DK164281B - 1-hydroxy-3-(n,n-dialkylamino)propan-1,1-diphosphonsyre og derivater heraf, fremgangsmaade til fremstilling deraf, laegemidler, der indeholder disse forbindelser, samt anvendelse af forbindelserne til fremstilling af laegemidler - Google Patents
1-hydroxy-3-(n,n-dialkylamino)propan-1,1-diphosphonsyre og derivater heraf, fremgangsmaade til fremstilling deraf, laegemidler, der indeholder disse forbindelser, samt anvendelse af forbindelserne til fremstilling af laegemidler Download PDFInfo
- Publication number
- DK164281B DK164281B DK109688A DK109688A DK164281B DK 164281 B DK164281 B DK 164281B DK 109688 A DK109688 A DK 109688A DK 109688 A DK109688 A DK 109688A DK 164281 B DK164281 B DK 164281B
- Authority
- DK
- Denmark
- Prior art keywords
- hydrogen
- formula
- hydroxy
- carbon atoms
- diphosphonic acid
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- 229910052757 nitrogen Inorganic materials 0.000 title claims description 4
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- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 9
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- 230000007017 scission Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019871 vegetable fat Nutrition 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)]
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/405—Esters of poly(thio)phosphonic 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)
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- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- 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)
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Description
i
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Den foreliggende opfindelse angår en hidtil ukendt 1-hydroxy- 3-(N,N-dialkylamino)propan-l,1-diphosphonsyre og derivater heraf, fremgangsmåder til fremstilling deraf, lægemidler, der indeholder disse forbindelser, samt anvendelse af disse for-5 bindeiser til fremstilling af lægemidler.
I DE-offentiiggørelsesskrift 18 13 659 beskrives diphosphonsy-rederivater, af hvilke 1-hydroxy-ethan-l,1-diphosphonsyre har opnået betydning som middel til behandling af Morbus Paget.
10 I DE-offentiiggørelsesskrift 29 43 498, DE-offentiiggørelsesskrift 27 02 631, EP 96-931-A samt i Z. Anorg. Allg. Chem. 457, 214 (1979) beskrives l-hydroxy-3-(N,Ndialkylamino)propan- 1,1-diphosphonsyrer, der er kendt som gode calciumkompleks-15 dannere, men som også kan anvendes ved behandling af forhøjet knogleresorption. I DE-offentliggørelsesskrift 25 34 391 er l-hydroxy-3-(N-methyl-N-propylami no)propan-1,1-diphosphonsyre omfattet af den almene formel, men ikke anført som eksempel ej heller nævnt som foretrukken forbindelse. De i dette skrift 20 omhandlede diphosphonater angives bl.a. at kunne anvendes mod lokale forstyrrelser af knoglestofskiftet samt kalkindlej rende vævstumorer.
Helt overraskende har man nu fundet frem til, at de ved nitro-25 genatomet usymmetrisk dialkylerede forbindelser ifølge krav 1, udover en ligeledes særlig god calciumkompleksdannelse, udviser en i forhold til de i sidstnævnte DE-offentiiggørelsesskrift beskrevne forbindelser betydelig bedre virkning med hensyn til reduktion af hypercalcæmi ved en god forligelighed, 30 hvilket også fremgår af det efterfølgende forsøg.
Forbindelserne ifølge opfindelsen kan især anvendes der, hvor knogleopbygningen og knoglenedbrydningen er forstyrret, det vil sige den egner sig til behandling af sygdomme i skeletsy-35 stemet, såsom f.eks. oesteoporose. Morbus Paget, Morbus Bech-terew og andre sygdomme.
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2 På grund af disse egenskaber finder de ligeledes anvendelse ved terapien af knoglemetastaser, urolithiasis og til forhindring af heterotrop ossi fikation. Ved deres indvirkning på calciumstofskiftet fremkommer endvidere grundlag til behand-5 lingen af rheumatoid arthritis, osteoarthritis og degenerativ arthrose.
Den foreliggende opfindelse angår l-hydroxy-3-(N-methyl-N-pro-pylamino)propan-l,1-diphosphonsyre og derivater heraf, som er 10 ejendommelige ved formlen I
ORi /
0 = P
\ 15 0R2 10 H3C-CH2-CH2 \ N-CH2-CH2-C-OH (I) / h3c or3 /
20 0=P
\ OR4 hvor Rj er hydrogen eller en Ci-C4~alkylgruppe, R2 er hydrogen eller en C!-C4-alkylgruppe, R3 er hydrogen eller en C!-C4~al-25 kylgruppe, og R4 er hydrogen eller en C!-C4-alkylgruppe, under den forudsætning, at enten 1) betegner R^ R2, R3 og R4 alle hydrogen, eller 2) to af symbolerne R1-R4 betegner hydrogen, og de andre to af disse symboler betegner C!~C4-alkylgrupper, eller 3Q 3) betegner R^ R2, R3 og R4 alle Ci-C4~alkylgrupper, og farmakologisk acceptable salte deraf.
Ved di- eller tetraesterne ifølge opfindelsen drejer det sig fortrinsvis om methyl-, ethyl- eller isobutylesterne.
Forbindelserne med formlen I kan fremstilles på i og for sig kendt måde. Den foreliggende opfindelse angår endvidere en 35
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3 fremgangsmåde til fremstilling af forbindelserne ifølge krav 1, som er ejendommelig ved, at man
a) omsætter en carboxylsyre med formlen II S
h3c-ch2-ch2 \ N-CH2-CH2-C00H (II) / H3c 10 med en. blanding af phosphorsyr 1 ing eller pho.sphorsyre og med et phosphorhalogenid eller phosphorylhalogenid og herefter forsæber til den frie l-hydroxy-3-(N-methyl-N-propylamino)-propan-1,1-diphosphonsyre, eller
15 b) omsætter et carboxylsyrechlorid med formlen III
H3C-CH2-CH2 \ N-CH2“CH2-C0C1 (III) / h3c 20 ύ
med et trialkylphosphit med den almene formel IV
P(0R*)3 (IV)
25 hvor R' er alkylgrupper med 1-4 carbonatomer, fortrinsvis methyl, ethyl eller isobutyl, til et acy1phosphonat med formlen V
H3C-CH2-CH2 0 0
30 \ II II
0 N-CH2-CH2-C-P(0Rr)2 (V) / h3c hvor R* har den ovenfor anførte betydning,
35 herefter lader acy1phosphonatet med formlen V reagere med et dialkylphosphit med den almene formel VI
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4
O
II
H-P(OR')2 (VI)
g hvor R' har den ovenfor anførte betydning, til et diphospho-nat med formlen VII
0
II
10 P(OR-)2 h3c-ch2-ch2 \ N-CH2-CH2-C-0H (VII) / ) h3c i P(OR')2
15 II
0 hvor R' har den ovenfor anførte betydning, og om ønsket forsæber de fremkomne tetraestere til diestere eller 20 til den frie l-hydroxy-3-(N-methyl-N-propylamino)propan-l,l-diphosphonsyre, eller
c) methylerer en forbindelse med den almene formel VIII
25 0=P(OR1)2 H3C-CH2-CH2-N-CH2-CH2-C-OH (VIII)
H
0=P(OR')2 30 hvor R' har den ovenfor anførte betydning, og om ønsket forsæber de fremkomne tetraestere til diestere eller til den frie 1-hydroxy-3-(N-methyl-N-propylami no)propan-1,1-diphosphonsyre, og at man om ønsket overfører de således fremstillede forbindelser til deres farmakologi sk acceptable salte.
