• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention relates to organophosphorus substances, in particular the preparation of diophosphonic acid derivatives of the general formula 1 HET-AC [OH] [P (O) (OH) 2 ] 2 , where HET = pyridyl, 1,2,4-triazolyl, imidazolyl [it can be substituted by benzyl], 1,2,3-triazolyl [it may be substituted by benzyl, 4-methylbenzyl or 4-aminomethylbenzyl] Or izonasyschenna AH- C 2 -4-chain or sodium salts thereof, which exert an effect on calcium metabolism and can be used in medicine. The purpose of the invention is the creation of new, more active compounds of the indicated class. The synthesis of the target compounds is carried out by the reaction of the carboxylic acid of the general formula p: HET-AC [O] OH, where HET and A (see above) are reacted with phosphorous acid and phosphorus trichloride in chlorobenzene under heating and then hydrolyzed with hydrochloric acid under heating the selection of the target product in the form of a free derivative of diphosphonic acid or its salt. New compounds reduce hypercalcemia at a dose of 0.1-1.0 mg / kg and have low toxicity [against 10 mg] kg for 1-hydroxyethane-1,1-diphosphonic acid] 1 table.
    公开号:SU1475487A3
    申请号:SU853935742
    申请日:1985-08-01
    公开日:1989-04-23
    发明作者:Бозиес Эльмар；Галл Руди
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    J 1
    Changes in medical practice for the treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis and other diseases of the skeletal system.
    The purpose of the invention is to develop an affordable method for the preparation of new diphosphonic acid derivatives of general formula (I).
    Example 1. 1-Oxy-3- (4-imide zolyl) -propane-1,1-diphosphonic acid.
    3.53 g (20 mmol) of 3- (4-imidazolyl) -propionic acid hydrochloride together with 2.26 N phosphorous acid in 10 ml of chlorobenzene are heated to 4.12 g (30 mmol) of phosphorus trichloride while stirring heat the following
    4h at 110 ° C. After cooling, chlorine benzene is decanted and the residue together
    with 15 ml 6n. hydrochloric acid is refluxed for
    5 hours. Allow to cool, mix with activated carbon, filter and concentrate the solution. The residue is treated with 10 ml of water, adjusted to pH 5.5 with aqueous sodium bicarbonate solution, and mixed with methanol until precipitation stops. The residue is filtered off with suction, washed with methanol and dried. Yield 3.23 g (48% of theory).
    The substance is obtained as a mono-sodium salt with 1 mol of water of crystallization. P-NMR: 22.1 m „d. (ppm); P-NMR data given hereinafter referred to as phosphoric acid as an internal standard.
    Found,%: C 22.83; H 4.12; N 8.44; P 18.61; Na 7.31.
    Calculated,%: C 22.01; H 3.99; N 8.59; R 19.02; Na 7.06.
    According to the procedure of Example 1, the following compounds are prepared.
    a) From 3- (3-pyridyl) -propionic acid, 1-hydroxy-3- (3-pyridyl propane-1,1-diphosphonic acid is obtained in 25% yield. The substance is formed as a monosodium salt with 1.5 mol of water of crystallization
    P-NMR: 20.8 ppm
    Found,%: C 27.55; H 4.38; N 3.92; P 17.68; Na 6.67.
    Calculated,%: C 27.75; H 4.34; N 4.05; P 17.92; Na 6.65.





    15
    20
    25
    40
    0
    thirty
    b) From -3-1-benzyl-4- (1,2,3-tri-amp & zolyl) -propionic acid (mp. 110-112 °) is obtained by hydrogenation5 3 3-1-benzyl-4- (1,2,3-triazolyl) acrylic acid 3-1-benzyl-4- (1,2,3-triazolyl-1-hydroxypropro-1,1-diphosphonic acid) is obtained in 48% yield. The substance is obtained. in the form of the disodium salt with 1 mole of crystals of indoor water.
    P-NMR: 21.6 ppm
    Found,%: C 32.62; H 3.90; N 9.39; R 14.06; Na 10.73.
