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1. 发明授权

US5519013A Heterocycle-substituted diphosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism 失效
标题翻译：杂环取代的二膦酸盐化合物，药物组合物和治疗异常钙和磷酸盐代谢的方法
公开(公告)号：US5519013A
公开(公告)日：1996-05-21
申请号：US224615
申请日：1994-04-07
申请人： Frank H. Ebetino , James J. Benedict
发明人： Frank H. Ebetino , James J. Benedict
IPC分类号： C07F9/59 , C07F9/6509 , C07F9/6512 , C07F9/6521 , A61K31/675
CPC分类号： C07F9/65122 , C07F9/592 , C07F9/598 , C07F9/650917 , C07F9/650941 , C07F9/650964 , C07F9/650988 , C07F9/65127 , C07F9/65212 , C07F9/65217
摘要： The present invention relates to novel heterocycle-substituted diphosphonic acids, and the pharmaceutically-acceptable salts and esters thereof, in which the diphosphonate-substituted carbon atom moiety is attached to a carbon atom in a nitrogen-containing six membered ring heterocycle, preferably a piperidine ring. The heterocycle-substituted diphosphonic acid compounds have the general structure: ##STR1## wherein Z is a nitrogen-containing six membered ring heterocycle moiety selected from piperidinyl, diazinyl and triazinyl; m, n and m+n are from 0 to 10; Q is a covalent bond or a moiety selected from oxygen, sulfur or nitrogen; and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are substituent groups.The present invention further relates to pharmaceutical compositions containing these novel compounds. Finally this invention relates to methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.
摘要翻译：本发明涉及新颖的杂环取代二膦酸及其药学上可接受的盐和酯，其中二膦酸酯取代的碳原子部分连接到含氮六元环杂环中的碳原子上，优选哌啶环。杂环取代的二膦酸化合物具有以下一般结构：其中Z是选自哌啶基，二嗪基和三嗪基的含氮六元环杂环部分。 m，n和m + n为0〜10; Q是共价键或选自氧，硫或氮的部分; 并且R1，R2，R3和R4是取代基。本发明还涉及含有这些新化合物的药物组合物。最后本发明涉及利用本发明的化合物或药物组合物治疗或预防以异常钙和磷酸盐代谢为特征的疾病的方法。

2. 发明授权

US5334586A Heterocycle-substituted diphosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism 失效
标题翻译：杂环取代的二膦酸盐化合物，药物组合物和治疗异常钙和磷酸盐代谢的方法
公开(公告)号：US5334586A
公开(公告)日：1994-08-02
申请号：US779705
申请日：1991-10-21
申请人： Frank H. Ebetino , James J. Benedict
发明人： Frank H. Ebetino , James J. Benedict
IPC分类号： C07F9/59 , C07F9/6509 , C07F9/6512 , C07F9/6521 , A61K31/675
CPC分类号： C07F9/65122 , C07F9/592 , C07F9/598 , C07F9/650917 , C07F9/650941 , C07F9/650964 , C07F9/650988 , C07F9/65127 , C07F9/65212 , C07F9/65217
摘要： The present invention relates to novel heterocycle-substituted diphosphonic acids, and the pharmaceutically-acceptable salts and esters thereof, in which the diphosphonate-substituted carbon atom moiety is attached to a carbon atom in a nitrogen-containing six membered ring heterocycle, preferably a piperidine ring. The heterocycle-substituted diphosphonic acid compounds have the general structure: ##STR1## wherein Z is a nitrogen-containing six membered ring heterocycle moiety selected from piperidinyl, diazinyl and triazinyl; m, n and m+n are from 0 to 10; Q is a covalent bond or a moiety selected from oxygen, sulfur or nitrogen; and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are substituent groups.The present invention further relates to pharmaceutical compositions containing these novel compounds. Finally this invention relates to methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.
摘要翻译：本发明涉及新颖的杂环取代二膦酸及其药学上可接受的盐和酯，其中二膦酸酯取代的碳原子部分连接到含氮六元环杂环中的碳原子上，优选哌啶环。杂环取代的二膦酸化合物具有以下一般结构：其中Z是选自哌啶基，二嗪基和三嗪基的含氮六元环杂环部分。 m，n和m + n为0〜10; Q是共价键或选自氧，硫或氮的部分; 并且R1，R2，R3和R4是取代基。本发明还涉及含有这些新化合物的药物组合物。最后本发明涉及利用本发明的化合物或药物组合物治疗或预防以异常钙和磷酸盐代谢为特征的疾病的方法。

