FI85026B - Foerfarande foer framstaellning av ett farmakologiskt aktivt difosfonsyraderivat. - Google Patents
Foerfarande foer framstaellning av ett farmakologiskt aktivt difosfonsyraderivat. Download PDFInfo
- Publication number
- FI85026B FI85026B FI881134A FI881134A FI85026B FI 85026 B FI85026 B FI 85026B FI 881134 A FI881134 A FI 881134A FI 881134 A FI881134 A FI 881134A FI 85026 B FI85026 B FI 85026B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- methyl
- cho
- propane
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- -1 acyl phosphonate Chemical compound 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- 150000005690 diesters Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- CHCBFCDPOXDKTN-UHFFFAOYSA-N [1-hydroxy-3-[methyl(propyl)amino]-1-phosphonopropyl]phosphonic acid Chemical compound CCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O CHCBFCDPOXDKTN-UHFFFAOYSA-N 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 229910014033 C-OH Inorganic materials 0.000 claims 4
- 229910014570 C—OH Inorganic materials 0.000 claims 4
- 239000013256 coordination polymer Substances 0.000 claims 2
- 235000019714 Triticale Nutrition 0.000 claims 1
- JFYHAAFAGOSSLF-UHFFFAOYSA-N [1-[methyl(propyl)amino]-1-phosphonopropyl]phosphonic acid Chemical compound CCCN(C)C(CC)(P(O)(O)=O)P(O)(O)=O JFYHAAFAGOSSLF-UHFFFAOYSA-N 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 241000228158 x Triticosecale Species 0.000 claims 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical class OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 abstract description 4
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 2
- 229910052760 oxygen Chemical group 0.000 abstract 2
- 239000001301 oxygen Chemical group 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
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- 206010002556 Ankylosing Spondylitis Diseases 0.000 abstract 1
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- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 230000003913 calcium metabolism Effects 0.000 abstract 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 1
- 230000003412 degenerative effect Effects 0.000 abstract 1
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- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
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- 150000002829 nitrogen Chemical class 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
- 230000020477 pH reduction Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 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
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 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
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- 238000004448 titration Methods 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]
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- 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
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- 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
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- 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
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- 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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Description
1 85026
Menetelmä farmakologieeeti aktiivisen di foefonihappojohdannaisen valmistamiseksi Tämä keksintö kohdistuu menetelmään farmakologisesti aktiivisen 1-hydoksi-3-(N-metyyli-N-propyyliamino)propaani-1,1-di-fosfonihapon valmistamiseksi.
DE-OS-julkaisussa 18 13 659 on selostettu difoefonihappojohdannaisia, joista 1-hydroksi-etaani-1,1-difosfonihappo on saanut merkitystä hoidettaessa Pagetin tautia.
Patenttijulkaisuissa DE-OS 29 43 49Θ, DE-OS 27 02 631, EP-96-931-A sekä julkaisussa Z. Anorg. Allg. Chem. 457. 214 <1979), on selostettu 1-hydroksi-3-(N,N-dialkyyliamino)propaa-ni-1,1 difoefonihappoja, jotka ovat hyviä kalsiumkompleksin muodostajia, mutta joita voidaan myös käyttää kohonneen luu-resorption hoitoon. l-hydroksi-3-(N-metyyli-N-propyyliami-no)propaani-l,1-difoefonihappo sisältyy DE-OS-julkaisussa 25 34 391 esitettyyn yleiseen kaavaan, mutta siitä ei ole esimerkkiä eikä sitä ole mainittu edullisena yhdisteenä.
Nyt on yllättäen havaittu, että tämä typen suhteen epäsymmetrisesti dialkyloitu yhdiste tässä patenttijulkaisussa selostettuihin yhdisteisiin verrattuna erittäin hyvän kalsiumkom-pleksoinnin ohella omaa selvästi paremman vaikutuksen luuai-neenvaihduntasairauksissa hyvän siedettävyyden lisäksi.
Keksinnön mukaan on yhdiste ennen kaikkea niissä tapauksissa erittäin käyttökelpoinen, joissa luun liukeneminen ja muodostuminen on häiriintynyt, toisin sanoen se on käyttökelpoinen hoidettaessa sellaisia luuston sairauksia kuin esimerkiksi osteoporoosia, Pagetin tautia, Beehterewin tautia jne.
2 85026 Näiden ominaisuukeienea ansiosta sillä on käyttöä hoidettaessa luuhaarapesäkkeitä, virtsakivitautia ja ehkäistäessä virheellistä luutumista. Vaikutuksensa ka 1siumaineenvaihduntaan ansiosta muodostaa se sen lisäksi perustan hoidettaessa nivelreumaa, luunive1 tulehdusta ja nivelrappeumaa.
Tämä keksintö kohdistuu 1-hydroksi-3-(N-metyy1i-N-propyy1i-amino)propaani-1,1-difosfonihappoon, jolla on kaava I
( I ) 0=P<OR>2 H3C-CH2-CH2 j ^ n-ch2-ch2-c-oh H3c// 0= P(OR > 2 jossa R on vety tai - C^alkyyliryhmä, ja farmakologisesti hyväksyttäviin suoloihin. Keksinnön mukaiset di- tai tetraes-terit ovat edullisesti metyyli-, etyyli- tai isobutyyliesteri.