    Calculated,%: C 32.80; H 3.87; N 9.57; R 14.12; At 10.48.
    c) From 5-1-benzst-4- (1,2,3-triazolyl) valeric acid (m.p. 83-85 ° C) is obtained by hydrogenation
    5-J-benzyl-4- (1,2,3-triazolyl) -2,4-pentadienoic acid, benzyl-4- (1,2,3-triazolyl-1-oxo-pentane-1,1-diphosphonic) are obtained. acid with a yield of 53% o The substance is formed in the form of disodium salt with 1 mol of water of crystallization.
    P-NMR: 21.4 ppm
    Found,%: C 35.59; H 4.34; N 8.61; R 12.85; Na 10.46.
    Calculated,%: C 35.97; H 4.50; N 8.99; R 13.28; Na 9,850
    g) From 3- (4-pyridyl -) - propionic acid get 1-hydroxy-3- (4-pyridyl) propane-1,1-diphosphonic acid with
    35 yield of 56% o The substance is formed in the form of a monosodium salt with 2 mol of water of crystallization.
    P-NMR: 21.8 ppm
    Found,%: C 26.96; H 4.72; N 3.80; P 17.17; Na 6.43.
    Calculated,%: C 27.04; H 4.51; N 3.94; R 17.46; Na 6.48.
    d) From 3- (2-pyridyl) -propionic 5 acid get 1-hydroxy-3- (2-pyridyl) -propan-1,1-diphosphonic acid with a yield of 54%. The substance is formed as a monosodium salt with 2 mol of water of crystallization.
    P-NMR: 20.9 ppm
    Found,%: C 26.87; H 4.69; N 3.74; R 17.42; Na 6.30.
    Calculated,%: C 27.04; H 4.51; N 3.94; R 17.46; Na 6,480 S e) 3- (2-benzimidazolyl) -1-hydroxypropane-1,1-diphosphonic acid is obtained from 3- (2-benzylimidazolyl) -propionic acid in 24% o The substance is obtained in the form of monosodium
    salts with 1.5 mol of crystallization into odes
    P-NMR: 20.4 MOD.
    Found,%: C 31.05; H 4.31; N 7.18; R 15.74; Na 6.12.
    Calculated,%: C 31.17; H 4.16; N 7.27; P 16.10; Na 5.97.
    g) From 3-Ј1- (4-methylbenzyl) -1,2,3- | Triazol-4-yl-propionic acid
    1-oxy-3- 1 - (, 4-methylbenzyl) 1,2, 3-triazol-4-yl-propane-1,1-diphos-fonoic acid is obtained in a yield of 40%. The vesicles are obtained in the form of disodium salt with 1 , 5 mol of water of crystallization.
    P-NMR: 20.9 ppm
    Found,%: C 33.81; H 4.45; N 8.95; R 13.28; Na 10.27.
    Calculated,%: C 33.77; H 4.33; N 9.09; P 13.42; Na 9.96.
    h) From (4-aminomethylbenzyl) 1, 2,3-triazol-4-yl-propionic acid (m.p. 207-210 C) is obtained by catalytic hydrogenation of (4-cyanbenzyl) -1,2,3- triazol-4-yl} acrylic acid (m.p. 168-170 ° C), which in turn is obtained by oxidation of the corresponding 3- 1- (4-cyanbenzyl) -1,2,3-triazole 4-acrolein ( mp 152-155 C) (4-aminomethylbenzyl) -1, 2,3-triazol-4-yl -1-hydroxypropane-1,1-diphosphonic acid is obtained with a yield of 41%. The substance is obtained in the form of the disodium salt 1 mol of water of crystallization.
    P-NMR: 21.1 ppm
    Found,%: C 33.16; H 4.32; N, 11.76; R 12.86; Na 9,980
    Calculated,%: C 33.33; H 4.27; N 11.97; P 13.25; Na 9.83.
    i) From 3- (1,2,4-triazol-1-yl) -propionic acid, 1-hydroxy-3- (1,2,4-triazol-1-yl) propan-1,1-di phosphonic acid with a yield of 45%. The substance is obtained in the form of the disodium salt with 1.5 mol of crystallization vbdy.
    P-NMR: 21.4 m „d.