3. 发明授权

US5071840A Certain heterocyclic substituted diphosphonate compounds pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism 失效
标题翻译：某些杂环取代的二膦酸盐化合物药物组合物，以及治疗异常钙和磷酸盐代谢的方法
公开(公告)号：US5071840A
公开(公告)日：1991-12-10
申请号：US378530
申请日：1989-07-11
申请人： Frank H. Ebetino , James J. Benedict
发明人： Frank H. Ebetino , James J. Benedict
IPC分类号： C07F9/59 , C07F9/6509 , C07F9/6512 , C07F9/6521
CPC分类号： C07F9/65122 , C07F9/592 , C07F9/598 , C07F9/650917 , C07F9/650941 , C07F9/650964 , C07F9/650988 , C07F9/65127 , C07F9/65212 , C07F9/65217
摘要： The present invention relates to novel heterocycle-substituted diphosphonic acids, and the pharmaceutically-acceptable salts and esters thereof, in which the diphosphonate-substituted carbon atom moiety is attached to a carbon atom in a nitrogen-containing six membered ring heterocycle, preferably a piperidine ring. The heterocycle-substituted diphosphonic acid compounds have the general structure: ##STR1## wherein Z is a nitrogen-containing six membered ring heterocycle moiety selected from piperidinyl, diazinyl and triazinyl; m, n and m+n are from 0 to 10; Q is a covalent bond or a moiety selected from oxygen, sulfur or nitrogen; and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are substituent groups.The present invention further relates to pharmaceutical compositions containing these novel compounds. Finally this invention relates to methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.
摘要翻译：本发明涉及新颖的杂环取代二膦酸及其药学上可接受的盐和酯，其中二膦酸酯取代的碳原子部分连接到含氮六元环杂环中的碳原子上，优选哌啶环。杂环取代的二膦酸化合物具有以下一般结构：其中Z是选自哌啶基，二嗪基和三嗪基的含氮六元环杂环部分。 m，n和m + n为0〜10; Q是共价键或选自氧，硫或氮的部分; 并且R1，R2，R3和R4是取代基。本发明还涉及含有这些新化合物的药物组合物。最后本发明涉及利用本发明的化合物或药物组合物治疗或预防以异常钙和磷酸盐代谢为特征的疾病的方法。

4. 发明授权

US5104863A Certain bicycloalkane and azabicycloalkane-1,1-diphosphonic acid derivatives useful for treating diseases associated with abnormal calcium and phosphate metabolism 失效
标题翻译：某些用于治疗与钙和磷酸盐代谢异常有关的疾病的双环烷烃和氮杂双环链烷-1,1-二膦酸衍生物
公开(公告)号：US5104863A
公开(公告)日：1992-04-14
申请号：US547646
申请日：1990-07-03
申请人： James J. Benedict , Karen Y. Johnson , James J. Benedict , Karen Y. Johnson
发明人： James J. Benedict , Karen Y. Johnson , James J. Benedict , Karen Y. Johnson
IPC分类号： C07F9/38 , C07F9/576
CPC分类号： C07F9/3856 , C07F9/3852 , C07F9/5765
摘要： This invention relates to pyrindine-diphosphonic acid derivatives which are useful in treating or preventing diseases characterized by abnormal calcium and phosphate matabolism, in particular those which are characterized by abnormal bone metabolism. This invention further relates to pharmaceutical compositions which contain the novel compounds of the present invention, and to a method of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism utilizing a compound of the present invention.
摘要翻译：本发明涉及嘧啶二膦酸衍生物，其可用于治疗或预防以异常钙和磷酸盐分解为特征的疾病，特别是以异常骨代谢为特征的疾病。本发明还涉及含有本发明新化合物的药物组合物，以及利用本发明化合物治疗或预防以异常钙和磷酸盐代谢为特征的疾病的方法。

