KR0137455B1 - 4-아미노-1-하이드록시부틸리덴-1, 1-비스포스폰산 또는 이의 염의 제조방법 - Google Patents
4-아미노-1-하이드록시부틸리덴-1, 1-비스포스폰산 또는 이의 염의 제조방법Info
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- KR0137455B1 KR0137455B1 KR1019900008394A KR900008394A KR0137455B1 KR 0137455 B1 KR0137455 B1 KR 0137455B1 KR 1019900008394 A KR1019900008394 A KR 1019900008394A KR 900008394 A KR900008394 A KR 900008394A KR 0137455 B1 KR0137455 B1 KR 0137455B1
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- Prior art keywords
- amino
- bisphosphonic acid
- hydroxybutylidene
- acid
- salts
- Prior art date
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- 239000002253 acid Substances 0.000 title claims description 17
- 150000003839 salts Chemical class 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 9
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 4
- 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 claims description 4
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- -1 Monosodium Salt Trihydrate Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000009838 combustion analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007706 flame test Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000005954 phosphonylation reaction Methods 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 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)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Seasonings (AREA)
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Abstract
내용없음
Description
본 발명은 최종 생성물이 원-폿 공정(one-procedure)으로 특히 순수한 형태 및 고수율로 수득되는 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염을 제조하는 개선된 방법에 관한 것이다.
미합중국 특허 제4,407,761호에는 아미노카복실산과 포스폰화 반응물질을 반응시킨 다음, 반응 혼합물을 가열하면서 진한 염산을 가하여 가수분해시킴으로써 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 제조하는 방법이 공지되어 있다. 이러한 방법의 문제점은 균일한 상태로 유지되지 않고 국소적인 고화가 발생된다는 점이다. 이러한 고화는 일정치 않은 수율을 야기시키고, 이는 열점(hot spot)을 전개시키는 반응의 발열성에 부분적인 원인이 있다. 또한, 선행기술 방법을 이용하여 나트륨염을 제조하기 위해서는 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 분리시켜야 하며 일나트륨염으로 전환시키는 추가의 단계가 필요하다.
본 발명은 반응물을 액체상태 및 균일한 상태로 유지되도록 함으로써 상업적인 제조가 가능해지고, 공정단계의 수가 감소하며 분리수율이 약 45 내지 50%로부터 약 85 내지 90%로 크게 향상됨으로써 상기와 같은 문제점을 해결한다.
본 발명은 (a) 4-아미노부티르산을 메탄설폰산의 존재하에서 아인산과 PCl3과의 혼합물과 반응시키고, (b) 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염을 회수함을 포함하여, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염을 제조하는 방법을 제공한다.
이 반응은, 경우에 따라, 반응 생성물이 용해되지 않는 불활성 유기 희석제의 존재하에서 약 45내지 125℃의 온도에서 수행될 수 있지만, 이는 메탄설폰산이 사용될 경우에는 필요하지 않다.
놀랍게도, 본 발명의 방법을 사용할 경우, 순수한 결정성 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염이 높은 수율로 수득된다는 사실이 밝혀졌다. 본 발명은 메탄설폰산 존재하에 아미노알칸 카복실산과 포스폰화 반응물질의 반응 및 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염의 회수를 포함한다. 이 화합물은 급냉, 가수분해 및 약 4.3으로의 pH조정 후, 추가의 정제단계를 필요로 하지 않고서 반응 혼합물로부터 약 90%의 수율로 직접 결정화된다.
사용될 수 있는 아미노알칸 카복실산은 4-아미노부티르산이다. 포스포닐화 반응은 일반적으로 45내지 125℃의 온도, 바람직하게는 약 65에서 일어난다.
