower alkenyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic ring and R1 and R2, independently of each other, may be hydrogen, lower alkyl, cycloalkyl or arylmethyl, plus pharmacologically acceptable salts of these compounds. The invention also concerns methods of preparing such compounds and drugs containing them for the treatment of metabolic disorders relating to calcium.

Description

Neue 2.4-Diphosphonoglutarsäurederivate,New 2,4-diphosphonoglutaric acid derivatives,

Verfahren zu deren Herstellung und diese Verbindungen enthaltende ArzneimittelProcess for their preparation and pharmaceutical compositions containing them

Die vorliegende Erfindung betrifft neue 2.4-Diphosphonoglutarsäurederivate, Verfahren zu deren Herstellung sowie Arzneimittel, die diese Substanzen enthalten.The present invention relates to new 2,4-diphosphonoglutaric acid derivatives, processes for their preparation and medicaments which contain these substances.

In Angew. Chemie 92, 43 (1980) und Can. J. Chem. 60, 840 (1982) ist der 2.4-Diphosphonoglutarsäurehexaethylester beschrieben, in J. Org. Chem. 25, 1232 (1960) ist der 2.4-Diphosphono-3-phenylglutarsäurehexaethylester angeführt, eine pharmakologische Wirkung dieser Verbindungen ist jedoch nicht bekannt. Es wurde nun gefunden, daß die freie 2.4-Diphosphonoglutarsäure und Derivate hiervon eine ausgezeichnete Wirkung auf den Calcium-Stof wechsel zeigen und damit zur breiten Behandlung von Calciumstoffwechselstörungen geeignet sind. Sie lassen sich vor allem sehr gut dort einsetzen, wo der Knochenauf- und -abbau gestört ist, d. h. sie sind geeignet zur Behandlung von Erkrankungen des Skelettsystems, wie z. B. Osteoporose, Morbus Paget, Morbus Bechterew u. a. Aufgrund dieser Eigenschaften finden sie aber auch Verwendung in der Therapie der Urolithiasis und zur Verhinderung heterotoper Ossifikationen. Durch ihre Beeinflussung des Calciumstoffwechsels bilden sie weiter¬ hin eine Grundlage für die Behandlung der rheumatoiden Arthritis, der Osteoarthritis und der degenerativen Arthrose. Durch die ausgesprochen gute Affinität zum Kno- chenmineral eignen sich die 2.4-Diphosphonoglutarsäure und ihre Derivate auch her¬ vorragend, um pharmakologisch wirksame Verbindungen direkt an den Knochen zu transportieren. Gegenstand der vorliegenden Erfindung sind Verbindungen der allgemeinen Formel IIn Angew. Chemie 92, 43 (1980) and Can. J. Chem. 60, 840 (1982) describes the 2,4-diphosphonoglutaric acid hexaethyl ester, in J. Org. Chem. 25, 1232 (1960) the 2,4-diphosphono-3-phenylglutaric acid hexaethyl ester is mentioned, but no pharmacological action of these compounds is known . It has now been found that the free 2,4-diphosphonoglutaric acid and derivatives thereof have an excellent effect on the calcium metabolism and are therefore suitable for the broad treatment of calcium metabolism disorders. Above all, they can be used very well where the bone build-up and breakdown is disturbed, ie they are suitable for the treatment of diseases of the skeletal system, such as. B. osteoporosis, Paget's disease, Bechterew's disease etc. Because of these properties, they are also used in the treatment of urolithiasis and to prevent heterotopic ossifications. By influencing the calcium metabolism, they also form a basis for the treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis. Due to the extremely good affinity for the bone mineral, the 2,4-diphosphonoglutaric acid and its derivatives are also excellent for transporting pharmacologically active compounds directly to the bone. The present invention relates to compounds of the general formula I.

Figure imgf000004_0001
Figure imgf000004_0001

in derin the

R = Wasserstoff, niederes Alkyl, das gegebenenfalls durch Hydroxy, Alkoxy,R = hydrogen, lower alkyl, which may be replaced by hydroxy, alkoxy,

Amino, Dialkylamino, Alkylmercapto, Alkylsulfinyl, Alkansulfonyl, Cycloalkyl, Aryl oder einen heterocyclischen Ring substituiert sein kann, niederes Alkenyl, Cycloalkyl, Cycloalkenyl, Aryl oder einen hetero¬ cyclischen Ring,Amino, dialkylamino, alkylmercapto, alkylsulfinyl, alkanesulfonyl, cycloalkyl, aryl or a heterocyclic ring may be substituted, lower alkenyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic ring,

R\ und R2 unabhängig voneinander jeweils Wasserstoff, niederes Alkyl, Cycloalkyl oder Arylmethyl sein können,R \ and R2 can each independently be hydrogen, lower alkyl, cycloalkyl or arylmethyl,

sowie deren pharmakologisch unbedenkliche Salze.and their pharmacologically acceptable salts.

Niederes Alkyl soll in allen Fällen eine geradkettige oder verzweigte Ci-Cö-Alkyl- gruppe, wie z. B. Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, Pentyl oder Hexyl, insbesondere Methyl, Ethyl, Isopropyl, Butyl und Hexyl darstellen. Niederes Alkenyl bedeutet ungesättigte Reste mit 3 - 6 Kohlenstoffatomen, wie z. B. Allyl, But-2-enyl, Hexa-2.4-dienyl, vor allem jedoch Allyl.Lower alkyl should in all cases be a straight-chain or branched Ci-Cö-alkyl group, such as. B. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, isopropyl, butyl and hexyl. Lower alkenyl means unsaturated residues with 3 - 6 carbon atoms, such as. B. allyl, but-2-enyl, hexa-2,4-dienyl, but especially allyl.

Cycloalkyl bedeutet einen 3- bis 7gliedrigen Ring, wie den Cyclopropyl-, Cyclobutyl-, Cyclopentyl-, Cyclohexyl- oder den Cycloheptylring, vorzugsweise den Cyclopentyl- und Cyclohexylring.Cycloalkyl means a 3- to 7-membered ring, such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring, preferably the cyclopentyl and cyclohexyl ring.

Cycloalkenyl soll einen ungesättigten 5-7-Ring darstellen, wie den Cyclopentenyl-, Cyclohexenyl- und Cycloheptenylring. Unter Alkoxy versteht man Reste wie den Methoxy-, Ethoxy-, Propoxy-, Isopropoxy-, Butoxy- oder Pentoxyrest, insbesondere den Methoxy-, Ethoxy-, Isopropoxy- und Butoxyrest.Cycloalkenyl is said to be an unsaturated 5-7 ring, such as the cyclopentenyl, cyclohexenyl and cycloheptenyl ring. Alkoxy is understood to be radicals such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy or pentoxy radical, in particular the methoxy, ethoxy, isopropoxy and butoxy radical.

Dialkylamino soll eine Aminogruppe mit zwei gleichen oder verschiedenen C1-C5- Alkylresten, wie z. B. Dimethylamino, Methylpropylamino, Methylpenlylamino, Diethylamino oder Dipropylamino, vor allem Dimethylamino, Methylpropylamino und Methylpentylamino darstellen.Dialkylamino is said to be an amino group with two identical or different C1-C5 alkyl radicals, such as. B. dimethylamino, methylpropylamino, methylpenlylamino, diethylamino or dipropylamino, especially dimethylamino, methylpropylamino and methylpentylamino.