Den ved fremgangsmåde a) anvendte carboxylsyre med formel II omsættes fortrinsvis med 1-5, såsom med 2-3 mol phosphorsyr- 35
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5 ling eller phosphorsyre og, fortrinsvis 1-5, såsom 2-3 mol phosphorhalogenid eller phosphorylhalogenid ved temperaturer på fortrinsvis 80-130eC, såsom 80-100°C. Man kan gennemføre reaktionen også i nærværelse af fortyndingsmidler, såsom halo-5 gencarbonhydrider, navnlig chlorbenzen, tetrachlorethan eller også dioxan. Den efterfølgende forsæbning sker fortrinsvis ved kogning med vand, eventuelt passende imidlertid med halvkon-centreret saltsyre eller hydrogenbromidsyre.
10 Som phosphorhalogenid kommer ved ovenfor anførte fremgangsmåde eksempelvis phosphortrichlorid eller phosphortribromid på tale, som phosphorylhalogenid egner sig phosphorylchlorid.
Ved fremgangsmåde b) omsætter man syrechloridet med formel III 15 med trialkylphosphittet med den almene formel IV fortrinsvis ved temperaturer på mellem 0 og 60eC, fortrinsvis ved 20-40eC. Man kan arbejde uden opløsningsmidler eller også i nærværelse af inerte opløsningsmidler, såsom diethylether, tetrahydrofu-ran, dioxan eller også halogenerede carbonhydrider, såsom 20 f.eks. methylenchlorid. Det som mellemprodukt fremkomne acyl-phosphonat med den almene formel V kan isoleres eller direkte videreomsættes. Den efterfølgende reaktion gennemfører man fortrinsvis i nærværelse af en svag base, fortrinsvis en see.-amin, såsom f.eks. dibutylamin ved en temperatur for-25 trinsvis fra 0-60eC, fortrinsvis ved 10-30°C.
Ved den reduktive alkylering (fremgangsmåde c)) kan man behandle en blanding af den sekundære amin med den almene formel VIII og formaldehyd eller dets acetal i nærværelse af en hy-30 drogeneringskatalysator, såsom palladium på carbon, eller nikkel, med hydrogen under atmosfærisk tryk eller forhøjet tryk eller man kan tilsætte myresyre som reduktionsmiddel.
Herefter kan gennemføres methylering af den sekundære amin med 35 den almene formel VIII, særligt fordelagtigt ved faseoverføringsfremgangsmåden med dimethylsulfat.
6
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Ved fremgangsmåde b) og c) kan fremkomne tetraalkylestere forsæbes til diestere eller til den frie l-hydroxy-3(N-methyl-N-propylamino)propan-l,1-diphosphonsyre. Forsæbningen til diestere sker i reglen ved, at man behandler tetraalkyl esteren 5 med et alkalihalogenid, fortrinsvis natriumjodid i et passende opløsningsmiddel, såsom f.eks. acetone, ved stuetemperatur.
Herved fremkommer det symmetriske diester/dinatriumsalt, som eventuelt kan omdannes ved hjælp af en sur ionbytter til di-10 esteren/disyren. Forsæbningen til den frie diphosphonsyre sker i reglen ved kogning med salt- eller hydrogenbromidsyre. Man kan imidlertid også foretage en spaltning med trimethylsilyl-halogenid, fortrinsvis med bromidet eller jodidet. Omvendt kan den frie diphosphonsyre igen overføres til tetraalkylesterne 15 ved kogning med orthomyresyrealkylestere. l-hydroxy-3-(N-me-thyl-N-propylamino)propan-l,l-diphosphonsyren med formel I kan isoleres som fri syre eller i form af dets mono- eller dialkalisalt. Alkalisaltene kan i reglen oprenses ved omfældning fra vand/methanol eller vand/acetone.
20
Som farmakologisk acceptable salte anvendes især alkali- eller ammoniumsalte, der fremstilles på sædvanlig måde f.eks. ved titration af forbindelsen med uorganiske eller organiske baser, såsom f.eks. natrium- eller kaliumhydrogencarbonat, na-25 tronlud, kalilud, vandig ammoniak eller aminer, såsom f.eks. trimethy1amin eller triethylamin.
Opfindelsen angår også et lægemiddel, som er ejendommeligt ved, at det omfatter en forbindelse ifølge krav 1 samt sædvan-30 lige farmakologiske bærere og/eller hjælpestoffer. Opfindelsen angår desuden anvendelse af en forbindelse ifølge krav 1 til fremstilling af lægemidler.
De hidtil ukendte forbindelser ifølge krav 1 kan anvendes i 35 flydende eller fast form, enteralt eller parenteralt. Hertil kommer alle sædvanlige applikationsformer på tale, f.eks. tabletter, kapsler, drager, sirupper, opløsninger, suspensioner 7 osv. Som injektionsmedium kommer fortrinsvis vand til anvendelse, som indeholder de ved injektionsopløsninger sædvanlige tilsætninger, såsom stabiliseringsmidler, opløsningsformidlere og puffere. Sådanne tilsætninger er f.eks. tartrat- og citrat-5 puffere, ethanol, kompleksdannere (såsom ethylendiamintetraed-dikesyre og dens ikke toksiske salte), højmolekylære polymerer (såsom flydende polyethylenoxid) til viskositetsregulering. Flydende bærestoffer til injektionsopløsninger skal være sterile og fyldes fortrinsvis på ampuller. Faste bærestoffer 10 er f.eks. stivelse, lactose, mannit, methylcellulose, talkum, højdisperse kiselsyrer, højere molekylære fedtsyrer (såsom stearinsyre), gelatiner, agar-agar, calciumphosphat, magnesi-umstearat, animalske og vegetabilske fedtstoffer, faste højmolekylære polymerer (såsom polyethylenglycoler); til oral ap-15 plikation passende formuleringer kan eventuelt indeholde smags- og sødestoffer.
Doseringen kan afhænge af forskellige faktorer, såsom indgivelsesmåde, individet, alder og/eller individuel tilstand. De 20 daglige doser, der skal indgives, ligger på ca. 1-1000 mg/75 kg legemsvægt, fortrinsvis på 10-200 mg/75 kg legemsvægt og kan indtages på en gang eller fordelt på flere gange.
I de efterfølgende eksempler vises nogle af fremgangsmådeva-25 rianterne, som kan anvendes til fremstilling af forbindelsen l-hydroxy-3-(N-methyl-N-propyl ami no)propan-1,1-diphosphonsyre ifølge opfindelsen. Denne forbindelses struktur er identificeret ved hjælp af *H- og 31P-NMR-spektroskopi, renheden ved hjælp af 3lp-NMR-spektroskopi, tyndtlagselektroforese (cellu-30 lose, oxalatpuffer med pH » 4,0) og ved hjælp af C, Η, N, P, Na-analyse. Til stoffets karakterisering angives Mre-|-værdien (= relativ mobilitet) beregnet på pyrophosphat (Mrei = 1,0).
