NO178228B - Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,2-bisfosfonsyresalter - Google Patents
Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,2-bisfosfonsyresalter Download PDFInfo
- Publication number
- NO178228B NO178228B NO941726A NO941726A NO178228B NO 178228 B NO178228 B NO 178228B NO 941726 A NO941726 A NO 941726A NO 941726 A NO941726 A NO 941726A NO 178228 B NO178228 B NO 178228B
- Authority
- NO
- Norway
- Prior art keywords
- amino
- hydroxybutylidene
- reaction
- acid
- bisphosphonic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 239000002253 acid Substances 0.000 title claims description 7
- 150000003839 salts Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 13
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- CAKRAHQRJGUPIG-UHFFFAOYSA-M sodium;[4-azaniumyl-1-hydroxy-1-[hydroxy(oxido)phosphoryl]butyl]-hydroxyphosphinate Chemical compound [Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O CAKRAHQRJGUPIG-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- -1 e.g. caleium Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Seasonings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Foreliggende oppfinnelse -angår en forbedret fremgangsmåte for. fremstilling av 4-amino-l-hydroxybutyliden-l,1-bisfosfonsyresalter hvori sluttproduktet erholdes i særlig ren form og med høye utbytter i en én-karsprosedyre.
Det er kjent i henhold til US patentskrift 4.407.761 å fremstille 4-amino-l-hydroxybutyliden-l,1-bisfosfonsyre ved omsetning av en aminocarboxylsyre med en blanding av fosforsyrling og PC13 og deretter hydrolysering av reaksjonsblandingen ved tilsetning av konsentrert saltsyre under opp-varming. Problemer oppstår fra denne reaksjon hvorved den ikke forblir homogen, og lokal stivning oppstår. Denne stivning forårsaker variable utbytter som delvis er et resultat av den eksoterme natur av reaksjonen med utvikling av varme soner. For å fremstille natriumsaltet krevde de kjente fremgangsmåter isolering av 4-amino-l-hydroxybutyliden-l,1-bisfosfonsyre og et ytterligere trinn for å omdanne mononatriumsaltet.
Foreliggende oppfinnelse løser disse problemer ved å tillåte at reaksjonsblandingen blir flytende og homogen, hvilket muliggjør en kommersiell fremstilling, reduserer an-tallet ffemgangsmåtetrinn og tilveiebringer en stor forbedring i isolert utbytte på fra 45-50% til 85-90%.
Foreliggende oppfinnelse angår således en fremgangsmåte for fremstilling av 4-amino-l-hydroxybutyliden-l,1-bis-fosfonsyresalter av formel (I)
hvori M betegner NH4<+>, Na<+>, K<+>, Ca<2+>, Mg<2+>, ved omsetning av 4-aminosmørsyre med en blanding av fosforsyrling og PC13 ved en temperatur på fra 45°C til 125°C, fortrinnsvis 65°C, hvilken fremgangsmåte er kjennetegnet ved at reaksjonen utføres i nærvær av methansulfonsyre, og at reaksjonsblandingen inne-holdende den dannede forbindelse av formel
behandles med en forbindelse valgt fra M(OH)n, (M)nC03 og (M)nP04, hvori n = 1 eller 2, ved en temperatur på 20-25°C og ved en pH på tilnærmet 4,3, hvoretter produktet gjenvinnes.
Reaksjonen kan utføres, om ønsket, i nærvær av et inert, organisk fortynningsmiddel som ikke oppløseliggjør reaksjonsproduktet og ved en temperatur på fra 45° til 125°C, selv om dette ikke er nødvendig når methansulfonsyre an-vendes .
Det er funnet at rene, krystallinske 4-amino-l-hydroxybutyliden-l , 1-bisf osf onsyresalter overraskende kan erholdes i høye utbytter når prosedyren ifølge oppfinnelsen an-vendes. Forbindelsen krystalliseres direkte fra reaksjonsblandingen i ca. 90% utbytte etter stansing av reaksjonen, hydrolyse og pH-justering til ca. 4,3 og hvor ingen ytterligere rensing er nødvendig.
Reaksjonen finner sted ved temperaturer på fra 45° til 125°C, fortrinnsvis ca. 65°C.