Unter Alkylmercapto, Alkylsulfinyl bzw. Alkansulfonyl sind vorzugsweise Methyl- mercapto, Methylsulfinyl bzw. Methansulfonyl zu verstehen.Alkyl mercapto, alkylsulfinyl or alkanesulfonyl are preferably methyl mercapto, methylsulfinyl or methanesulfonyl.

Aryl bedeutet den Phenyl- oder Naphthylrest, der gegebenenfalls ein- oder mehrfach durch niederes Alkyl, Halogen, Hydroxy, Alkoxy, Amino, Dialkylamino, Alkyl¬ mercapto, Alkylsulfinyl, Alkansulfonyl, Carboxamido, das ein- oder zweifach durch niederes Alkyl substituiert sein kann, Carboxyl, Alkoxycarbonvl oder Cyano substitu¬ iert sein kann.Aryl means the phenyl or naphthyl radical, which may be mono- or polysubstituted by lower alkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, alkyl mercapto, alkylsulfinyl, alkanesulfonyl, carboxamido, which may be mono- or disubstituted by lower alkyl, Carboxyl, Alkoxycarbonvl or Cyano can be substituted.

Unter einem heterocyclischen Ring ist ein 5- bis 7gliedriger, gesättigter oder ungesät¬ tigter Ring, wie z. B. der Pyrrolidin-, Piperidin-, Azepin-, Tetrahydrofuran-, Tetrahy- dropyran-, Morpholin-, Dioxan-, Furan-, Thiophen-, Pyridin-, Pyrazol-, Imidazol-, Thiazol-, Oxazol-, Pyrimidin- oder Pyrazinring, vorzugsweise der Pyrrolidin-, Piperi¬ din-, Morpholin-, Furan-, Thiophen-, Pyridin- und Imidazolring zu verstehen, wobei das Ringsystem ein- oder mehrfach durch Halogen, niederes Alkyl oder Alkoxy substituiert sein kann.Under a heterocyclic ring is a 5- to 7-membered, saturated or unsaturated ring, such as. B. the pyrrolidine, piperidine, azepine, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, furan, thiophene, pyridine, pyrazole, imidazole, thiazole, oxazole, pyrimidine or Pyrazine ring, preferably the pyrrolidine, piperidine, morpholine, furan, thiophene, pyridine and imidazole ring to understand, where the ring system can be substituted one or more times by halogen, lower alkyl or alkoxy.

Halogen soll Fluor, Chlor, Brom und Jod, insbesondere Fluor und Chlor darstellen.Halogen is said to represent fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine.

Verbindungen der allgemeinen Formel I enthalten mindestens zwei asymmetrische Kohlenstoffatome; daher sind auch optisch aktive Verbindungen der allgemeinen Formel I Gegenstand der vorliegenden Anmeldung.Compounds of the general formula I contain at least two asymmetric carbon atoms; Therefore, optically active compounds of general formula I are the subject of the present application.

Verbindungen der allgemeinen Formel I werden nach an sich bekannten Verfahren hergestellt, vorzugsweise dadurch, daß man a) für den Fall, daß R\ und R2 Wasserstoff sind, einen Hexaester der allgemei¬ nen Formel IICompounds of the general formula I are prepared by processes known per se, preferably by a) in the event that R \ and R2 are hydrogen, a hexaester of the general formula II

Figure imgf000006_0001
in der R die oben angegebene Bedeutung hat und R\ - R-5 unabhängig vonein¬ ander niederes Alkyl, Cycloalkyl oder Arylmethyl sind, zu den entsprechenden Säuren der allgemeinen Formel I verseift, oder
Figure imgf000006_0001
in which R has the meaning given above and R \ - R-5 are independently lower alkyl, cycloalkyl or arylmethyl, saponified to the corresponding acids of the general formula I, or

b) für den Fall, daß R\ und R2 niederes Alkyl, Cycloalkyl oder -Arylmethyl sind, einen Hexaester der allgemeinen Formel IIb) in the event that R \ and R2 are lower alkyl, cycloalkyl or arylmethyl, a hexaester of the general formula II

Figure imgf000006_0002
in der R die oben angegebene Bedeutung hat und Rj - R5 niederes Alkyl, Cycloalkyl oder Arylmethyl ist, teilweise zu Diphosphonsäuren-Dicarbon- säureestern der allgemeinen Formel I verseift,
Figure imgf000006_0002
in which R has the meaning given above and Rj - R5 is lower alkyl, cycloalkyl or arylmethyl, partially saponified to give diphosphonic acid dicarboxylic acid esters of the general formula I,

und anschließend gewünschtenfalls die erhaltenen Verbindungen in ein physiologisch verträgliches Salz überführt.and then, if desired, converting the compounds obtained into a physiologically acceptable salt.

Die im Verfahren a beschriebene vollständige Verseifung der Phosphon- und Carbon¬ säureester läßt sich durch Kochen mit Halogenwasserstoffsäure, vorzugsweise mit halbkonzentrierter Salzsäure durchführen.The complete saponification of the phosphonic and carboxylic acid esters described in process a can be carried out by boiling with hydrohalic acid, preferably with semi-concentrated hydrochloric acid.

Die in Verfahren b beschriebene teilweise Verseifung der Phosphonester in Gegenwart der Carbonestergnippierungen erfolgt in der Regel ohne Lösungsmittel oder in einem inerten Lösungsmittel wie Methylenchlorid durch ein Trimethylsilylhalogenid, wie Trimethylsilylbromid oder -jodid, bei einer Temperatur zwischen - 50 °C und Raum¬ temperatur, vorzugsweise bei 0 °C.The partial saponification of the phosphonic esters described in process b in the presence of the carbonic ester gauges is generally carried out without a solvent or in an inert solvent such as methylene chloride using a trimethylsilyl halide such as Trimethylsilyl bromide or iodide, at a temperature between - 50 ° C and room temperature, preferably at 0 ° C.

Liegen in Verbindungen der allgemeinen Formel II Benzylester vor, so lassen sich diese hydrogenolytisch in Gegenwart von z. B. Palladium/Kohle in die entsprechenden Phosphon- bzw. Carbonsäuren überführen.Are benzyl esters present in compounds of the general formula II, these can be hydrogenolytically in the presence of z. B. convert palladium / carbon into the corresponding phosphonic or carboxylic acids.

Verbindungen der allgemeinen Formel II sind in Angew. Chemie 92, 43 (1983), Can. J. Chem. 60, 840 (1982) und J. Org. Chem. 25, 1232 (1960) beschrieben und lassen sich nach den dort angegebenen Verfahren herstellen.Compounds of general formula II are in Angew. Chemistry 92, 43 (1983), Can. J. Chem. 60, 840 (1982) and J. Org. Chem. 25, 1232 (1960) and can be prepared by the processes specified there.

Als pharmakologisch verträgliche Salze werden vor allem Mono- bzw. Dialkali- oder Ammomumsalze verwendet, die in üblicher Weise, z. B. durch Titration der Verbin¬ dungen mit anorganischen Basen, wie z. B. Natrium- oder Kaliumhydrogencarbonat, Natronlauge, Kalilauge, wäßrigem Ammomak oder Aminen, wie z. B. Trimethyl- oder Triethylamin, hergestellt werden.As pharmacologically acceptable salts, especially mono- or dialkali or ammonium salts are used, which in the usual way, for. B. by titration of the connections with inorganic bases, such as. B. sodium or potassium hydrogen carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous Ammomak or amines, such as. B. trimethyl or triethylamine.