    Found,%: C 16.44; H 3.54; N 11.52; R 17.25; Na 13.05
    Calculated,%: C 16.76; H 3.35; N 11.73; R 17.32; Na 12.85.
    k) From 3- (1,2,4-triazole 1-yl) butyric acid get 1-hydroxy-3- (1, 2,4-triazol-1-yl) -butane-1,1-diphosphonic acid with a yield of 44%. Substance receive in the form of disodium salt with 1.5 mol of water of crystallization
    P-NMR: 21.5 ppm
    Found,%: C 19.21; H 3.85; N 11.33; P 16.47; Na 12.75.
    Calculated,%: C 19.36; H 3.76; N 11.29; P 1.6,66; Na 12.37.
    l) From 5- (1,2,4-triazol-1-yl) -valananoic acid, 1-hydroxy-5- (1,2,4-triazol-1-yl) -pentane-1,1-1 is obtained diphosphonic acid with a yield of 53% o The substance is obtained in the form of disodium salt with 1.5 mol of crystallization
    WATER O
    P-NMR: 21.7 m „d.
    Found,%: C 21.76; H 4.18; N 10.85; R 15.95; Na 12.01.
    Calculated,%: C, 21.76; H 4.15; N 10.88; P 16.06; Na 11.92.
    m) From 3- (1-benzyl-imidazol-2-yl) -propionic acid, benzyl-imidazol-2-yl- (1-hydroxypropane) 1,1-diphosphonic acid is obtained with a yield of 71%. 0 The substance is isolated as free acids with so pl. 230-232 ° C (foaming).
    P-NMR: 21.8 ppm
    m) From 5- (1,2,3-triazol-4-yl) -valerianic acid, 1-hydroxy-5- (1,2,3-triazol-4-yl) -pentane-1,1-1 is obtained. diphosphonic acid with a yield of 43%. The compound is obtained in the form of the disodium salt with 2 mol of water of crystallization. I
    P-NMR: 21.6 m. To
    Found,%: C 21.5; H 4.25; N 10.70; P 15.6; Na 11.54.
    Calculated,%: C, 21.32; H 4.47; N 10.52; R 15.36; Na 11.88.
    o) From 3- (imidazol-2-yl) -propionic acid, 1-hydroxy-3 (imidazol-2-yl) propane-1,1-diphosphonic acid is obtained with a yield of 37% 0 T. mp 234- 244 C,
    P-NMR: 21.7 m, d
    Example 2. Tests of the compounds obtained.
    Male rats weighing approximately 160 g on the first day of the tiroparathyroid isometized. Calceamino was determined on the fifth day after the night of fasting. Starting from this day, all animals receive the same amount of feed. In addition, they receive subcutaneous injections successively for three days.
    Moreover, some receive 25 µg of synthetic retinoid (to induce hypercalcemia), others receive the tested diphosphonate.
    Additionally, all animals on the first and last days undergo treatment with 2 µg of pyroxinzo 24 hours after the last injection of retinoid and diphos fonate and after an overnight fasting period. , etheric anesthesia retroorbital run rets blood.
    By absorbing the atoms, the calcium concentration in the plasma is determined.
    Diphosphonates are administered initially at a dose of 0.1 mg / kg in a volume of 2 ml / kg, less actively additionally administered at a dose of 1 mg / kg and 10 mg / kg.
    The table shows the test data in comparison with 1-hydroxy-ethane-1,1-diphosphonic acid.
    In animal experiments, no recognized Ki toxicity was found. Therefore, the compounds obtained can be classified as low-toxic compounds.

