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text:
Core strength.
The Colony Oak Elementary School reconstruction project is looking at an aggressive timeline.
A first book of its kind by author Harry E. Pacheco "Gladys Glasses" is being introduced in Give Every Child a Chance after school tutoring classes to help stem the tide in the bullying of young elementary school students.
Burglaries shot up 21.58 percent in Manteca during 2015.
There's a new gas station that may be coming to Manteca.
Three men suspected of robbing Mantecans as they walked on residential sidewalks after dark at three separate locations have been arrested by Manteca Police officers.
The backdrop was fitting.
Medically focused college students are being offered scholarships by the Doctors Hospital of Manteca Auxiliary volunteers to help them shoulder the costs of their education beyond their second year of study.
The biggest employer in the South County is looking to hire more than 200 new employees.
The book is titled, "Revolution Revisited: The 1986 Philippine Revolution."
Want to know the hardest thing about getting healthy?
A handful of topics were on the table when candidates for political offices ranging from Congress to county supervisor appealed for support at the San Joaquin County Republican Party's Candidate Forum.
Dropping gas prices that in turn have reduced municipal sales tax collected at the pump has stalled growth in the Measure M public sales tax fund.
STOCKTON - One of the most historic veterans organizations in California has fallen on hard times and, according to its commander, Danny Wren, the group is at wits end on what to do.
TAINAN, Taiwan (AP) - The death toll from a powerful earthquake that toppled a high-rise apartment building in Taiwan rose to at least 34, according to government figures Monday, with rescuers digging through rubble for survivors more than 48 hours after the quake struck.
Page 22 of 884
Altamont Corridor Express trains will start running down the tracks to downtown Manteca, Ripon and Modesto if the California High Speed Rail Authority votes to ...
Editor's note: This is part of an occasional series on rivers, lakes, reservoirs, the Delta, innovations and the weather that play a key role ...
It's "All or Nuttin' 2016" for the May 7 Rina's Run.
Colony Oak School classes often took place at Stouffer Park 25 years ago when teachers would take their students away from the ongoing construction and ...
The growth might not be there yet, but Lathrop will be prepared when companies come calling.
Page 18 of 18
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text:
Extract, Transform and Load (ETL) Jobs in the East of England
Jobs 1 to 8 of 8
SQL Developer
Experience of AMCS is preferred - Knowledge of data warehousing, data modeling and ETL design is desirable - Honors Degree or equivalent qualification in Software Engineering or Computer Science... - Experience with other reporting tools, such as Crystal Reports, Reporting Services, Business Objects, Business Objects Web Intelligence, Brio or Cognos is required. - Strong...
Huntingdon, Cambridgeshire -
Mick George
Salary: DOE NegotiablePosted: 21 days ago
Head of Data- SSRS, CRM, BI
Head of Data - BI, SQL, SSRS, Dynamics CRM, ETL, Data Warehouse, Drupal... * To oversee the ongoing development of the company's bespoke CRM (Microsoft Dynamics)... Essential requirements: * In depth knowledge of all business systems (Microsoft Dynamics CRM, SQL Server, Drupal) * In depth knowledge of reporting software SSRS (SQL Server Reporting...
Watford, Hertfordshire -
Salary: £60000 - £65000 per annumPosted: 2 hours ago
Senior Tester - ETL, Datawarehouse, - Dunstable, Luton
Senior Test Analyst - ETL - Data warehouse, Dataflow... Test, Tester, QA, Quality Assurance, Data flow, Data warehouse, ETL... At least 2 years ETL, Data warehouse, Data flow testing experience. Experience of working within an Agile methodology - Waterfall experience accepted. Strong experience of SQL, Oracle and other RDBMS. SQL scripting to a...
Luton, Bedfordshire -
Testing Circle Ltd
Salary: £35000 - £45000 per annum + Travel, Pension, Bonus and morePosted: 4 days ago
Data Analyst / Engineer (SQL Server, Access, VB / VBA)
ETL, Data warehousing, data conversion, data cleansing, data manipulation and/or data mining experience would be of interest... Key skills for the Data Analyst / Engineer (SQL Server, Access, VB / VBA, Data Analysis) Experience working as an Analyst, Consultant, Programmer or Developer role (some DBA skills could also be of interest)...