Kaavan I yhdiste valmistetaan sinänsä tunnetulla tavalla, edullisesti siten, että
a) karboksyy1ihappo, jolla on kaava II
< 11) h3c-ch2-ch2
^N-CHo-CHo-COOH
S
h3c saatetaan reagoimaan fosforihapokkeen tai fosforihapon ja fosforihalogenidin tai fosforyy1ihalogenidin seoksen kanssa ja saippuoidaan sen jälkeen vapaaksi di-fosfonihapoksi, 3 85026 tai
b> karboksyylihappokloridi, jolla on kaava III
< I I I > h3c-ch2-ch2 ^N-CH,-CH,-C0C1 / 2 2 h3c
saatetaan reagoimaan trialkyy1ifoefiitin kanssa, jolla on yleinen kaava IV
( IV) P < OR')3
joeea R' on 1-4 hiiliatomia sisältävä alkyyli, edullisesti metyyli, etyyli ja isobutyyli, asyylifosfonaatiksi, jolla on kaava V
(V)
HoC-CHo-CHo O O
3 2 Il II
N-CH2CH2-C-P<OR') 2
HgC
jossa R' tarkoittaa samaa kuin yllä, jonka sen jälkeen annetaan reagoida, di-alkyylifosfiitin kanssa, jolla on yleinen kaava VI
(VI >
O
H-l»<OR'>2 4 85026
jossa R' tarkoittaa samaa kuin yllä, difosfonaatiksi jolla on kaava VII
(VII) 0
II
P(OR')2
h3c ch2-ch2 J
'v'n-ch2-ch2-c-oh h3c P( OR')o a jossa R' tarkoittaa samaa kuin yllä, ja mahdollisesti saippuoimalla syntynyt tetraesteri diesteriksi tai vapaaksi 1-hyd-roksi-3-< N-metyy1i-N-proyy1iamino)propaani-l,1-difosf onihapoksi, jolla on kaava I, tai
c) metyloidaan yhdiste, jolla on yleinen kaava VIII
(VIII) 0 = P(OR')o h3c -ch2-ch2-n-ch2-ch2-c-oh h | 0=P(0R'>2 jossa R' tarkoittaa samaa kuin yllä, ja mahdollisesti saippuoidaan syntynyt tetraesteri diesteriksi tai vapaaksi 1-hyd-roksi-3-(N-metyyli-N-propyyliamino)propaani-l,1-di fosfoniha-poksi, jolla on kaava I, ja näin saadut yhdisteet muunnetaan mahdollisesti farmakologisesti hyväksyttäviksi suoloikseen.
5 85026
Menetelmässä a) lisätty karboksyy1ihappo, jolla on kaava II, saatetaan reagoimaan 1-5, edullisesti 2-3 moolin kanssa fosfo- rihapoketta tai fos f orihappoa ja 1-5, edullisesti 2-3 moolin kanssa fosforitrihalogenidia tai fosforyylihalogenidia o o 80-130 C:ssa, edullisesti 80-100 C:ssa. Reaktio voidaan myös suorittaa laimentimen kuten ha1ogenihii1ivedyn, erityisesti klooribentseenin, tetrakloorietaanin tai myös dioksaanin läsnäollessa. Seuraava hydrolyysi suoritetaan keittämällä vedellä, edullisesti kuitenkin puoliväkevällä suola- tai bromive-tyhapolla.
Fosforitrihalogenidina tulevat yllämainituissa menetelmissä kysymykseen esimerkiksi fos foritrikloridi- tai fos foritribro-midi, f os foryy1ihalogenidiksi soveltuu fosforioksikloridi.
Menetelmässä b) annetaan kaavan III happokloridi reagoida yleisen kaavan IV trialkyy1ifosfiitin kanssa lämpötiloissa, o o jotka ovat välillä 0 ja 60 C, edullisesti 20-40 C. Voidaan myös työskennellä ilman liuotinta tai myös inerttien liuottimien kuten dietyy1ieetterin, tetrahydrofuraanin, dioksaanin tai myös halogenoitujen hiilivetyjen, kuten esimerkiksi mety-leenikloridin läsnäollessa. Välituotteena syntyvä asyylifos-fonaatti, jolla on yleinen kaava V, voidaan eristää tai saattaa suoraan regoimaan edelleen. Seuraava reaktio suoritetaan heikon emäksen, edullisesti sek. amiinin kuten esimerkiksi o dibutyy1iamiinin läsnäollessa lämpötilassa 0-60 C, edullisesti o 10-30 C.
Pelkistävässä alkyloinnissa (menetelmä c>> käsitellään yleisen kaavan VIII sekundäärisen amiinin ja formaldehydin tai sen asetaalin seosta hydrauskatalyytin kuten palladiumin hiilellä tai nikkelin läsnäollessa vedyllä atmosfäärin tai kohotetussa paineessa tai murahaishappoa lisätään pelkistimiseksi.