아미노카복실산 1mol당 H3PO3는, 바람직하게는 1내지 2mol, 특히 바람직하게는 1.5mol 사용되고 PCl3는 1내지 2.5mol, 특히 2.4mol 사용된다. 경우에 따라, 반응 생성물이 용해되지 않는 불활성 유기희석제, 특히 헥산 또는 염소화 탄화수소(예 : 클로로벤젠, 테트라클로로에탄, 테트랄로로에틸렌 및 트리클로로에틸렌)가 반응에 사용될 수 있다. 메탄설폰산을 반응에 사용할 경우에는 희석제를 사용할 필요가 없다.
일반적으로, 가수분해는 반응용액의 크로마토그래피 시험에 의해 나타난 바와 같이, 환류하에서 약 3시간 동안 비등시킨 후에 완결된다.
반응의 도식은 다음과 같다.
본 명세서에서 기술된 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 -1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨염 삼수화물은 골흡수(bone resorption)를 포함한 질환의 치료 또는 예방을 위한 약제학적 조성물로서 유용하다. 악성의 과칼슘혈증, 페제트병 및 골다공증과 같은 질환은 본 발명의 방법에 따라 제조된 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨염 삼수화물에 의해 유효하게 치료된다.
다른 약제학적으로 허용되는 염, 예를 들어 칼슘염 및 칼륨염은 본 발명의 방법에 따라 제조될 수 있으며 본 발명의 범주내에 포함된다.
하기의 실시예는 본 발명의 실시를 예시하는 것이며, 어떤 방법으로도 본 발명을 제한하지는 않는다.
[실시예 1]
4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산
[일나트륨염 삼수화물의 제조]
250ml 플라스크에 기계적 교반기, 열전쌍, 적가펀넬 및 -20℃ 염수가 순환되는 환류 응축기를 장치한다. 이 시스템을 시스템에 7 내지 10psi의 배압을 걸리게 하는 가성세정기(caustic scrubber)에 연결한다. 시스템을 질소로 세척하고 아미노부티르산 20g(0.19mol), 메탄설폰산 80ml 및 아인산 24g(0.29mol)을 충전시킨다. 보다 큰 규모로 조작하기 위해서는, 메탄설폰산을 먼저 충전시키고, 이어서 4-아미노부티르산 및 아인산을 충전시킬 수 있다. 혼합하면 중화열 및 용해열이 반응온도를 75℃로 상승시킨다. 현탁액을 70 내지 75℃에서 15분동안 숙성시켜 투명한 무색의 용액을 생성시킨다. 용액을 35℃로 냉각시키고, 삼염화인(PCl3) 40ml(0.46mol)를 조심스럽게 20분에 걸쳐 가한다. 이어서, 반응물을 65℃로 가열하고 그 온도에서 20시간 동안 숙성시킨다. 반응물은 65℃를 초과하지 않도록 해야한다. 반응물은 85℃ 이상으로 자체 가열되며 단열 조건하에서 온도는 꾸준히 상승할 것이다. 약 150℃에서는 많은 가압 방출에 의해 수반된 발열 반응이 일어난다. 그러므로 온도가 85℃에 도달할 경우 반응물을 즉시 급냉각시키는 것이 바람직하다. 이어서 반응물을 25℃로 냉각시키고 탈이온수 200ml에 5분 동안 가한다. 플라스크를 추가의 물 100ml로 세정하고, 합한 요액을 95 내지 100℃에서 5시간 동안 숙성시킨다. 반응물을 20℃로 냉각시키고 20 내지 25℃에서 유지시키면서 약 80ml의 50% NaOH를 사용하여 pH를 4.3으로 조정한다. 이어서 생성된 백색 현탁액을 0 내지 5℃로 냉각시키고 1시간 동안 숙성시킨다. 경우에 따라, pH를 4.3으로 다시 조정하고, 현탁액을 0 내지 5℃에서 추가로 2시간 동안 숙성시킨다. 생성물을 여과하여 수집하고, 50ml의 냉수(0 내지 5℃)로 2회 세척하고, 100ml의 95% EtOH로 세척한다. 일정한 중량이 되도록 40℃에서 공기건조시킨 후의 수율은 56.4g(90%)이다.
[실시예 2]
4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산
[일나트륨 삼수화물의 분석]
실시예 1의 반응 생성물을 분석한 결과는 다음과 같다.