Stevenage, Hertfordshire -
Understanding Recruitment
Salary: £40000.00 - £50000.00 per annum + BenefitsPosted: 3 days ago
Application Support Analyst - Luton - Permanent
You'll be responsible for production MI and Yield applications and their interfaces, understanding corporate systems, their interdependencies and how they support the business, monitor system generated alerts and act upon those alerts that require Service Delivery attention, together with any overnight processes to ensure that all applications are available...
Luton -
Interquest - IQ Tech
Salary: £35000 - £37000 per annum + BenefitsPosted: 2 days ago
Technical Specialist - up to £45k - Luton, Bedfordshire
An exciting opportunity has arisen to join a global organisation specialising in business transformation... Business Analysis. Change management... Project management... Full software development lifecycle experience. Technical environment (*High level awareness is very desirable) Microsoft .net. Java / J2EE. Agile. KANBAN. PCI / DSS. Object Oriented architectures / approaches. SOA / ESB / DEVOPS. ETL technologies.
Luton, Bedfordshire -
Deerfoot IT Resources Ltd
Salary: £40000 - £45000 per annum + 10% bonus + excellent benefitsPosted: 8 hours ago
Application Support Engineer
Change Management... Release Management... Configuration Management... HP Service Desk, ServiceNow, BMC etc.), Incident, Change and Problem management. SQL, RDBMS (SQL Server and / or Oracle) IIS or equivalent Web Server, Server Administration (predominantly Windows) DNS and AD... (Messaging, FTP, SFTP, ETL, Web Services etc.) ITIL... Application Support, Support, VBA, Asset Management,...
Peterborough, Cambridgeshire -
Quant Capital
Salary: From £40,000 to £50,000 per annum + benefitsPosted: 2 days ago
SAP Master Data Manager - Permanent - Hertfordshire
Minimum core attributes: You will have experience of managing master data for large a SAP solution in an international and highly regulated industry along with experience with ETL and data quality management... Ideally you will also have SAP MDG, SAP Data Services and business analysis experience, hold a Project Management...
Hertfordshire -
Salary: £65,000 - £75,000 per year + bonus & benefitsPosted: 3 days ago
ETL Jobs in the East of England


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Energy companies could be most exposed to the effects of a Brexit, said Brian Jacobsen, chief portfolio strategist at Wells Fargo Funds Management. » Read More
NEW YORK— The largest U.S. financial institutions have enough armor to withstand the turmoil of a major and prolonged national and global recession, the Federal Reserve said Thursday. The central bank's annual "stress tests" show that the 33 largest financial institutions— including JPMorgan Chase, Citigroup, Bank of America and Wells Fargo— all hold more...
Jim Cramer was shocked by an unusual pattern discovered with oil stocks. Are forces overseas changing the rules for black gold?
JD.com Inc., up 93 cents to $21.06. China's second largest e-commerce site announced a deal with Wal-Mart, which will take a 5 percent stake in JD.com. FedEx Corp., up $2.22 to $164.47.
NEW YORK— The latest on developments in global financial markets:. Stocks are closing solidly higher as investors grow more optimistic that Britain will remain in the European Union. Stocks are solidly higher as investors grow more optimistic that Britain will remain in the European Union.
NEW YORK— Global stocks are climbing Monday as investors grow more hopeful that Britain will remain in the European Union. BRITISH VOTE: The British pound rose sharply as the latest opinion polls and betting markets suggest it's more likely Britain will stay in the European Union than leave when citizens vote on the issue Thursday. The pound jumped to $1.4652...
The media wanted to believe in Theranos, but the blood-testing start-up has always been a "scam," Sam Waksal said.
David Katz, Matrix Asset Advisors, and Matt Maley, Millertabak, discuss the Fed decision and its impact on the financial sector.
Jim Cramer is only willing to say yes to one high-yield mortgage REIT. This and more, in his take on various caller favorite stocks.
Synchrony Financial, down $4 to $26.44. Wells Fargo& Co., down $1.10 to $46.87. Motorcar Parts of America Inc., up $2.79 to $30.53.
The largest banks are reportedly increasing the amount of overdraft fees they collect from their customers.