Lopuksi suoritetaan yleisen kaavan VIII sekundäärisen amiinin metylointi erityisen edullisesti dimetyy1isulfaati1la suoritetun faaeinsiirtomenetelmän jälkeen.
6 85026
Menetelmissä b> ja c> mahdollisesti saostuva tetra-alkyy-liesteri voidaan saippuoida diesteriksi tai vapaaksi 1-hyd-roksi-3-< N-metyy1i-N-propyy1iamino)propaani -1,l-difosf onihapoksi. Hapotus diesteriksi tapahtuu yleensä siten, että tet-ra-alkyyliesteriä käsitellään aika1ihalogenidi1la, edullisesti natriumjodidilla sopivassa 1iuottimessa, kuten esimerkiksi asetonissa, huoneen lämpötilassa.
Tällöin syntyy symmetrinen diesteri/dinatriumsuola, joka mahdollisesti happamalla ioninvaihdolla voidaan muuntaa dieste-ri/dihapokei. Saippuointi vapaaksi difosfonihapoksi tapahtuu yleensä keittämällä suola- tai bromivetyhapolla. Voidaan kuitenkin myös suorittaa pilkkoaminen trimetyylisilyylihalogeni-dilla, edullisesti bromidilla tai jodidilla. Vapaa difosfoni-happo voidaan käänteisesti keittämällä ortomuurahaishappoal-kyy1iesteri1lä muuttaa takaisin tetra-alkyyliesteriksi. 1-hyd-roksi-3-(N-metyy1i-N-propyy1iamino)propaani-l,l-difosf onihap-po, jolla on kaava I, voidaan eristää vapaana happona tai sen mono- tai dialkalisuolan muodossa. Alkalisuola on yleensä hyvin puhdistettavissa uudelleen saostamalla vesi/metanolista tai vesi/asetonista.
Farmakologisesti hyväksyttävinä suoloina käytetään ennen kaikkea alkali- tai ammoniumsuoloja, jotka valmistetaan tavanomaiseen tapaan esimerkiksi titraamalla yhdistettä epäor-ganisilla tai organisilla emäksillä, kuten esimerkiksi natrium- tai kaliumvetykarbonaatilla, natrioniipeällä, kalili-peällä, ammoniakin vesiliuoksella tai amiineilla, kuten esimerkiksi trimetyyli- tai trietyy1iamiini 1la.
Kaavan I keksinnön mukaisia uusia yhdisteitä ja niiden suoloja voidaan antaa nestemäisessä tai kiinteässä muodossa ruuansulatuskanavan sisäisesti tai ulkoisesti. Tällöin tulevat kaikki tavanomaiset antotavat kysymykseen, esimerkiksi tabletit, kapselit, rakeet, siirapit, liuokset, suspensiot jne.
Injektiovällaineena on vesi erityisen edullinen, joka eisäl- 7 85026 tää injektioliuoksissa tavanomaisia lisäaineita kuten stabilointiaineita, liuos- ja puekurointiaineita. Tällaisia lisäaineita ovat esimerkiksi tartraatti- ja sitraattipuekuri, etanoli, kompleksimuodostajät (kuten etyleenidiamiinitetra-etikkahappo ja sen myrkyttömät suolat), suurmolekyy1iset polymeerit (kuten nestemäinen polyetyleenioksidi) viskositeetin säätämiseksi. Nestemäisten kantaja-aineiden tulee injektioliuoksia varten olla steriilejä ja täytetään edullisesti ampulleihin. Kiinteitä kantaja-aineita ovat esimerkiksi tärkkelys, laktoosi, manniitti, metyyliselluloosa, talkki, hyvin dispergoidut piihapot, suurmolekyyliset rasvahapot (kuten steariinihappo), gelatiini, agaragar, kalaiumfos faatti, magnesiums t earaat t i , eläin- ja kasvisrasvat, kiinteät suurmole-kyyliset polymeerit (kuten polyetyleeniglykoli); suun kautta annettavat valmisteet voivat haluttaessa sisältää makuja ma-keutusaineita.
Annostus voi riippua erilaisista tekijöistä, kuten antotavasta, lajista, iästä ja/tai yksilöllisestä tilasta. Päiväannokset ovat välillä noin 1-1000 mg/ihminen, edullisesti 10-200 mg/ihminen ja voidaan antaa yhdessä tai useammassa erässä.
