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WO1993000348A1 - Acides dimethylamino-hydroxy-alcane-diphosphoniques et compositions pharmaceutiques les contenant - Google Patents

Acides dimethylamino-hydroxy-alcane-diphosphoniques et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1993000348A1
WO1993000348A1 PCT/IT1992/000058 IT9200058W WO9300348A1 WO 1993000348 A1 WO1993000348 A1 WO 1993000348A1 IT 9200058 W IT9200058 W IT 9200058W WO 9300348 A1 WO9300348 A1 WO 9300348A1
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WO
WIPO (PCT)
Prior art keywords
dimethylamino
acid
hydroxy
diphosphonic
alkan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IT1992/000058
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English (en)
Inventor
Giuseppe Guainai-Ricci
Sergio Rosini
Murizio Mian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Istituto Gentili SpA
Original Assignee
Istituto Gentili SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Istituto Gentili SpA filed Critical Istituto Gentili SpA
Priority to JP5501416A priority Critical patent/JPH06508833A/ja
Priority to EP92913148A priority patent/EP0592488A1/fr
Publication of WO1993000348A1 publication Critical patent/WO1993000348A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to new dimethyl- amino-hydroxy-alkan diphosphonic acids and the salts 0 thereof.
  • the invention relates to a method for their production, as well as the pharmaceutical compositions containing these products.
  • the above group of compounds has been used with advantage, inter alia, in the pharmaceutical field for the treatment of diseases associated with disturbances of the bone metabolism, 0 such as osteoporosis, Paget's disease, osteolysys caused by tumourand hyperparathyrodism, osteoarthrosis, arthritis and the like.
  • diseases associated with disturbances of the bone metabolism 0 such as osteoporosis, Paget's disease, osteolysys caused by tumourand hyperparathyrodism, osteoarthrosis, arthritis and the like.
  • the 4-amino-l-hydroxy-butan-l,1-diphosphonic acid and its derivatives has proven particularly effective in this respect.
  • the above compound is active and effective at concentrations much lower than other similar diphosphonic compounds with correspondingly lower unwanted side effects.
  • Dimethylamino-hydroxy-alkan diphosphonic acids and their derivatives are also known which show similar properties and activity when alkyl group is propyl or butyl.
  • US patent No.4054598 discloses, inter alia, the 3-dimethylamino-hydroxy-propan-l,l- diphosphonic acid, its preparation and uses
  • US patent No.4624947 discloses the 4-dimethylamino- hydroxy-butan-1,1-diphosphonic acid, its preparation and uses, under the form both of the acid and of its water soluble salts.
  • the latter compounds are also described as possbile radionuclide carriers to particular biological tissues, such as for example the bone tissue, for the execution of scintigraphic analyses (see for instance Europeant patents No.96932 and 96933) .
  • the known processes for the preparation of phosphonic acids and in particular of amino-hydroxy- alkan-diphosphonic acids comprise reacting the corresponding amino-carboxylic acid with a mixture of phosphorous acid and phosphorus halide, such as phosphorus trichloride, and hydrolyzing the polyemeric products thus obtained in order to give the wanted diphosphonic acid to be recovered under purified form, for example, by crystallization.
  • a mixture of phosphorous acid and phosphorus halide such as phosphorus trichloride
  • the reaction is conducted in the presence of an organic inert substance, for example a chlorinated hydrocarbon such as chlorobenzene, while the hydrolysis is conducted with a not oxidizing strong acid.
  • an organic inert substance for example a chlorinated hydrocarbon such as chlorobenzene
  • the same reaction is conducted without either solvents or inert substances and with different reactants molar ratios, using water as hydrol zing agent and recovering the wanted amino diphosphonic acid by precipitation with an alcohol which is added to the hydrolized solution.