An anonymous bidder has agreed to pay more than $3.4 million for a private lunch with billionaire Warren Buffett.
Mylan shares shed more than 5 percent after Wells Fargo Securities analysts said they were worried about the firm's pricing practices.
Quontic Bank, an FDIC-insured community lender, is offering "Lite Doc" loans, requiring only job verification and two months of bank statements.
Fintech has created a host of start-ups intent on stealing market share from old-school banks, but there are plenty of obstacles ahead.
Senior banking analyst at Barclays Jason Goldberg talks about the outlook for banks, raising dividends and expectations for cash returns.
An payment network launched by big banks is processing billions of dollars in cash transfers that once went to financial technology companies.
Former Wells Fargo chief Richard Kovacevich is not discounting the possibility of three Federal Reserve rate hikes in 2016.
Former FDIC Chair Sheila Bair says she isn't completely comfortable with the idea of allowing borrowers to put down 3 percent on a new home.
Market fears are being scaled back globally, and it's great news for banks in the U.S. and abroad.
CNBC's Diana Olick reports the nation's largest mortgage lender is now offering home loans to borrowers with a minimum of three percent down and a FICO score of 620.


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Over the years I seen many people use the word "generics", I honestly have not a clue what it means, whatever it is I most likely use it but just don't know that it was called that. :p
closed as not a real question by Juliet, Artem Barger, John Kugelman, Peter Štibraný, John Saunders Aug 20 '09 at 0:34
It's difficult to tell what is being asked here. This question is ambiguous, vague, incomplete, overly broad, or rhetorical and cannot be reasonably answered in its current form. For help clarifying this question so that it can be reopened, visit the help center.If this question can be reworded to fit the rules in the help center, please edit the question.
From http://java.sun.com/j2se/1.5.0/docs/guide/language/generics.html
Sorry for the direct c&p but I found that this write up was better than something I could have written.
Edit to include a good point made in the comments:
It basically boils down to a reduction in the number of times you have to cast. ;-)
Generics are just Java's Implementation of Parametric Polymorphism. They work just like Parametric Polymorphism in any other language.


text:
|By Bob Gourley
Article Rating:
|August 15, 2014 09:15 AM EDT
By Ted Navarro
Think of a cloud provider. I'd bet that for the majority of people reading this article, the first that comes to mind is AWS. Amazon Web Services were a trailblazer in the cloud space, and they still lead adoption rates at all levels of the market, from SMBs to multinationals. In some ways that's great: Amazon constantly innovate and refine their product. But, at the same time, it's not entirely healthy for a market to be completely dominated by one vendor. Google's Compute Engine is snapping at Amazon's heels, but ideally we'd like to see a flourishing market with many competitors. A market in which the word "cloud" doesn't immediately bring one vendor to mind.
Two things are making that market a possibility: open standards and cloud marketplaces or cloud brokerages.
Open Standards
Vendor lock-in imposes a brake on innovation by reducing the competitive forces that compel vendrs to improve their products. If a company is not free to move between vendors, following their own interests and needs, then there is very little incentive for that vendor to provide optimal service. All their energy will go into gaining new sales, and very little into satisfying existing clients because the cost of moving from a proprietary, non-standard environment is prohibitively expensive.
Once a company is locked into one product, the vendor can then leverage that status to sell compatible products — products only they can produce. The operating system and productivity software market in the 1990s and 2000s is a perfect example of this process.
Open standards allow cloud platform users to move their data and workloads between vendors with ease. The burden is on vendors to provide levels of service and cost that keep their clients happy.
Cloud Marketplaces
One benefit of sticking with a single cloud vendor for multiple products is reduced complexity. Multi-cloud environments, where clients build platforms comprised of several vendors' solutions, are inherently more complex. Added complexity results in inflated costs.
Cloud marketplaces, especially those that incorporate a cloud management platform, reduce that complexity to a manageable level by making it easy to compare cloud products and control them. They provide a layer on top of cloud products that help with integration and control.
By reducing the complexity of building multi-cloud environments on platforms with open standards, cloud marketplaces help cultivate a vibrant and competitive market; one that isn't dominated by a small number of vendors. That can only be good for cloud users — it helps them to build the cloud that they want and adapt as their needs change.