Seuraavissa esimerkeissä kuvataan muutamia menetelmävaihtoeh-toja, joita voidaan käyttää syntetisoitaessa keksinnön mukaisia yhdisteitä. Niitä ei pidä kuitenkaan pitää keksintöä rajoittavina. Näiden yhdisteiden rakenne on varmistettu H-3 lp 31p ja -NMR-spektroskopialla, puhtaus -NMR-spektroskopialla, ohutkerroselektroforesi1la (selluloosa, oksalaattipuskuri ph = 4,0) ja C, H, N, P, Na-analyysillä. Aineen karakteri-soimikseksi on Mrel~arvo (= suhteellinen liikkuvuus) ilmaistu pyrofosfaatin (Mrel = 1,0) suhteen.
e 85026
Esimerkki 1 1-hydroke i-3-<N-metyy1i-N-propyy1iamino)propaani-l,l-difosfo-nihappo 18 g 3-<N-metyy1i-N-propyyliamino)-propionihappoa pidettiin 15 g:n kanssa fos forihapoketta ja 32 ml:n kanssa fosforitrik- o loridia 90 ml:ssa klooribentseeniä 12 tuntia 100 C:ssa. Liuotin erotettiin dekantoima1la ja jäännös sekoitettiin 250 ml :n kanssa 6 N suolahappoa 2 tuntia palautusjäähdyttaen. Pieni määrä liukenematonta erotettiin suodattamalla, suodate väke- + voitiin ja kaadettiin Amberlite-kolonnille IR 120, H -muoto. Eluointi vedellä suoritettiin elektroforeettisesti. Halutut fraktiot puhdistettiin, väkevöitiin, sekoitettiin asetoni/me-tanoliin ja saadut kiteet erotettiin. Näin saatiin 14,1 g raakatuotetta. Uudelleenkiteyttämällä vesi/metanolista saatiin 9,8 g = 27 % analyysipuhdasta tuotetta jne.
Lähtöaine saatiin seuraavasti: N-metyyli-N-propyyliamiinia (JACS 79., 4720 <1957)) saatettiin toluolissa reagoimaan akryylihappo-metyyliesterin kanssa moolisuhteessa 1:3 ja 84 %:n saantona saatu esteri saippuoitiin tislaamatta 1 N natrolipeällä. Näin saatiin 92 %:n saantona öljymäistä happoa, jota käytettiin ilman jatkopuhdistus-ta .
Esimerkki 2 10 g 3-<N-metyyli-N-propyyliamino)propionihappoa ja 11,4 g o fosforihapoketta sulatettiin yhdessä 10 minuttia 80 C:ssa.
öljyhaude poistettiin, lisättiin hitaasti 12 ml fosforitrik- o loridia tipoittain ja kuumennettiin vielä 16 tuntia 80 C:ssa.
Sen jälkeen ylimäärä fosforitrikloridia poistettiin tislaamalla, lisättiin 140 ml 6 N suolahappoa ja sekoitettiin 3 o tuntia 100 C:ssa Pieni määrä liukenematonta poistettiin suo- 9 85026 dattamalla, liuotin poistettiin tyhjössä ja puhdistettiin ioninvaihto- kromatografiällä Amberlitella IR-120 (H -muoto), kuten esimerkissä 1 on selostettu.
Esimerkki 3 15 g 3-<N-metyy1i-N-proyy1iamino>propionihappoa kuumennettiin analogisesti esimerkin 2 kanssa 17 g:n kanssa H3PO3 ja lisättiin 19 ml POCI3.
o 1Θ tunnin jälkeen 80 C:ssa poistettiin ylimäärä POCI3 tislaamalla ja hydrolysoitiin lisäämällä 210 ml 6 N suolahappoa ja o kuumentamalla 2 tuntia 100 C:ssa Raakatuote puhdistettiin (kuten) esimerkissä 1 on selostettu) ioninvaihto-kromatogra- fialla Amberlite IR-120 (H -muoto). Mre^ = 0,4, saanto 16,2 g = 54 % uudelleenkiteytyksen jälkeen vesi/metanolista, o 5p. 96-102 C.
Koepövtäkir -ia
Uropuolieilta noin 160 g:n painoisilta Wistar-rotilta poistettiin leikkaamalla tyroparatyroidi päivänä 1. Päivänä 5 tarkkailtiin leikkauksen seurausta siten, että kalkkiverisyys määritettiin yhden yön paaston jälkeen. Tästä päivästä saivat kaikki eläimet yhtä suuren määrän ravintoa. Lisäksi ne saivat 3 päivää peräkkäin ihonalaisia ruiskeita, joista toiset sisälsivät 25 pg synteettistä retinoidia (1iikakalkkisuuden aiheuttamiseksi veressä), toiset testattavaa di fosfonaattia. Kaikki eläimet saivat lisäksi käsittelyn ensimmäisenä ja viimeisenä päivänä 2 pg tyroksiinia. 24 tuntia viimeisen reti-noidi- ja di fosfonaatti-injektion jälkeen ja yhden yön paaston jälkeen otettiin silmäkuopan takaosasta verta eetterinukutuk-sesea. Plasma-kalsiumpitoisuus määritettiin atomiabsortiolla.
Difosfonaatti annettiin ensiksi 0,1 mg P/kg annoksena tilavuudessa 2 ml/kg, sen jälkeen 0,01 ja 0,001 mg P/kg:n annoksena.
10 85026 mg P/kg β.c.