시 험 결 과
색, 형태, 외관 자유 유동하는 백색의 미세결정성 분말
입자크기 10-100μ, 평균 50μ미만
융 점 245℃에서 삽입, 257℃에서 응용 개시, 262.5℃에서 분해
정량 분석
(NaOH 적정) 99.7%
정량분석(착적정) 99.9%
HPLC 99.5%
카알 피셔(Karl Fisher) 16.6%(이론치 16.6%)
건조시 손실 16.7%
GC-잔여 에탄올 ＜0.01%
다른 산에 대한 TLC ＜0.01%(미검출)
중금속 ＜20ppm
0.5% H2O 용액의 pH 4.36
IR 일치
X-선 일치
Na에 대한 불꽃 시험 일치
미량화학 분석
이론치 실측치
탄 소 14.77 14.67
수 소 5.54 5.58
질 소 4.31 4.22
나트륨*7.08 7.00
인 19.08 19.00
잔여 염화물 ＜0.05
** AA 측정
[실시예 3]
[4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산의 제조]
비스포스폰산을 분리하기 위해서는, 다음과 같이 pH를 4.32가 아닌 1.8로 조정한다. 반응물을 20℃로 냉각시키고 20 내지 25℃에서 유지시키면서 50% NaOH를 80ml사용하여 pH를 1.0으로 조정한다. 이어서, 생성된 백색 현탁액을 0 내지 5℃로 냉각시키고 1시간 동안 숙성시킨다. pH를 1.8로 조정하고 현탁액을 0 내지 5℃에서 추가로 2시간 동안 숙성시킨다. 생성물을 여과하여 수집하고 100ml의 타리온수(20℃)로 세척한 후, 40℃에서 공기 건조시켜 44.0g(86% 수율)의 백색 미세 결정성 생성물을 수득한다.
[실시예 4]
[4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산의 분석]
실시예 3의 반응 생성물을 분석한 결과는 다음과 같다.
시 험 결 과
색, 형태, 외관 깨끗한 백색의 결정성 분말
NaOH 적정 99.5%
착적정 99.8%
건조시 손실 6.79%(이론치 6.74%)
0.5% 용액의 pH 2.15
[C4H13NO7P2.H2O에 대한 미량화학 분석]
이론치 실측치
탄 소 17.97 17.84
수 소 5.62 5.55
질 소 5.24 5.16
나트륨*- 0.05*
인 23.21 23.02
*원자 흡수 분광분석, 다른 원소들은 연소분석에 의해 측정되었다.
전술한 특정 양태는 본 발명의 실시를 예시하는 것이다. 그러나, 본 발명의 개념 또는 첨부된 특허청구 범위의 범주를 벗어남이 없이 본 분야의 숙련가에게 공지되어 있거나 본 명세서에 기술된 다른 방법들이 적용될 수 있을 것이다.
Claims (10)
- 4-아미노부티브산을 메탄설폰산의 존재하에서 아인산과 PCl3과의 혼합물과 반응시킨 다음, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염을 회수함을 포함하여, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염을 제조하는 방법.
- 제1항에 있어서, 반응이 45내지 125℃의 온도에서 수행되는 방법.
- 제2항에 있어서, 반응이 약 65℃의 온도에서 수행되는 방법.
- 제3항에 있어서, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨염 삼수화물을 회수하는 방법.
- 제3항에 있어서, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨염 삼수화물을 회수하는 방법.
- 다음 일반식(Ⅱ)의 화합물을 MOH, MCO3, 및 MPO4중에서 선택되는 염기로 20 내지 25℃ 및 pH 약 4.3에서 처리한 다음, 생성물을 회수함을 포함하여, 다음 일반식 (Ⅰ)의 화합물을 형성하는 방법.
상기식에서, M은 NH4 +, Na+, K+, Ca2+및 Mg2+중에서 선택된다. - 제6항에 있어서, 염기가 MOH인 방법.