35 8
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l-hvdroxv-3- (N-methvl-N-propylannno)propan-l.l-diphosphonsvre Eksempel 1 5 18 g 3-(N-methyl-N-propylamino)-propionsyre opvarmes sammen med 15 g phosphorsyr 1 ing og 32 ml phosphortrichlorid i 90 ml chlorbenzen i 12 timer ved 100°C. Herefter fradekanterer man opløsningsmidlet og omrører resten med 250 ml 6N saltsyre i 2 timer under tilbagesvaling. Man frafiltrerer noget af det her-10 ved fremkomne uopløselige materiale, opkoncentrerer filtratet og fører det på en Amberiite-søjle IR 120, H+-form. Elueringen med vand følges elektroforetisk. De ønskede fraktioner opsamles, inddampes, udrøres med acetone/methanol og de fremkomne krystaller isoleres.
15
Man opnår således 14,1 g råprodukt. Efter omkrystallisation fra vand/methanol får man 9,8 g = 27% analyserent produkt (x 1,5 H2O), Mre]: 0,4, smp. 96-102°C (108°C dekomponer ing).
20 Udgangsmaterialet opnås som følger: N-methyl-N-propylamin (JACS 79, 4720 (1957)) omsættes i toluen med acrylsyre-methylester i molforhold 1:3, og den i 84%'s udbytte opnåede ester forsæbes uden destillation med IN na-25 tronlud. Man opnår således den olieagtige syre i 92%'s ud bytte, som anvendes uden yderligere oprensning.
Eksempel 2 30 10 g 3-(N-methyl-N-propylamino)propionsyre sammensmeltes med 11»4 g phosphorsyrling i 10 minutter ved 80eC. Man fjerner oliebadet, tildrypper langsomt 12 ml phosphortrichlorid og opvarmer yderligere i 16 timer til 80°C. Herefter fradesti 1 lerer man det overskydende phosphortrichlorid, tilsætter 140 ml 6N 35 saltsyre og omrører i 3 timer ved 100°C. Man frafiltrerer noget af det herved fremkomne uopløselige materiale, fjerner opløsningsmidlet under vakuum og renser ved ionbytter-kromato- grafi på Amberlite IR-120 (H+-form), som beskrevet under ek sempel 1. Mrei = 0,4, udbytte 6,95 g = 35% (x 1,5 H20). Smp.: 96-102°C (108°C dekomponering).
9 5 Eksempel 3 15 g 3-(N-methyl-N-propylamino)propionsyre opvarmes analogt eksempel 2 med 17 g H3PO3 og omsættes med 19 ml P0C13.
10 Efter 18 timer ved 80°C fradesti 11 erer man det overskydende POCI3 og hydrolyserer ved tilsætning af 210 ml 6N saltsyre og opvarmning til 100°C i 2 timer. Råproduktet oprensedes (som beskrevet i eksempel 1) ved ionbytter-kromatografi på Amberlite IR-120 (H+-form). Mrel = 0,4, udbytte 16,2 g = 54% efter 15 omkrystallisation fra vand/methanol. Smp.: 96-102eC (108°C dekomponer! ng).
Forsøgsprotokol 20 Wistar-hanrotter med en legemsvægt på ca. 160 g fik ved operativt indgreb fjernet biskjoldbruskkirtlerne på dag 1. På dag 5 kontrolleredes operationsresultatet ved, at man bestemmer cal-cæmien efter 1 nats faste. Fra på denne dag får alle dyr (5 dyr per forsøgsgruppe) den samme mængde foder. Desuden modtag-25 er de tre dage i træk subkutane injektioner, idet den ene indeholder 25 pg af et syntetisk retinoid (ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethy1)-2-naphthyl]benzoat) (til indu-cering af en hypercalcæmi), den anden disphosphatet, der skal afprøves. Derudover får alle dyr på den første og sidste be-30 handlingsdag 2 pg thyroxin. 24 timer efter den sidste retinoid- og diphosphonat-injektion og efter en nats faste aftappes blod retroorbitalt under etheranæstesi. Plasma-calciumkoncen-trationen bestemmes ved hjælp af atomabsorption.
35 Diphosphonaterne indgives først i en dosis på 0,1 mg P/kg legemsvægt af rotte i et volumen på 2 ml/kg legemsvægt af rotte, herefter i en dosis på 0,01 og 0,001 mg P/kg legemsvægt af rotte.
Claims (4)
- 25 Forsøgsresultaterne viser, at en reduktion af hypercalcæmi svarende til den med forbindelse C i følge opfi ndel sen opnåede reduktion af hypercalcæmi først ses med en 10 gange højere dosis af de i DE offentliggørelsesskrift nr. 2.534.391 omhandlede analoge forbindelser. 30 Patentkrav. 1. l-hydroxy-3-(N,N-dialkylamino)propan-l,l-diphosphonsyre 35 og derivater heraf, kendetegnet ved, at de har formlen I OR! /0. P \ or2 h3c-ch2-ch2 5 \ N-CH2-CH2-C-OH (I) / h3c or3 / 0=P 10 or4 hvor Ri er hydrogen eller en Ci-C4-alkylgruppe, R2 er hydrogen eller en Ci-C4-alkylgruppe, R3 er hydrogen eller en Cj-C^-al-kylgruppe, og R4 er hydrogen eller en Ci-C4-a1kylgruppe, under den forudsætning, at enten 1. betegner Rj, R2» R3 °9 R4 all© hydrogen, eller 2. to af symbolerne Ri~R4 betegner hydrogen, og de andre to af disse symboler betegner Ci-C4-alkylgrupper, eller 3. betegner Rlf R2, R3 og R4 alle -C4-alkylgrupper, samt 20 farmakologisk acceptable salte deraf.
- 2. Fremgangsmåde til fremstilling af forbindelserne ifølge krav 1, kendetegnet ved, at man 25 a) omsætter en carboxylsyre med formlen II H3C-CH2-CH2 \ N-CH2-CH2-C00H (II) / h3c 30 med en blanding af phosphorsyr1 ing eller phosphorsyre og med et phosphorhalogenid eller phosphorylhalogenid og herefter forsæber til den frie l-hydroxy-3-(N-methy1-N-propylami no)-propan-1,1-diphosphonsyre, eller 1 35 omsætter et carboxylsyrechlorid med formlen III DK 164281 B H3C-CH2-ch2^ n-ch2-ch2-coci (III) / h3c 5 med et trial kylphosphit med den almene formel IV P(0R’)3 (IV) hvor R' betyder en alkylgruppe med 1-4 carbonatomer, fortrins-10 vis methyl, ethyl eller isobutyl, til et acylphosphonat med formlen V h3c-ch2-ch2 0 0 \ II II N-CH2-CH2-C-P(OR')2 (V) 15 / h3c hvor R1 har den ovenfor anførte betydning, herefter lader acy1phosphonatet med formlen V reagere med et 20 dialkylphosphit med den almene formel VI 0 II H-P(OR')2 (VI) 25 hvor R' har den ovenfor anførte betydning, til et diphospho-nat med formlen VII 1 35 O H P(OR')2 h3c-ch2-ch2 \5 N-CH2-CH2-C-0H (VII) / h3c P(0R')2 II o hvor R1 har den ovenfor anførte betydning, og om ønsket forsæber de fremkomne tetraestere til diestere eller til den frie l-hydroxy-3-(N-methyl-N-propylamino)propan-l,1-diphosphonsyre, eller 15 c) methylerer en forbindelse med den almene formel VIII 0=P(OR')2 H3C-CH2-CH2-N-CH2-CH2-C-OH (VIII) 20 h0. P{OR 1)2 hvor R' har den ovenfor anførte betydning, og om ønsket forsæber de fremkomne tetraestere til diestere eller til den frie 1-hydroxy-3-(N-methyl-N-propylamino)propan-l,l-diphosphonsyre, og at man om ønsket overfører de således fremstillede forbindelser til farmakologisk acceptable salte deraf.
