DK168629B1 - 1-hydroxy-omega-aminoalkan-1,1-diphosphonsyrederivater og fremgangsmåde til fremstilling deraf samt lægemidler indeholdende disse forbindelser - Google Patents
1-hydroxy-omega-aminoalkan-1,1-diphosphonsyrederivater og fremgangsmåde til fremstilling deraf samt lægemidler indeholdende disse forbindelser Download PDFInfo
- Publication number
- DK168629B1 DK168629B1 DK350987A DK350987A DK168629B1 DK 168629 B1 DK168629 B1 DK 168629B1 DK 350987 A DK350987 A DK 350987A DK 350987 A DK350987 A DK 350987A DK 168629 B1 DK168629 B1 DK 168629B1
- Authority
- DK
- Denmark
- Prior art keywords
- general formula
- hydroxy
- diphosphonic acid
- acid
- methyl
- Prior art date
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- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- ZWKFEVVFVAGPDE-UHFFFAOYSA-N methyl 3-[methyl(pentyl)amino]propanoate Chemical compound CCCCCN(C)CCC(=O)OC ZWKFEVVFVAGPDE-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- QKYWADPCTHTJHQ-UHFFFAOYSA-N n,2-dimethylpropan-1-amine Chemical compound CNCC(C)C QKYWADPCTHTJHQ-UHFFFAOYSA-N 0.000 description 1
- ZZFNBVPVZOECOF-UHFFFAOYSA-N n-(2-methylpropyl)-1-phenylmethanimine Chemical compound CC(C)CN=CC1=CC=CC=C1 ZZFNBVPVZOECOF-UHFFFAOYSA-N 0.000 description 1
- ZELJLECFTLYULH-UHFFFAOYSA-N n-benzyl-2-methylpropan-1-amine Chemical compound CC(C)CNCC1=CC=CC=C1 ZELJLECFTLYULH-UHFFFAOYSA-N 0.000 description 1
- SQSWACUMFXIPIF-UHFFFAOYSA-N n-benzyl-n,2-dimethylpropan-1-amine Chemical compound CC(C)CN(C)CC1=CC=CC=C1 SQSWACUMFXIPIF-UHFFFAOYSA-N 0.000 description 1
- BCMVZMXWSSTNLU-UHFFFAOYSA-N n-benzyl-n-methylnonan-1-amine Chemical compound CCCCCCCCCN(C)CC1=CC=CC=C1 BCMVZMXWSSTNLU-UHFFFAOYSA-N 0.000 description 1
- UFSKFPGJTHUMBE-UHFFFAOYSA-N n-benzyl-n-methylpentan-1-amine Chemical compound CCCCCN(C)CC1=CC=CC=C1 UFSKFPGJTHUMBE-UHFFFAOYSA-N 0.000 description 1
- XUSMAGTYLITCIN-UHFFFAOYSA-N n-benzylnonan-1-amine Chemical compound CCCCCCCCCNCC1=CC=CC=C1 XUSMAGTYLITCIN-UHFFFAOYSA-N 0.000 description 1
- GSSNBCHDTWIOLI-UHFFFAOYSA-N n-benzylpentan-1-amine Chemical compound CCCCCNCC1=CC=CC=C1 GSSNBCHDTWIOLI-UHFFFAOYSA-N 0.000 description 1
- OUMBFMLKPJUWDQ-UHFFFAOYSA-N n-benzylpropan-1-amine Chemical compound CCCNCC1=CC=CC=C1 OUMBFMLKPJUWDQ-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- NNTVKFAXDYRERB-UHFFFAOYSA-N n-pentyl-1-phenylmethanimine Chemical compound CCCCCN=CC1=CC=CC=C1 NNTVKFAXDYRERB-UHFFFAOYSA-N 0.000 description 1
- JACMPVXHEARCBO-UHFFFAOYSA-N n-pentylpentan-1-amine Chemical compound CCCCCNCCCCC JACMPVXHEARCBO-UHFFFAOYSA-N 0.000 description 1
- FLSRMWBZKWEQHA-UHFFFAOYSA-N n-propylnonan-1-amine Chemical compound CCCCCCCCCNCCC FLSRMWBZKWEQHA-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000011865 skeletal system disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 241000894007 species Species 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
- 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
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- 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
- 238000005303 weighing Methods 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)]
- C07F9/40—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)
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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)
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- General Chemical & Material Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Description
i DK 168629 B1
Den foreliggende opfindelse angår hidtil ukendte l-hydroxy-ω-amino-l,l-diphosphonsyrederivater, en fremgangsmåde til fremstilling deraf samt lægemidler, der indeholder disse forbindelser.