0,001 0,01 0,1 A o + ++++ B + + + + o = 1iikaka1kkisuuden alenemia - 0,99 - + 0,99 mg % ( + ) = " " 1,0 1,99 " += " " 2,0 2,99 " + += '* " 3,0 — 3,99" +++ = " " 4,0 - 4,99 " + + + + = " >5,0 A = 1-hydroksi-3-(N,N-dimetyyliamino) propaani-1,1-difosfoni-happo (DE-OS 25 34 391) B = 3-(N,N-dietyy1iamino)-1-hydroxipropaani-1,1-difosfonihappo (DE-OS 25 34 391) C = 1-hydrokei-3-(N-metyyli-N-prolyyliamino) propaani-1,1-di-f os f onihappo
Claims (4)
11 85026 Patenttivaatimus Menetelmä farmakologisesti aktiivisen 1-hydroksi-3-(N-metyy1i-N-propyy1iamino)propaani-l,l-difosfonihapon valmistamiseksi, jolla on kaava I < I ) 0=P<0R>2 h3c-ch2-ch2 j >>^n-ch2-ch2-c-oh h3c/ I 0=P(0R)2 jossa R on vety tai Cj - C^-alkyyliryhmä, sekä sen farmakologisesti hyväksyttävien suolojen valmistamiseksi, tunnettu siitä, että a) karboksyy1ihappo, jolla on kaava II (II) h3c-ch2-ch2 Vs'N-CH2-CH2-COOH H3C^ saatetaan reagoimaan fos forihapokkeen tai fosforihapon ja fosforihalogenidin tai fos foryy1ihalogenidin seoksen kanssa ja sen jälkeen saippuoidaan vapaaksi difosf onihapoksi, jolla on kaava I tai b) karboksyylihappokloridi, jolla on kaava III 12 85026 ( I I I ) h3c-ch2-ch2 ^n-ch2-ch2-coci H3c/ saatetaan reagoimaan yleisen kaavan IV tria 1 kyy1if os fiitin kanssa ( IV) P < OR')g jossa R' on 1-4 hiiliatomia sisältävä alkyy1itähde, edullisesti metyyli, etyyli ja isobutyyli, asyy1ifosfonaatiksi, jolla on kaava V (V) HoC-CH,-CH, O O 3 2 2 1} i ^N-CH2CH2-C-P(OR'>2 .;· h3c/ jossa R' tarkoittaa samaa kuin edellä, jonka sen jälkeen annetaan reagoida, dialkyylifosfiitin kanssa, jolla on yleinen kaava VI (VI) O H-£(OR'>2 jossa R' tarkoittaa samaa kuin edellä, difosfonaatiksi, jolla on kaava VII 13 85026 (VII )
0 II P < OR')2 h3c-ch2-ch2 I Ns'N-CH2-CH2-C-OH h3c I P(OR')j jossa R' tarkoittaa samaa kuin edellä, ja mahdollisesti saippuoidaan syntynyt tetraesteri diesteriksi tai vapaaksi 1-hydr-okei-3-< N-metyyli-N-propyyliamino)propaani-1,1-di f oef onihapoksi, jolla on kaava I, tai c) metyloidaan yhdiste, jolla on yleinen kaava VIII (VIII) 0=P<OR')2 H3C -CH2-CH2-N-CH2-CH2-C-0H h I 0=P(0R')2 jossa R' tarkoittaa samaa kuin edellä, ja mahdollisesti saippuoidaan syntynyt tetraesteri diesteriksi tai vapaaksi l-hydrokei-3-(N-metyyli-N-propyyliamino)propaani-1,1-difosfo-nihapoksi, jolla on kaava I, ja näin saadut yhdisteet muunnetaan mahdollisesti farmakologisesti hyväksyttäviksi suoloik-seen. 14 85026 Förfarande för framställning av en farmakologiekt aktiv 1-hydroxi-3-(N-mety1-N-propy1amino)propan-1,1-difoefoneyra med f ormeIn I < I >
0. P(OR > 2 H3C-CH2-CHo v'N-CH2-CH2-C-OH H3C// I 0=P(0R)2 väri R betecknar väte eller en Cj - C^-alkylgrupp, eamt farmakologiekt acceptable salter därav, kännetecknat av att man a) omeätter en karboxyleyra med formeln II (II) h3c-ch2 ~ch2 "N -ch2-ch2-cooh H3c/ med en blandning av foeforeyrlighet eller foeforeyra och en foeforhalogenid eller foeforylhalogenid och därefter förtvA-lar tili fri difoefoneyra med formeln I, eller b) omeätter en karboxyleyraklorid med formeln III (III) h3c-ch2-ch2 ^N-CHo-CHo-COCl h3c^ ( IV) 15 85026 med ett trialkylfoefit med den allmänna formeln IV P < OR')3 väri R' betecknar en alkylreat med 1-4 kolatomer, foretradee-vie metyl, etyl och ieobutyl, till ett acylfosfonat med formeln V (V) HoC-CHo-CH, 0 0 3 2 2\ II H N-CH2CH2-C-P(OR'>2 h3C^ väri R' har ovan angiven betydelee, eom man därefter omeätter med ett dialkylfoefit med den almänna formeln VI (VI) :.-. 0 H-P<OR/)2 väri R' har ovan angiven betydelee, till ett difoefonat med f ormeln VI I (VI I ) 0 II P(0R'>2 H3C-CH2-CHo I ^N-CHo-CHo-C-OH h3c/ I Jj* < OR')2 0 ie 85026 väri R' har ovan angiven betydelee, och eventuellt förtvälar den bildade tetraestern tili en diester eller tili fri 1-hydroxi-3-<N-mety1-N-proylamino)propan-1,1-difoefonsyra med formeln I, eller c) metylerar en förening med den allmänna formeln VIII (VIII)
0. P < OR'>2 h3c-ch2-ch2-^-ch2-ch2-c-oh H I 0=P(0R')2 väri R' har ovan angiven betydelee, och eventuellt förtvälar den bildade tetraestern tili en dieeter eller tili fri l-hydroxi-3-(N-mety1-N-propylamino)propan-1,1-dif oef oneyra med formeln I, och överför de pä ei eätt erhällna föreningar-na eventuellt tili farmakologiekt acceptabla ealter därav.