Die Salze werden in der Regel durch Umfallen aus Wasser/ Aceton gereinigt.The salts are usually cleaned by falling over from water / acetone.

Es lassen sich jedoch auch Calcium-, Magnesium- oder Zinksalze verwenden, die in der Regel in Wasser schwer löslich, bisweilen jedoch auch leicht löslich sind. Diese Salze können dadurch hergestellt werden, daß man ein Calcium-, Zink- oder Magne¬ siumsalz, wie z. B. Calciumcarbonat, Calciumhydrogencarbonat, Calciumhydroxid, Calciumchlorid, Zinkcarbonat, Zinkhydrogencarbonat, Zinkhydroxid, Zinkchlorid, Magnesiumcarbonat, Magnesiumhydrogencarbonat, Magnesiumhydroxid oder Magnesiumchlorid als wäßrige Lösung oder Suspension im Verhältnis 1 : 1 oder 2 : 1 mit einer wäßrigen Lösung oder Suspension der 2.4-Diphosphonoglutarsäure bei 20 - 120 °C rühren läßt, den Niederschlag anschließend absaugt oder die wäßrige Lösung anschließend einengt. Die erfindungsgemäßen neuen Substanzen der Formel I und ihre Salze können in jeder für das Erreichen einer effektiven Dosis geeigneten flüssigen oder festen Form, z. B. oral, rectal, topisch, parenteral, subcutan, ocular, nasal, buccal, intravenös und transdermal appliziert werden. Hierbei kommen alle üblichen Appli- kationsformen in Frage, beispielsweise Tabletten, Kapseln, Dragees, Sirupe, Lösungen, Suspensionen, Pflaster etc. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Zusätze wie Stabilisierungs- mittel, Lösungsvermittler und Puffer enthält. Derartige Zusätze sind z. B. Tartrat- und Citrat-Puffer, Ethanol, Komplexbildner (wie Ethylendiamintetraessigsäure und deren nichttoxische Salze), hochmolekulare Poly¬ mere (wie flüssiges Polyethylenoxid) zur Viskositätsregelung. Flüssige Trägerstoffe für Injektionslösungen müssen steril sein und werden vozugsweise in Ampullen abge¬ füllt. Feste Trägerstoffe sind z. B. Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäuren, höhermolekulare Fettsäuren (wie Sterinsäure), Gelatine, Agar-Agar, Calciumphosphat, Magnesiumstearat, tierische und pflanzliche Fette, feste hochmolekulare Polymere (wie Polyethylenglykole); für orale Applikation geeignete Zubereitungen können gewünschtenfalls Geschmacks- und Süßstoffe enthalten. Die Dosierung kann von verschiedenen Faktoren, wie Applikationsweise, Spezies, Alter und/oder individuellem Zustand abhängen. Die täglich zu verabreichenden Dosen lie¬ gen bei etwa 10 - 1000 mg/Mensch, vorzugsweise bei 100 - 500 mg/Mensch und kön¬ nen auf einmal oder mehre Male verteilt eingenommen werden.However, calcium, magnesium or zinc salts can also be used, which are usually poorly soluble in water, but are sometimes also slightly soluble. These salts can be prepared by adding a calcium, zinc or magnesium salt, such as. B. calcium carbonate, calcium hydrogen carbonate, calcium hydroxide, calcium chloride, zinc carbonate, zinc hydrogen carbonate, zinc hydroxide, zinc chloride, magnesium carbonate, magnesium hydrogen carbonate, magnesium hydroxide or magnesium chloride as an aqueous solution or suspension in a ratio of 1: 1 or 2: 1 with an aqueous solution or suspension of 2,4-diphosphonoglutaric acid Allows to stir 20 - 120 ° C, then the precipitate is suctioned off or the aqueous solution is then concentrated. The novel substances of formula I and their salts according to the invention can be in any liquid or solid form suitable for achieving an effective dose, e.g. B. orally, rectally, topically, parenterally, subcutaneously, ocular, nasally, buccally, intravenously and transdermally. All the usual forms of application are possible here, for example tablets, capsules, dragees, syrups, solutions, suspensions, plasters, etc. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers. Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as steric acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); Preparations suitable for oral administration can optionally contain flavorings and sweeteners. The dosage can depend on various factors, such as the mode of administration, species, age and / or individual condition. The doses to be administered daily are approximately 10-1000 mg / person, preferably 100-500 mg / person and can be taken in one or more times distributed.

Eine pharmazeutische Formulierung dieser 2.4-Diphosphonoglutarsäuren kann auch intermittierend verabreicht werden. Einer Gabe von z. B. 1 - 90 Tagen kann eine sub¬ stanzfreie Zeit von z. B. 30 - 180 Tagen folgen, wonach sich wieder eine Substanzgabe von 1 - 90 Tagen anschließen kann.A pharmaceutical formulation of these 2,4-diphosphonoglutaric acids can also be administered intermittently. A dose of e.g. B. 1 - 90 days a substance-free time of z. B. 30 - 180 days follow, after which a substance administration of 1 - 90 days can follow.

Bevorzugt im Sinne der vorliegenden Erfindung sind außer den in den Beispielen ge¬ nannten Verbindungen und durch Kombination aller in den Ansprüchen genannten Bedeutungen der Substituenten ableitbaren Verbindungen die folgenden 2.4-Diphos- phonoglutarsäurederivate sowie deren Natrium-, Kalium-, Ammonium-, Calcium-, Zink- und Magnesiumsalze, Carbonsäuremethyl-, -ethyl- oder -benzylester.For the purposes of the present invention, preference is given, in addition to the compounds mentioned in the examples and by combining all of the compounds of the substituents mentioned in the claims, to the following 2,4-diphosphonophoglutaric acid derivatives and their sodium, potassium, ammonium, calcium, Zinc and magnesium salts, carboxylic acid methyl, ethyl or benzyl esters.

2.4-Diphosphono-3-methyl-glutarsäure2,4-diphosphono-3-methyl-glutaric acid

2.4-Diphosphono-3-ethyl-glutarsäure2,4-diphosphono-3-ethyl-glutaric acid

2.4-Diphosphono-3-isopropyl-glutarsäure2,4-diphosphono-3-isopropyl-glutaric acid

2.4-Diphosphono-3-hexyl-glutarsäure2,4-diphosphono-3-hexyl-glutaric acid

2.4-Diphosphono-3-hydroxymethyl-glutarsäure2,4-diphosphono-3-hydroxymethyl-glutaric acid

2.4-Diphosphono-3 -(3 -hydroxypropyl)glutarsäure2.4-diphosphono-3 - (3-hydroxypropyl) glutaric acid

2.4-Diphosphono-3-(4-hydroxybutyl)glutarsäure2,4-diphosphono-3- (4-hydroxybutyl) glutaric acid

2.4-Diphosphono-3-(2-methoxyethyl)glutarsäure2,4-diphosphono-3- (2-methoxyethyl) glutaric acid

2.4-Diphosphono-3-butoxymethyl-glutarsäure2,4-diphosphono-3-butoxymethyl-glutaric acid