5 I tysk offentliggørelsesskrift nr. 1.813.659 er beskrevet di-phosphonsyrederivater, hvoraf 1-hydroxy-ethan-1,1-diphosphon-syren har fået betydningen som middel til behandling af Morbus Paget. I BE patentskrift nr. 896.453, US patentskrift nr. 4.134.969, DE offentliggørelsesskrift nr. 2.534.391 samt EP 10 offentliggørelsesskrift nr. 96.931 er aminoalkan-l,l-diphos-phonsyrer beskrevet som værende gode ca1ciumkomp1eksdannere, der også kan benyttes til behandling af forøget knogleresorption. Sådanne forbindelser udviser ved terapeutisk virksom dosering hyppigt bivirkninger. Der forelå den opgave at finde 15 frem til aminoalkandiphosphonater, som udøver deres terapeutiske virkning ved så lav dosering som muligt. Det har nu vist sig, at med disse forbindelser analoge derivater, hvori nitrogenatomet er fuldstændig alkyleret, hvorved en alkylgruppe har mindst 4 carbonatomer, er væsentligt mere effektive som calci-20 umkompl eks danner e til bredere behandling af calciumstof skifteforstyrrelser. De kan frem for alt anvendes meget godt i det tilfælde, at knogleop- og -nedbrydningen er forstyrret, dvs. at de er egnede til behandling af skelet systemets sygdomme, såsom f.eks. osteoporose, Morbus Paget, Morbus Bechterew o.a.
25 på grund af disse egenskaber finder de imidlertid også anvendelse til behandling af knoglemetastaser, urolithiasis og til forhindring af heterotope ossifikationer. Ved deres påvirkning af calciumstofskiftet danner de endvidere grundlag for behandling af rheumatoid arthritis, osteoarthritis og degenerativ 30 arthrose.
Den foreliggende opfindelse angår følgelig 1-hydroxy-ω-amino-
1,1-diphosphonsyrederivater, der er ejendommelige ved, at de har den almene formel I
DK 168629 Bl 2 0=P(0Ξ),
*1^ I
- X - C - OH (I),
*2^ I
5 0=P (OH) 2 hvori R^ betyder en methyl- eller n-propylgruppe, betyder en isobutyl-, pentyl-, nonyl- eller benzylgruppe og X betyder en methylen-, ethylen- eller propylengruppe, samt farmakologisk acceptable salte deraf.
10 Foretrukne forbindelser ifølge den foreliggende opfindelse er forbindelser med den almene formel I, hvori R^ betegner en me-thylgruppe, og R2 betegner en gruppe med 5 carbonatomer, især forbindelsen 1-hydroxy-3- (N-methyl-N-pentylamino) -propan-1,1-diphosphonsyre.
15 Den foreliggende opfindelse angår endvidere en i og for sig kendt fremgangsmåde til fremstilling af forbindelserne med den almene formel I, hvilken fremgangsmåde er ejendommelig ved, at
a) man omsætter en carboxylsyre med den almene formel VIII
Rl\ 20 N - X - COOH (VIII),
S
hvori Ri, R2 og X har de ovenfor anførte betydninger, med en blanding af phosphorsyrling eller phosphorsyre og et phosphor-halogenid og derpå forsæber til dannelse af den frie diphos-25 phonsyre med den almene formel I, eller
b) man omsætter et carboxylsyrechlorid med den almene formel IX
Rl\ N - X - COC1 (IX), 30 R/ DK 168629 B1 3
hvori R-^, R2 og X har de ovenfor anførte betydninger, med et trialkylphosphit med den almene formel X
P(OR')3 (X)
hvori R' betyder C1_4-alkyl, til dannelse af et acylphosponat 5 med den almene formel XI
0 0
*r\ I I
^N-X-C-P(OR')2 (XI) *2^
10 hvori R-^, R2, X og R' har de ovenfor anførte betydninger, som man derpå lader reagere med et dialkylphosphit med den almene formel XII
0 i 15 H-P(0R')2 (XII),
hvori R' har den ovenfor anførte betydning, til dannelse af et diphosphonat med den almene formel XIII
0 20 P(OR')o ^ N-X-C-OH (XIII),
^2 I
P(OR')2 25 1 Å
O
hvori R^, R2, X og R' har de ovenfor anførte betydninger, og forsæber de dannede tetraestere til syrer med den almene formel I, eller
30 c) man mono- eller dialkylerer en forbindelse med den almene formel XIV
4 DK 168629 B1 H 0=P (OR-a ) n
II
r4-n-x-c-oh (XIV), 5 0=P(0R3)2 hvori X har den ovenfor anførte betydning, og R4 betegner hydrogen eller R2, til dannelse af syrer med den almene formel I, og om ønsket omdanner de således fremstillede forbindelser til farmakologisk acceptable salte deraf.