- 3. Lægemiddel, kendetegnet ved, at det indeholder en forbindelse ifølge krav 1 samt sædvanlige farmakologiske 3° bærere og/eller hjælpestoffer.
- 4. Anvendelse af en forbindelse ifølge krav 1 til fremstilling af lægemidler. 35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863623397 DE3623397A1 (de) | 1986-07-11 | 1986-07-11 | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| DE3623397 | 1986-07-11 | ||
| EP8700368 | 1987-07-09 | ||
| PCT/EP1987/000368 WO1988000590A1 (fr) | 1986-07-11 | 1987-07-09 | Derives d'acide diphosphonique et medicaments les contenant |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK109688D0 DK109688D0 (da) | 1988-03-01 |
| DK109688A DK109688A (da) | 1988-03-01 |
| DK164281B true DK164281B (da) | 1992-06-01 |
| DK164281C DK164281C (da) | 1992-11-16 |
Family
ID=6304949
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK350987A DK168629B1 (da) | 1986-07-11 | 1987-07-07 | 1-hydroxy-omega-aminoalkan-1,1-diphosphonsyrederivater og fremgangsmåde til fremstilling deraf samt lægemidler indeholdende disse forbindelser |
| DK109688A DK164281C (da) | 1986-07-11 | 1988-03-01 | 1-hydroxy-3-(n,n-dialkylamino)propan-1,1-diphosphonsyre og derivater heraf, fremgangsmaade til fremstilling deraf, laegemidler, der indeholder disse forbindelser, samt anvendelse af forbindelserne til fremstilling af laegemidler |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK350987A DK168629B1 (da) | 1986-07-11 | 1987-07-07 | 1-hydroxy-omega-aminoalkan-1,1-diphosphonsyrederivater og fremgangsmåde til fremstilling deraf samt lægemidler indeholdende disse forbindelser |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US4927814A (da) |
| EP (2) | EP0252504B1 (da) |
| JP (2) | JP2563954B2 (da) |
| KR (2) | KR950008997B1 (da) |
| AT (2) | ATE80633T1 (da) |
| AU (2) | AU598279B2 (da) |
| BG (1) | BG60839B2 (da) |
| CA (2) | CA1296739C (da) |
| CS (1) | CS265242B2 (da) |
| DD (1) | DD263992A5 (da) |
| DE (4) | DE3623397A1 (da) |
| DK (2) | DK168629B1 (da) |
| ES (2) | ES2043622T3 (da) |
| FI (2) | FI87221C (da) |
| GE (1) | GEP20084347B (da) |
| GR (2) | GR3000616T3 (da) |
| HK (1) | HK87093A (da) |
| HU (2) | HU201950B (da) |
| IE (2) | IE60219B1 (da) |
| IL (2) | IL83149A (da) |
| LU (1) | LU88844I2 (da) |
| MX (1) | MX9203375A (da) |
| NL (1) | NL960032I2 (da) |
| NZ (2) | NZ221028A (da) |
| PT (1) | PT85301B (da) |
| WO (1) | WO1988000590A1 (da) |
| ZA (1) | ZA874877B (da) |
Families Citing this family (161)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6458772B1 (en) | 1909-10-07 | 2002-10-01 | Medivir Ab | Prodrugs |
| DE3623397A1 (de) * | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| EP0317505A1 (de) * | 1987-11-13 | 1989-05-24 | Ciba-Geigy Ag | Neue Azacycloalkylalkandiphosphonsäuren |
| US5190930A (en) * | 1987-12-11 | 1993-03-02 | Ciba-Geigy Corporation | Araliphatylaminoalkanediphosphonic acids |
| US5110807A (en) * | 1988-12-01 | 1992-05-05 | Ciba-Geigy Corporation | Araliphatylaminoalkanediphosphonic acids |
| ES2054868T3 (es) * | 1987-12-11 | 1994-08-16 | Ciba Geigy Ag | Acidos aralifatilaminoalcanodifosfonicos. |
| JPH07629B2 (ja) * | 1988-01-20 | 1995-01-11 | 山之内製薬株式会社 | （シクロアルキルアミノ）メチレンビス（フォスフォン酸）および該化合物を有効成分とする医薬 |
| US4933472A (en) * | 1988-04-08 | 1990-06-12 | Yamanouchi Pharmaceutical Co., Ltd. | Substituted aminomethylenebis(phosphonic acid) derivatives |
| DE3822650A1 (de) * | 1988-07-05 | 1990-02-01 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| DE68926310T2 (de) * | 1988-11-01 | 1996-10-24 | Arch Dev Corp | Verfahren zur abtrennung von metallischen ionen mit phosphonsäuren als complexbildner |
| GB8825589D0 (en) * | 1988-11-02 | 1988-12-07 | Albright & Wilson | Purification |
| TW198039B (da) * | 1988-11-28 | 1993-01-11 | Ciba Geigy Ag | |
| US5154843A (en) * | 1989-02-08 | 1992-10-13 | The Lubrizol Corporation | Hydroxyalkane phosphonic acids and derivatives thereof and lubricants containing the same |
| PH26923A (en) * | 1989-03-08 | 1992-12-03 | Ciba Geigy | N-substituted amino alkanediphosphonic acids |
| US4987767A (en) * | 1989-06-09 | 1991-01-29 | Research Corporation Technologies, Inc. | Exposive detection screening system |
| MX21453A (es) * | 1989-07-07 | 1994-01-31 | Ciba Geigy Ag | Preparaciones farmaceuticas que se administran en forma topica. |
| MX21452A (es) * | 1989-07-07 | 1994-01-31 | Ciba Geigy Ag | Preparaciones farmaceuticas que se administran en forma topica. |
| US5139786A (en) * | 1989-07-07 | 1992-08-18 | Ciba-Geigy Corporation | Topical formulations |
| US5324519A (en) * | 1989-07-24 | 1994-06-28 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
| US5487897A (en) * | 1989-07-24 | 1996-01-30 | Atrix Laboratories, Inc. | Biodegradable implant precursor |
| DE69023844T2 (de) * | 1989-09-06 | 1996-06-20 | Merck & Co Inc | Acyloxymethylester der Bisphonsäuren als Knochenresorptions-Inhibitoren. |
| US5356887A (en) * | 1990-01-31 | 1994-10-18 | Merck & Co., Inc. | Pharmaceutical compositions containing insoluble calcium salts of amino-hydroxybutylidene bisphoshonic acids |
| FI89364C (fi) * | 1990-12-20 | 1993-09-27 | Leiras Oy | Foerfarande foer framstaellning av nya, farmakologiskt anvaendbara metylenbisfosfonsyraderivat |
| IT1244698B (it) * | 1991-02-01 | 1994-08-08 | Gentili Ist Spa | Acidi aril-o arilalchil-acil ammino-alchil-idrossidifosfonici, procedimento per la loro preparazione e loro uso in terapia osteo-articolare e dei tessuti connettori in generale |
