PL148892B1 - Method of obtaining novel derivatives of methylene diphosphonic acid - Google Patents
Method of obtaining novel derivatives of methylene diphosphonic acid Download PDFInfo
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- PL148892B1 PL148892B1 PL1985262371A PL26237185A PL148892B1 PL 148892 B1 PL148892 B1 PL 148892B1 PL 1985262371 A PL1985262371 A PL 1985262371A PL 26237185 A PL26237185 A PL 26237185A PL 148892 B1 PL148892 B1 PL 148892B1
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- Poland
- Prior art keywords
- group
- alk
- alkyl group
- derivatives
- acid
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- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical class OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 title claims abstract 3
- 238000000034 method Methods 0.000 title claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 150000002367 halogens Chemical class 0.000 claims abstract 2
- 125000005842 heteroatom Chemical group 0.000 claims abstract 2
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 2
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract 2
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 2
- 239000011593 sulfur Substances 0.000 claims abstract 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 230000003356 anti-rheumatic effect Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract 2
- 239000001257 hydrogen Substances 0.000 abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 206010003246 arthritis Diseases 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- -1 2-pyridylthio Chemical group 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- JDJVDSQKIBHWCZ-UHFFFAOYSA-N 4-cyclohexylsulfanylbutanenitrile Chemical compound N#CCCCSC1CCCCC1 JDJVDSQKIBHWCZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010036030 Polyarthritis Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 208000030428 polyarticular arthritis Diseases 0.000 description 2
- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ZFCFBWSVQWGOJJ-UHFFFAOYSA-N 4-chlorobutanenitrile Chemical compound ClCCCC#N ZFCFBWSVQWGOJJ-UHFFFAOYSA-N 0.000 description 1
- IUQQLRKTOFNJPZ-UHFFFAOYSA-N 4-cyclohexylbutanenitrile Chemical compound N#CCCCC1CCCCC1 IUQQLRKTOFNJPZ-UHFFFAOYSA-N 0.000 description 1
- UCTRMDIAXYRCPQ-UHFFFAOYSA-N 5-pyridin-2-ylsulfanylpentanenitrile Chemical compound N#CCCCCSC1=CC=CC=N1 UCTRMDIAXYRCPQ-UHFFFAOYSA-N 0.000 description 1
- PHOSWLARCIBBJZ-UHFFFAOYSA-N 6-bromohexanenitrile Chemical compound BrCCCCCC#N PHOSWLARCIBBJZ-UHFFFAOYSA-N 0.000 description 1
- ARBKOBWNWWJGEW-UHFFFAOYSA-N 6-propylsulfanylhexanenitrile Chemical compound CCCSCCCCCC#N ARBKOBWNWWJGEW-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- CMKBCTPCXZNQKX-UHFFFAOYSA-N cyclohexanethiol Chemical compound SC1CCCCC1 CMKBCTPCXZNQKX-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
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)]
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- 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)]
- C07F9/44—Amides thereof
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Dental Preparations (AREA)
- Medicinal Preparation (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Liquid Developers In Electrophotography (AREA)
- Detergent Compositions (AREA)
- Anti-Oxidant Or Stabilizer Compositions (AREA)
- Steroid Compounds (AREA)
- External Artificial Organs (AREA)