Applications Claiming Priority (4)
| 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 |
| EP8700368 | 1987-07-09 | ||
| PCT/EP1987/000368 WO1988000590A1 (en) | 1986-07-11 | 1987-07-09 | Diphosphonium acid derivates and medicines containing the same |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI881134A0 FI881134A0 (fi) | 1988-03-10 |
| FI881134A FI881134A (fi) | 1988-03-10 |
| FI85026B true FI85026B (fi) | 1991-11-15 |
| FI85026C FI85026C (fi) | 1992-02-25 |
Family
ID=6304949
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI873058A FI87221C (fi) | 1986-07-11 | 1987-07-10 | Foerfarande foer framstaellning av nya difosfonsyraderivat |
| FI881134A FI85026C (fi) | 1986-07-11 | 1988-03-10 | Foerfarande foer framstaellning av ett farmakologiskt aktivt difosfonsyraderivat. |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI873058A FI87221C (fi) | 1986-07-11 | 1987-07-10 | Foerfarande foer framstaellning av nya difosfonsyraderivat |
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| Country | Link |
|---|---|
| US (2) | US4942157A (fi) |
| EP (2) | EP0252505B1 (fi) |
| JP (2) | JP2563954B2 (fi) |
| KR (2) | KR950008997B1 (fi) |
| AT (2) | ATE54000T1 (fi) |
| AU (2) | AU598279B2 (fi) |
| BG (1) | BG60839B2 (fi) |
| CA (2) | CA1305166C (fi) |
| CS (1) | CS265242B2 (fi) |
| DD (1) | DD263992A5 (fi) |
| DE (4) | DE3623397A1 (fi) |
| DK (2) | DK168629B1 (fi) |
| ES (2) | ES2043622T3 (fi) |
| FI (2) | FI87221C (fi) |
| GE (1) | GEP20084347B (fi) |
| GR (2) | GR3000616T3 (fi) |
| HK (1) | HK87093A (fi) |
| HU (2) | HU201950B (fi) |
| IE (2) | IE60219B1 (fi) |
| IL (2) | IL83148A (fi) |
| LU (1) | LU88844I2 (fi) |
| MX (1) | MX9203375A (fi) |
| NL (1) | NL960032I2 (fi) |
| NZ (2) | NZ221027A (fi) |
| PT (1) | PT85301B (fi) |
| WO (1) | WO1988000590A1 (fi) |
| ZA (1) | ZA874877B (fi) |
Families Citing this family (160)
| 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 |
| ATE90353T1 (de) * | 1987-12-11 | 1993-06-15 | Ciba Geigy Ag | Araliphatylaminoalkandiphosphonsaeuren. |
| US5110807A (en) * | 1988-12-01 | 1992-05-05 | Ciba-Geigy Corporation | Araliphatylaminoalkanediphosphonic acids |
| 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 |
| EP0449942B1 (en) * | 1988-11-01 | 1996-04-17 | Arch Development Corporation | Method for separating metal ions using phosphonic acids as complexants |
| GB8825589D0 (en) * | 1988-11-02 | 1988-12-07 | Albright & Wilson | Purification |
| TW198039B (fi) * | 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 |
| 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 |
| MX21453A (es) * | 1989-07-07 | 1994-01-31 | Ciba Geigy Ag | Preparaciones farmaceuticas que se administran en forma topica. |
| 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 |
| EP0416689B1 (en) * | 1989-09-06 | 1995-11-29 | Merck & Co. Inc. | Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors |
| 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 |
| DE69224830D1 (en) * | 1991-06-19 | 1998-04-23 | Upjohn Co | Dialkyl (dialkoxyphosphinyl)methyl phosphate als antientzündungsmittel |
| 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 |
| DK0531253T3 (da) * | 1991-08-27 | 1997-01-27 | Ciba Geigy Ag | N-substituerede aminomethandiphosphonsyrer |
| 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 |
| US6406714B1 (en) | 1992-12-02 | 2002-06-18 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids |
| 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 |
| WO1994014455A1 (en) * | 1992-12-23 | 1994-07-07 | Merck & Co., Inc. | Bisphosphonate/estrogen therapy for treating and preventing bone loss |
| US6399592B1 (en) | 1992-12-23 | 2002-06-04 | Merck & Co., Inc. | Bishphosphonate/estrogen synergistic therapy for treating and preventing bone loss |
| 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 |
| JPH11511041A (ja) | 1995-06-06 | 1999-09-28 | メルク エンド カンパニー インコーポレーテッド | 整形外科的埋め込み装置の無菌性動揺を防止するビスホスホネートセメント組成物 |
| EP0753523A1 (en) * | 1995-07-10 | 1997-01-15 | Gador S.A. | Amino-substituted bisphosphonic acids |