- 제7항에 있어서 M이 Na+, K+또는 Ca2+인 방법.
- 제8항에 있어서, M이 Na+인 방법.
- 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨염 삼수화물.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US363820 | 1989-06-09 | ||
| US363,820 | 1989-06-09 | ||
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR910000768A KR910000768A (ko) | 1991-01-30 |
| KR0137455B1 true KR0137455B1 (ko) | 1998-05-01 |
Family
ID=23431886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019900008394A KR0137455B1 (ko) | 1989-06-09 | 1990-06-08 | 4-아미노-1-하이드록시부틸리덴-1, 1-비스포스폰산 또는 이의 염의 제조방법 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4922007A (ko) |
| EP (1) | EP0402152B1 (ko) |
| JP (2) | JPH0662651B2 (ko) |
| KR (1) | KR0137455B1 (ko) |
| AT (1) | ATE129713T1 (ko) |
| AU (1) | AU625704C (ko) |
| CA (1) | CA2018477C (ko) |
| CH (1) | CH0402152H1 (ko) |
| CY (1) | CY1894A (ko) |
| DE (1) | DE69023280T2 (ko) |
| DK (1) | DK0402152T3 (ko) |
| ES (1) | ES2080116T3 (ko) |
| FI (1) | FI93219C (ko) |
| GR (1) | GR3018379T3 (ko) |
| HK (1) | HK69596A (ko) |
| HU (1) | HU211908A9 (ko) |
| IE (1) | IE69564B1 (ko) |
| IL (1) | IL94612A (ko) |
| LV (1) | LV11472B (ko) |
| NO (2) | NO177997C (ko) |
| NZ (1) | NZ233972A (ko) |
| PT (1) | PT94306B (ko) |
| ZA (1) | ZA904446B (ko) |
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 |
| US5039819A (en) * | 1990-09-18 | 1991-08-13 | Merck & Co., Inc. | Diphosphonate intermediate for preparing an antihypercalcemic agent |
| US5159108A (en) * | 1990-09-18 | 1992-10-27 | Merck & Co., Inc. | Process 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 |
| HUT69731A (en) * | 1992-05-29 | 1995-09-28 | Procter & Gamble Pharma | Thio-substituted nitrogen-containing heterocyclic phosphonate compounds for treating abnormal calcium and phosphate metabolism |
| 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 |
| 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 |
| ATE195317T1 (de) * | 1992-05-29 | 2000-08-15 | Procter & Gamble Pharma | Schwefel-enthaltende phosphonat-verbindungen zur behandlung von abnormalem calzium- und phosphat- metabolismus |
| DK0646119T3 (da) * | 1992-05-29 | 1998-12-14 | Procter & Gamble Pharma | Phosphonatforbindelser indeholdende kvaternært nitrogen til behandling af unormalt calcium- og phosphatstofskifte samt tan |
| 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 (ko) * | 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 |
| CN1181012A (zh) * | 1995-02-17 | 1998-05-06 | 麦克公司 | 减小非椎骨骨折危险的方法 |
| EP0824341A4 (en) * | 1995-05-12 | 1999-07-07 | Merck & Co Inc | PREVENTING TOOTH LOSS THROUGH ADMINISTRATION OF ALENDRONATE OR ITS SALTS |
| JPH11506757A (ja) * | 1995-06-06 | 1999-06-15 | メルク エンド カンパニー インコーポレーテッド | 二ナトリウムアレンドロネート製剤 |
| WO1996039107A1 (en) | 1995-06-06 | 1996-12-12 | Merck & Co., Inc. | Bisphosphonate cement composition to prevent aseptic loosening of orthopedic implant devices |
| DK0833643T3 (da) * | 1995-06-06 | 2005-05-30 | Merck & Co Inc | Formuleringer af vandfrit mononatriumsalt af alendronat og deres anvendelse til behandling af knoglesygdomme |