- Fireproofing Substances (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Opis patentowy opublikowano: 1990 03 312 148 892 W przypadku gdy n równe zero a Alk oznacza grupe -CH2-CH2-, wariant sposobu polega na reakcji tiolu R1SH z akrylonitrylem w obecnosci zasady organicznej, zgodnie z procedura opisana w pracy CD. Hurda i L.L. Gershbeina, J. Am. Chem. Soc, 69 2328 /1947/. Takotrzymany nitryl ogrzewa sie nastepnie w obecnosci kwasu fosforowego w temperaturze 140-200°C w ciagu od 1 godziny do kilku godzin. Otrzymane w ten sposób kwasy fosforowe moga byc przeksztalcone w sole znanymi sposobami. Reakcje prowadzi sie w goracym rpzpuszczalniku, tak aby przy ochlo¬ dzeniu krystalizowala sól, ewentualnie po dodaniu jednej trzeciej czesci rozpuszczalnika.Zwiazki wytwarzane sposobem wedlug wynalazku moga byc korzystnie stosowane jako leki przciwzapalne i przeciwreumatyczne. Ich wlasciwosci farmakologiczne stwierdzono w sposób nastepujacy. Badanie in vivo: zapalenie stawu pod wplywem srodka pomocniczego. Wstrzykniecie mycobacterium wywoluje u szczura zapalenie wielostawowe, przypominajace pod pewnymi wzgle¬ dami zapalenie stawu u czlowieka podobne do goscca.Protokól z przeprowadzonych prób: Zawiesine Mycobacterium Tuberculosis/0,4 mg/ w oleju parafinowym /0,05 ml/ wstrzyknieto droga sródskórna w ogon samców szczurów Sprague-Dawley o srednim ciezarze 150 g. Po 15 dniach wybrano zwierzeta wykazujace nasilniejsze objawy zapale¬ nia stawu. Zwierzeta te podzielono na 2 grupy po 14 zwierzat. Zwierzeta z pierwszej grupy traktowano 6 dni/tydzien w ciagu 3 tygodni: badz droga podskórna dawkami od 0,32 mikromoli do 32 mikromoli/kg/dzien, badz droga doustna dawka 0,16mmola/kg/dzien. Druga grupa otrzymala placebo i sluzyla jako kontrola.Po 3 tygodniach polowe zwierzat z kazdej grupy usmiercono, druga polowe zachowano w ciagu dalszych 2 tygodni bez traktowania zwiazkami a nastepnie usmiercono. Po usmierceniu, tylna prawa lape szczurów odcieto na wysokosci stawu skokowo-goleniowego i zwazono. Dla kazdej pólgrupy oznaczono sredni ciezar i blad standardowy. Aktywnosc produktu wyrazono przez zmiane w % sredniego ciezaru lap szczurów z zapaleniem stawu potraktowano zwiazkami otrzymanymi sposobem wedlug wynalazku w stosunku do sredniego ciezaru lap szczurów kontrol¬ nych. Rezultaty otrzymane dla róznych produktów otrzymanych sposobem wedlug wynalazku zestawiono w tabeli ponizej. Dla kazdego z badanych produktów aktywnosci terapeutyczna wyrazono w % inhibitowania ciezaru lapy po 3 tygodniach traktownia.Przedstawiono równiez rezultat uzyskany po 5 tygodniach, tzn. po 3 tygodniach traktowania i dalszych 2 tygodniach bez traktownia.Tabela Produkt SR nr 42 708 A 42 708 A Droga podawania doustna doustna % inhibitowania po zakonczeniu traktowania /3 tygodnie/ 28 0 ciezaru lapy po 2 tygodniach od zakonczenia traktowania 22 14 Przytoczone rezultaty wykazuja wysoka aktywnosc przeciwreumatyczna zwiazków otrzyma¬ nych sposobem wedlug wynalazku po 3 tygodniach traktowania.Nalezy zaznaczyc, ze aktywnosc ta utrzymuje sie na wysokim poziomie a niekiedy rosnie nawet po 2 tygodniach od zakonczenia traktowania.Produkty otrzymane sposobem wedlug wynalazku sa ponadto malo toksyczne. Moga one byc stosowane w leczeniu ludzi do zwalczania chorób o podlozu zapalnym, a zwlaszcza w leczeniu zapalenia stawów. Zwiazki te nadaja sie szczególnie do leczenia zapalenia wielostawowego przy¬ pominajacego gosciec i przygotowuje sie je w postaci kompozycji farmaceutycznych zawierajacych jako skladnik aktywny zwiazek otrzymany sposobem wedlug wynalazku, w polaczeniu z nosnikiem farmaceutycznie dopuszczalnym. Kompozycje takie moga wystepowac w postaciach nadajacych