10 De ved fremgangsmåden a) benyttede carboxylsyrer med den almene formel VIII omsættes med 1-2, fortrinsvis 1,5 mol phos-phorsyrling eller phosphorsyre og 1-2, fortrinsvis 1,5 mol phosphortri halogenid ved temperaturer på 80-130eC, fortrinsvis 100-110°C. Man kan også gennemføre reaktionen i nærværelse af 15 fortyndingsmidler, såsom halogenhydrocarboner, især chlorben-zen og tetrachlorethan, eller dioxan. Den efterfølgende hydrolyse sker ved kogning med vand, men hensigtsmæssigt med halv-koncentreret saltsyre eller hydrogenbromidsyre.
Ved fremgangmsåden b) lader man syrechloridet med den al- 2q mene formel IX reagere med trialkylphosphitet med den almene formel X ved temperaturer mellem 0°C og 60eC, fortrinsvis ved 20-40°C. Man kan arbejde uden opløsningsmidler eller i nærværelse af indifferente opløsningsmidler, såsom diethylether, tetrahydrofuran, dioxan eller halogenerede hydrocarboner, så-25 som f.eks. methylenchlorid. Det som mellemprodukt dannede acylphosphonat med den almene formel XI kan isoleres eller direkte videreomsættes. Den påfølgende reaktion gennemfører man i nærværelse af en svag base, fortrinsvis en sekundær amin, såsom f.eks. dibutylamin, ved en temperatur på 0-60°C, for-3Q trinsvis ved 10-30°C.
Som phosphortrihalogenider kommer eksempelvis phosphortrichlo-rid eller phosphortribromid på tale til den ovenfor nævnte fremgangsmåde.
DK 168629 B1 5 I tilfælde af fremgangsmåden c) gælder den under b anførte beskrivelse analogt.
De ved fremgangsmåderne eventuelt fremkomne tetraalkylestere forsæbes til de frie tetrasyrer.
5 Forsæbningen til frie diphosphonsyrer sker i reglen ved kogning med saltsyre eller hydrogenbromidsyre. Man kan imidlertid også foretage en spaltning med trimethylsilylhalo-genid, fortrinsvis bromidet eller jodidet. De frie diphosphonsyrer med den almene formel I kan isoleres som frie syrer 10 eller i form af deres mono- eller dialkalisal te. Alkalisaltene kan i reglen renses godt ved omfældning fra vand/methanol eller vand/acetone.
Som farmakologisk acceptable salte anvendes først og fremmest alkali- eller ammoniumsalte, som man fremstiller på sædvanlig måde, f.eks. ved titrering af forbindelserne med uorganiske 15 eller organiske baser, såsom eksempelvis natrium- eller kali-umhydrogencarbonat, natronlud, kalilud, vandig ammoniak eller aminer, såsom eksempelvis trimethyl- eller triethylamin.
De hidtil ukendte forbindelser med formlen I ifølge opfindelsen og deres salte kan i flydende eller fast form administre- o n res enteralt eller parenteralt. Herved kommer alle sædvanlige administrationsformer på tale, eksempelvis tabletter, kapsler, dragéer, sirupper, opløsninger, suspensioner etc. Som injektionsmedium anvendes fortrinsvis vand, som indeholder de i injektionsopløsninger sædvanlige tilsætninger, såsom stabilise-25 ringsmidler, opløsningsformidlere og puffere. Sådanne tilsætninger er f.eks. tartrat- og citratpuffer, ethanol, kompleks-dannere (såsom ethylendiamintetraeddikesyre og ikke-toksiske salte deraf) og højmolekylære polymerer (såsom flydende poly- ethylenoxid) til viskositetsregulering. Flydende bærerstoffer 30 6 DK 168629 B1 til injektionsopløsninger skal være sterile og fyldes fortrinsvis på ampuller. Faste bærerstoffer er f.eks. stivelse, lactose, mannitol, methylcellulose, talkum, højdisperse kiselsyrer, højere-molekylære fedtsyrer (såsom stearinsyre), gela-5 tine, agar-agar, calciumphosphat, magnesiumstearat, animalske og vegetabilske fedtstoffer og faste højmolekylære polymerer (såsom polyethylenglycoler). Til oral administration egnede præparater kan om ønsket indeholde smags- og sødestoffer.