| TR199900730T2 (xx) * | 1996-10-04 | 1999-07-21 | Merck & Co., Inc | S�v� alendronat form�lasyonlar� |
| JP2824453B2 (ja) * | 1996-10-15 | 1998-11-11 | 株式会社ワカ製作所 | コネクター |
| CA2197267C (en) * | 1997-02-11 | 2000-02-08 | Yong Tao | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
| IL122009A0 (en) * | 1997-10-21 | 1998-03-10 | Unipharm Ltd | Salt of a bisphosphonic acid derivative |
| US20030078211A1 (en) * | 1998-06-24 | 2003-04-24 | Merck & Co., Inc. | Compositions and methods for inhibiting bone resorption |
| EP1088333A4 (en) | 1998-06-24 | 2005-08-10 | Merck & Co Inc | METHOD AND COMPOSITIONS FOR CONNECTING OSTEOPROSIS |
| US6008207A (en) * | 1998-08-13 | 1999-12-28 | Merck & Co., Inc. | Anhydrous alendronate monosodium salt formulations |
| PL346347A1 (en) * | 1998-08-27 | 2002-02-11 | Teva Pharma | Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof |
| EP1702924A3 (en) * | 1998-08-27 | 2007-07-18 | Teva Pharmaceutical Industries Ltd | Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof |
| US6331533B1 (en) | 1998-11-16 | 2001-12-18 | Merck & Co., Inc. | Method for inhibiting dental resorptive lesions |
| US6160165A (en) * | 1998-12-10 | 2000-12-12 | Aesgen, Inc. | Method for preparation of disodium pamidronate |
| US6794536B1 (en) | 1998-12-10 | 2004-09-21 | Aesqen, Inc. | Method for preparation of disodium pamidronate |
| US6963008B2 (en) * | 1999-07-19 | 2005-11-08 | Teva Pharmaceutical Industries Ltd. | Hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof |
| ES2153794B1 (es) * | 1999-08-06 | 2001-10-16 | Medichem Sa | Procedimiento para la obtencion del acido 4-amino-1-hidroxibutiliden-1,1-bisfosfonico y de su sal monosodica trihidratada. |
| 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 |
| AU7902800A (en) * | 1999-10-26 | 2001-05-08 | A/S Gea Farmaceutisk Fabrik | Novel salts of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, their preparation and use |
| US6476006B2 (en) | 2000-06-23 | 2002-11-05 | Teva Pharmaceutical Industries, Ltd. | Composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates |
| US6558702B2 (en) | 2001-04-13 | 2003-05-06 | Alkermes Controlled Therapeutics, Inc. | Method of modifying the release profile of sustained release compositions |
| US20060269602A1 (en) * | 2001-04-13 | 2006-11-30 | Dasch James R | Method of modifying the release profile of sustained release compositions |
| TR200101250A2 (tr) * | 2001-05-10 | 2003-04-21 | E�S Eczaciba�I �Zg�N K�Myasal �R�Nler Sanay� A.�. | 4-amino-1-hidroksibutiliden-1,1-bifosfonik asit veya tuzlarının hazırlanmasına ilişkin proses |
| CA2372450A1 (en) * | 2001-05-10 | 2001-09-19 | Pharmaceutical Partners Of Canada Inc. | Liquid injectable formulation of disodium pamidronate |
| GB2383042A (en) * | 2001-10-18 | 2003-06-18 | Cipla Ltd | Amorphous alendronate sodium |
| CN100479823C (zh) * | 2001-12-21 | 2009-04-22 | 宝洁公司 | 双膦酸盐在制造药物套盒中的用途以及用于增加骨质的套盒 |
| US20050070504A1 (en) * | 2001-12-21 | 2005-03-31 | The Procter & Gamble Co. | Risedronate compositions and their methods of use |
| AU2002364051A1 (en) * | 2002-01-24 | 2003-09-02 | Children's Medical Center Corporation | Anti-cancer combination and use thereof |