Generelt er hydrolysen fullført etter ca. 3 timers kokning "under tilbakeløpskjøling som vist ved kromatografisk test av reaksjonsløsningen.
Reaksjonen er vist skjematisk som følger:
4-amino-l-hydroxybuty1iden-1,1-bisfosfonsyremono-natriumsalt-trihydrat beskrevet her, er anvendbar som et farmasøytisk preparat og for behandling eller forhindring av sykdommer innbefattende benresorpsjon. Slike sykdommer som hypercalcemi av ondartet type, Pagets sykdom og osteoporose behandles med fordel med 4-amino-l-hydroxybutyliden-l,1-bis-fosfonsyremononatriumsalt-trihydrat ifølge oppfinnelsen.
Andre farmasøytisk akseptable salter slik som f.eks. caleium-, kaliumsalter, kan fremstilles i henhold til frem-gangsmåten ifølge oppfinnelsen.
Det etterfølgende eksempel illustrerer oppfinnelsen.
Eksempel
Fremstilling av 4- amino- l- hydroxybutyliden- l, 1- bisfosfonsyre-mononatriumsalt- trihydrat
En 250 ml kolbe ble utstyrt med en mekanisk rører,
.et termometer, en tilsetningstrakt og en tilbakeløpskjøler gjennom hvilken saltvann ble sirkulert ved -20°C. Systemet var koblet til en kautisk "scrubber" som forårsaker et bak-trykk på 0,49-0,71 kg/cm 2 på systemet. Systemet ble spylt med nitrogen og fylt med 20 g (0,19 mol) aminosmørsyre, 80 ml methansulfonsyre og 24 g (0,29 mol) fosforsyre. For operasjoner i større målestokk kan methansulfonsyren til-settes først, etterfulgt av 4-aminosmørsyre og fosforsyre. Etter blanding økte varmen av nøytralisasjonen og løsningen reaksjonstemperaturen til 75°C. Suspensjonen ble aldret i 15 minutter ved 70-75°C som ga en klar, fargeløs løsning, -lysningen ble avkjølt til 35°C, og fosfortriklorid (PCl^)/ 40 ml (0,46 mol) ble tilsatt forsiktig i løpet av 20 minutter. Reaksjonsblandingen ble deretter oppvarmet til 65°C og aldret ved denne temperatur i 20 timer. Reaksjonsblandingen skal ikke tillates å gå særlig over 65°C. Reaksjonsblandingen blir selvoppvarmende over 85°C, og under adiabat-iske betingelser vil temperaturen stadig øke. Ved 150° oppstår en eksoterm ledsaget av et stort trykkfall. Det anbe-fales derfor at reaksjonen umiddelbart stanses i kaldt vann hvis temperaturen når 85°C. Reaksjonsblandingen ble deretter avkjølt til 25°C og ble tilsatt til 200 ml avionisert vann i løpet av 5 minutter. Kolben ble skyllet med ytterligere 100 ml vann, og den kombinerte løsning ble aldret ved 95-100°C i 5 timer. Reaksjonsblandingen ble avkjølt til 20°C og opp-rettholdt ved 20-25'°C mens pH ble justert til 4,3 med ca. 80 ml 50% NaOH. Den resulterende, hvite suspensjon ble deretter avkjølt til 0-5°C og aldret i 1 time. pH ble rejustert til_4,3 om nødvendig, og suspensjonen ble aldret ved 0-5°C i ytterligere 2 timer. Produktet ble oppsamlet ved filtrering og deretter vasket med 2 x 50 ml kaldt (0-5°C) vann og 100 ml 95% EtOH. Utbyttet etter lufttørking ved 40°C til konstant vekt var 56,4 g (90%).
Analyse av 4- amino- l- hydroxvbutyliden- l, 1- bisfosfonsyre-mononatriumsalt- trihydrat
Reaksjonsproduktet ble analysert med følgende resul-tater:
Claims (4)
1. Fremgangsmåte for fremstilling av 4-amino-l-hydroxybutyliden-l , 2-bisf osf onsyresalter av formel (I)
hvori M betegner NH4<+>, Na<+>, K<+>, Ca<2+>, Mg<2+>, ved omsetning av 4-aminosmørsyre med en blanding av fosforsyrling og PC13 ved en temperatur på fra 45°C til 125°C, fortrinnsvis ved 65°C, karakterisert ved at reaksjonen utføres i nærvær av methansulfonsyre, og at reaksjonsblandingen inne-holdende den dannede forbindelse av formel
behandles med en forbindelse valgt fra M(OH)n, (M)nC03 og (M)nP04, hvori n = 1 eller 2, ved en temperatur på 20-25 °C og ved en pH på tilnærmet 4,3, hvoretter produktet gjenvinnes.