| WO1997012619A1 (en) * | 1995-09-29 | 1997-04-10 | Novartis Ag | Method of treating the navicular disease in horses |
| 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 |
| US6255359B1 (en) | 1997-12-23 | 2001-07-03 | Board Of Regents Of The University Of Texas System | Permeable compositions and methods for their preparation |
| 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 |
| 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 |
| ES2359973T3 (es) * | 1998-03-19 | 2011-05-30 | MERCK SHARP & DOHME CORP. | Composiciones poliméricas líquidas para la liberación controlada de sustancias bioactivas. |
| 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 |
| TR200101546T2 (tr) | 1998-12-04 | 2001-11-21 | Roche Diagnostics Gmbh | İç-protezlerde kemik entegrasyonunu iyileştirmek üzere ibandronat kullanılması. |
| EP1178810B8 (en) * | 1999-05-21 | 2005-07-27 | Novartis AG | Use of bisphosphonic acids for treating angiogenesis |
| 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 |
| PE20011061A1 (es) | 2000-02-01 | 2001-11-20 | Procter & Gamble | Cristalizacion selectiva del acido 3-piridil-1-hidroxi-etiliden-1,1-bisfosfonico sodio como el hemipentahidrato o el monohidrato |
| SE0000382D0 (sv) | 2000-02-07 | 2000-02-07 | Astrazeneca Ab | New process |
| EP1284754B1 (en) | 2000-05-05 | 2006-01-04 | F. Hoffmann-La Roche Ag | Gel-like pharmaceutical composition for subcutaneous administration comprising bisphosphonic acids or their salts |
| 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 |
| KR100638122B1 (ko) * | 2001-12-21 | 2006-10-24 | 더 프록터 앤드 갬블 캄파니 | 골 장애의 치료 방법 |
| WO2003061566A2 (en) * | 2002-01-24 | 2003-07-31 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Anti-cancer combination and use thereof |
| WO2003086415A1 (en) * | 2002-04-05 | 2003-10-23 | Merck & Co., Inc. | Method for inhibiting bone resorption with an alendronate and vitamin d formulation |
| PT1506041E (pt) * | 2002-05-10 | 2007-12-28 | Hoffmann La Roche | Ácido ibandrónico para o tratamento e a prevenção da osteoporose |
| KR100681282B1 (ko) * | 2002-05-17 | 2007-02-12 | 테바 파마슈티컬 인더스트리즈 리미티드 | 특정 희석제를 사용하는 비스포스폰산 및 그 염의 제조방법 |
| EP1513523A1 (en) * | 2002-06-06 | 2005-03-16 | Merck Frosst Canada & Co. | 1,5-disubstituted imidazolidin-2-one derivatives for use as ep4 receptor agonists in the treatment of eye and bone diseases |
| AU2003258433A1 (en) * | 2002-08-28 | 2004-03-19 | Merck Frosst Canada Ltd | 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 |
| SI1790347T1 (sl) | 2002-12-20 | 2015-03-31 | F. Hoffmann-La Roche Ag | Formulacija z visokim odmerkom ibandronata |
| WO2004065397A1 (en) * | 2003-01-17 | 2004-08-05 | Teva Pharmaceutical Industries Ltd. | Risedronate sodium having a very low content of iron |
| ATE451380T1 (de) * | 2003-08-21 | 2009-12-15 | Sun Pharmaceuticals Ind Ltd | Verfahren zur herstellung von bisphosphonsäureverbindungen |
| US7312353B2 (en) | 2003-08-21 | 2007-12-25 | Merck Frost Canada & Co. | Cathespin cysteine protease inhibitors |
| JP2007505886A (ja) * | 2003-09-19 | 2007-03-15 | ファイザー・プロダクツ・インク | ２−メチレン−１９−ノル−ビタミンｄ誘導体及びビスホスフォネートの組み合わせを含む医薬組成物及び方法 |
| ATE508134T1 (de) * | 2003-12-23 | 2011-05-15 | Alchymars S P A | Amorphe form das natriumsalzes der ibandronsäure |
| 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 |
| NZ587774A (en) | 2004-05-24 | 2012-03-30 | 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. |
| WO2006024024A2 (en) * | 2004-08-23 | 2006-03-02 | Teva Pharmaceutical Industries Ltd. | Solid and crystalline ibandronate sodium and processes for preparation thereof |
| 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 |
| US7214818B2 (en) * | 2004-10-29 | 2007-05-08 | Hoffmann-La Roche Inc. | Method for synthesizing bisphosphonate |
| WO2006062072A1 (ja) * | 2004-12-10 | 2006-06-15 | Tmrc Co., Ltd. | 転移癌治療剤および癌転移抑制剤 |
| SI1848727T1 (sl) * | 2005-02-01 | 2015-09-30 | F. Hoffmann-La Roche Ag | Polimorf b ibandronata |
| TR201902609T4 (tr) | 2005-02-01 | 2019-03-21 | Atnahs Pharma Uk Ltd | İbandronat polimorf A nın tıbbi kullanımı. |