| ITMI20020146A1 (it) * | 2002-01-29 | 2003-07-29 | Lyogen Ltd | Alendronato monosodico amorfo e processo per la sua preparazione |
| ITMI20020908A1 (it) * | 2002-04-29 | 2003-10-29 | Chemi Spa | Processo di preparazione di sodio alendronato |
| ES2532393T3 (es) * | 2002-05-10 | 2015-03-26 | F. Hoffmann-La Roche Ag | Acidos bisfosfónicos para tratamiento y prevención de osteoporosis |
| US7038083B2 (en) | 2002-05-17 | 2006-05-02 | Teva Pharmaceutical Industries, Ltd. | Process for making bisphosphonic acids using diluents other than halogenated hydrocarbons |
| 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 |
| JP4485117B2 (ja) * | 2002-06-27 | 2010-06-16 | 日東電工株式会社 | 保護剥離用フィルム |
| JP2006504679A (ja) * | 2002-08-28 | 2006-02-09 | メルク フロスト カナダ アンド カンパニー | 緑内障の治療においてｅｐ４受容体作動薬として使用するためのオキサゾリジン−２−オンおよびチアゾリジン−２−オン誘導体 |
| US20040138180A1 (en) * | 2002-10-03 | 2004-07-15 | Barr Laboratories, Inc. | Bisphosphonate composition and process for the preparation thereof |
| NZ536273A (en) * | 2002-12-20 | 2007-08-31 | Hoffmann La Roche | High dose ibandronate formulation |
| US20040206932A1 (en) * | 2002-12-30 | 2004-10-21 | Abuelyaman Ahmed S. | Compositions including polymerizable bisphosphonic acids and methods |
| HUP0300227A2 (hu) * | 2003-01-28 | 2004-09-28 | Richter Gedeon Vegyészeti Gyár Rt. | Eljárás nagy tisztaságú 2-szubsztituált -1-(hidroxi-etilidén)-1,1-biszfoszfonsavak és sóik előállítására |
| CA2535556C (en) * | 2003-08-12 | 2014-01-07 | 3M Innovative Properties Company | Self-etching dental compositions and methods |
| CA2535359A1 (en) | 2003-08-21 | 2005-03-03 | Merck Frosst Canada Ltd. | Cathepsin cysteine protease inhibitors |
| DE602004024545D1 (de) | 2003-08-21 | 2010-01-21 | Sun Pharmaceuticals Ind Ltd | Indungen |
| WO2005027921A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and a bisphosphonate |
| WO2005035542A1 (en) * | 2003-10-14 | 2005-04-21 | Pliva-Istrazivanje I Razvoj D.O.O. | Solid-state form of alendronate sodium and preparation thereof |
| US20050261250A1 (en) * | 2004-05-19 | 2005-11-24 | Merck & Co., Inc., | Compositions and methods for inhibiting bone resorption |
| ATE475412T1 (de) | 2004-05-24 | 2010-08-15 | Warner Chilcott Co Llc | Enterische feste orale dosierform eines bisphosphonats mit einem chelate |
| UA87854C2 (en) | 2004-06-07 | 2009-08-25 | Мерк Энд Ко., Инк. | N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators |
| US8465284B2 (en) * | 2004-07-08 | 2013-06-18 | 3M Innovative Properties Company | Dental methods, compositions, and kits including acid-sensitive dyes |
| WO2006020760A1 (en) * | 2004-08-11 | 2006-02-23 | 3M Innovative Properties Company | Self-adhesive compositions including a plurality of acidic compounds |
| US7361761B2 (en) * | 2004-09-28 | 2008-04-22 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of bisphosphonic acid |
| US7214818B2 (en) | 2004-10-29 | 2007-05-08 | Hoffmann-La Roche Inc. | Method for synthesizing bisphosphonate |
| CN1304401C (zh) * | 2004-12-28 | 2007-03-14 | 浙江工业大学 | 一种阿伦膦酸的制备方法 |