sie do podawania droga doustna, doodbytnicza i pozajelitowa. Moga to byc zwlaszcza kapsluki zelatynowe lub tabletki zawierajace 10-500 mg zwiazku aktywnego najednostke. Dzienna dawka tych produktów dla doroslego moze wynosic od 100 mg do 5 g i byc podzielona na kilka porcji.148892 3 Ponizsze przyklady ilustruja sposób wedlug wynalazku.Przyklad I. Sól czterosodowa kwasu l-amino-4-cykloheksylotio-butylidendifosfonowe- go-1,1, jednowodna /SR 42 684 A/ Ri = cykloheksyl, n = 0, Alk = /CH2/3, a/ 4-Cykloheksylotio-butyronitryl. Do roztworu 3,5 g sodu w 75 ml metanolu dodano 18 g cykloheksanotiolu. Mieszano w tempraturze 20°C w ciagu 1 godziny, po czym dodano 14,2 ml 4-chlorobutyronitrylu. Mieszanine ogrzewano w temeraturze wrzenia pod chlodnica zwrotna w ciagu 3 godzin, po czym zatezono pod próznia. Pozostalosc rozpuszczono w 300 ml eteru. Roztwór przemyto woda, osuszono i zatezono. Z pozostalosci destylowanej pod cisnieniem 4 Pa otrzymano 20,8 g bezbarwnego oleju destylujacego w temperaturze 120-125°C. Takotrzymany 4-cykloheksy- lo-butyronitryl charakteryzowal sie Rf = 0,70 w chromatografii cienkowarstwowej na krzemionce /Kieselgel 60 F 54 Merck/, przy stosowaniu eteru izopropylowego jako eluenta. b/ Sól czterosodowa kwasu l-amino-4-cykloheksylo-tio-butylidendifosfonowego-l,l, jedno- wodna. Mieszanine lig kwasu fosforowego i 10g 4-cykloheksylotio-butyronitrylu ogrzewano w temperaturze 160°C w ciagu 3 godzin. Po oziebieniu do mieszaniny dodano 40 ml wody. Wykrysta¬ lizowal osad barwy zóltej, który przemyto kolejno woda, acetonem i eterem. Zwiazek ten rozpu¬ szczono w roztworze 1,5 g wodorotlenku sodowego w 70 ml wody destylowanej. Mieszanine ogrzewano przy mieszaniu w temperaturze 50°C do calkowitego rozpuszczenia, pozostawiono do oziebienia i dodano 250 ml metanolu. Otrzymany bezbarwny osad odsaczono, przemyto metano¬ lem i wysuszono w temperaturze 80°C pod cisnieniem 13,3 Pa. Temperatura topnienia powyzej 300°C.Analiza elementarna z 1 czasteczka wody: Obliczono, % C 26,49 H 4,67 N 3,08 Znaleziono, %C 25,93 H 4,90 N 3,04 Przyklad II. Sól dwusodowa kwasu l-amino-5-/2-pirydylotio/pentylidendifosfonowego- 1,1 /SR 42 709 A/ Ri = 2-pirydyl, n = 0, Alk = /CH2/4, a/ 5-/2-Pirydylotio/waleronitryl. Do roztworu 2,26 g sodu w 200 ml metanolu dodano kolejno 10 g 2-merkaptopirydyny i 20 g 6-bromowaleronitrylu. Po 3 godzinach ogrzewania w temperaturze wrzenia pod chlodnica zwrotna mieszanine zatezono pod próznia. Pozostalosc rozpuszczono w 200 ml eteru. Roztwór przemyto woda, wysuszono i zatezono. Otrzymano 15 g oczekiwanego nitrylu charakteryzujacego sie Rf = 0,39 w chromatografii cienkowarstwowej na krzemionce /Kieselgel 60 F 54 Merck/, przy stosowaniu eteru izopropylowego jako eluenta. b/ Sól dwusodowa kwasu l-amino-5-/2-pirydylotio/-pentylidendifosfonowego-l,l. Miesza¬ nine 10,2 g 5-/2-pirydylotio/waleronitrylu i 12 g kwasu fosforowego ogrzewano w temperaturze 150°C w ciagu 1 godziny a nastepnie w temperaturze 170°C w ciagu 3 godzin. Po oziebieniu do mieszaniny dodano 100 ml wody i 2,5 g octanu sodowego. Mieszanine ekstrahowano dwukrotnie eterem i oddzielono faze wodna. Dodano do niej 300 ml metanolu, odsaczono wytracony osad, przemyto metanolem a nastepnie eterem i przekrystalizowano z mieszaniny woda — metanol /60 : 40/. Otrzymano 4,2 g oczekiwanego produktu o temperaturze topnienia powyzej 300°C.Analiza elementarna: Obliczono, % C 30,00 H 4,03 N 7,00 Znaleziono, % C 30,00 H 4,20 N 7,02 Przykladni. Sól dwusodowa kwasu l-amino-6-propylotio-heksylidenodifosfonowego- 1,1 /SR 42 708 A/. Ri = -/CH2/2-CH3, n = 0, Alk = /CH2/5, a/ l-Cyjano-5-propylotio-pentan. Do roztworu 8 g sodu w 600 ml etanolu dodano kolejno 26 g propanotiolu i 45 g l-cyjano-5-bromopentanu. Po 6 godzinach ogrzewania w temperaturze wrzenia pod chlodnica zwrotna odparowano rozpuszczalnik a pozostalosc rozpuszczono w 500 ml wody i ekstrahowano eterem. Warstwe organiczna zatezono i chromatografowano na kolumnie z krze¬ mionka /0,062 — 0,053 mm/. Otrzymano 28 g oczekiwanego nitrylu charakteryzujacego sie Rf = 0,60 w chromatografii cienkowarstwowej na zelu krzemionkowym /Kieselgel 60 F 54 Merck/ przy uzyciu jako eluenta eteru izopropylowego /Rf = 0,10 gdy jako eluent stosowano mieszaniny aceton — heksan 1: 9/. b/ Sól dwusodowa kwasu l-amino-6-propylotio-heksylidenodifosfonowego-l,l. Roztwór 17,5 g l-cyjano-5-propylotiopentanu i 20 g kwasu fosforawego ogrzewano w temperaturze 150°C w ciagu 1 godziny a nastepnie w temperaturze 180°C w ciagu 2 godzin. Po oziebieniu osad rozpu-4 148 892 szczono w acetonie, przesaczono i wysuszono. Osad rozpuszczono w roztworze 40 g octanu sodowego w 400 ml wody. Mieszanine mieszano w ciagu 1 godziny i przesaczono. Nastepnie do wodnego roztworu dodano 400 ml metanolu i odsaczono osad. Po wysuszeniu otrzymano 11,5 g oczekiwanego produktu o temperaturze topnienia powyzej 300°C.Analiza elementarna: Obliczono, %C28,6 H 5,57 N 3,7 Znaleziono, %C28,1 H 5,84 N 3,46 PL PL
Claims (1)
1. Zastrzezenie patentowe Sposób wytwarzania pochodnych kwasu metylenodifosfonowego o wzorze ogólnym przed¬ stawionym na zalaczonym rysunku, w którym: Ri oznacza grupe alkilowa o 1-6 atomach wegla, grupe cykloalkilowa o 5-7 atomach wegla, grupe fenylowa ewentualnie podstawiona jednym lub kilkoma podstawnikami takimi jak atomy chlorowca lub grupe alkilowa o 1-6 atomach wegla lub grupe trifluorometylowa; pierscien heterocykliczny o 5 lub 6 czlonach zawierajacy 1 lub 2 heteroa¬ tomy takie jak azot i siarka, Alk oznacza grupe alkilenowa prosta lub rozgaleziona o 1-6 atomach wegla, n oznacza liczbe calkowita 0, 1 lub 2, z tym, ze Ri nie oznacza grupy CH3 gdy Alk oznacza grupe -CH2-CH2-, a n jest równe 0, oraz soli wymienionych pochodnych z zasadami mineralnymi lub organicznymi, znamienny tym, ze ogrzewa sie nitryl o wzorze Ri S/O/n-Alk-CN, w którym Ri i n maja znaczenie podane poprzednio, w obecnosci kwasu fosforowego w temperaturze 140-200°C i ewentualnie przeksztalca otrzymany kwas w jedna z jego soli. HO 0 NH2 0 OH Pracownia Poligraficzna UP RP. Naklad 100 egz. Cena 1500 zl PL PL
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8401214A FR2558837B1 (fr) | 1984-01-26 | 1984-01-26 | Derives de l'acide methylenediphosphonique, procede d'obtention et medicaments antirhumatismaux les contenant |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PL148892B1 true PL148892B1 (en) | 1989-12-30 |
Family
ID=9300506
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL1985262371A PL148892B1 (en) | 1984-01-26 | 1985-01-25 | Method of obtaining novel derivatives of methylene diphosphonic acid |
| PL1985251700A PL142493B1 (en) | 1984-01-26 | 1985-01-25 | Process for preparing novel derivatives of methylenediphosphonic acid |
| PL1985263722A PL144353B1 (en) | 1984-01-26 | 1985-01-25 | Method of obtaining novel derivatives of methylenediophosphonic acid |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL1985251700A PL142493B1 (en) | 1984-01-26 | 1985-01-25 | Process for preparing novel derivatives of methylenediphosphonic acid |