About Ted Navarro- Ted is the technical writer and inbound marketer for ComputeNext, an innovative cloud marketplace company. Check out the ComputeNext blog for the latest in cloud computing and IaaS technology. Follow them on Twitter, Like them on Facebook, and engage in the discussion at https://www.computenext.com/blog/.
The cloud market growth today is largely in public clouds. While there is a lot of spend in IT departments in virtualization, these aren't yet translating into a true "cloud" experience within the enterprise. What is stopping the growth of the "private cloud" market? In his general session at 18th Cloud Expo, Nara Rajagopalan, CEO of Accelerite, explored the challenges in deploying, managing, and getting adoption for a private cloud within an enterprise. What are the key differences between wh...
Jun. 26, 2016 01:00 PM EDT Reads: 692
The initial debate is over: Any enterprise with a serious commitment to IT is migrating to the cloud. But things are not so simple. There is a complex mix of on-premises, colocated, and public-cloud deployments. In this power panel at 18th Cloud Expo, moderated by Conference Chair Roger Strukhoff, Randy De Meno, Chief Technologist - Windows Products and Microsoft Partnerships at Commvault; Dave Landa, Chief Operating Officer at kintone; William Morrish, General Manager Product Sales at Interou...
Jun. 26, 2016 12:45 PM EDT Reads: 741
"A lot of times people will come to us and have a very diverse set of requirements or very customized need and we'll help them to implement it in a fashion that you can't just buy off of the shelf," explained Nick Rose, CTO of Enzu, in this SYS-CON.tv interview at 18th Cloud Expo, held June 7-9, 2016, at the Javits Center in New York City, NY.
Jun. 26, 2016 12:30 PM EDT Reads: 1,001
It is one thing to build single industrial IoT applications, but what will it take to build the Smart Cities and truly society changing applications of the future? The technology won't be the problem, it will be the number of parties that need to work together and be aligned in their motivation to succeed. In his Day 2 Keynote at @ThingsExpo, Henrik Kenani Dahlgren, Portfolio Marketing Manager at Ericsson, discussed how to plan to cooperate, partner, and form lasting all-star teams to change t...
Jun. 26, 2016 12:30 PM EDT Reads: 1,089
The 19th International Cloud Expo has announced that its Call for Papers is open. Cloud Expo, to be held November 1-3, 2016, at the Santa Clara Convention Center in Santa Clara, CA, brings together Cloud Computing, Big Data, Internet of Things, DevOps, Digital Transformation, Microservices and WebRTC to one location. With cloud computing driving a higher percentage of enterprise IT budgets every year, it becomes increasingly important to plant your flag in this fast-expanding business opportuni...
Jun. 26, 2016 12:00 PM EDT Reads: 1,256
There is little doubt that Big Data solutions will have an increasing role in the Enterprise IT mainstream over time. Big Data at Cloud Expo - to be held November 1-3, 2016, at the Santa Clara Convention Center in Santa Clara, CA - has announced its Call for Papers is open. Cloud computing is being adopted in one form or another by 94% of enterprises today. Tens of billions of new devices are being connected to The Internet of Things. And Big Data is driving this bus. An exponential increase is...
Jun. 26, 2016 12:00 PM EDT Reads: 1,316
In his general session at 18th Cloud Expo, Lee Atchison, Principal Cloud Architect and Advocate at New Relic, discussed cloud as a 'better data center' and how it adds new capacity (faster) and improves application availability (redundancy). The cloud is a 'Dynamic Tool for Dynamic Apps' and resource allocation is an integral part of your application architecture, so use only the resources you need and allocate /de-allocate resources on the fly.
Jun. 26, 2016 12:00 PM EDT Reads: 1,040
More and more companies are looking to microservices as an architectural pattern for breaking apart applications into more manageable pieces so that agile teams can deliver new features quicker and more effectively. What this pattern has done more than anything to date is spark organizational transformations, setting the foundation for future application development. In practice, however, there are a number of considerations to make that go beyond simply "build, ship, and run," which changes ho...
