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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- A61P3/14—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 | ||
| PCT/EP1987/000368 WO1988000590A1 (fr) | 1986-07-11 | 1987-07-09 | Derives d'acide diphosphonique et medicaments les contenant |
| EP8700368 | 1987-07-09 |
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) | EP0252505B1 (da) |
| JP (2) | JP2563954B2 (da) |
| KR (2) | KR950008997B1 (da) |
| AT (2) | ATE54000T1 (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) | IE60345B1 (da) |
| IL (2) | IL83149A (da) |
| LU (1) | LU88844I2 (da) |
| MX (1) | MX9203375A (da) |
| NL (1) | NL960032I2 (da) |
| NZ (2) | NZ221027A (da) |
| PT (1) | PT85301B (da) |
| WO (1) | WO1988000590A1 (da) |
| ZA (1) | ZA874877B (da) |
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| 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 |
| 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 |
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| SU1002300A1 (ru) * | 1981-10-29 | 1983-03-07 | Ордена Ленина институт элементоорганических соединений им.А.Н.Несмеянова | Способ получени @ -аминозамещенных- @ -оксипропилидендифосфоновых кислот |
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| 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
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1987
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- 1987-07-07 AU AU75291/87A patent/AU598279B2/en not_active Expired
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- 1987-07-09 DE DE1996175038 patent/DE19675038I2/de active Active
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- 1987-07-09 AT AT87109899T patent/ATE54000T1/de active
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- 1987-07-09 LU LU88844C patent/LU88844I2/fr unknown
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- 1987-07-09 DE DE8787109899T patent/DE3763314D1/de not_active Expired - Lifetime
- 1987-07-09 KR KR1019880700274A patent/KR950008997B1/ko not_active Expired - Fee Related
- 1987-07-09 AU AU76487/87A patent/AU598569B2/en not_active Ceased
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- 1987-07-10 IE IE186187A patent/IE60345B1/en not_active IP Right Cessation
- 1987-07-10 NZ NZ221027A patent/NZ221027A/en unknown
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