| PL1985263722A PL144353B1 (en) | 1984-01-26 | 1985-01-25 | Method of obtaining novel derivatives of methylenediophosphonic acid |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US4876247A (pl) |
| EP (1) | EP0151072B1 (pl) |
| JP (1) | JPS60174792A (pl) |
| KR (1) | KR850005449A (pl) |
| AT (1) | ATE32900T1 (pl) |
| AU (1) | AU570764B2 (pl) |
| CA (1) | CA1263397A (pl) |
| CS (2) | CS247192B2 (pl) |
| DD (1) | DD233847A5 (pl) |
| DE (1) | DE3561819D1 (pl) |
| DK (1) | DK168573B1 (pl) |
| EG (1) | EG16903A (pl) |
| ES (1) | ES539833A0 (pl) |
| FI (1) | FI77664C (pl) |
| FR (1) | FR2558837B1 (pl) |
| GR (1) | GR850160B (pl) |
| HU (1) | HU192664B (pl) |
| IE (1) | IE57971B1 (pl) |
| IL (1) | IL74117A (pl) |
| MA (1) | MA20331A1 (pl) |
| NO (1) | NO161678C (pl) |
| NZ (1) | NZ210945A (pl) |
| OA (1) | OA07941A (pl) |
| PH (1) | PH20913A (pl) |
| PL (3) | PL148892B1 (pl) |
| PT (1) | PT79859B (pl) |
| SG (1) | SG43289G (pl) |
| SU (3) | SU1382402A3 (pl) |
| YU (2) | YU11785A (pl) |
| ZA (1) | ZA85390B (pl) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4902679A (en) * | 1985-12-13 | 1990-02-20 | Norwich Eaton Pharmaceuticals, Inc. | Methods of treating diseases with certain geminal diphosphonates |
| IL84731A0 (en) * | 1986-12-19 | 1988-05-31 | Norwich Eaton Pharma | Heterocycle-substituted diphosphonic acids and salts and esters and pharmaceutical compositions containing them |
| IE912115A1 (en) * | 1990-06-25 | 1992-01-01 | Takeda Chemical Industries Ltd | Bisphosphonic acid derivatives, their production and use |
| IE914417A1 (en) * | 1990-12-19 | 1992-07-01 | Takeda Chemical Industries Ltd | Bisphosphonic acid derivatives, their production and use |
| WO1993005052A1 (fr) * | 1991-09-05 | 1993-03-18 | Toray Industries, Inc. | Derive d'acide methanediphosphonique, sa production et son utilisation comme remede |
| EP0541037A3 (en) * | 1991-11-06 | 1997-02-26 | Takeda Chemical Industries Ltd | Squalene synthetase inhibitory composition and use thereof |
| RU2126414C1 (ru) * | 1992-05-29 | 1999-02-20 | Дзе Проктер энд Гэмбл Фармасьютикалз, Инк. | Содержащие четвертичный азот фосфонаты для лечения анормального кальциевого и фосфатного метаболизма, а также профилактики и лечения зубных налетов и зубных камней, фармацевтические композиции и способ лечения |
| US5753634A (en) * | 1992-05-29 | 1998-05-19 | The Procter & Gamble Company | Quaternary nitrogen containing phosphonate compounds, pharmaceutical compostions, and methods for treating abnormal calcium and phosphate metabolism |
| US5391743A (en) * | 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 |
| SK144694A3 (en) * | 1992-05-29 | 1995-06-07 | Procter & Gamble Pharma | Thio-substituted nitrogen containing heterocyclic phosphate compounds for treating calcium and phosphate metabolism |
| NZ253524A (en) * | 1992-05-29 | 1997-01-29 | Procter & Gamble Pharma | Sulphur-containing phosphonate derivatives and medicaments (for treating abnormal calcium and phosphate metabolism) |
| US5763611A (en) * | 1992-05-29 | 1998-06-09 | The Procter & Gamble Company | Thio-substituted cyclic phosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
| AU675796B2 (en) * | 1992-06-30 | 1997-02-20 | Procter & Gamble Pharmaceuticals, Inc. | Compositions for the treatment of arthritis containing phosphonates and NSAIDS |
| KR100272907B1 (ko) * | 1992-07-10 | 2001-03-02 | 히라이 가쯔히꼬 | 메탄디포스폰산 유도체, 이의 제조방법 및 이의 의약 용도 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1958123C3 (de) * | 1969-11-19 | 1978-09-28 | Henkel Kgaa, 4000 Duesseldorf | Verfahren zur Herstellung von 1 -Aminoalkan-1,1 -diphosphonsäuren oder deren Salzen |