Doseringen kan afhænge af forskellige faktorer, såsom admini-10 strationsmåde, art, alder og/eller individuel tilstand. Doserne til daglig indtagelse ligger ved ca. 1-1000 mg/menneske, fortrinsvis ved 10-200 mg/menneske, og kan indtages på én gang eller fordelt over flere gange.
Forsøgsrapport 15 Whistar-hanrotter med en vægt på ca. 160 g thyroparathyroidek-tomiseres på dag 1. På den 5. dag kontrolleres operationsresultatet ved, at man efter en nat med faste bestemmer calcæ-mien. Fra denne dag modtager alle dyr den samme mængde foder. Endvidere får de 3 dage efter hinanden subkutane injektioner, 20 hvoraf den ene indeholder 25 μg af et syntetisk retinoid (til fremkaldelse af en hypercalcami), og de andre indeholder det til afprøvning bestemte diphosphonat. Endvidere modtager alle dyr på den første og den sidste dag af behandlingen 2 ^g thyroxin. 24 timer efter den sidste retinoid- og diphosphonat-25 injektion og efter en nats faste udtages blod retroorbialt under etherbedøvelse. Plasma-calciumkoncentrationen bestemmes ved hjælp af atomabsorption.
Diphosphonaterae bliver til at begynde med indtaget i en dosis på 0,1 mg P/kg i et volumen på 2 ml/kg, mindre aktive desuden 30 i en dosis på 1 og 10 mg P/kg.
DK 168629 B1 7
Tabalt
Forbindelse mg p/kg _0/001_0/01_0j_l_1,0 A 0 + 5 B 0 + ++++ C + +++ D (+) +++ _E_( + )_ ++_
Eks.2 (+) ++++ 10 Eks. 4 + ++++
Eks * 5A (hh) +++ ++++
Eks. 5B (+) ++ ++++
Formindskelse af hypercalcæmien (i mg %) ved forskellige doseringer.
15 0 = værdier mellem - 0,99 og 0,99 mg % (+) = 1/0 og 1,99 mg % + = " " 2,0 og 2,99 mg % ++ ss " " 3,0 og 3,99 mg % +++ = " " 4,0 og 4,99 mg % 20 ++++ s" " >5,0 mg%
Eksempel A ss 1-hydroxy-3-aminopropan-1,1-diphosphoasyre (ATO) (US patentskrift nr. 4.134.969) B = l-hydroxy-3-(N, N-dimethylamino) propan-1,1-di- phosphonsyre (US patentskrift nr. 4.134.969) 25 C ss l-hydroxy-3-(Ν,Ν-diethylamino)propan-1,1-di- phosphonsyre (US patentskrift nr. 4.134.969) D ss l-hydroxy-3-(N,N-dipropylamino)propan-l,l-di- phosphonsyre (US patentskrift nr. 4.134.969) E =s l-hydroxy-3-(N-ethyl-N-propylamino)propan-l, 1- 30 diphosphonsyre (US patentskrift nr. 4.134.969) 8 DK 168629 B1
De efterfølgende eksempler viser nogle af de fremgangsmådevarianter, der kan anvendes til syntesen af forbindelserne ifølge opfindelsen. Disse forbindelsers struktur er fastlagt ved H- og P-NMR-spektroskopi, og renheden er bestemt ved hjælp af 5 P-NMR-spektroskopi, tyndtlagselektroforese (cellulose, oxalat-puffer med pH = 4,0) ved hjælp af C, Η, N, P, Na-analyse. Til karakterisering af de enkelte forbindelser angives Mre·^-værdierne (= relativ mobilitet), regnet i forhold til pyrophosphat (Mrei = 1/0) .