| CA2102303A1 (en) * | 1991-06-19 | 1992-12-20 | Roy Allen Johnson | Dialkyl (dialkoxyphosphinyl) methyl phosphates as anti-inflammatory agents |
| IT1247034B (it) * | 1991-06-26 | 1994-12-12 | Gentili Ist Spa | Acidi dimetilamino-idrossi alchil difosfonici e loro sali, loro procedimento produttivo e composizioni farmaceutiche che li comprendono |
| ES2096061T3 (es) * | 1991-08-27 | 1997-03-01 | Ciba Geigy Ag | Acidos aminometanodifosfonicos n-substituidos. |
| EP0541037A3 (en) * | 1991-11-06 | 1997-02-26 | Takeda Chemical Industries Ltd | Squalene synthetase inhibitory composition and use thereof |
| DE4228552A1 (de) * | 1992-08-27 | 1994-03-03 | Boehringer Mannheim Gmbh | Diphosphonsäuren und deren Salze enthaltende Arzneimittel |
| EP0600834A1 (en) * | 1992-11-30 | 1994-06-08 | Ciba-Geigy Ag | Use of methanebisphosphonic acid derivatives for the manufacture of a medicament for fracture healing |
| AU670337B2 (en) | 1992-11-30 | 1996-07-11 | Novartis Ag | Use of certain methanebisphosphonic acid derivatives in fracture healing |
| DE59309360D1 (de) * | 1992-12-02 | 1999-03-18 | Hoechst Ag | Guanidinalkyl-1, 1-bisphosphonsäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung |
| US5358941A (en) * | 1992-12-02 | 1994-10-25 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids with lactose |
| US6406714B1 (en) | 1992-12-02 | 2002-06-18 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids |
| US6399592B1 (en) | 1992-12-23 | 2002-06-04 | Merck & Co., Inc. | Bishphosphonate/estrogen synergistic therapy for treating and preventing bone loss |
| EP0675723A4 (en) * | 1992-12-23 | 1998-08-05 | Merck & Co Inc | THERAPY USING BISPHOSPHONATES AND STROGENS TO TREAT AND PREVENT BONE RESORPTION. |
| US5728650A (en) * | 1993-10-07 | 1998-03-17 | Zeneca Limited | Herbicidal aza bisphosphonic acids and compositions containing the same |
| TW401276B (en) * | 1993-10-07 | 2000-08-11 | Zeneca Ltd | Novel compounds and a method of controlling growth of plants |
| US5591730A (en) * | 1993-10-12 | 1997-01-07 | The Regents Of The University Of California | Inhibition of urinary calculi growth |
| US5681873A (en) * | 1993-10-14 | 1997-10-28 | Atrix Laboratories, Inc. | Biodegradable polymeric composition |
| US20010007863A1 (en) * | 1998-06-18 | 2001-07-12 | Merck & Co., Inc. | Wet granulation formulation for bisphosphonic acids |
| US5780455A (en) * | 1994-08-24 | 1998-07-14 | Merck & Co., Inc. | Intravenous alendronate formulations |
| WO1996039107A1 (en) | 1995-06-06 | 1996-12-12 | Merck & Co., Inc. | Bisphosphonate cement composition to prevent aseptic loosening of orthopedic implant devices |
| EP0753523A1 (en) | 1995-07-10 | 1997-01-15 | Gador S.A. | Amino-substituted bisphosphonic acids |
| ES2239774T3 (es) * | 1995-09-29 | 2005-10-01 | Novartis Ag | Metodo de tratamiento de la enfermedad navicular en caballos. |
| GB9607945D0 (en) * | 1996-04-17 | 1996-06-19 | Univ Nottingham | Bisphosponates as Anti-inflammatory agents |
| DE19615812A1 (de) * | 1996-04-20 | 1997-10-23 | Boehringer Mannheim Gmbh | Pharmazeutische Zubereitung enthaltend Diphosphonsäuren zur oralen Applikation |
| KR100192215B1 (ko) * | 1996-09-03 | 1999-06-15 | 강재헌 | 3-아미노-1-히드록시프로판-1,1-디포스폰산의 제조방법 |
| DE19719680A1 (de) | 1997-05-09 | 1998-11-19 | Boehringer Mannheim Gmbh | Verwendung von Diphosphonsäuren zur präventiven Behandlung von Spätfolgen bei Harnblasenerweiterung oder Harnblasenersatz |
| US20010031244A1 (en) * | 1997-06-13 | 2001-10-18 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
| US6432932B1 (en) | 1997-07-22 | 2002-08-13 | Merck & Co., Inc. | Method for inhibiting bone resorption |
| US5994329A (en) | 1997-07-22 | 1999-11-30 | Merck & Co., Inc. | Method for inhibiting bone resorption |
| US6187329B1 (en) | 1997-12-23 | 2001-02-13 | Board Of Regents Of The University Of Texas System | Variable permeability bone implants, methods for their preparation and use |
| US6255359B1 (en) | 1997-12-23 | 2001-07-03 | Board Of Regents Of The University Of Texas System | Permeable compositions and methods for their preparation |
| CN1061661C (zh) * | 1997-12-24 | 2001-02-07 | 国家医药管理局上海医药工业研究院 | (环庚基胺基)亚甲基二膦酸二钠一水合物制备方法 |
| US20020128301A1 (en) * | 1998-02-13 | 2002-09-12 | Medivir AB | Non-nucleoside reverse transcriptase inhibitors |
| US6733767B2 (en) * | 1998-03-19 | 2004-05-11 | Merck & Co., Inc. | Liquid polymeric compositions for controlled release of bioactive substances |
| US7128927B1 (en) | 1998-04-14 | 2006-10-31 | Qlt Usa, Inc. | Emulsions for in-situ delivery systems |
| EP0998932A1 (de) | 1998-10-09 | 2000-05-10 | Boehringer Mannheim Gmbh | Feste pharmazeutische Darreichungsform enthaltend Diphosphonsäure oder deren Salze und Verfahren zu ihrer Herstellung |
| EP0998933A1 (de) | 1998-10-09 | 2000-05-10 | Boehringer Mannheim Gmbh | Verfahren zur Herstellung von bisphosphonathaltigen pharmazeutischen Zusammensetzungen zur oralen Applikation |
| US6680307B1 (en) | 1998-12-04 | 2004-01-20 | Roche Diagnostics Gmbh | Use of ibandronate for promoting osseointegration of endoprostheses |
| KR100763064B1 (ko) * | 1999-05-21 | 2007-10-04 | 노파르티스 아게 | 제약 조성물 및 용도 |
| AR024462A1 (es) | 1999-07-01 | 2002-10-02 | Merck & Co Inc | Tabletas farmaceuticas |
| US8226598B2 (en) * | 1999-09-24 | 2012-07-24 | Tolmar Therapeutics, Inc. | Coupling syringe system and methods for obtaining a mixed composition |
| AR021347A1 (es) | 1999-10-20 | 2002-07-17 | Cipla Ltd | Una composicion farmaceutica que contiene acido(s) bisfosfoncio o sal(es) del mismo y un proceso de preparacion de la misma |