  • the dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids can be prepared from the corresponding dimethylamino-l-amino-alkan-l-hydroxy-1,1-diphosphonic acids by reaction with nitrous acid, salts thereof and compounds forming nitrous acid under the reaction conditions,while the reactant acid can be obtained from the corresponding nitrile by reaction with phosphorous halide under anhydrous conditions in the presence of a solvent or an inert inorganic diluent followed by hydrolysis in water.
  • the reactant acid can be obtained by phosphonylation of the corresponding dimethylated aminoacid with phosphorous acid in the presence of PCI3 or by other phosphonylation reactions well known to the person skilled in the art.
  • Another object of the invention is to provide pharmaceutical compositions comprising the dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids, their derivatives and water soluble salts according to the present invention for the administration to patients suffering from diseases associated with disturbances of bone metabolism.
  • the compounds according to the present invention are the 5-dimethylamino-l-hydroxy- pentan-1,1-diphosphonic acid (DAPeDP) and the 6- dimethyla_ ⁇ ino-l-hydroxy-hexan-l,1-diphosphonic acid (DAEDP) , as well as their non-toxic, pharmaceutically acceptable, water-soluble salts.
  • DAPeDP 5-dimethylamino-l-hydroxy- pentan-1,1-diphosphonic acid
  • DEDP 6- dimethyla_ ⁇ ino-l-hydroxy-hexan-l,1-diphosphonic acid
  • both DAPeDP and DABDP can be obtained respectively from the 5-dimethylamino-l-amino-pentan-l,1-diphosphonic acid and from the 6-dimethyl-l-amino-esan-l,l-diphosphonic acid by reaction with nitrous acid or with reactants capable of forming nitrous acid under the reaction conditions.
  • the dimethylated amino-alkyl diphosphonic acids used as reactants can be obtained by reaction of 5-dimethylamino-valeronitrile and, respectively, of 6- dimethylamino-capronitrile with an amount of PBr3 slightly higher than the stoichiometric under anhydrous conditions and in the presence of an inert solvent or diluent.
  • the product obtained in this way is then treated with hot water to hydrolize the polymers thus formed.
  • the molar ratios among the reactants are quite variable, generally comprised between 1:1:1 and 1:20:5 according to whether a solvent is used or not. Preferred molar ratio of 1:5:2 in the absence of a solvent is used.
  • the product obtained in this way is subjected to hydrolysis which can be performed both with a non- oxidizing strong acid in aqueous solution and for a longer time with water only.
  • the 5-dimethylamino valeric acid and the 6-dimethylamino caproic acid can be obtained by dialkylation according to methods known in the art.
  • n is equal to 4 or 5.
  • the method consists in reacting the 5-amino valeric acid, or respectively- the 6-amino caproic acid with formic acid and formaldehyde 40% solution with molar ratios generally comprised between 1:2:2 and 1:10:4 under reflux for a time variable from 0.5 and 3 hours.
  • the mixture of reaction is then concentrated under vacuum and at a temperature of 100-120°C until distillation has gone to end and the residual product thus obtained is directly passed to the reaction with H3PO3 and PX3 in the previously indicated, known molar ratio without the need of isolating any intermediate product.
  • the product resulting from the reaction can be easily recrystallized from water if necessary.
  • Example 1 131,2 g (1 mole) of 6-amino-caproic acid are dissolved in 190 ml (5 moles) of 99% formic acid and 170 ml (2,2 moles) of a 40% solution formic aldehyde; the solution is kept under reflux for 3 hours and then concentrated under vacuum up to about 110°C until the end of distillation.
  • the reaction apparatus is placed under nitrogen and 246 g (3 moles) of H3PO3 are added; the temperature is raised to 90°C and 363 ml (4,14 moles) of PCI3 are gradually added. The mixture is kept under low reflux for 3 hours and then cooled.
  • Example 2 164.8 g (0,54 moles) of 6-dimethylamino-hydroxy- hexan-l,l-diphosphonic acid are obtained whose identity and high purity are confirmed with the analyses.