10 Eksempel 1 (sammenlignings eksempel) l-hvdroxv-3 - (Ν,Ν-di-pent-ylamino) propan-1,1-diphosphonsvre 13,3 g 3-N,N-di-pentylamino-propionsyre bliver sammen med 7,1 g phosphor syr ling og 14,8 ml phosphortrichlorid i 67 ml chlor-benzen holdt ved 100°C i 20 timer. Derpå fradekanterer man 15 opløsningsmidlet og omrører resten med 180 ml 6N saltsyre i 8 timer Tinder tilbagesvaling. Man frafiltrerer noget uopløseligt materiale, inddamper filtratet og påfører det på en "Amberlite"-søjle IR 120, H+-form. Eluering med vand følges elektroforetisk. De ønskede fraktioner forenes, inddampes, 20 udrøres med acetone, og de opnåede krystaller isoleres.
Man opnår således 12,9 g råprodukt. Efter to ganges omkrystal-1 isat ion fra vand opnår 4,7 g = 22% analyserent produkt som halvhydrat. Smeltepunkt 114°C under sintring, 189-191°C under dekomponering (Mre]: 0,24).
Udgangsmaterialet opnås som følger:
Dipentylamin omsættes i toluen med acrylsyremethylester i molforholdet 1:3. Man opnår 22% af olieagtige dipentyl-aminopro-pionester, som forsæbes med IN natronlud og resulterer i 56% af den ønskede syre med smeltepunkt 47-49eC.
DK 168629 B1 9
Eksempel 2 l-hvdroxv-3-(N-methvl-N-nonylamino)propan-l.1-diphosphonsvre På analog måde som i eksempel 1 beskrevet opnår man ud fra 3-N-methyl-N-nonylamino-propionsyren det tilsvarende diphospho-nat i et udbytte på 10% med smeltepunkt 159°C under sintring, 178-184°C (Mrei: 0,22).
Udgangsmaterialet opnås som følger:
Nonylamin omsættes med benzaldehyd til dannelse af den olieag-tige Schiff-base i et udbytte på 96%. Hydrogenering med palla-dium-carbon-katalysator resulterer i N-benzyl-N-nonylamin som 10 olie i et udbytte på 94%. Derfra opnår man med formalin og myresyre 98% af den olieagtige N-benzyl-N-methyl-N-nonylamin. Hydrogenolytisk fraspaltning af benzylgruppen med palladium-carbon-katalysator fører kvantitativt til den sekundære amin som olie, der som beskrevet i eksempel 1 omsættes med methyl -15 acrylat og forsæbes. Udbytte af ester er 81% olie, af syre 95% pastaagtigt materiale.
Eksempel 3 (sammenligningseksempel) 3-(N-cvklohexvl-N-methvlamino)-1-hvdroxv-propan-l,1-diphos-phonsvre.
o n 15 g 3-N-cyklohexyl-N-methylamino-propionsyre, der er fremstillet ud fra N-cyklohexyl-N-methylamin (handelspræparat) og methylacrylat i toluen (76% udbytte af ester med smeltepunkt 131-134°C; 92% udbytte af syre med smeltepunkt 101-105eC), opvarmes sammen med 13,3 g phosphorsyrling til 80°C. Smelten ^ tilsættes 14,1 ml phosphortrichlorid og holdes ved samme temperatur i 16 timer.
Derpå tilsætter man 240 ml vand og omrører i 1 dag ved 100°C. Man filtrerer, inddamper under vakuum og udhælder olien i 1 liter acetone, hvorved krystallisation indtræder. Han opløser DK 168629 B1 10 1 vand og renser ved hjælp af ionbytningskromatografi som beskrevet i eksempel 1. Udbytte: 4,5 g = 16,9% monohydrat med smeltepunkt 142eC under sintring, 182eC under dekomponer ing (Mrel: 0*3).
5 Eksempel 4 l-hvdroxv-3-(N-nonvl-N-propvlamino)propan-l,1-diphosphonsvre På analog måde som i eksempel 3 beskrevet opnår man ud fra 3-N-nonyl-N-propylamino-propionsyren den tilsvarende diphos-phonsyre med smeltepunkt 100-105°C i 50% udbytte (Mre-|: 0,23).