Jun. 26, 2016 12:00 PM EDT Reads: 855
The pace of innovation, vendor lock-in, production sustainability, cost-effectiveness, and managing risk… In his session at 18th Cloud Expo, Dan Choquette, Founder of RackN, discussed how CIOs are challenged finding the balance of finding the right tools, technology and operational model that serves the business the best. He also discussed how clouds, open source software and infrastructure solutions have benefits but also drawbacks and how workload and operational portability between vendors ...
Jun. 26, 2016 11:00 AM EDT Reads: 776
In his keynote at 18th Cloud Expo, Andrew Keys, Co-Founder of ConsenSys Enterprise, provided an overview of the evolution of the Internet and the Database and the future of their combination – the Blockchain. Andrew Keys is Co-Founder of ConsenSys Enterprise. He comes to ConsenSys Enterprise with capital markets, technology and entrepreneurial experience. Previously, he worked for UBS investment bank in equities analysis. Later, he was responsible for the creation and distribution of life sett...
Jun. 26, 2016 11:00 AM EDT Reads: 1,024
Your business relies on your applications and your employees to stay in business. Whether you develop apps or manage business critical apps that help fuel your business, what happens when users experience sluggish performance? You and all technical teams across the organization – application, network, operations, among others, as well as, those outside the organization, like ISPs and third-party providers – are called in to solve the problem.
Jun. 26, 2016 10:00 AM EDT Reads: 609
Machine Learning helps make complex systems more efficient. By applying advanced Machine Learning techniques such as Cognitive Fingerprinting, wind project operators can utilize these tools to learn from collected data, detect regular patterns, and optimize their own operations. In his session at 18th Cloud Expo, Stuart Gillen, Director of Business Development at SparkCognition, discussed how research has demonstrated the value of Machine Learning in delivering next generation analytics to imp...
Jun. 26, 2016 09:45 AM EDT Reads: 544
It's easy to assume that your app will run on a fast and reliable network. The reality for your app's users, though, is often a slow, unreliable network with spotty coverage. What happens when the network doesn't work, or when the device is in airplane mode? You get unhappy, frustrated users. An offline-first app is an app that works, without error, when there is no network connection. In his session at 18th Cloud Expo, Bradley Holt, a Developer Advocate with IBM Cloud Data Services, discussed...
Jun. 26, 2016 08:45 AM EDT Reads: 755
There are several IoTs: the Industrial Internet, Consumer Wearables, Wearables and Healthcare, Supply Chains, and the movement toward Smart Grids, Cities, Regions, and Nations. There are competing communications standards every step of the way, a bewildering array of sensors and devices, and an entire world of competing data analytics platforms. To some this appears to be chaos. In this power panel at @ThingsExpo, moderated by Conference Chair Roger Strukhoff, Bradley Holt, Developer Advocate a...
Jun. 26, 2016 08:45 AM EDT Reads: 696
Digital Initiatives create new ways of conducting business, which drive the need for increasingly advanced security and regulatory compliance challenges with exponentially more damaging consequences. In the BMC and Forbes Insights Survey in 2016, 97% of executives said they expect a rise in data breach attempts in the next 12 months. Sixty percent said operations and security teams have only a general understanding of each other's requirements, resulting in a "SecOps gap" leaving organizations u...
Jun. 26, 2016 08:15 AM EDT Reads: 985
SaaS companies can greatly expand revenue potential by pushing beyond their own borders. The challenge is how to do this without degrading service quality. In his session at 18th Cloud Expo, Adam Rogers, Managing Director at Anexia, discussed how IaaS providers with a global presence and both virtual and dedicated infrastructure can help companies expand their service footprint with low "go-to-market" costs.
Jun. 26, 2016 01:00 AM EDT Reads: 792
Cognitive Computing is becoming the foundation for a new generation of solutions that have the potential to transform business. Unlike traditional approaches to building solutions, a cognitive computing approach allows the data to help determine the way applications are designed. This contrasts with conventional software development that begins with defining logic based on the current way a business operates. In her session at 18th Cloud Expo, Judith S. Hurwitz, President and CEO of Hurwitz & ...
Jun. 25, 2016 03:00 PM EDT Reads: 1,555
A strange thing is happening along the way to the Internet of Things, namely far too many devices to work with and manage. It has become clear that we'll need much higher efficiency user experiences that can allow us to more easily and scalably work with the thousands of devices that will soon be in each of our lives. Enter the conversational interface revolution, combining bots we can literally talk with, gesture to, and even direct with our thoughts, with embedded artificial intelligence, wh...