| PL1855674T3 (pl) | 2005-03-02 | 2015-01-30 | Merck Sharp & Dohme | Kompozycja do hamowania katepsyny K |
| US8158153B2 (en) * | 2005-03-17 | 2012-04-17 | Alkermes Pharma Ireland Limited | Nanoparticulate bisphosphonate compositions |
| WO2006134603A1 (en) * | 2005-06-13 | 2006-12-21 | Jubilant Organosys Limited | Process for producing bisphosphonic acids and forms thereof |
| AR054673A1 (es) | 2005-07-28 | 2007-07-11 | Gador Sa | Una forma cristalina del acido zoledronico, un proceso para su obtencion y la composicion farmaceutica que la comprende |
| US8003820B2 (en) * | 2005-10-20 | 2011-08-23 | Dr. Reddy's Laboratories Limited | Process for preparing bisphosphonic acids |
| JP5001292B2 (ja) | 2005-10-31 | 2012-08-15 | キャボット コーポレイション | 変性着色剤及び変性着色剤を含むインクジェットインキ組成物 |
| PT1803727E (pt) * | 2005-12-27 | 2009-06-15 | Ipca Lab Ltd | Processo melhorado para o fabrico de ácido 4-amino-hidroxibutilideno-1,1 bisfosfónico e seus sais |
| WO2007083240A2 (en) | 2006-01-20 | 2007-07-26 | Aurobindo Pharma Limited | An improved process for the preparation of bisphosphonic acids |
| CA2570949A1 (en) * | 2006-12-12 | 2008-06-12 | Apotex Pharmachem Inc. | Ibandronate sodium propylene glycol solvate and processes for the preparation thereof |
| CN101557791B (zh) | 2006-12-13 | 2013-05-22 | 3M创新有限公司 | 使用具有酸性组分和可光漂白染料的牙科用组合物的方法 |
| WO2008125483A2 (en) | 2007-04-11 | 2008-10-23 | F. Hoffmann-La Roche Ag | Multi step synthesis of ibandronate |
| WO2008157050A1 (en) * | 2007-06-19 | 2008-12-24 | Albemarle Corporation | Processes for manufacturing bisphosphonic acids |
| WO2009050731A2 (en) * | 2007-06-20 | 2009-04-23 | Alkem Laboratories Ltd | Novel process for preparing risedronic acid |
| US20090170815A1 (en) * | 2007-12-28 | 2009-07-02 | Roxane Laboratories Incorporated. | Alendronate oral liquid formulations |
| WO2009100107A2 (en) * | 2008-02-05 | 2009-08-13 | Actavis Group Ptc Ehf | Alendronate formulations, method of making and method of use thereof |
| WO2010003704A2 (en) * | 2008-07-11 | 2010-01-14 | Synthon B.V. | Process for making 1-hydroxyalkylidene-1,1-biphosphonic acids |
| US20100130746A1 (en) * | 2008-11-26 | 2010-05-27 | Martin Kas | Process for Making Zoledronic Acid |
| WO2010143193A1 (en) | 2009-06-11 | 2010-12-16 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | Targeted liposomes comprising n-containing bisphosphonates and uses thereof |
| WO2011023280A1 (en) | 2009-08-28 | 2011-03-03 | Synthon B.V. | Process for making 1-hydroxyalkylidene-1,1-biphosphonic acids |
| JP5489126B2 (ja) | 2009-09-30 | 2014-05-14 | 大日本印刷株式会社 | インク組成物 |
| CA2738045C (en) | 2010-05-28 | 2019-02-19 | Simon Fraser University | Conjugate compounds, methods of making same, and uses thereof |
| EP2609101B1 (en) | 2010-07-14 | 2015-01-28 | Pharmathen S.A. | Process for the preparation of 3-(n-methyl-n-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid salt or derivatives thereof |
| EP3378906A1 (en) | 2010-07-30 | 2018-09-26 | Cabot Corporation | Inkjet composition |
| TR201903835T4 (tr) | 2010-12-06 | 2019-04-22 | Effrx Pharmaceuticals Sa | Hızlı çözünme özelliklerine sahip stabil efervesan bifosfonat formülasyonları. |