| US6677320B2 (en) | 2000-01-20 | 2004-01-13 | Hoffmann-La Roches Inc. | Parenteral bisphosphonate composition with improved local tolerance |
| PE20011065A1 (es) | 2000-02-01 | 2001-11-21 | Procter & Gamble | Proceso para fabricar bisfosfonatos geminales |
| US6410520B2 (en) | 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 |
| SE0000382D0 (sv) | 2000-02-07 | 2000-02-07 | Astrazeneca Ab | New process |
| ATE314862T1 (de) | 2000-05-05 | 2006-02-15 | Hoffmann La Roche | Gelartige pharmazeutische zusammensetzung zur subcutanen anwendung enthaltend bisphosphonsäuren oder deren salze |
| TWI315982B (en) | 2001-07-19 | 2009-10-21 | Novartis Ag | Combinations comprising epothilones and pharmaceutical uses thereof |
| US20050070504A1 (en) * | 2001-12-21 | 2005-03-31 | The Procter & Gamble Co. | Risedronate compositions and their methods of use |
| RU2294203C2 (ru) * | 2001-12-21 | 2007-02-27 | Дзе Проктер Энд Гэмбл Компани | Способ лечения костных нарушений |
| CA2472578A1 (en) * | 2002-01-24 | 2003-07-31 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Anti-cancer combination and use thereof |
| CA2480814A1 (en) * | 2002-04-05 | 2003-10-23 | Merck & Co., Inc. | Method for inhibiting bone resorption with an alendronate and vitamin d formulation |
| RU2387451C2 (ru) | 2002-05-10 | 2010-04-27 | Ф.Хоффманн-Ля Рош Аг | Бисфосфоновые кислоты, предназначенные для лечения и профилактики остеопороза |
| KR100681282B1 (ko) * | 2002-05-17 | 2007-02-12 | 테바 파마슈티컬 인더스트리즈 리미티드 | 특정 희석제를 사용하는 비스포스폰산 및 그 염의 제조방법 |
| JP2005534653A (ja) * | 2002-06-06 | 2005-11-17 | メルク フロスト カナダ アンド カンパニー | 眼及び骨疾患の治療に於いてｅｐ４受容体作動薬として使用するための１，５−二置換イミダゾリジン−２−オン誘導体 |
| CA2495917A1 (en) * | 2002-08-28 | 2004-03-11 | Merck Frosst Canada & Co. | Oxazolidin-2-one and thiazolidin-2-one derivatives for use as ep4 receptor agonists in the treatment of glaucoma |
| US20040138180A1 (en) * | 2002-10-03 | 2004-07-15 | Barr Laboratories, Inc. | Bisphosphonate composition and process for the preparation thereof |
| US20040097468A1 (en) * | 2002-11-20 | 2004-05-20 | Wimalawansa Sunil J. | Method of treating osteoporosis and other bone disorders with upfront loading of bisphosphonates, and kits for such treatment |
| HRP20041013B1 (hr) | 2002-12-20 | 2013-10-25 | F. Hoffmann - La Roche Ag | Formulacija visoke doze ibandronata |
| DE602004015407D1 (de) * | 2003-01-17 | 2008-09-11 | Teva Pharma | Verfahren zur reduzierung des eisengehalts bei risedronat natrium |
| JP4642762B2 (ja) * | 2003-08-21 | 2011-03-02 | サン・ファーマシューティカル・インダストリーズ・リミテッド | ビスホスホン酸化合物の製造方法 |
| CN1839114A (zh) | 2003-08-21 | 2006-09-27 | 默克弗罗斯特加拿大有限公司 | 组织蛋白酶半胱氨酸蛋白酶抑制剂 |
| WO2005027921A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and a bisphosphonate |
| CA2551230A1 (en) | 2003-12-23 | 2005-07-14 | Lyogen Limited | A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
| WO2005090370A1 (en) * | 2004-02-05 | 2005-09-29 | The Regents Of The University Of California | Pharmacologically active agents containing esterified phosphonates and methods for use thereof |
| US20050261250A1 (en) * | 2004-05-19 | 2005-11-24 | Merck & Co., Inc., | Compositions and methods for inhibiting bone resorption |
| NZ551118A (en) | 2004-05-24 | 2010-09-30 | Warner Chilcott Co Llc | Enteric solid oral dosage form of bisphosphonate containing a chelating agent |
| UA87854C2 (en) | 2004-06-07 | 2009-08-25 | Мерк Энд Ко., Инк. | N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators |
| MX2007000087A (es) * | 2004-06-23 | 2007-11-06 | Teva Pharma | Acido ibandronico solido y cristalino. |
| EP1930011B1 (en) * | 2004-08-23 | 2011-08-17 | Teva Pharmaceutical Industries Ltd | Crystalline form of ibandronate sodium |
| US7358361B2 (en) * | 2004-10-08 | 2008-04-15 | The Board Of Trustees Of The University Of Illinois | Biophosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases |
| WO2008128056A1 (en) * | 2004-10-08 | 2008-10-23 | The Board Of Trustees Of The University Of Illinois | Bisphosphonate compounds and methods with enhanced potency for multiple targets including fpps, ggpps, and dpps |
| US7687482B2 (en) * | 2006-03-17 | 2010-03-30 | The Board Of Trustees Of The University Of Illinois | Bisphosphonate compounds and methods |
| US7214818B2 (en) * | 2004-10-29 | 2007-05-08 | Hoffmann-La Roche Inc. | Method for synthesizing bisphosphonate |
| JPWO2006062072A1 (ja) * | 2004-12-10 | 2008-08-07 | テムリック株式会社 | 転移癌治療剤および癌転移抑制剤 |
| RU2368617C2 (ru) | 2005-02-01 | 2009-09-27 | Ф.Хоффманн-Ля Рош Аг | Полиморфная модификация а ибандроната |
| EP2363401A1 (en) * | 2005-02-01 | 2011-09-07 | F. Hoffmann-La Roche AG | Ibandronate polymorph B |
| AU2006302797B2 (en) | 2005-03-02 | 2012-02-02 | Merck Canada Inc. | Composition for inhibition of cathepsin K |
| BRPI0606280A2 (pt) * | 2005-03-17 | 2009-06-09 | Elan Pharma Int Ltd | composições de bisfosfonato nanoparticulado |
| EP2842559A3 (en) * | 2005-04-08 | 2015-03-18 | Chimerix, Inc. | Compounds, compositions and methods for the treatment of viral infections and other medical disorders |
| US8642577B2 (en) | 2005-04-08 | 2014-02-04 | Chimerix, Inc. | Compounds, compositions and methods for the treatment of poxvirus infections |
| WO2007013097A1 (en) * | 2005-07-25 | 2007-02-01 | Natco Pharma Limited | Improved process for the preparation of ibandronate sodium |
| US8362086B2 (en) | 2005-08-19 | 2013-01-29 | Merial Limited | Long acting injectable formulations |