Jun. 25, 2016 01:45 PM EDT Reads: 892
19th Cloud Expo, taking place November 1-3, 2016, at the Santa Clara Convention Center in Santa Clara, CA, will feature technical sessions from a rock star conference faculty and the leading industry players in the world. Cloud computing is now being embraced by a majority of enterprises of all sizes. Yesterday's debate about public vs. private has transformed into the reality of hybrid cloud: a recent survey shows that 74% of enterprises have a hybrid cloud strategy. Meanwhile, 94% of enterpri...
Jun. 25, 2016 01:15 PM EDT Reads: 1,233
What does it look like when you have access to cloud infrastructure and platform under the same roof? Let's talk about the different layers of Technology as a Service: who cares, what runs where, and how does it all fit together. In his session at 18th Cloud Expo, Phil Jackson, Lead Technology Evangelist at SoftLayer, an IBM company, spoke about the picture being painted by IBM Cloud and how the tools being crafted can help fill the gaps in your IT infrastructure.
Jun. 25, 2016 12:00 PM EDT Reads: 586


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Home > News > Feature - Fusion of disciplines powers Russian grid infrastructure
September 26th, 2007
Feature - Fusion of disciplines powers Russian grid infrastructure
Established in September 2003, development of RDIG, or the Russian Data Intensive Grid, was at first driven by the high energy physics community, which still remains the largest user of the RDIG infrastructure.
Four years on, demand for RDIG infrastructure is now coming from scientists in nanotechnology, computational chemistry, biology, earth sciences, business and more.
"The load on RRC KI computing resources was growing, but thanks to our work on the grid infrastructure we could involve the computing resources of other institutions, like the Skobeltsin Institute of Nuclear Physics at Moscow State University. As a result, we can solve our problems about 50 times faster."
"New application areas, like nanotechnologies, are center of attention for the RDIG consortium," he says.
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No need in supercomputers: Russian scientists suggest a PC to solve complex problems tens of times faster than with massive supercomputers June 30th, 2016
Surprising qualities of insulator ring surfaces: Surface phenomena in ring-shaped topological insulators are just as controllable as those in spheres made of the same material June 30th, 2016
Building a smart cardiac patch: 'Bionic' cardiac patch could one day monitor and respond to cardiac problems June 28th, 2016
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NATO to extend counter-piracy mission until 2016
Written by defenceWeb, Friday, 06 June 2014
Since August 2009, NATO ships have patrolled the waters off the Horn of Africa as part of Operation Ocean Shield. Their mission is to contribute to international efforts to fight maritime piracy and to help build the capacity of regional navies. Operation Ocean Shield works closely with other naval forces patrolling the Indian Ocean including US-led maritime forces and EU naval forces, such as CTF-151 and EU Navfor.
As part of the broad international effort, Ocean Shield has helped to significantly reduce pirate activity in the region, NATO said in a statement. In 2011, pirates captured 24 ships and NATO recorded 129 pirate attacks off Somalia. In 2012, the number of attacks had fallen to 20. Not a single ship has been captured off Somalia since May 2012, and no merchant ships are currently held by Somali pirates, according to NATO.
Despite the successes, piracy remains a threat, the organisation cautioned. "NATO assesses that pirates continue to possess the intent and capacity to attack ships. NATO ships continue to detect attempts by pirates to capture vessels. In addition, the root causes of piracy inside Somalia remain."
Some 90 per cent of all global trade is carried by sea, about half of that passes through the Indian Ocean. In 2013, the World Bank estimated that piracy costs the world economy $18 billion per year. NATO counter-piracy efforts help reduce that cost.
READ MOREEuropean Union donates speedboat to Seychelles Coast Guard
Busy April for NATO counter piracy task force
Kiwis now part of anti-piracy Operation Ocean Shield
Ships from Spain, Italy and Turkey are currently part of the NATO fleet which operates roughly from the Arabian Gulf to the north, the Seychelles in the south, the Gulf of Aden to the west and the Maldives in the east, covering an area greater than 2 million square miles or the size of Western Europe.