5. 发明授权

US09101694B2 Pliable medical device and method of use 有权
标题翻译：柔韧的医疗器械及使用方法
公开(公告)号：US09101694B2
公开(公告)日：2015-08-11
申请号：US12086557
申请日：2006-12-15
申请人： James J. Benedict , Greg Allen Brewster , Donald Barclay Freeman
发明人： James J. Benedict , Greg Allen Brewster , Donald Barclay Freeman
IPC分类号： A61F2/00 , A61K38/18 , A61L27/52 , A61L27/28 , A61L27/56
CPC分类号： A61L27/3608 , A61L27/20 , A61L27/28 , A61L27/52 , A61L27/54 , A61L27/56 , A61L2430/02 , C08L1/28
摘要： A firm but pliable medical device for use as a bone graft substitute or bone graft extender retains its shape without the requirement of a containment device, such as a syringe. Because the device is solid, it is easy to locate or position in-vivo and, in the moist environment of the body, it will hold its shape well, for an extended time. Because the lyophilized pliable medical device is porous, it adsorbs blood and other beneficial cells containing body fluids, such as bone marrow, contributing to its superior bone repair efficacy in comparison to an analogous putty that has not been lyophilized. In addition these lyophilized pliable medical devices are easier to terminally steam sterilize than the analogous putty because there is no moisture present to boil and “blow-out” of the containment device (syringe). The glycerin that is present in the formulation lends pliability but has a low vapor pressure.
摘要翻译：用作骨移植物替代物或骨移植物延长剂的牢固但柔韧的医疗装置保持其形状，而不需要诸如注射器的容纳装置。因为该装置是固体，所以很容易在体内定位或定位，并且在身体的潮湿环境中，其将保持良好的形状，长时间。因为冻干的柔韧的医疗装置是多孔的，因此与没有被冻干的类似的腻子相比，它吸收含有体液如骨髓的血液和其它有益细胞，有助于其优异的骨修复功效。此外，这些冻干的柔韧的医疗设备比类似的油灰更容易终止蒸汽消毒，因为不存在水分以便将容器（注射器）煮沸和“吹出”。存在于制剂中的甘油具有柔韧性但具有低蒸气压。

6. 发明申请

US20110027332A1 PLIABLE MEDICAL DEVICE AND METHOD OF USE 有权
标题翻译：可塑医疗器械及其使用方法
公开(公告)号：US20110027332A1
公开(公告)日：2011-02-03
申请号：US12086557
申请日：2006-12-15
申请人： James J. Benedict , Greg Allen Brewster , Donald Barclay Greeman
发明人： James J. Benedict , Greg Allen Brewster , Donald Barclay Greeman
IPC分类号： A61F2/28 , A61K47/30 , A61K47/32 , A61K47/36 , A61K47/38 , A61K33/42 , A61K38/17 , A61P19/00
CPC分类号： A61L27/3608 , A61L27/20 , A61L27/28 , A61L27/52 , A61L27/54 , A61L27/56 , A61L2430/02 , C08L1/28
摘要： A firm but pliable medical device for use as a bone graft substitute or bone graft extender retains its shape without the requirement of a containment device, such as a syringe. Because the device is solid, it is easy to locate or position in-vivo and, in the moist environment of the body, it will hold its shape well, for an extended time. Because the lyophilized pliable medical device is porous, it adsorbs blood and other beneficial cells containing body fluids, such as bone marrow, contributing to its superior bone repair efficacy in comparison to an analogous putty that has not been lyophilized. In addition these lyophilized pliable medical devices are easier to terminally steam sterilize than the analogous putty because there is no moisture present to boil and “blow-out” of the containment device (syringe). The glycerin that is present in the formulation lends pliability but has a low vapor pressure.
摘要翻译：用作骨移植物替代物或骨移植物延长剂的牢固但柔韧的医疗装置保持其形状，而不需要诸如注射器的容纳装置。因为该装置是固体，所以很容易在体内定位或定位，并且在身体的潮湿环境中，其将保持良好的形状，长时间。因为冻干的柔韧的医疗装置是多孔的，因此与没有被冻干的类似的腻子相比，它吸收含有体液如骨髓的血液和其它有益细胞，有助于其优异的骨修复功效。此外，这些冻干的柔韧的医疗设备比类似的油灰更容易终止蒸汽消毒，因为不存在水分以便将容器（注射器）煮沸和“吹出”。存在于制剂中的甘油具有柔韧性但具有低蒸气压。