10 Udgangsmaterialet opnås som følger: 2 mol nonylamin omsættes kvantitativt med 1 mol propionylchlo-rid til opnåelse af syreamidet, som reduceres med lithiumalu-miniumhydrid til dannelse af den sekundære amin med 71% udbytte (kogepunkt 113-117*0/16). 1 mol N-nonyl-N-propylamin omsæt- 15 tes med 3 mol methylacrylat i toluen og resulterer i 81% af en olie, som forsæbes med IN natronlud og resulterer i 14% af den ønskede syre med smeltepunkt 45-47eC.
På analog måde som i eksempel 2 beskrevet fremstilles: DK 168629 B1 11 _Udbytte_Sip._ A. Mellemprodukter: N-benzyliden-pentylamin 94% olie 5 N-benzyl-N-pentylamin 74% pasta N-benzyl-N-methyl-N-pentylamin 95% olie N-raethyl-N-pentylamin 49% olie 3-(N-methyl-N-pentylamino)propion- syre-methylester 93% olie i o 3-(N-methyl-N-pentylamino)propionsyre 34% henflydende krystal ler
Slutprodukt; 15 l-hvdroxv-3-(N-methvl-N-pentv!ami nol-
propan-1.1-diphosphonsvre Mrei = 0,44 12% 84*C
under dekom-ponering B. Mellemprodukter; 20 N-benzyliden-isobutylamin 96% olie N-benzyl-N-isobutylamin 71% olie N-benzyl-N-isobutyl-N-methylamin 93% olie N-isobutyl-N-methylamin 96% olie 25 3-(N-isobutyl-N-methylamino)- propionsyre-methyl-ester 90% olie 3-(N-isobutyl-N-methylamino)propionsyre 57% olie
Slutprodukt; 30 l-hvdroxy-3-(N-i sobutvi-N-methvlami nol- propan-1,1-di phosphonsvre Mre-j = 0,40 (monohydrat)
Udbytte 39% Smp. 140°C
under dekomponer i ng 35 DK 168629 B1 12
De olieagtige mellemprodukter videreomsættes direkte uden destillation. Slutprodukternes rensning sker ved hjælp af ionby tningskroma tograf i .
Eksempel 6 5 3-(N-benzvl-N-methvlamino)propan-l-hvdroxv-l,1-diphosphonsvre
Analogt med eksempel 3 opnår man ud fra 3-N-benzyl-N-methyla-minopropionsyren med 36% udbytte den ønskede diphosphonsyre som monohydrat med dekomponeringspunkt 117°C (Mre-j: 0,37).
Udgangsmaterialet opnås som følger: 10 N-benzyl-N-methylamin omsættes analogt med eksempel 1 med me-thylacrylat, og den i et udbytte på 76% opnåede olieagtige ester forsæbes uden destillation med IN natronlud. Man opnår således med 67% udbytte den olieagtige syre, der anvendes uden yderligere rensning.
15 TElrgamp»! 7 3-(N-benzvl-N-propvlamino)propan-1-hvdroxv-l.1-diphosphonsvre
Analogt med eksempel 3 opnår man ud fra 3-(N-benzyl-N-propyl-amino)propionsyren med 35% udbytte den ønskede forbindelse. Smp. 112-115°C under dekomponering (Mre-|: 0,33).
20
Udgangsmaterialet opnås som følger:
Den olieagtige Schiff-base af propylamin og benzaldehyd (86% udbytte) hydrogeneres i nærværelse af Pd-katalysator og fører med 81% udbytte til N-benzyl-N-propylamin. Den olieagtige sekundære amin omsættes derpå med methylacrylat: 69% olieagtig 25 ester, og ud fra denne opnås ved alkalisk forsæbning den ligeledes olieagtige syre med 88% udbytte.
Claims (6)
- 5 Slutprodukt; l-hvdroxy-4- (N-methvl-N-nonvl- 11% > 300°C amino1butan-l,l-diphosphonsyre- dinatriumsalt-dihvdrat Mrel: 0,25
- 10 De olieagtige nel lenprodukter omsættes direkte uden destillation. Strukturen er spektroskopisk sikret. Rensningen af slutprodukterne sker ved hjælp af ionbytningskronatografi. Patentkrav. 15 1. l-hydroxy-<o-aminoalkan-l,l-diphosphonsyrederivater, ken detegnet ved, at de har den almene formel I 0=P(OH)0 N - X - C - OH (I) ,
- 20 R2' I 0=P (OH) 2 hvori R-l betyder en methyl- eller n-propylgruppe, R2 betyder en isobutyl-, pentyl-, nonyl- eller benzylgruppe og X betyder en methylen-, ethylen- eller propylengruppe, samt farmakolo-25 gisk acceptable salte deraf. DK 168629 B1 2. 1-hydroxy-3 - (N-me thyl-N-pen ty lamino) propan-1,1-diphosphon- syre.