2.4-Diphosphono-3-ethoxymethyl-glutarsäure2,4-diphosphono-3-ethoxymethyl-glutaric acid

2.4-Diphosphono-3-(2-aminoethyl)glutarsäure 2.4-Diphosphono-3-(4-aminobutyl)glutarsäure2,4-diphosphono-3- (2-aminoethyl) glutaric acid 2,4-diphosphono-3- (4-aminobutyl) glutaric acid

2.4-Diphosphono-3 -(2-N-methyl-N-pentyl-aminoethyl)glutarsäure2.4-diphosphono-3 - (2-N-methyl-N-pentylaminoethyl) glutaric acid

2.4-Diphosphono-3-(2-dimemylaminoethyl)glutarsäure2,4-diphosphono-3- (2-dimemylaminoethyl) glutaric acid

2.4-Diphosphono-3-(2-N-memyl-N-propylaminoethyl)glutarsäure2,4-diphosphono-3- (2-N-memyl-N-propylaminoethyl) glutaric acid

2.4-Diphosphono-3-methylmercaptomeτhyl-glutarsäure2,4-diphosphono-3-methylmercaptomeτhyl-glutaric acid

2.4-Diphosphono-3-methylsulfinylmethyl-glutarsäure2,4-diphosphono-3-methylsulfinylmethyl-glutaric acid

2.4-Diphosphono-3-methansulfonylmethyl-glutarsäure2,4-diphosphono-3-methanesulfonylmethyl glutaric acid

2.4-Diphosphono-3-(2-cyclohexylethyl)glutarsäure2,4-diphosphono-3- (2-cyclohexylethyl) glutaric acid

2.4-Diphosphono-3-benzyl-glutarsäure2.4-diphosphono-3-benzyl-glutaric acid

2.4-Diphosphono-3-(2-phenylethyl)glutarsäure2,4-diphosphono-3- (2-phenylethyl) glutaric acid

2.4-Diphosphono-3-(4-chlorbenzyl)glutarsäure2.4-diphosphono-3- (4-chlorobenzyl) glutaric acid

2.4-Diphosphono-3-[2-(4-methylphenyl)ethyl]glutarsäure2,4-diphosphono-3- [2- (4-methylphenyl) ethyl] glutaric acid

2.4-Diphosphono-3-(3.4-dichlorbenzyl)glutarsäure2.4-diphosphono-3- (3.4-dichlorobenzyl) glutaric acid

2.4-Diphosphono-3-[2-(5 Chlor-2-methoxyphenyl)ethyl]glutarsäure2,4-diphosphono-3- [2- (5 chloro-2-methoxyphenyl) ethyl] glutaric acid

2.4-Diphosphono-3-[2-(2-pyridyl)ethyl]glutarsäure2,4-diphosphono-3- [2- (2-pyridyl) ethyl] glutaric acid

2.4-Diphosphono-3-[2-(3-pyridyl)ethyl]glutarsäure2,4-diphosphono-3- [2- (3-pyridyl) ethyl] glutaric acid

2.4-Diphosphono-3-[2-(4-pyridyl)ethyl]glutarsäure2,4-diphosphono-3- [2- (4-pyridyl) ethyl] glutaric acid

2.4-Diphosphono-3-(2-thenyl)glutarsäure2,4-diphosphono-3- (2-thenyl) glutaric acid

2.4-Diphosphono-3 -(3 -thenyl)glutarsäure2,4-diphosphono-3 - (3 -thenyl) glutaric acid

2.4-Diphosphono-3-(2-ftιr-ruryl)glutarsäure2.4-diphosphono-3- (2-ftιr-ruryl) glutaric acid

2.4-Diphosphono-3-[2-(2-imidazolyl)ethyl]glutarsäure2,4-diphosphono-3- [2- (2-imidazolyl) ethyl] glutaric acid

2.4-Diphosphono-3-( 1 -imidazolylmethyl)glutarsäure2,4-diphosphono-3- (1-imidazolylmethyl) glutaric acid

2.4-Diphosph-3-( 1 -pyπOlidinylmeτhyl)glutarsäure2.4-diphosph-3- (1 -pyπOlidinylmeτhyl) glutaric acid

2.4-Diphosphono-3-(l-piperidinyhnethyl)glutarsäure2,4-diphosphono-3- (l-piperidinyhnethyl) glutaric acid

2.4-Diphosphono-3-( 1 -morpholinylmethyl)glutarsäure2,4-diphosphono-3- (1 -morpholinylmethyl) glutaric acid

2.4-Diphosphono-2-allyl-glutarsäure2,4-diphosphono-2-allyl glutaric acid

2.4-Diphosphono-3-(but-2-enyl)glutarsäure2,4-diphosphono-3- (but-2-enyl) glutaric acid

2.4-Diphosphono-3-cyclopentyl-glutarsäure2,4-diphosphono-3-cyclopentyl-glutaric acid

2.4-Diphosphono-3-(3-pyridyl)-glutarsäure2,4-diphosphono-3- (3-pyridyl) glutaric acid

2.4-Diphosphono-3-(6-methyl-2-pyridyl)glutarsäure2,4-diphosphono-3- (6-methyl-2-pyridyl) glutaric acid

2.4-Diphosphono-3-(5-chlor-2-pyridyl)glutarsäure2.4-diphosphono-3- (5-chloro-2-pyridyl) glutaric acid

2.4-Diphosphono-3-(2-methyl-4-pyridyl)glutarsäure2,4-diphosphono-3- (2-methyl-4-pyridyl) glutaric acid

2.4-Diphosphono-3-(2-füryl)glutarsäure2.4-diphosphono-3- (2-furyl) glutaric acid

2.4-Diphosphono-3-(3-thienyl)glutarsäure2,4-diphosphono-3- (3-thienyl) glutaric acid

2.4-Diphosphono-3-(2-imidazolyl)glutarsäure2,4-diphosphono-3- (2-imidazolyl) glutaric acid