| JP2008531691A (ja) | 2005-03-02 | 2008-08-14 | メルク エンド カムパニー インコーポレーテッド | カテプシンｋ阻害組成物 |
| KR20070121759A (ko) * | 2005-03-17 | 2007-12-27 | 엘란 파마 인터내셔널 리미티드 | 나노입자형 비스포스포네이트 조성물 |
| US20070003608A1 (en) * | 2005-04-08 | 2007-01-04 | Almond Merrick R | 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 |
| AU2007226964B2 (en) * | 2006-03-17 | 2012-03-22 | The Board Of Trustees Of The University Of Illinois | Bisphosphonate compounds and methods |
| ATE473990T1 (de) | 2006-06-23 | 2010-07-15 | Cipla Ltd | Verfahren zur synthese von ibandronat-natrium |
| 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 |
| TW200829256A (en) * | 2006-11-16 | 2008-07-16 | Teva Pharma | Crystalline forms 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 |
| US20100179110A1 (en) * | 2006-12-20 | 2010-07-15 | Mostafa Akbarieh | Composition Containing a Bisphosphonic Acid in Combination with Vitamin D |
| WO2008074145A1 (en) * | 2006-12-20 | 2008-06-26 | Genpharm 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 |
| CN101679465B (zh) * | 2007-04-11 | 2013-08-21 | 霍夫曼-拉罗奇有限公司 | 伊班膦酸盐的制备方法 |
| AU2008240266A1 (en) * | 2007-04-12 | 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 |
| EP2316840A1 (en) | 2007-04-19 | 2011-05-04 | Dr. Reddy's Laboratories Limited | Ibandronate Sodium Polymorphs |
| US20090042839A1 (en) * | 2007-08-09 | 2009-02-12 | Sharon Avhar-Maydan | Crystalline forms of ibandronate sodium |
| US8366706B2 (en) | 2007-08-15 | 2013-02-05 | Cardiodex, Ltd. | Systems and methods for puncture 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 |
| EP2543368A1 (en) | 2007-12-11 | 2013-01-09 | Viamet Pharmaceuticals, Inc. | Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties |
| CA2709677C (en) | 2007-12-21 | 2017-03-14 | Lin Zhi | 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 |
| US8993542B2 (en) * | 2008-01-25 | 2015-03-31 | Chimerix Inc. | Methods of treating viral infections |
| 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 |
| US20120100206A1 (en) | 2009-06-11 | 2012-04-26 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | Targeted liposomes comprising n-containing bisphosphonates and uses thereof |
| US8614200B2 (en) | 2009-07-21 | 2013-12-24 | Chimerix, Inc. | Compounds, compositions and methods for treating ocular conditions |
| US20120164104A1 (en) | 2009-08-03 | 2012-06-28 | 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 |
| HUE025737T2 (en) | 2009-09-01 | 2016-05-30 | Univ Duke | Bisphosphonate compositions and methods for treating heart failure |
| 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 |
| AU2011248620B2 (en) | 2010-04-26 | 2015-11-26 | 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 |
| ES2819059T3 (es) | 2011-07-13 | 2021-04-14 | Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd | Liposomas que encapsulan conjuntamente un bifosfonato y un agente anfipático |
| JP6261512B2 (ja) | 2011-11-16 | 2018-01-17 | デューク ユニバーシティ | 心機能障害を治療及び／又は低減するためのビスホスホネート組成物並びに方法 |
| 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 |
| CA2923272A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| WO2015051479A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| 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 |
| US10328082B2 (en) | 2014-05-30 | 2019-06-25 | Pfizer Inc. | Methods of use and combinations |
| WO2019076269A1 (zh) | 2017-10-16 | 2019-04-25 | 清华大学 | 甲羟戊酸通路抑制剂及其药物组合物 |
| KR20200085441A (ko) | 2019-01-07 | 2020-07-15 | 엠에프씨 주식회사 | 이반드로네이트의 신규한 결정형 및 이의 제조방법 |
| 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 |
| US4134969A (en) * | 1974-02-04 | 1979-01-16 | Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) | Method of treatment of calcium disorders using aminoalkane-diphosphonic acids |
| 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 |
| 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 |
| DE3370443D1 (en) * | 1982-06-10 | 1987-04-30 | Mallinckrodt Inc | Radiographic imaging agents |
| 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 |
-
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Owner name: BOEHRINGER MANNHEIM GMBH |