7. 发明授权

US06627230B2 Method of preparing a bone product by removing cancellous bone matrix 失效
标题翻译：通过去除松质骨基质制备骨产品的方法
公开(公告)号：US06627230B2
公开(公告)日：2003-09-30
申请号：US09747166
申请日：2000-12-22
申请人： James J. Benedict , Frank Fisher , Colin Brock
发明人： James J. Benedict , Frank Fisher , Colin Brock
IPC分类号： A61F228
CPC分类号： A61K35/32 , A61F2/4644 , A61F2002/4646
摘要： A method and apparatus for preparing a bone product are provided. The method includes contacting an interior section of a cylindrical bone portion with a high pressure fluid medium such as at least about 1000 psi to remove at least a portion of cancellous bone matrix from the bone portion. Preferably the bone contains less than about 25% by weight cancellous bone. The apparatus includes multiple stations of opposing high pressure nozzles holding the cylindrical bone portion from each end and for contacting the interior surfaces of a bone portion with a fluid medium. The apparatus also includes a third nozzle for contacting the exterior surface of the bone portion with a fluid medium.
摘要翻译：提供了一种用于制备骨产品的方法和装置。该方法包括使圆柱形骨部分的内部部分与诸如至少约1000psi的高压流体介质接触以从骨部分去除至少一部分松质骨基质。优选地，骨含有小于约25重量％的松质骨。该装置包括相对的高压喷嘴的多个站，每个端口从每个端部保持圆柱形骨部分并且用于使骨部分的内表面与流体介质接触。该装置还包括用于使骨部分的外表面与流体介质接触的第三喷嘴。

8. 发明授权

US06511958B1 Compositions for regeneration and repair of cartilage lesions 有权
标题翻译：用于软骨损伤再生和修复的组合物
公开(公告)号：US06511958B1
公开(公告)日：2003-01-28
申请号：US09505209
申请日：2000-02-16
申请人： Brent Atkinson , James J. Benedict
发明人： Brent Atkinson , James J. Benedict
IPC分类号： A01N3718
CPC分类号： B82Y5/00 , A61B17/06166 , A61F2/30756 , A61F2002/2817 , A61F2002/30062 , A61F2002/30677 , A61F2210/0004 , A61F2310/00365 , A61L27/227 , A61L27/24 , A61L27/26 , A61L27/54 , A61L2300/252 , A61L2300/414 , A61L2300/45 , A61L2430/06 , Y10S530/84 , Y10S977/907 , Y10S977/908 , Y10S977/91 , Y10S977/912 , Y10S977/914 , Y10S977/915 , C08L89/06
摘要： Disclosed is a cartilage repair product that induces both cell ingrowth into a bioresorbable material and cell differentiation into cartilage tissue. Such a product is useful for regenerating and/or repairing both vascular and avascular cartilage lesions, particularly articular cartilage lesions, and even more particularly mensical tissue lesions, including tears as well as segmental defects. Also disclosed is a method of regenerating and repairing cartilage lesions using such a product.
摘要翻译：公开了一种软骨修复产品，其诱导细胞向生长可再生材料向内生长并将细胞分化为软骨组织。这种产品可用于再生和/或修复血管和非血管软骨损伤，特别是关节软骨病变，甚至更特别是包括眼泪以及节段性缺损的神经组织病变。还公开了使用这种产品再生和修复软骨损伤的方法。