    or their sodium salts, characterized in that the carboxylic acid of formula II
    Het-a-cooh
    where Het and A have the indicated meanings, interact with phosphorous acid and phosphorus trichloride in chlorobenzene under heating with subsequent hydrolysis with hydrochloric acid under heating and release of the target product in the form of a free diphosphonic acid derivative of the formula I or in the form of sodium with oligo
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives of diphosphonic acid of the formula I
    about
    and
    P (OH) g
    Het-A-C-OH
    P (OH) 2 O
    de Het - pyridyl, 1,2,4-triazolyl, unsubstituted or substituted on the benzyl group; imidazolyl, unsubstituted or substituted on the benzyl, 4-methylbenzyl or 4-aminomethylbenzyl group 1,2,3-triazolyl; A - linear or branched saturated carbon-carbon on a chain with 2-4 carbon atoms,
     thirty
    Note,
    O - decrease in hypercalcemia by from -0.99 to +99 kg%; (+) - reduction of hypercalcemia from 0.1 to 1.99 kg%; + - decrease in hypercalcemia from 2.0 to 2.99 kg%; ++ - reduction of hypercalcemia from 3.0 to 3.99 kg%; +++ - reduction of hyper. Calceamia more than 4.0 kg% 0
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    引用文献:
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    PH9776A|1967-12-11|1976-03-17|M Francis|Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue and method of use|
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    DE3203308A1|1982-01-27|1983-07-28|Schering Ag, 1000 Berlin Und 4619 Bergkamen|DIPHOSPHONIC ACID DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|
    DE3203309A1|1982-01-27|1983-07-28|Schering Ag, 1000 Berlin Und 4619 Bergkamen|DIPHOSPHONIC ACID DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|
    DE3428524A1|1984-08-02|1986-02-13|Boehringer Mannheim Gmbh, 6800 Mannheim|NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|DE3428524A1|1984-08-02|1986-02-13|Boehringer Mannheim Gmbh, 6800 Mannheim|NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    IL77243A|1984-12-21|1996-11-14|Procter & Gamble|Pharmaceutical compositions containing geminal diphosphonic acid compounds and certain such novel compounds|
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    US5641762A|1985-05-02|1997-06-24|Research Corporation Technologies, Inc.|Bone targeted inhibitors of carbonic anhydrase|
    DE3540150A1|1985-11-13|1987-05-14|Boehringer Mannheim Gmbh|NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    US4902679A|1985-12-13|1990-02-20|Norwich Eaton Pharmaceuticals, Inc.|Methods of treating diseases with certain geminal diphosphonates|
    EP0243173B1|1986-04-24|1991-06-26|Fujisawa Pharmaceutical Co., Ltd.|New diphosphonic acid compounds, processes for the preparation thereof and pharmaceutical composition comprising the same|
    DE3626058A1|1986-08-01|1988-02-11|Boehringer Mannheim Gmbh|NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    DE3776880D1|1986-11-21|1992-04-02|Ciba Geigy Ag|NEW SUBSTITUTED ALKANDIPHOSPHONIC ACIDS.|
    US5057505A|1986-11-21|1991-10-15|Ciba-Geigy Corporation|Substituted aminomethanediphosphonic acids and use in medicaments|
    US4871720A|1986-11-21|1989-10-03|Ciba-Geigy Corporation|Aromatically substituted azacycloalkyl-alkanediphosphonic acids useful for the treatment of illnesses that can be attributed to calcium metabolism disorders|
    DE3640938A1|1986-11-29|1988-06-01|Boehringer Mannheim Gmbh|NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND|
    US4868164A|1986-12-19|1989-09-19|Norwich Eaton Pharmaceuticals, Inc.|Octahydro-pyridine diphosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism|
    US5071840A|1986-12-19|1991-12-10|Norwich Eaton Pharmaceuticals, Inc.|Certain heterocyclic substituted diphosphonate compounds pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism|
    US4939265A|1987-02-25|1990-07-03|Bristol-Myers Company|Intermediates and process for the preparation of antihypercholesterolemic tetrazole compounds|
    US4973576A|1987-03-10|1990-11-27|Yamanouchi Pharmaceutical Co., Ltd.|Bisphophonic acid derivatives and pharmaceutical compositions containing the same|