2.4-Diphosphono-3-(4-imidazolyl)glutarsäure 2.4-Diphosphono-3 - (2-methyl-4-imidazolyl)glutarsäure 2.4-Diphosphono-3 (2-methoxyphenyl)glutarsäure 2.4-Diphosphono-3 (5-chlor-2-methoxyphenyl)glutarsäure 2.4-Diphosphono-3 (3.4-dichlorphenyl)glutarsäure 2.4-Diphosphono-3 (4-isopropoxyphenyl)glutarsäure 2.4-Diphosphono-3 - (4-methylphenyl)glutarsäure 2.4-Diphosphono-3 (2.4-dimethylphenyl)glutarsäure 2.4-Dipho sphono-3 (3 -hydroxyphenyl)glutarsäure 2.4-Diphosphono-3 (4-d-unethyla-minophenyl)glutarsäure 2.4-Diphosphono-3 - (4-N-memyl-N-pentyl--minophenyl)glutarsäure 2.4-Diphosphono-3 (4-methylmercaptophenyl)glutarsäure 2.4-Diphosphono-3 (4-methylsulfinylphenyl)glutarsäure 2.4-Diphosphono-3 (4-methansulfonylphenyl)glutarsäure 2.4-Diphosphono-3 - (4-carboxyphenyl)glutarsäure 2.4-Diphosphono-3 (4-ethoxycarbonylphenyl)glutarsäure 2.4-Diphosphono-3 - (4-carboxamidophenyl)glutarsäure 2.4-Diphosphono-3 (4-N,N-dimethylcarboxamidophenyl)glutarsäure 2.4-Diphosphono-3 - (3 -cyanophenyl)glutarsäure 2.4-Diphosphono-3- ( 1 -naphthyl)glutarsäure 2.4-Diphosphono-3 - (2-naphthyl)glutarsäure 2.4-Diphosphono-3 - (3 -indolyl)glutarsäure 2.4-Diphosphono-3- (3 -indoly lmethy l)glutarsäure 2.4-Diphosphono-3 - (2.3 -dihydroxypropyl)glutarsäure2,4-diphosphono-3- (4-imidazolyl) glutaric acid 2.4-diphosphono-3 - (2-methyl-4-imidazolyl) glutaric acid 2.4-diphosphono-3 (2-methoxyphenyl) glutaric acid 2.4-diphosphono-3 (5-chloro-2-methoxyphenyl) glutaric acid 2.4-diphosphono-3 (3.4- dichlorophenyl) glutaric acid 2.4-diphosphono-3 (4-isopropoxyphenyl) glutaric acid 2.4-diphosphono-3 - (4-methylphenyl) glutaric acid 2.4-diphosphono-3 (2.4-dimethylphenyl) glutaric acid 2.4-diphosphono-3 (3-hydroxyphenyl) glutaric acid 2.4 -Diphosphono-3 (4-d-unethyla-minophenyl) glutaric acid 2.4-diphosphono-3 - (4-N-memyl-N-pentyl - minophenyl) glutaric acid 2.4-diphosphono-3 (4-methylmercaptophenyl) glutaric acid 2.4-diphosphono- 3 (4-methylsulfinylphenyl) glutaric acid 2.4-diphosphono-3 (4-methanesulfonylphenyl) glutaric acid 2.4-diphosphono-3 - (4-carboxyphenyl) glutaric acid 2.4-diphosphono-3 (4-ethoxycarbonylphenyl) glutaric acid 2.4-diphosphono-3 - (4- carboxamidophenyl) glutaric acid 2.4-diphosphono-3 (4-N, N-dimethylcarboxamidophenyl) glutaric acid 2.4-diphosphono-3 - (3 -cyanophenyl) glutaric acid 2.4-diphosphono-3- (1-naphthy l) glutaric acid 2.4-diphosphono-3 - (2-naphthyl) glutaric acid 2.4-diphosphono-3 - (3-indolyl) glutaric acid 2.4-diphosphono-3- (3-indolylmethyl) glutaric acid 2.4-diphosphono-3 - (2.3 - dihydroxypropyl) glutaric acid

Die nachfolgenden Beispiele zeigen einige der Verfahrensvarianten, die zur Synthese der erfindungsgemäßen Verbindungen verwendet werden können. Sie sollten jedoch nicht eine Einschränkung des Erfindungsgegenstandes darstellen. Die Struktur der Verbindungen wurde durch IH-, 31p- und gegebenenfalls durch I^C-NMR-Spektro- skopie gesichert. Die Reinheit der Substanzen wurde mittels C. H, N, P, gegebenen¬ falls Na-Analyse sowie dünnschichtchromatographisch bzw. durch Dünnschichtelek¬ trophorese (Cellulose, Oxalat-Puffer von pH = 4.0) bestimmt. Allgemeine ArbeitsvorschriftenThe following examples show some of the process variants that can be used for the synthesis of the compounds according to the invention. However, they should not be a limitation of the subject matter of the invention. The structure of the compounds was confirmed by IH, 31p and, if appropriate, by I ^ C NMR spectroscopy. The purity of the substances was determined by means of C. H, N, P, if necessary Na analysis and by thin-layer chromatography or by thin-layer electrophoresis (cellulose, oxalate buffer of pH = 4.0). General work regulations

Die für die folgenden Beispiele benötigten α-Phosphonoacrylate wurden in Analogie zur Literatur synthetisiert: Chem. Ber. L2C 121-2 (1987).The α-phosphonoacrylates required for the following examples were synthesized in analogy to the literature: Chem. Ber. L2C 121-2 (1987).

Allgemeine Arbeitsvorschrift A:General working instruction A:

Zu einer Suspension aus Natriumhydrid (240 mg, 10 mmol) in 30 ml Methanol wird Phosphonoessigsäuretriethylester ( 2.0 ml, 10 mmol) gegeben. Nach 30 min Rühren bei Raumtemperatur wird eine Lösung aus 10 mmol α-Phosphonoacrylat in 10 ml Methanol langsam zugetropft. Nach 24 Stunden bei Raumtemperatur wird eineengt, mit gesättigter Ammoniumchlorid-Lösung (20 ml) versetzt und mit Essigsäureethyl- ester (2 x 50 ml) extrahiert. Die vereinigten organischen Phasen werden über Magne¬ siumsulfat getrocknet und eingeengt. Der Rückstand wird durch Chromatographie an Kieselgel gereinigt.Phosphonoacetic acid triethyl ester (2.0 ml, 10 mmol) is added to a suspension of sodium hydride (240 mg, 10 mmol) in 30 ml of methanol. After stirring for 30 min at room temperature, a solution of 10 mmol of α-phosphonoacrylate in 10 ml of methanol is slowly added dropwise. After 24 hours at room temperature, the mixture is concentrated, saturated ammonium chloride solution (20 ml) is added and the mixture is extracted with ethyl acetate (2 × 50 ml). The combined organic phases are dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel.

Allgemeine -Arbeitsvorschrift B:General Working Instructions B:

2 mmol des 2.4.-Diphosphonoglutarsäurehexaester-Derivates werden in 25 ml 6 N Salzsäure suspendiert und 18 Stunden am Rückfluß gekocht, abgekühlt und mit Essigsäureethylester (2 x 15 ml) extrahiert. Die wäßrige Phase wird eingeengt, mit Ethanol (2 x 20 ml) versetzt, eingeengt und in 10 ml Wasser aufgenommen. Die saure Lösung wird mit 1 N Natronlauge auf pH 7 (pH-Elektrode) eingestellt. Nach Abziehen des Wassers wird der Rückstand in Ethanol suspendiert, abfiltriert und mit Aceton nachgewaschen.2 mmol of the 2,4-diphosphonoglutaric acid hexaester derivative are suspended in 25 ml of 6N hydrochloric acid and refluxed for 18 hours, cooled and extracted with ethyl acetate (2 × 15 ml). The aqueous phase is concentrated, treated with ethanol (2 × 20 ml), concentrated and taken up in 10 ml of water. The acidic solution is adjusted to pH 7 (pH electrode) with 1 N sodium hydroxide solution. After the water has been stripped off, the residue is suspended in ethanol, filtered off and washed with acetone.