- 3. Fremgangsmåde til fremstilling af 1 - hydroxy - ω- aminoal kan - 1,1-diphosphonsyrederivater med den almene formel I 5 0=P(OH)o - X - C - OH (I) , *2^ I 0=P (OH) 2 10 hvori R]_ betyder en methyl- eller n-propylgruppe, R2 betyder en isobutyl-/ pentyl-, nonyl- eller beazylgruppe og X betyder en methylen-, ethylen- eller propylengruppe, samt farmakologisk acceptable salte deraf, kendetegnet ved, at man 15 a) omsætter en carboxylsyre med den almene formel VIII R\ ^/N-X-COOH (VIII) R2 hvori R^, R2 og X har de ovenfor anførte betydninger, med en blanding af phosphorsyrling eller phosphorsyre og et phosphor-halogenid, og derpå forsæber til dannelse af den frie diphos-phonsyre med den almene formel I, eller b) omsætter et carboxylsyrechlorid med den almene formel IX 20 ^N-X-COCl (IX) R2 hvori Rj, R2 og X har de ovenfor angivne betydninger, med et trialkylphosphit med den almene formel X P(0R')3 (X) DK 168629 B1 hvori R' betyder -alkyl, til dannelse af et acylphosphonat med den almene formel XI 0 0 Rix II N-X-C—P(0R*)2 (xi) hvori R^, Rj, X og R' har de ovenfor anførte betydninger/ som man derpå lader reagere med et dialkylphosphit med den almene 5 formel XII, S H-P(OR')2 (XII) hvori R' har den ovenfor anførte betydning, til dannelse af et diphosphonat med den almene formel XIII 0 il P(OR') 2 Rl\ >N-X-C-0H (XIII) R2^ P(OR * ) 2 il 0 hvori Rj_, Rq' x og R' har de ovenfor anførte betydninger, og forsæber de dannede tetraestere til syrer med den almene for-10 mel I, eller c) mono- eller dialkylerer en forbindelse med den almene formel XIV 0=Jj*(0R3) g R4-N-X-C-0H (XIV) H 0=P(0R3)2 hvori X har den ovenfor anførte betydning, og R4 betyder hydrogen eller R2, til dannelse af syrer med den almene formel DK 168629 Bl 1, og om ønsket omdanner de således fremstillede forbindelser til farmakologisk acceptable salte deraf.
- 4. Lægemiddel indeholdende mindst én forbindelse ifølge krav 1 eller 2 samt sædvanlige farmakologiske bærer- og/eller hjæl- 5 pestoffer.
- 5. Anvendelse af forbindelserne ifølge krav 1 eller 2 til fremstilling af lægemidler til behandling af calciumstofskiftesygdomme. 10
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3623397 | 1986-07-11 | ||
| DE19863623397 DE3623397A1 (de) | 1986-07-11 | 1986-07-11 | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK350987D0 DK350987D0 (da) | 1987-07-07 |
| DK350987A DK350987A (da) | 1988-01-12 |
| DK168629B1 true DK168629B1 (da) | 1994-05-09 |
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 After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
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| 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) | IL83148A (da) |
| LU (1) | LU88844I2 (da) |
| MX (1) | MX9203375A (da) |
| NL (1) | NL960032I2 (da) |
| NZ (2) | NZ221027A (da) |
| PT (1) | PT85301B (da) |
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| ZA (1) | ZA874877B (da) |
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1993
- 1993-08-26 HK HK870/93A patent/HK87093A/xx not_active IP Right Cessation
-
1994
- 1994-02-28 BG BG098610A patent/BG60839B2/bg unknown
-
1996
- 1996-12-19 NL NL960032C patent/NL960032I2/nl unknown
-
2006
- 2006-06-21 GE GEAP20069467A patent/GEP20084347B/en unknown
Also Published As
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| CTFF | Application for supplementary protection certificate (spc) filed |
Free format text: CA 1996 00024, 961211 |
|
| CTFG | Supplementary protection certificate (spc) issued |
Free format text: CA 1996 00024, 961211, EXPIRES: 20110625 |
|
| PUP | Patent expired |