2. Fremgangsmåte ifølge krav 1, karakterisert ved at forbindelsen er M(0H)n.
3. Fremgangsmåte ifølge krav 2, karakterisert ved at M er Na<+>, K<+> eller Ca<2+>.
4. Fremgangsmåte ifølge krav 3, karakterisert ved at M er Na<+>.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO941726A NO178228C (no) | 1989-06-09 | 1994-05-09 | Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,2-bisfosfonsyresalter |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/363,820 US4922007A (en) | 1989-06-09 | 1989-06-09 | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
| NO902559A NO177997C (no) | 1989-06-09 | 1990-06-08 | Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,1-bisfosfonsyre |
| NO941726A NO178228C (no) | 1989-06-09 | 1994-05-09 | Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,2-bisfosfonsyresalter |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO941726L NO941726L (no) | 1990-12-10 |
| NO941726D0 NO941726D0 (no) | 1994-05-09 |
| NO178228B true NO178228B (no) | 1995-11-06 |
| NO178228C NO178228C (no) | 1996-02-14 |
Family
ID=23431886
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO902559A NO177997C (no) | 1989-06-09 | 1990-06-08 | Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,1-bisfosfonsyre |
| NO941726A NO178228C (no) | 1989-06-09 | 1994-05-09 | Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,2-bisfosfonsyresalter |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO902559A NO177997C (no) | 1989-06-09 | 1990-06-08 | Fremgangsmåte for fremstilling av 4-amino-1-hydroxybutyliden-1,1-bisfosfonsyre |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4922007A (no) |
| EP (1) | EP0402152B1 (no) |
| JP (2) | JPH0662651B2 (no) |
| KR (1) | KR0137455B1 (no) |
| AT (1) | ATE129713T1 (no) |
| AU (1) | AU625704C (no) |
| CA (1) | CA2018477C (no) |
| CH (1) | CH0402152H1 (no) |
| CY (1) | CY1894A (no) |
| DE (1) | DE69023280T2 (no) |
| DK (1) | DK0402152T3 (no) |
| ES (1) | ES2080116T3 (no) |
| FI (1) | FI93219C (no) |
| GR (1) | GR3018379T3 (no) |
| HK (1) | HK69596A (no) |
| HU (1) | HU211908A9 (no) |
| IE (1) | IE69564B1 (no) |
| IL (1) | IL94612A (no) |
| LV (1) | LV11472B (no) |
| NO (2) | NO177997C (no) |
| NZ (1) | NZ233972A (no) |
| PT (1) | PT94306B (no) |
| ZA (1) | ZA904446B (no) |
Families Citing this family (118)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5356887A (en) * | 1990-01-31 | 1994-10-18 | Merck & Co., Inc. | Pharmaceutical compositions containing insoluble calcium salts of amino-hydroxybutylidene bisphoshonic acids |
| US5019651A (en) * | 1990-06-20 | 1991-05-28 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof |
| US5159108A (en) * | 1990-09-18 | 1992-10-27 | Merck & Co., Inc. | Process for preparing an antihypercalcemic agent |
| US5039819A (en) * | 1990-09-18 | 1991-08-13 | Merck & Co., Inc. | Diphosphonate intermediate for preparing an antihypercalcemic agent |
| US5763611A (en) * | 1992-05-29 | 1998-06-09 | The Procter & Gamble Company | Thio-substituted cyclic phosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
| SG47603A1 (en) * | 1992-05-29 | 1998-04-17 | Procter & Gamble Pharma | Thio-substitute nitrogen containing heterocyclic phosphonate compounds for treating abnormal calcium and phosphate metabolism |
| JPH07507315A (ja) * | 1992-05-29 | 1995-08-10 | プロクター、エンド、ギャンブル、ファーマスーティカルズ、インコーポレーテッド | カルシウムおよびホスフェート代謝異常治療用含硫ホスホネート化合物 |