NATO vessels verify the activity of shipping off Somalia, separating out legitimate maritime traffic from suspected pirate vessels. Commercial ships that are transiting the area are in many cases escorted to ensure their safe passage. NATO ships can actively pursue suspected pirate ships to prevent attacks. NATO boarding teams can board a suspect ship to determine if pirates are on board. As a means of last resort, NATO vessels can use force to stop pirates. Any detained pirates are transferred as soon as possible to national law enforcement agencies, NATO said.
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- Mid-life upgrades for SA Navy Valour Class frigates
- The Navy puts its best foot forward in Durban
- Durban to host World Hydrography Day this month
- SA Navy not commenting on fire aboard SAS Amatola
- Pakistan Navy Chief of Naval Staff calls on SA Navy Flag Officer Fleet
Company News
A first for Nautic
by Nautic Africa, 29 June 2016
The company has become the first shipyard in SA to achieve certification to the revised International Quality Management Standard, ISO 9001:2015.
AT4 Roquette NG, Carl-Gustaf M4 and NLAW lands at Eurosatory 2016
by Saab, 14 June 2016
These will be presented at Eurosatory 2016 in Paris, including AT4 Roquette NG, Carl-Gustaf M4, and NLAW.
Intelligent camouflage: the future step for Saab Barracuda
by Saab, 14 June 2016
At Eurosatory 2016 Saab highlights new concepts within the field of intelligent camouflage to the attending audience.


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Unlike their first meeting against the Islanders in October, the Bruins did not launch a torrid three-goal rally leading to a spirited overtime win. No, this time Boston received yet another message that this year is not last year, respect has to be earned not assumed and playoff positions are far from guaranteed.
With Matt Moulson netting a pair of goals and rookie star John Tavares adding a third-period tally, the Islanders skated away with a 4-1 win over the punchless Bruins on Monday night. (Recap here.)
The Islanders played a gritty, well-balanced road game to earn standings points in a fifth straight game. Far from a conference bottom-feeder, the upstart Islanders (8-6-7) could be one of the many teams that will be looking to knock the suddenly mediocre Bruins (8-8-4) from their lofty perch of last season.
Here are three lessons we can glean about the Bruins' current state of affairs from their third straight loss.
The power play continues to be a real problem for the Bruins.
The B's entered the game mired in a pathetic 3-for-30 stretch with a man advantage over the past 10 games. The pattern continued, as Boston failed to capitalize on five power-play chances against an Islanders penalty-killing unit that was in the bottom third (20th) of the league.
After being set up with a five-on-three power play for 1:35 late in the first, the Bruins failed to produce anything other than slap shots from Zdeno Chara and Dennis Wideman that failed to hit the net.
"It sucks," said center David Krejci, echoing a sentiment shared by many in the crowd of 16,865 that booed the home team as it left the ice. "It's the NHL; if you get a two-minute power play, five-on-three, you've got to score a goal."
An early second-period man advantage was cut short by a cross-checking call on Mark Recchi. Presented with another Bruins power play minutes later, Blake Wheeler had a couple of whacks at the puck just outside the crease but could not move it past Islanders goalie Dwayne Roloson. Bruins coach Claude Julien was quick to express his frustration with the team's lack of power-play success.
"Obviously, our best players are not at their best. When that happens you can't expect results. That is that bottom line," Julien said. "We are not moving the puck with any assertiveness. There isn't the confidence or the determination right now that we need to be successful."
Now one week removed from his bout with the H1N1 virus (swine flu), Krejci is back to displaying some of his usual trademark speed and puck savvy.
With the Bruins trailing 1-0 in the second, Krejci fended off a check and wheeled to the net. He lost the puck and it skittered across the crease to Daniel Paille, who slid it past Roloson just as Tavares was knocking the net off its moorings.
"Krejci brought it to the net, that's something we have to do more," Paille said. "I don't know if he saw me, but he was trying to bring it there. I just snuck in and tapped it a couple of times."
Two officials of the Czech Republic Olympic team attended Monday's game to watch Krejci play. They will be evaluating NHL players for two weeks and were happy with the early results scouting Krejci for possible participation in the 2010 Olympics in Vancouver.
"He's playing well, so we're impressed," one team official said.