| DE2115737C3 (de) * | 1971-03-31 | 1979-11-08 | Henkel Kgaa, 4000 Duesseldorf | Verfahren zur Herstellung von 1 - Aminoalkan-1,1 -diphosphonsäuren |
| DE2405254C2 (de) * | 1974-02-04 | 1982-05-27 | Henkel KGaA, 4000 Düsseldorf | Verwendung von 3-Amino-1-Hydroxypropan-1, 1-diphosphonsäure oder ihrer wasserlöslichen Salze bei der Beeinflußung von Calciumstoffwechselstörungen im menschlichen oder tierischen Körper |
| US4100167A (en) * | 1977-05-09 | 1978-07-11 | Nalco Chemical Company | Production of 1-aminoalkane-1, 1-diphosphonic acids using phosphorous acid and nitriles in a non-aqueous system |
| DE2754821C3 (de) * | 1977-12-09 | 1981-08-13 | Benckiser-Knapsack Gmbh, 6802 Ladenburg | Verfahren zur Herstellung von 1-Aminoalkan-1,1-diphosphonsäuren |
| GB2043072B (en) * | 1979-02-13 | 1983-11-23 | Symphar Sa | Diphosphonate compounds |
| DE3225469A1 (de) * | 1982-07-05 | 1984-01-05 | Schering AG, 1000 Berlin und 4709 Bergkamen | Diphosphonsaeure-derivate und diese enthaltende pharmazeutische praeparate |
| FR2531088B1 (fr) * | 1982-07-29 | 1987-08-28 | Sanofi Sa | Produits anti-inflammatoires derives de l'acide methylenediphosphonique et leur procede de preparation |
-
1984
- 1984-01-26 FR FR8401214A patent/FR2558837B1/fr not_active Expired
-
1985
- 1985-01-17 CA CA000472285A patent/CA1263397A/en not_active Expired
- 1985-01-17 ZA ZA85390A patent/ZA85390B/xx unknown
- 1985-01-17 PH PH31729A patent/PH20913A/en unknown
- 1985-01-21 AU AU37940/85A patent/AU570764B2/en not_active Ceased
- 1985-01-21 IL IL74117A patent/IL74117A/xx unknown
- 1985-01-21 GR GR850160A patent/GR850160B/el unknown
- 1985-01-22 DK DK029285A patent/DK168573B1/da not_active IP Right Cessation
- 1985-01-23 IE IE140/85A patent/IE57971B1/en not_active IP Right Cessation
- 1985-01-23 PT PT79859A patent/PT79859B/pt not_active IP Right Cessation
- 1985-01-24 FI FI850319A patent/FI77664C/fi not_active IP Right Cessation
- 1985-01-24 AT AT85400113T patent/ATE32900T1/de not_active IP Right Cessation
- 1985-01-24 DE DE8585400113T patent/DE3561819D1/de not_active Expired
- 1985-01-24 EP EP85400113A patent/EP0151072B1/fr not_active Expired
- 1985-01-25 NZ NZ210945A patent/NZ210945A/en unknown
- 1985-01-25 HU HU85302A patent/HU192664B/hu not_active IP Right Cessation
- 1985-01-25 NO NO850315A patent/NO161678C/no unknown
- 1985-01-25 KR KR1019850000466A patent/KR850005449A/ko not_active Application Discontinuation
- 1985-01-25 ES ES539833A patent/ES539833A0/es active Granted
- 1985-01-25 DD DD85272782A patent/DD233847A5/de unknown
- 1985-01-25 JP JP60012348A patent/JPS60174792A/ja active Granted
- 1985-01-25 YU YU00117/85A patent/YU11785A/xx unknown
- 1985-01-25 SU SU853846603A patent/SU1382402A3/ru active
- 1985-01-25 PL PL1985262371A patent/PL148892B1/pl unknown
- 1985-01-25 MA MA20555A patent/MA20331A1/fr unknown
- 1985-01-25 PL PL1985251700A patent/PL142493B1/pl unknown
- 1985-01-25 OA OA58514A patent/OA07941A/xx unknown
- 1985-01-25 PL PL1985263722A patent/PL144353B1/pl unknown
- 1985-01-26 EG EG49/85A patent/EG16903A/xx active
- 1985-01-28 CS CS85582A patent/CS247192B2/cs unknown
- 1985-01-28 CS CS855573A patent/CS247199B2/cs unknown
-
1986
- 1986-04-18 SU SU864027243A patent/SU1419520A3/ru active
- 1986-05-07 SU SU864027412A patent/SU1410865A3/ru active
-
1987
- 1987-06-17 YU YU01137/87A patent/YU113787A/xx unknown
- 1987-10-30 US US07/115,615 patent/US4876247A/en not_active Expired - Fee Related
-
1989
- 1989-07-17 SG SG43289A patent/SG43289G/en unknown
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