9. 发明申请

US20090297605A1 Composition And Device For In Vivo Cartilage Repair 审中-公开
标题翻译：用于体内软骨修复的组合物和装置
公开(公告)号：US20090297605A1
公开(公告)日：2009-12-03
申请号：US12463108
申请日：2009-05-08
申请人： Brent L. Atkinson , Pedro Bittman , James J. Benedict , John Ranieri , Marsha L. Whitney , Donald Chickering
发明人： Brent L. Atkinson , Pedro Bittman , James J. Benedict , John Ranieri , Marsha L. Whitney , Donald Chickering
IPC分类号： A61K9/10 , A61K9/14 , A61K38/02
CPC分类号： A61K9/5153 , A61B17/06166 , A61F2/30756 , A61F2002/2817 , A61F2002/30036 , A61F2002/30062 , A61F2002/30677 , A61F2210/0004 , A61F2250/0035 , A61F2310/00365 , A61L27/227 , A61L27/24 , A61L27/26 , A61L27/48 , A61L27/50 , A61L27/54 , A61L2300/252 , A61L2300/30 , A61L2300/624 , A61L2400/12 , A61L2430/06 , B82Y5/00 , Y10S977/91 , Y10S977/914 , C08L89/06 , C08L5/08
摘要： The composition as described serves for in vivo cartilage repair. It basically consists of a naturally derived osteoinductive and/or chondroinductive mixture of factors (e.g. derived from bone) or of a synthetic mimic of such a mixture combined with a nanosphere delivery system. A preferred mixture of factors is the combination of factors isolated from bone, known as BP and described by Poser and Benedict (WO 95/13767). The nanosphere delivery system consists of nanospheres defined as polymer particles of less than 1000 nm in diameter (whereby the majority of particles preferably ranges between 200-400 nm) in which nanospheres the combination of factors is encapsulated. The nanospheres are loaded with the mixture of factors in a weight ratio of 0.001 to 17% (w/w), preferably of 1 to 4% (w/w) and have a release profile with an initial burst of 10 to 20% of the total load over the first 24 hours and a long time release of at least 0.1 per day during at least seven following days. The nanospheres are composed of e.g. ((D,L)lactic acid/glycolic acid)-copolymer (PLGA). The loaded nanospheres are e.g. made by phase inversion. The composition is advantageously utilized as a device comprising any biodegradable matrix in which the nanospheres loaded with the factor combination is contained.
摘要翻译：所述的组合物用于体内软骨修复。其基本上由天然衍生的成骨诱导和/或软骨诱导的因子（例如衍生自骨）的混合物或与纳米球递送系统组合的这种混合物的合成模拟物组成。因素的优选混合物是从骨分离的因子（称为BP）并由Poser和Benedict（WO 95/13767）描述的组合。纳米球传递系统由纳米球定义为直径小于1000nm的聚合物颗粒（其中大多数颗粒的范围优选在200-400nm之间），其中纳米球包封因子的组合。纳米球以重量比为0.001至17％（w / w），优选1至4％（w / w）的因子混合物加载，并具有释放曲线，初始爆发为10至20％至少在接下来的七天内，前24小时的总负荷和每天至少0.1次的长时间释放。纳米球由例如，（（D，L）乳酸/乙醇酸） - 共聚物（PLGA）。负载的纳米球是例如。通过相位反演。组合物有利地用作包含其中包含加载因子组合的纳米球的任何可生物降解的基质的装置。

10. 发明授权

US06679918B1 Implantable putty material 失效
标题翻译：可植入腻子材料
公开(公告)号：US06679918B1
公开(公告)日：2004-01-20
申请号：US09023617
申请日：1998-02-13
申请人： James J. Benedict , Christopher J. Damien
发明人： James J. Benedict , Christopher J. Damien
IPC分类号： C07K100
CPC分类号： A61L27/24 , A61L24/102 , Y10S514/801
摘要： The present invention provides compositions for an implantable putty material for delivery of active compounds to a patient. More specifically, the present invention provides a material having a pH of between about 3 and 6 and possessing putty-like physical properties, wherein the composition of the material includes collagen and water. The present invention also provides a method for using the implantable putty material.
摘要翻译：本发明提供了用于将活性化合物递送至患者的可植入腻子材料的组合物。更具体地说，本发明提供pH为约3〜6，具有油灰状物理性质的材料，其中所述材料的组成包括胶原和水。本发明还提供了一种使用可植入腻子材料的方法。

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