Beispiel 1example 1

2.4-Diphosphonoglutarsäure-Trinatriumsalz2.4-diphosphonoglutaric acid trisodium salt

1.7 g (3.7 mmol) 2.4-Diphosphonoglutarsäurehexaethylester (Angew. Chemie 92, 43 (1980)) werden nach der allg. Arbeitsvorschrift B umgesetzt. Man erhält ein farbloses amorphes Pulver (1.2 g, 91 %): Beispiel 21.7 g (3.7 mmol) of 2,4-diphosphonoglutaric acid hexaethyl ester (Angew. Chemie 92, 43 (1980)) are reacted according to general working procedure B. A colorless amorphous powder (1.2 g, 91%) is obtained: Example 2

2.4-Diphosphono-3-phenyl-glutarsäure2,4-diphosphono-3-phenyl-glutaric acid

2.4-Diphosphono-3-phenyl-glutarsäure-hexaethylester2,4-Diphosphono-3-phenyl-glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-phenyl-glutarsäure2,4-diphosphono-3-phenyl-glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 69 %. H-NMR (D20) d = 7.40 (m, 5H), 4.0 - 3.75 (m, IH), 3.68 - 3.50 (m, 2H). 1P-NMR (D20) d = 19.27, 18.86.The presentation follows the general working procedure B. Yield: 69%. H-NMR (D 2 0) d = 7.40 (m, 5H), 4.0 - 3.75 (m, IH), 3.68 - 3.50 (m, 2H). 1 P NMR (D 2 0) d = 19.27, 18.86.

Beispiel 3Example 3

2.4-Diphosphono-3-(2-pyridyl)glutarsäure2.4-diphosphono-3- (2-pyridyl) glutaric acid

2,4-Diphosphono-3-(2-pyridyl)glutarsäure-hexaeτhylester2,4-Diphosphono-3- (2-pyridyl) -glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-(2-pyridyl)glutarsäure2.4-diphosphono-3- (2-pyridyl) glutaric acid

Die Darstellimg erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 96 %. ^H-NMR (D20) d = 8.70 (dd, IH), 8.5 (dd, IH), 8.2 (dt, IH), 7.9 (dt, IH). 31p-NMR (D20) d = 11.0, 10.34.The representation follows the general working procedure B. Yield: 96%. ^ H NMR (D 2 0) d = 8.70 (dd, IH), 8.5 (dd, IH), 8.2 (dt, IH), 7.9 (dt, IH). 31p NMR (D 2 0) d = 11.0, 10.34.

Beispiel 4Example 4

2.4-Diphosphono-3-(4-pyridyl)glutarsäure2.4-diphosphono-3- (4-pyridyl) glutaric acid

2,4-Diphosphono-3-(4-pyridyl)glutarsäure-hexaethylester2,4-Diphosphono-3- (4-pyridyl) hexaethyl glutarate

Die Darstellimg erfolgt nach der allg. Arbeitsvorschrift A. 2.4-Diphosphono-3-(4-pyridyl glutarsäureThe representation follows the general working instruction A. 2.4-diphosphono-3- (4-pyridyl glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 57 %. ^H-NMR (D 0) d = 8.65 (br. s, IH), 8.30 (br. s, IH), 5.05 (m, IH), 4.30 (m, IH), 3.85 - 3.62 (m, IH). 31P-NMR (D20) d = 12.72, 12.37.The presentation follows the general working procedure B. Yield: 57%. ^ H-NMR (D 0) d = 8.65 (br. S, IH), 8.30 (br. S, IH), 5.05 (m, IH), 4.30 (m, IH), 3.85 - 3.62 (m, IH) . 31 P NMR (D 2 0) d = 12.72, 12.37.

Beispiel 5Example 5

2.4-Diphosphono-3-(4-aminophenyl)glutarsäure2,4-diphosphono-3- (4-aminophenyl) glutaric acid

2.4-Diphosphono-3-(4-aminophenyl)glutarsäure-hexaeτhylester2,4-Diphosphono-3- (4-aminophenyl) glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-(4-aminophenyl)glutarsäure2,4-diphosphono-3- (4-aminophenyl) glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 83 %. IH-NMR (D20) d = 7.6 (d, 2H), 7.35 (d, 2H), 4.15 (m, IH), 4.0 (dd, IH), 3.7 (dd, IH). 31p. NMR (D20) d = 16.21, 15.96.The presentation follows the general working procedure B. Yield: 83%. IH NMR (D 2 0) d = 7.6 (d, 2H), 7.35 (d, 2H), 4.15 (m, IH), 4.0 (dd, IH), 3.7 (dd, IH). 31p. NMR (D 2 0) d = 16.21, 15.96.

Beispiel 6Example 6

2.4-Diphosphono-3-(4-chlorphenyl)glutarsäure2.4-diphosphono-3- (4-chlorophenyl) glutaric acid

2,4-Diphosphono-3-(4-chlorphenyl glutarsäure-hexaethylester2,4-Diphosphono-3- (4-chlorophenyl glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-(4-chlorphenyl glutarsäure2.4-diphosphono-3- (4-chlorophenyl glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 95 %. IH-NMR (D20) d = 7.4 (d, 2H), 7.2 (d, 2H), 4.05 - 3.85 (m, 1 H), 3.25 (dd, IH), 3.05. 31p. NMR (D20) d = 18.38, 18.03. Beispiel 7The presentation follows the general working procedure B. Yield: 95%. IH-NMR (D 2 0) d = 7.4 (d, 2H), 7.2 (d, 2H), 4:05 - 3.85 (m, 1 H), 3.25 (dd, IH), 3.05. 31p. NMR (D 2 0) d = 18.38, 18.03. Example 7

2.4-Diphosphono-3-(4-hydroxyphenyl)gIutarsäure2,4-diphosphono-3- (4-hydroxyphenyl) glutaric acid

2.4-Diphosphono-3-(4-hvdroxyphenyl)glutarsäure-hexaeτhylester2,4-Diphosphono-3- (4-hvdroxyphenyl) glutaric acid hexaeτhylester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-(4-hvdroxyphenyl)glutarsäure2,4-diphosphono-3- (4-hvdroxyphenyl) glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 68 %. iH-NMR (D20) d = 7.25 (d, 2H), 6.80 (d, 2H), 3.90 - 3.75 (m, IH), 3.70 - 3.5 (m, IH). iP- NMR (D20) d = 18.65, 18.03.The presentation follows the general working procedure B. Yield: 68%. iH-NMR (D 2 0) d = 7.25 (d, 2H), 6.80 (d, 2H), 3.90 - 3.75 (m, IH), 3.70 - 3.5 (m, IH). i P NMR (D 2 0) d = 18.65, March 18.

Beispiel 8Example 8

2.4-Diphosphono-3-(4-methoxyphenyI)glutarsäure2.4-diphosphono-3- (4-methoxyphenyl) glutaric acid

2,4-Diphosphono-3-(4-methoxyphenyl glutarsäure-hexaethylester2,4-Diphosphono-3- (4-methoxyphenyl glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-(4-methoxyphenyl)glutarsäure2,4-diphosphono-3- (4-methoxyphenyl) glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 91 %. iH-NMR (D20) d = 7.48 (d, 2H), 4.05 (m, 2H), 3.90 (s, 3H), 3.75 (m, IH). 3 lP-NMR (D20) d = 16.71, 16.54.The presentation follows the general working procedure B. Yield: 91%. iH NMR (D 2 0) d = 7.48 (d, 2H), 4.05 (m, 2H), 3.90 (s, 3H), 3.75 (m, IH). 3 lP NMR (D 2 0) d = 16.71, 16.54.