| KR20140009266A (ko) | 2010-12-27 | 2014-01-22 | 다이니폰 인사츠 가부시키가이샤 | 잉크젯 기록 방법 |
| WO2012112363A1 (en) | 2011-02-14 | 2012-08-23 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| WO2012132403A1 (ja) | 2011-03-29 | 2012-10-04 | 大日本印刷株式会社 | インクジェット記録方法、およびインクジェット記録用インクセット |
| EP2731591B1 (en) | 2011-07-13 | 2020-06-17 | Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. | Liposomes co-encapsulating a bisphosphonate and an amphipathic agent |
| GB201200868D0 (en) | 2012-01-19 | 2012-02-29 | Depuy Int Ltd | Bone filler composition |
| JP5722860B2 (ja) | 2012-10-11 | 2015-05-27 | 株式会社Ｄｎｐファインケミカル | 水性インクジェット受理溶液、この受理溶液を含むインクセット及びこのインクセットを用いたインクジェット記録方法 |
| AU2014332250B2 (en) | 2013-10-08 | 2018-07-19 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| WO2015051479A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| JP5779630B2 (ja) | 2013-11-27 | 2015-09-16 | 株式会社Ｄｎｐファインケミカル | インクジェット記録用インク組成物、及びその製造方法、並びに、インクジェット記録方法 |
| JP5676734B1 (ja) | 2013-12-27 | 2015-02-25 | 株式会社Ｄｎｐファインケミカル | インクジェット記録用インク組成物、インクジェット記録方法、及び印刷物の製造方法 |
| 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 |
| EP3148587B1 (en) | 2014-05-30 | 2021-02-24 | Pfizer Inc | Carbonitrile derivatives as selective androgen receptor modulators |
| US9650414B1 (en) | 2014-05-30 | 2017-05-16 | Simon Fraser University | Dual-action EP4 agonist—bisphosphonate conjugates and uses thereof |
| CN104072538A (zh) * | 2014-07-10 | 2014-10-01 | 陕西汉江药业集团股份有限公司 | 一种双膦酸盐类药物的合成方法 |
| WO2016199111A1 (en) | 2015-06-12 | 2016-12-15 | Simon Fraser University | Amide-linked ep4 agonist-bisphosphonate compounds and uses thereof |
| EP3827010A4 (en) | 2018-07-23 | 2022-03-16 | Brise Pharmaceuticals Co., Ltd. | BISPHOSPHONATE-DRUG CONJUGATES |
| WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2534391C2 (de) * | 1975-08-01 | 1983-01-13 | Henkel KGaA, 4000 Düsseldorf | 1-Hydroxy-3-aminoalkan-1,1-diphosphonsäuren |
| DE2745083C2 (de) * | 1977-10-07 | 1985-05-02 | Henkel KGaA, 4000 Düsseldorf | Hydroxydiphosphonsäuren und Verfahren zu deren Herstellung |
| DE2943498C2 (de) * | 1979-10-27 | 1983-01-27 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur Herstellung von 3-Amino-1-hydroxypropan-1,1-diphosphonsäure |
| DE3016289A1 (de) * | 1980-04-28 | 1981-10-29 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur herstellung von omega -amino-1-hydroxyalkyliden-1,1-bis-phosphonsaeuren |
| US4304734A (en) * | 1980-10-16 | 1981-12-08 | Vysoka Skola Chemicko-Technologicka | 6-Amino-1-hydroxyhexylidene diphosphonic acid, salts and a process for production thereof |
| IT1201087B (it) * | 1982-04-15 | 1989-01-27 | Gentili Ist Spa | Bifosfonati farmacologicamente attivi,procedimento per la loro preparazione e relative composizioni farmaceutiche |
| US4639338A (en) * | 1984-08-06 | 1987-01-27 | Ciba-Geigy Corporation | Preparation of crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate |
| IT1196315B (it) * | 1984-10-29 | 1988-11-16 | Gentili Ist Spa | Procedimento per la preparazione di acidi difosfonici |
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