| US20070049557A1 (en) * | 2005-08-24 | 2007-03-01 | Hashim Ahmed | Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers |
| WO2007074475A2 (en) * | 2005-12-27 | 2007-07-05 | Natco Pharma Limited | Novel polymorphic forms of ibandronate |
| US20070191315A1 (en) * | 2006-02-16 | 2007-08-16 | Bengt Bergstrom | Method for administering ibandronate |
| US8178712B2 (en) * | 2006-06-23 | 2012-05-15 | Cipla Ltd. | Process for the synthesis of Ibandronate sodium |
| BRPI0716539A2 (pt) | 2006-09-07 | 2016-11-01 | Emisphere Tech Inc | métodos para sintetização de ácido n-(8-[2-hidroxibenzoil]amino) caprílico e de sal de sódio deste |
| EP2009016A3 (en) | 2006-11-16 | 2009-02-25 | Teva Pharmaceutical Industries Ltd | Process for preparing crystalline form of ibandronate sodium |
| US20080139514A1 (en) * | 2006-11-29 | 2008-06-12 | Subhash Pandurang Gore | Diphosphonic acid pharmaceutical compositions |
| CA2570949A1 (en) * | 2006-12-12 | 2008-06-12 | Apotex Pharmachem Inc. | Ibandronate sodium propylene glycol solvate and processes for the preparation thereof |
| CA2671727C (en) * | 2006-12-20 | 2016-02-16 | Genpharm Ulc | A composition containing a bisphosphonic acid in combination with vitamin d |
| AU2007335156A1 (en) * | 2006-12-20 | 2008-06-26 | Mylan Pharmaceuticals Ulc | Pharmaceutical composition comprising a hot-melt granulated lubricant |
| EP2136814A4 (en) * | 2007-03-21 | 2012-05-30 | Univ Duke | MEDICAL KITS AND FORMULATIONS FOR PREVENTING, TREATING OR REDUCING SECONDARY FRACTURES FROM A PREVIOUS FRACTURE |
| BRPI0809548A8 (pt) | 2007-04-11 | 2018-10-16 | Hoffmann La Roche | processo para a preparação do sal ácido- (mono-hidratado)-3- (n-metil-n-pentil) amino-1-hidroxipropano-1, 1-difosfônico monossódico |
| CN101679466A (zh) * | 2007-04-12 | 2010-03-24 | 伊利诺伊大学评议会 | 对包括fpps、ggpps和dpps在内的多靶点效力提高的二膦酸盐化合物及方法 |
| AU2008242788A1 (en) * | 2007-04-19 | 2008-10-30 | Dr. Reddy's Laboratories Ltd. | Ibandronate sodium polymorphs |
| WO2009020483A1 (en) * | 2007-08-09 | 2009-02-12 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of ibandronate sodium |
| EP2182875A4 (en) | 2007-08-15 | 2011-08-24 | Cardiodex Ltd | SYSTEMS AND METHOD FOR PUNKING CLOSURE |
| US20090075944A1 (en) * | 2007-09-15 | 2009-03-19 | Protia, Llc | Deuterium-enriched ibandronate |
| WO2009042179A1 (en) * | 2007-09-24 | 2009-04-02 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of ibandronic acid and processeses for the preparation thereof |
| EP2128166A1 (en) | 2008-05-20 | 2009-12-02 | Chemo Ibérica, S.A. | Polymorphic forms of Ibandronate sodium and processes for preparation thereof |
| WO2009061336A1 (en) * | 2007-11-05 | 2009-05-14 | Teva Pharmaceutical Industries Ltd. | Amorphous and crystalline forms of ibandronate disodium |
| JP2011517313A (ja) | 2007-12-11 | 2011-06-02 | ビアメト ファーマシューティカルズ，インク． | 金属結合部分を標的化部分と組み合わせて使用する金属酵素阻害剤 |
| EP2222636B1 (en) | 2007-12-21 | 2013-04-10 | Ligand Pharmaceuticals Inc. | Selective androgen receptor modulators (sarms) and uses thereof |
| WO2009093258A2 (en) * | 2008-01-24 | 2009-07-30 | Fleming Laboratories Limited | A new and improved process for the preparation of ibandronate sodium monohydrate |
| ES2572631T3 (es) * | 2008-01-25 | 2016-06-01 | Chimerix, Inc. | Métodos de tratamiento de infecciones virales |
| WO2010035664A1 (ja) * | 2008-09-24 | 2010-04-01 | 田辺三菱製薬株式会社 | ビスホスホン酸誘導体の製法 |
| EP2180003A1 (en) | 2008-10-21 | 2010-04-28 | Zentiva, k.s. | Preparation of ibandronate trisodium |
| EP2210596A1 (en) | 2009-01-22 | 2010-07-28 | Laboratorios Liconsa, S.A. | Pharmaceutical composition of ibandronate sodium salt or a hydrate thereof |
| GB0906068D0 (en) | 2009-04-07 | 2009-05-20 | King S College London | Bisphosphonate Compounds for chelating radionuclides |
| EP2440250A1 (en) | 2009-06-11 | 2012-04-18 | Yissum Research Development Company of the Hebrew University of Jerusalem, Ltd. | Targeted liposomes comprising n-containing bisphosphonates and uses thereof |
| WO2011011519A1 (en) | 2009-07-21 | 2011-01-27 | Chimerix, Inc. | Compounds, compositions and methods for treating ocular conditions |
| CA2770282A1 (en) | 2009-08-03 | 2011-02-10 | Chimerix, Inc. | Composition and methods of treating viral infections and viral induced tumors |
| WO2011016738A1 (en) | 2009-08-05 | 2011-02-10 | Zaklady Farmaceutyczne Polpharma Sa | A process for the synthesis of 1-hydroxy-3-(n-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate |
| DK2473172T3 (da) | 2009-09-01 | 2015-06-15 | Univ Duke | Bisphosphonatsammensætninger og fremgangsmåder til behandling af hjerteinsufficiens |
| FR2954320B1 (fr) | 2009-12-17 | 2012-06-15 | Cll Pharma | Composition pharmaceutique orale suprabiodisponible contenant un acide biphosphonique ou un de ses sels |
| US9006218B2 (en) | 2010-02-12 | 2015-04-14 | Chimerix Inc. | Nucleoside phosphonate salts |
| CA2797601A1 (en) | 2010-04-26 | 2011-11-10 | Chimerix, Inc. | Methods of treating retroviral infections and related dosage regimes |
| WO2012007021A1 (en) | 2010-07-14 | 2012-01-19 | Pharmathen S.A. | Process for the preparation of 3-(n-methyl-n-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid salt or derivatives thereof |
| TR201100151A2 (tr) | 2011-01-06 | 2012-07-23 | Bi̇lgi̇ç Mahmut | İbandronate formülasyonu. |
| US8791162B2 (en) | 2011-02-14 | 2014-07-29 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| RS61235B1 (sr) | 2011-07-13 | 2021-01-29 | Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd | Lipozomi koji ko-inkapsuliraju bisfosfonat i amfipatički agens |