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    TW198039B|1988-11-28|1993-01-11|Ciba Geigy Ag|
    US5110807A|1988-12-01|1992-05-05|Ciba-Geigy Corporation|Araliphatylaminoalkanediphosphonic acids|
    DE3917153A1|1989-05-26|1990-11-29|Boehringer Mannheim Gmbh|NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    MX21452A|1989-07-07|1994-01-31|Ciba Geigy Ag|PHARMACEUTICAL PREPARATIONS THAT ARE TOPICALLY ADMINISTERED.|
    US5139786A|1989-07-07|1992-08-18|Ciba-Geigy Corporation|Topical formulations|
    EP0510066A4|1990-01-12|1992-12-02|Rhone-Poulenc Rorer InternationalInc.|1-azetidyl and 1-hexamethylenimine alkyl or aryl bisphosphonic acids and their use as pharmacological agents|
    US5204334A|1990-10-18|1993-04-20|Ciba-Geigy Corporation|Benzoheterocyclylalkylaminoalkanediphosphonic acids, compositions thereof, and use thereof in the treatment of calcium metabolism disorders|
    AU666741B2|1992-05-29|1996-02-22|Procter & Gamble Pharmaceuticals, Inc., The|Thio-substituted nitrogen-containing heterocyclic phosphonate compounds for treating abnormal calcium and phosphate metabolism|
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    US5391743A|1992-05-29|1995-02-21|Procter & Gamble Pharmaceuticals, Inc.|Quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental calculus and plaque|
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    CA2136825C|1992-05-29|1997-10-28|Frank H. Ebetino|Quaternary nitrogen-containing phosphonate compounds, for treating abnormal calcium and phosphate metabolism as well as dental calculus and plaque|
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    AU670337B2|1992-11-30|1996-07-11|Novartis Ag|Use of certain methanebisphosphonic acid derivatives in fracture healing|
    JPH06298779A|1993-04-15|1994-10-25|Hoechst Japan Ltd|Heterocyclic iminobismethylenebisphosphonic acid derivaitve|
    GB9324143D0|1993-11-24|1994-01-12|Schering Agrochemicals Ltd|Triazole phosphonate pesticides|
    ES2239774T3|1995-09-29|2005-10-01|Novartis Ag|METHOD OF TREATMENT OF NAVICULAR DISEASE IN HORSES.|
    IL150059D0|1999-12-17|2002-12-01|Ariad Pharma Inc|Novel heterocycles|
    EP1248790A1|1999-12-17|2002-10-16|Ariad Pharmaceuticals, Inc.|Proton pump inhibitors|
    IL150062D0|1999-12-17|2002-12-01|Ariad Pharma Inc|Proton pump inhibitors|
    US6677320B2|2000-01-20|2004-01-13|Hoffmann-La Roches Inc.|Parenteral bisphosphonate composition with improved local tolerance|
    US6410520B2|2000-02-01|2002-06-25|The Procter & Gamble Company|Selective crystallization of 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphonic acid sodium as the hemipentahydrate or monohydrate|
    CA2372450A1|2001-05-10|2001-09-19|Pharmaceutical Partners Of Canada Inc.|Liquid injectable formulation of disodium pamidronate|
    RU2387451C2|2002-05-10|2010-04-27|Ф.Хоффманн-Ля Рош Аг|Bisphosphonic acids intended for treatment and prevention of osteoporosis|
    JP4485117B2|2002-06-27|2010-06-16|日東電工株式会社|Protective peeling film|
    AU2003250190A1|2002-07-30|2004-02-23|Novartis Ag|Combination of an aromatase inhibitor with a bisphosphonate|
    TW200413381A|2002-11-04|2004-08-01|Hoffmann La Roche|Novel amino-substituted dihydropyrimido [4,5-d]pyrimidinone derivatives, their manufacture and use as pharmaceutical agents|
    US20040206932A1|2002-12-30|2004-10-21|Abuelyaman Ahmed S.|Compositions including polymerizable bisphosphonic acids and methods|
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    US20050065171A1|2003-06-25|2005-03-24|Shakespeare William C.|Substituted purine derivatives|
    JP5001006B2|2003-08-12|2012-08-15|スリーエムイノベイティブプロパティズカンパニー|Self-etching dental compositions and methods|
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    PL407922A1|2014-04-16|2015-10-26|Wrocławskie Centrum Badań Eit + Spółka Z Ograniczoną Odpowiedzialnością|New bisphosphonates and their applications|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3428524A|DE3428524A1|1984-08-02|1984-08-02|NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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