  • Example 2 206 g (1,5 moles) of PCI3 are dissolved in a mixture of 5-dimethylamino-valerianic acid (145,2 g, 1 mole) and H3PO3 (246 g, 3 moles) by a dropwise addition under anhydrous conditions, under vacuum and stirring; the solution is kept under slow PCI3 reflux for 3 hours and then caused to cool.
  • PCI3 206 g (1,5 moles) of PCI3 are slowly added under stirring to a suspension obtained by mixing 159.2 g (1 mole) of 6-dimethylamino caproic acid with 164 g (2 moles) of H3PO3 in 500 ml of chlorobenzene brought to 90°C under a nitrogen stream; the mixture is moderately refluxed for 3 hours and then is caused to cool. 500 ml of distilled water are then added slowly and under stirring, once any solid matter possibly present is separated and the acqueous phase is refluxed for 6 hours. After cooling and filtering with decolorizing charcoal an equal volume of methanol is added and the mixture is left under stirring for 24 hours.
  • the yield is equal to 63%.
  • the water-soluble salts of the acids according to the present invention can be obtained by complete or partial neutralization with inorganic, organic bases or quaternary ammonium, such as NaOH, KOH, NH OH, alkaline carbonates, alkanolamines, and the like, and isolating the salt by a following concentration up to crystallization or, alternately and more simply, by precipitation with a C1-C3 alcohol or acetone.
  • the diphosphonic acids according to the present invention and their saline derivatives are suitable for the preparation of pharmaceutical compositions useful in the therapeutic or preventive treatment of diseases associated with disturbances of bone metabolism, such as osteoporosis, Paget's disease, osteolysis caused by tumours and hyperparathyroidsm, osteoarthrosis, arthrytis and the like.
  • the toxicological studies which have been carried out have shown a toxicity of the compounds of the invention much lower than that of the corresponding non-methylated products. The results of these studies are summarized herebelow. a) 6-dimethylamino-l-hydroxy-hexan-l ,1- diphosphonic acid (DAEDP) .
  • compositions according to the present invention can be prepared in the form of: - tablets, capsules, granules, pills, for oral administration;
  • compositions are advantageously prepared in combination with inert excipients, such as sugars (saccharose, glucose, lactose) , starch and derivatives, cellulose and derivatives, fatty acids and salts thereof, polyalcohols, talc, aromatic esters.
  • inert excipients such as sugars (saccharose, glucose, lactose) , starch and derivatives, cellulose and derivatives, fatty acids and salts thereof, polyalcohols, talc, aromatic esters.
  • One capsule contains DAPeDP 25 mg lactose 84 mg hydrolyzed starch 5 mg talc 5 mg magnesium stearate 1 mg
  • One ampoule contains
  • DEDP 6- dimethylamino-hydroxyhexan-1,1-diphosphonic acid
  • the dosage range of the diphosphonic acids according to the present invention and of the relevant water-soluble saline derivative, according to the therapeutic use and referred to 1 Kg of body weight can be the following:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Acides diméthylamino-1-hydroxy-alcane-1,1-diphosphoniques répondant à la formule (I), dans laquelle n vaut 4 ou 5, leur procédé de production, et leur utilisation pour le traitement des maladies liées aux troubles du métabolisme osseux.
PCT/IT1992/000058 1991-06-26 1992-05-27 Acides dimethylamino-hydroxy-alcane-diphosphoniques et compositions pharmaceutiques les contenant Ceased WO1993000348A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5501416A JPH06508833A (ja) 1991-06-26 1992-05-27 ジメチルアミノ−ヒドロキシ−アルカンジホスホン酸類およびこれらを含有する医薬組成物
EP92913148A EP0592488A1 (fr) 1991-06-26 1992-05-27 Acides dimethylamino-hydroxy-alcane-diphosphoniques et compositions pharmaceutiques les contenant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITFI/91/A/000160 1991-06-26
ITFI910160A IT1247034B (it) 1991-06-26 1991-06-26 Acidi dimetilamino-idrossi alchil difosfonici e loro sali, loro procedimento produttivo e composizioni farmaceutiche che li comprendono