| WO2013074587A1 (en) | 2011-11-16 | 2013-05-23 | Duke University | Bishophonate compositions and methods for treating and/or reducing cardiac dysfunction |
| US8748097B1 (en) | 2011-12-02 | 2014-06-10 | President And Fellows Of Harvard College | Identification of agents for treating calcium disorders and uses thereof |
| TR201200588A2 (tr) | 2012-01-18 | 2012-07-23 | Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇ | Sodyum ibandronat monohidrat polimorflarini ve polimorflu karışımlarını hazırlamak için prosesler. |
| GB201200868D0 (en) | 2012-01-19 | 2012-02-29 | Depuy Int Ltd | Bone filler composition |
| CN103396332A (zh) * | 2013-08-19 | 2013-11-20 | 四川协力制药有限公司 | 3—[（n—甲基—n—戊基）氨基]丙酸盐酸盐的制备方法 |
| WO2015051479A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| CN105593230B (zh) | 2013-10-08 | 2018-07-06 | 默沙东公司 | 组织蛋白酶半胱氨酸蛋白酶抑制剂 |
| WO2015120580A1 (en) | 2014-02-11 | 2015-08-20 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| PL407922A1 (pl) | 2014-04-16 | 2015-10-26 | Wrocławskie Centrum Badań Eit + Spółka Z Ograniczoną Odpowiedzialnością | Nowe bisfosfoniany i ich zastosowanie |
| ES2864079T3 (es) | 2014-05-30 | 2021-10-13 | Pfizer | Derivados de carbonitrilo como moduladores selectivos del receptor de andrógenos |
| KR20200066690A (ko) | 2017-10-16 | 2020-06-10 | 칭화대학교 | 메발로네이트 경로 억제제 및 이의 약제학적 조성물 |
| KR20200085441A (ko) | 2019-01-07 | 2020-07-15 | 엠에프씨 주식회사 | 이반드로네이트의 신규한 결정형 및 이의 제조방법 |
| WO2020214834A1 (en) | 2019-04-19 | 2020-10-22 | Ligand Pharmaceuticals Inc. | Crystalline forms and methods of producing crystalline forms of a compound |
| KR20220115062A (ko) | 2021-02-09 | 2022-08-17 | (주)오스티오뉴로젠 | 크로몬 구조의 화합물을 포함하는 골다공증의 예방 및 치료용 약학적 조성물 |
| WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH9776A (en) * | 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 |
| US3733270A (en) * | 1971-03-08 | 1973-05-15 | Monsanto Co | Methods of scale inhibition |
| 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 |
| US4134969A (en) * | 1974-02-04 | 1979-01-16 | Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) | Method of treatment of calcium disorders using aminoalkane-diphosphonic acids |
| DE2534391C2 (de) * | 1975-08-01 | 1983-01-13 | Henkel KGaA, 4000 Düsseldorf | 1-Hydroxy-3-aminoalkan-1,1-diphosphonsäuren |
| SU739076A1 (ru) * | 1976-05-19 | 1980-06-05 | Институт Химической Кинетики И Горения Со Ан Ссср | Способ получени -аминоэтилидендифосфоновых кислот |
| DE2702631A1 (de) * | 1977-01-22 | 1978-07-27 | Henkel Kgaa | Verfahren zur herstellung von 1-hydroxy-3-amino-propan-1,1-diphosphonsaeuren |
| DE2943498C2 (de) * | 1979-10-27 | 1983-01-27 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur Herstellung von 3-Amino-1-hydroxypropan-1,1-diphosphonsäure |
| SU1002300A1 (ru) * | 1981-10-29 | 1983-03-07 | Ордена Ленина институт элементоорганических соединений им.А.Н.Несмеянова | Способ получени @ -аминозамещенных- @ -оксипропилидендифосфоновых кислот |
| DE3365492D1 (en) * | 1982-01-27 | 1986-10-02 | Schering Ag | Diphosphonic acid derivatives and pharmaceutical preparations containing them |
| IT1201087B (it) * | 1982-04-15 | 1989-01-27 | Gentili Ist Spa | Bifosfonati farmacologicamente attivi,procedimento per la loro preparazione e relative composizioni farmaceutiche |
| ATE26071T1 (de) * | 1982-06-10 | 1987-04-15 | Mallinckrodt Inc | Roentgen-sichtbarmachungsmittel. |
| DE3434667A1 (de) * | 1984-09-21 | 1986-04-03 | Henkel KGaA, 4000 Düsseldorf | 4-dimethylamino-1-hydroxybutan-1,1-diphosphonsaeure, deren wasserloesliche salze, verfahren zu ihrer herstellung sowie ihre verwendung |
| DE3540150A1 (de) * | 1985-11-13 | 1987-05-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| DE3623397A1 (de) * | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
-
1986
- 1986-07-11 DE DE19863623397 patent/DE3623397A1/de not_active Withdrawn
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1987
- 1987-07-06 ZA ZA874877A patent/ZA874877B/xx unknown
- 1987-07-07 DK DK350987A patent/DK168629B1/da not_active IP Right Cessation
- 1987-07-07 AU AU75291/87A patent/AU598279B2/en not_active Expired
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- 1987-07-09 DE DE8787109900T patent/DE3781730D1/de not_active Expired - Lifetime
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- 1987-07-09 HU HU873826A patent/HU201950B/hu not_active IP Right Cessation
- 1987-07-09 DE DE1996175038 patent/DE19675038I2/de active Active
- 1987-07-09 ES ES198787109899T patent/ES2036190T3/es not_active Expired - Lifetime
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- 1987-07-09 DD DD87304795A patent/DD263992A5/de not_active IP Right Cessation
- 1987-07-09 DE DE8787109899T patent/DE3763314D1/de not_active Expired - Lifetime
- 1987-07-09 US US07/071,471 patent/US4927814A/en not_active Expired - Lifetime
- 1987-07-09 KR KR1019880700274A patent/KR950008997B1/ko not_active Expired - Fee Related
- 1987-07-09 IL IL83148A patent/IL83148A/xx not_active IP Right Cessation
- 1987-07-09 US US07/071,320 patent/US4942157A/en not_active Expired - Fee Related
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- 1987-07-10 CA CA000541755A patent/CA1296739C/en not_active Expired - Lifetime
- 1987-07-10 PT PT85301A patent/PT85301B/pt unknown
- 1987-07-10 KR KR1019870007485A patent/KR960010418B1/ko not_active Expired - Lifetime
- 1987-07-10 IE IE186287A patent/IE60219B1/en not_active IP Right Cessation
- 1987-07-10 NZ NZ221028A patent/NZ221028A/xx unknown
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