| US5391743A (en) * | 1992-05-29 | 1995-02-21 | Procter & Gamble Pharmaceuticals, Inc. | Quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental calculus and plaque |
| CZ297094A3 (en) * | 1992-05-29 | 1995-12-13 | Procter & Gamble Pharma | Phosphate compounds containing quaternary nitrogen, their use and pharmaceutical compositions containing thereof |
| US5753634A (en) * | 1992-05-29 | 1998-05-19 | The Procter & Gamble Company | Quaternary nitrogen containing phosphonate compounds, pharmaceutical compostions, and methods for treating abnormal calcium and phosphate metabolism |
| FR2694558B1 (fr) * | 1992-08-05 | 1994-10-28 | Sanofi Elf | Monohydrate du sel disodique de l'acide 4-chlorophénylthiométhylène bisphosphonique, sa préparation, les compositions pharmaceutiques en contenant. |
| US6406714B1 (en) | 1992-12-02 | 2002-06-18 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids |
| US6399592B1 (en) | 1992-12-23 | 2002-06-04 | Merck & Co., Inc. | Bishphosphonate/estrogen synergistic therapy for treating and preventing bone loss |
| FR2703590B1 (fr) * | 1993-04-05 | 1995-06-30 | Sanofi Elf | Utilisation de derives d'acide bisphosphonique pour la preparation de medicaments destines a favoriser la reparation osseuse . |
| TW257765B (no) * | 1993-08-25 | 1995-09-21 | Merck & Co Inc | |
| US5510517A (en) * | 1993-08-25 | 1996-04-23 | Merck & Co., Inc. | Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids |
| US5854227A (en) * | 1994-03-04 | 1998-12-29 | Hartmann; John F. | Therapeutic derivatives of diphosphonates |
| US20010007863A1 (en) * | 1998-06-18 | 2001-07-12 | Merck & Co., Inc. | Wet granulation formulation for bisphosphonic acids |
| US5462932A (en) * | 1994-05-17 | 1995-10-31 | Merck & Co., Inc. | Oral liquid alendronate formulations |
| US5449819A (en) * | 1994-06-06 | 1995-09-12 | Merck & Co., Inc. | Process for removing waste pox, alendronate and its by products |
| US5589691A (en) * | 1994-06-06 | 1996-12-31 | Merck & Co., Inc. | Process for recovery and recycle of methanesulfonic acid and phosphorous acid |
| US5780455A (en) * | 1994-08-24 | 1998-07-14 | Merck & Co., Inc. | Intravenous alendronate formulations |
| EP0809502A4 (en) * | 1995-02-17 | 2001-12-05 | Merck & Co Inc | PROCESS FOR REDUCING THE RISK OF BONE FRACTURES OTHER THAN VERTEBRAL FRACTURES |
| EP0824341A4 (en) * | 1995-05-12 | 1999-07-07 | Merck & Co Inc | PREVENTING TOOTH LOSS THROUGH ADMINISTRATION OF ALENDRONATE OR ITS SALTS |
| EP0831756A1 (en) | 1995-06-06 | 1998-04-01 | Merck & Co., Inc. | Bisphosphonate cement composition to prevent aseptic loosening of orthopedic implant devices |
| ATE289199T1 (de) * | 1995-06-06 | 2005-03-15 | Merck & Co Inc | Formulierungen mit dem wasserfreien mononatriumsalz von alendronat und deren verwendung zur behandlung von knochenkrankheiten |
| EP0837863A4 (en) * | 1995-06-06 | 1999-06-16 | Merck & Co Inc | DISODIUM ALENDRONATE PREPARATIONS |
| AU723357B2 (en) * | 1996-10-04 | 2000-08-24 | Merck & Co., Inc. | Liquid alendronate formulations |
| JP2824453B2 (ja) * | 1996-10-15 | 1998-11-11 | 株式会社ワカ製作所 | コネクター |
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| DE3016289A1 (de) * | 1980-04-28 | 1981-10-29 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur herstellung von omega -amino-1-hydroxyalkyliden-1,1-bis-phosphonsaeuren |
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