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WO1993000348A1 true WO1993000348A1 (fr) 1993-01-07

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PCT/IT1992/000058 Ceased WO1993000348A1 (fr) 1991-06-26 1992-05-27 Acides dimethylamino-hydroxy-alcane-diphosphoniques et compositions pharmaceutiques les contenant

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EP (1) EP0592488A1 (fr)
JP (1) JPH06508833A (fr)
AU (1) AU2150792A (fr)
CA (1) CA2112250A1 (fr)
IT (1) IT1247034B (fr)
MX (1) MX9203205A (fr)
PT (1) PT100624B (fr)
WO (1) WO1993000348A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008425A1 (fr) * 2001-07-16 2003-01-30 Universite Paris 13 Nouveaux derives de bisphosphonates, leurs preparations et utilisations
US6573252B1 (en) 1998-07-28 2003-06-03 Nicox, S.A. Medicine nitrate salts

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102014115154A1 (de) * 2014-10-17 2016-04-21 SCV-SpezialChemikalien-Vertrieb GmbH Konjugierte Bisphosphonate für die Diagnostik und Therapie von Knochenerkrankungen

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2499408A1 (fr) * 1981-02-12 1982-08-13 Gentili Ist Spa Composition pharmaceutique pour le traitement de l'osteopathie, a base d'acide 6-amino-1-hydroxyhexane-1,1-diphosphonique
GB2118042A (en) * 1982-04-15 1983-10-26 Gentili Ist Spa Pharmaceutical compositions containing biphosphonic acids
EP0175315A2 (fr) * 1984-09-21 1986-03-26 Henkel Kommanditgesellschaft auf Aktien Acide diméthylamino-4 hydroxy-1 butanediphosphonique-1,1, leurs sels solubles dans l'eau, leur procédé de préparation insi que leur utilisation
EP0252504A1 (fr) * 1986-07-11 1988-01-13 Roche Diagnostics GmbH Dérivés d'acides diphosphoniques, procédé pour les préparer et médicaments contenant ces composés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2499408A1 (fr) * 1981-02-12 1982-08-13 Gentili Ist Spa Composition pharmaceutique pour le traitement de l'osteopathie, a base d'acide 6-amino-1-hydroxyhexane-1,1-diphosphonique
GB2118042A (en) * 1982-04-15 1983-10-26 Gentili Ist Spa Pharmaceutical compositions containing biphosphonic acids
EP0175315A2 (fr) * 1984-09-21 1986-03-26 Henkel Kommanditgesellschaft auf Aktien Acide diméthylamino-4 hydroxy-1 butanediphosphonique-1,1, leurs sels solubles dans l'eau, leur procédé de préparation insi que leur utilisation
EP0252504A1 (fr) * 1986-07-11 1988-01-13 Roche Diagnostics GmbH Dérivés d'acides diphosphoniques, procédé pour les préparer et médicaments contenant ces composés

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6573252B1 (en) 1998-07-28 2003-06-03 Nicox, S.A. Medicine nitrate salts
WO2003008425A1 (fr) * 2001-07-16 2003-01-30 Universite Paris 13 Nouveaux derives de bisphosphonates, leurs preparations et utilisations

Also Published As

Publication number Publication date
EP0592488A1 (fr) 1994-04-20
AU2150792A (en) 1993-01-25
ITFI910160A0 (it) 1991-06-26
JPH06508833A (ja) 1994-10-06
CA2112250A1 (fr) 1993-01-07
PT100624A (pt) 1993-10-29
PT100624B (pt) 1999-07-30
MX9203205A (es) 1994-06-30
IT1247034B (it) 1994-12-12
ITFI910160A1 (it) 1992-12-26

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