Beispiel 9Example 9

2.4-Diphosphono-3-cyclohexyI-gIutarsäure2,4-diphosphono-3-cyclohexyl-glutaric acid

2,4-Diphosphono-3-cvclohexyl-glutarsäure-hexaethylester2,4-Diphosphono-3-cvclohexyl-glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A. 2.4-Diphosphono-3-cvclohexyl-glutarsäureThe presentation follows the general working instruction A. 2,4-diphosphono-3-cvclohexyl-glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 71 %. H-NMR (D20) d = 3.65 - 3.49 (m, IH), 2.90 - 2.60 (m, IH), 1.85 - 1.60 (m, 6H), 1.40 - 1.10 (m, 5H). 3 1P-NMR (D20) d = 18.94, 17.82).The presentation follows the general working procedure B. Yield: 71%. H-NMR (D 2 0) d = 3.65 - 3.49 (m, IH), 2.90 - 2.60 (m, IH), 1.85 - 1.60 (m, 6H), 1.40 - 1.10 (m, 5H). 3 1 P NMR (D 2 0) d = 18.94, 17.82).

Beispiel 10Example 10

2.4-Diphosphono-3-butyl-glutarsäure2,4-diphosphono-3-butyl-glutaric acid

2,4-Diphosphono-3-butyl-glutarsäure-hexaeτhylester2,4-Diphosphono-3-butyl-glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-butyl-glutarsäure2,4-diphosphono-3-butyl-glutaric acid

Die Darstellung erfolgt nach der allg. Arbeits Vorschrift B. Ausbeute: 72 %. iH-NMR (D20) d = 3.80 - 3.60 (m, IH), 3.49 - 3.32 (m, IH), 2.85 - 2.65 (m, IH), 1.99 - 1.75 (m, 2H), 1.50 -1.25 (m, 4H), 0.9 (br.t, 3H). 31P-NMR (D 0) d = 18.32, 17.79.The presentation follows the general working instruction B. Yield: 72%. iH-NMR (D 2 0) d = 3.80 - 3.60 (m, IH), 3.49 - 3.32 (m, IH), 2.85 - 2.65 (m, IH), 1.99 - 1.75 (m, 2H), 1.50 -1.25 ( m, 4H), 0.9 (br.t, 3H). 31 P NMR (D 0) d = 18.32, 17.79.

Beispiel 11Example 11

2.4-Diphosphono-3-benzyl-glutarsäure2.4-diphosphono-3-benzyl-glutaric acid

2,4-Diphosphono-3-benzyl-glutarsäure-hexaeτhylester2,4-Diphosphono-3-benzyl-glutaric acid hexaethylester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3 -benzyl-glutarsäure2,4-diphosphono-3-benzyl-glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 83 %. iH-NMR (D20) d = 7.40 (m, 5H), 3.70 - 3.35 (m, 2H), 3.30 - 3.0 (m, 3H). 3 lp-NMR (D20) d = 18.24, 16.98. Beispiel 12The presentation follows the general working procedure B. Yield: 83%. iH NMR (D 2 0) d = 7.40 (m, 5H), 3.70 - 3.35 (m, 2H), 3.30 - 3.0 (m, 3H). 3 lp NMR (D 2 0) d = 18.24, 16.98. Example 12

2.4-Diphosphono-3-(2-thienyl)glutarsäure2,4-diphosphono-3- (2-thienyl) glutaric acid

2,4-Diphosphono-3-(2-thienyl glutarsäure-hexaethylester2,4-Diphosphono-3- (2-thienyl glutaric acid hexaethyl ester

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift A.The presentation follows the general working instruction A.

2.4-Diphosphono-3-(2-thienyl glutarsäure2.4-diphosphono-3- (2-thienyl glutaric acid

Die Darstellung erfolgt nach der allg. Arbeitsvorschrift B. Ausbeute: 63 %. iH-NMR (D20) d = 7.40 (d, IH), 7.20 (d, IH), 7.0 (dd, IH), 4.3 (m, IH). 3.6 (dd, 2H). 3 1P- NMR (D20) d = 17.60, 17.49.The presentation follows the general working procedure B. Yield: 63%. iH-NMR (D 2 0) d = 7.40 (d, IH), 7.20 (d, IH), 7.0 (dd, IH), 4.3 (m, IH). 3.6 (dd, 2H). 3 1 P NMR (D 2 0) d = 17.60, 17.49.

Beispiel 13Example 13

Pharmakologische TestsPharmacological tests

Inhibierung der nicht-stimulierten Knochenresorption durch die Bestimmung der HJ-Tetracyclin-Ausscheidung im UrinInhibition of non-stimulated bone resorption by determining the urinary excretion of HJ tetracycline

Von Geburt an erhalten Ratten zweimal wöchentlich eine Injektion mit steigenden Mengen einer Lösung aus 3.7 x 105 Bq/ml (10 μCi/ml) [7- H]-Tetracyclin ([3H]TC); New England Nuclear, Boston, MA) der spezifischen Aktivität 679 mCi/mmol. Das Volumen pro Injektion wird von 50 μl/Woche auf 250 μl in der fünften Woche ge¬ steigert und für eine weitere Woche beibehalten. Die Gesamtmenge an appliziertem [3H]TC betrug 20 μCi pro Ratte. 51 Tage alte Ratten werden in individuelle Stoff- wechselkäfige umgesetzt und erhalten eine Gruppenfütterung mit Futter, das 0.5 % Ca und 0.35 % P enthält. Dieses Futter wurde durch Zusatz von entsprechenden Mengen Calciumglucagonat und neutralem Natrimphosphat aus Futter mit -niedrigem Calcium- und Phosphatgehalt (SODI 2134, Klingenthalmühle) hergestellt. Während der gesam¬ ten Versuchsdauer erhielten die Tiere Aqua dest. ad libitum. Nach 61 Tagen wurde mit dem Sammeln des 24 h Urins begonnen. Der Urin wurde täglich um 11 Uhr gesam¬ melt; zu dieser Zeit erhielten die Tiere auch Futter. Am sechsten Tag nach Beginn der Urinsammlung erhielten die Tiere zwei s.c. Injektionen mit Substanz (um 8 Uhr bzw. 17 Uhr). Die Inhibierung der -Knochenresorption wird durch die verminderte [ H]- Tetracyclinausscheidung am Tag 8 nach Beginn der Urinsammlung angegeben. Das 3H-TC im Urin wurde durch Flüssigkeitsszintillation bestimmt, indem zu 1 ml Urin 10 ml des Szintillators Pico-Fluor 30 (packard International, Zürich, Schweiz) zugesetzt wurde.From birth, rats are injected twice a week with increasing amounts of a solution of 3.7 x 10 5 Bq / ml (10 μCi / ml) [7- H] tetracycline ([ 3 H] TC); New England Nuclear, Boston, MA) specific activity 679 mCi / mmol. The volume per injection is increased from 50 μl / week to 250 μl in the fifth week and maintained for a further week. The total amount of [ 3 H] TC applied was 20 μCi per rat. Rats 51 days old are put into individual metabolism cages and fed a group with food containing 0.5% Ca and 0.35% P. This feed was produced by adding appropriate amounts of calcium glucagonate and neutral sodium phosphate from feed with a low calcium and phosphate content (SODI 2134, Klingenthal mill). During the entire duration of the experiment, the animals received aqua dest. ad libitum. The collection of the 24-hour urine was started after 61 days. The urine was collected daily at 11 a.m. at that time the animals were also fed. On the sixth day after the start of urine collection, the animals received two sc injections with substance (at 8 a.m. and 5 p.m., respectively). The inhibition of bone resorption is reduced by the [H] - Tetracycline excretion indicated on day 8 after the start of urine collection. The 3 H-TC in the urine was determined by liquid scintillation by adding 10 ml of the scintillator Pico-Fluor 30 (packard International, Zurich, Switzerland) to 1 ml urine.

[Xcpmτag5 - (Ccpmτag8 - Ccρmτag5)] - Xcpmτag8 % rel. Inhibierung = x 100 %[Xcpmτ ag 5 - (Ccpmτ ag 8 - Ccρmτ ag5 )] - Xcpmτ ag 8% rel. Inhibition = x 100%

[Xcpmτag5 - (Ccpnττag8 - CcpmTag5)][Xcpmτ ag 5 - (Ccpnττ ag8 - Ccpm day 5 )]

X = Behandelte Tiere C = KontrolltiereX = treated animals C = control animals

Beispiel Verbindung 2 20 2 x 6 mg/kg mg/kgExample compound 2 20 2 x 6 mg / kg mg / kg

1 2.4-Diphosphono-Glutarsäure 57 %1 2.4-diphosphono-glutaric acid 57%

2 2.4-Diphosphono-3-phenyl-Glutarsäure 43 %2 2,4-diphosphono-3-phenyl-glutaric acid 43%

3 2.4-Diphosphono-3-(2-pyridyl)GJutarsäure 38 %3 2.4-diphosphono-3- (2-pyridyl) Gjutaric acid 38%

4 2.4-Diphosphono-3-(4-pyridyl)Glutarsäure 28 %4 2.4-diphosphono-3- (4-pyridyl) glutaric acid 28%

5 2.4-Diphosphono-3-(4-aminophenyl)Glutarsäure 52 %5 2.4-diphosphono-3- (4-aminophenyl) glutaric acid 52%

6 2.4-Diphosphono-3-(4-chlorophenyl)Glutarsäure 41 %6 2.4-diphosphono-3- (4-chlorophenyl) glutaric acid 41%

9 2.4-Diphosphono-3-cyclohexyl-Glutarsäure 28 %9 2.4-diphosphono-3-cyclohexyl-glutaric acid 28%

10 2.4-Diphosphono-3-butyl-Glutarsäure 35 %10 2,4-diphosphono-3-butyl-glutaric acid 35%

11 2.4-Diphosphono-3-benzyl-Glutarsäure 35 % 11 2,4-diphosphono-3-benzyl-glutaric acid 35%

Claims

Patentanspruch e Claim e 2.4-Diphosphonoglutarsäure-Derivate der Formel I2.4-diphosphonoglutaric acid derivatives of the formula I.
Figure imgf000018_0001
in der
Figure imgf000018_0001
in the R = Wasserstoff, niederes Alkyl, das gegebenenfalls durch Hydroxy, Alkoxy,R = hydrogen, lower alkyl, which may be replaced by hydroxy, alkoxy, Amino, Dialkylamino, Alkylmercapto, Alkylsulfinyl, Alkansulfonyl, Cycloalkyl, Aryl oder einen heterocyclischen Ring substituiert sein kann, niederes Alkenyl, Cycloalkyl, Cycloalkenyl, Aryl oder einen hetero¬ cyclischen Ring,Amino, dialkylamino, alkylmercapto, alkylsulfinyl, alkanesulfonyl, cycloalkyl, aryl or a heterocyclic ring may be substituted, lower alkenyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic ring, R\ und R2 unabhängig voneinander jeweils Wasserstoff, niederes Alkyl, Cycloalkyl oder Arylmethyl sein können,R \ and R2 can each independently be hydrogen, lower alkyl, cycloalkyl or arylmethyl, sowie deren pharmakologisch unbedenkliche Salze.and their pharmacologically acceptable salts. 2. Verfahren zur Herstellung von 2.4-Diphosphonoglutarsäure-Derivaten der Formel I2. Process for the preparation of 2,4-diphosphonoglutaric acid derivatives of the formula I.
Figure imgf000018_0002
in der
Figure imgf000018_0002
in the R = Wasserstoff, niederes Alkyl, das gegebenenfalls durch Hydroxy, Alkoxy,R = hydrogen, lower alkyl, which may be replaced by hydroxy, alkoxy, Amino, Dialkylamino, Alkylmercapto, Alkylsulfinyl, Alkansulfonyl, Cycloalkyl, Aryl oder einen heterocyclischen Ring substituiert sein kann, niederes Alkenyl, Cycloalkyl, Cycloalkenyl, Aryl oder einen hetero¬ cyclischen Ring,Amino, dialkylamino, alkylmercapto, alkylsulfinyl, alkanesulfonyl, cycloalkyl, aryl or a heterocyclic ring may be substituted, lower alkenyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic ring, Rl und R2 unabhängig voneinander jeweils Wasserstoff, niederes Alkyl, Cycloalkyl oder Arylmethyl sein können,R1 and R2 can each independently be hydrogen, lower alkyl, cycloalkyl or arylmethyl, sowie deren pharmakologisch unbedenkliche Salze,and their pharmacologically acceptable salts, dadurch gekennzeichnet, daß man in an sich bekannter Weisecharacterized in that in a manner known per se a) für den Fall, daß R\ und R2 Wasserstoff sind, einen Hexaester der allgemei¬ nen Formel IIa) in the event that R \ and R2 are hydrogen, a hexaester of the general formula II
Figure imgf000019_0001
in der R die oben angegebene Bedeutung hat und R - R unabhängig vonein¬ ander niederes Alkyl, Cycloalkyl oder Arylmethyl sind, zu den entsprechenden Säuren der allgemeinen Formel I verseift,
Figure imgf000019_0001
in which R has the meaning given above and R - R are saponified independently of one another, lower alkyl, cycloalkyl or arylmethyl, to give the corresponding acids of the general formula I, oderor b) für den Fall, daß R\ und R2 niederes Alkyl, Cycloalkyl oder Arylmethyl sind, einen Hexaester der allgemeinen Formel II
Figure imgf000020_0001
b) in the event that R \ and R2 are lower alkyl, cycloalkyl or arylmethyl, a hexaester of the general formula II
Figure imgf000020_0001
 in der R die oben angegebene Bedeutung hat und R\ - R-g niederes Alkyl, Cycloalkyl oder Arylmethyl ist, teilweise zu Diphosphonsäuren-Dicarbon- säureestern der allgemeinen Formel I verseift,in which R has the meaning given above and R \ - R-g is lower alkyl, cycloalkyl or arylmethyl, partially saponified to give diphosphonic acid dicarboxylic acid esters of the general formula I, und anschließend gewünschtenfalls die erhaltenen Verbindungen in ein pharma- kologisch unbedenkliches Salz überführt.and then, if desired, the compounds obtained are converted into a pharmacologically acceptable salt. 3. Arzneimittel, enthaltend mindestens eine Verbindung gemäß Anspruch 1 neben üblichen Träger- und Hilfsstoffen.3. Medicament containing at least one compound according to claim 1 in addition to conventional carriers and auxiliaries. 4. Verwendung von Verbindungen gemäß Anspruch 1 zur Herstellung von Arzneimitteln zur Behandlung von Calciumstoffwechselstörungen. 4. Use of compounds according to claim 1 for the manufacture of medicaments for the treatment of calcium metabolic disorders.
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