Krejci was not happy with his contributions and the team's play.
"We had our chances, but for what? The result was the same," Krejci said. "We have to bury them."
Islander forward Richard Park may have also helped his case for the U.S. team, picking up assists on three New York goals.
Tavares, the top overall pick in the 2009 draft, continues to show he is more than NHL-ready.
The 19-year-old notched a goal and an assist Monday, extending a five-game point streak during which he has generated four goals and five assists.
"He sees the ice real, real well," Bruins defenseman Derek Morris said. "He's got a good shot and made some great passes again tonight. But when we're not sharp, guys like that will look a lot better."
Tavares leads NHL rookies in scoring (9 goals, 11 assists). He has four points (2 goals, 2 assists) in two games against the Bruins this season.
Dale, Michael and Jerry dig into the details of this draft for the Patriots with ESPN's Mike Reiss.
Giardi and Price discuss the Tom Brady appeal getting overturned and Roger Goodell's victory tour. The guys can't believe the victory lap and some of his behavior. The more you listen to him, the more frustrating his behavior becomes.
Giardi and Price break down how the teams in the AFC East altered their futures after the NFL Draft weekend.
Danny Ainge joins Glenn and Christian to explain the Celtics draft process; and he also discusses the trade rumors that permeated the night.
Mut is flying solo the last hour, but he's giving reaction and analysis as the Celtics draft a power forward out of France by the name of Guerschon Yabusele and getting some early grades for the Celtics
Mut and Kirk are talking more about the Celtics pick of Jaylen Brown and can't seem to find anyone who thinks it's a good pick or can make a case for why the Celtics took him third overall.
Joe, Tim, and Lou talk with Red Sox shortstop Xander Bogaerts after his walk-off RBI single propelled the Red Sox past the White Sox 8-7.
Mut recaps the Red Sox 8-6 loss to the White Sox.
Mut recaps the Sox 3-1 loss in the series opener against the White Sox.
DJ and Pete continue to assess the season that was for the Bruins and look toward the future for the franchise and how they can improve.
DJ and Pete are together for the final Sunday Skate of the season. They get into their overall thoughts on the season, the Bruins keeping Claude Julien on as head coach and the end-of-season press conferences last week. They discuss the rebuild process, what the Bruins need and how they can obtain it. Plenty of callers have their own theories and opinions on all of these topics as well.
Butch is joined by two-thirds of the Sunday Skate show in DJ and Pete. The guys discuss the problems with Bruins including leadership and grit, who should stay and who should go and if Claude is to blame.
Who would you like to see in Dino's chair, Gary or Mut?
The debate heats up as the discussion turns towards O.J. Simpson
On a Friday edition of Headlines, Gary presents us with some thrilling erotica talk.
Danny Ainge joins Glenn and Christian to explain the Celtics draft process; and he also discusses the trade rumors that permeated the night.
Jackie MacMullen talks about Jaylen Brown, the Celtics thought process, and what may happen in Free Agency.
Glenn and Christian discuss last night's underwhelming draft by the Celtics
Dale Holley and Thornton talk NBA draft.
Dale and Holley's Final Drive 06-24-16
Laroy Streat comes back at it again! Talking the Celtics Draft and his take on the Celtics 3rd Draft pick. Catch Laroy every friday with the Dale & Holley Show 5:45- 6PM.
Former Celtics General Manager Jan Volk joins Kirk Minihane for a discussion that any Celtics fan will love. Kirk and Jan talk about the legendary 85/86 Celtics and how the team was constructed and of course the decision to draft Len Bias and his tragic death.
Kirk Minihane sits down with John Tomase to talk about the current political landscape, John's desire to write about social issues, and of course Spygate is discussed.
Kirk Minihane is joined by one of his radio heroes, Artie Lange. They discuss everything from Artie's comedy career, his time with Howard Stern, his issues with drugs and prostitutes, and the comedy show to benefit slain Officer Ronald Tarentino Jr.
Ben, Russ & Alex recap the 4-0 loss the USMNT suffered to Argentina in the COPA America Centenario semifinal. Then they catch up with the EURO's, and recap if their predicted winners are still in the tournament.
Former Celtics General Manager Jan Volk joins Kirk Minihane for a discussion that any Celtics fan will love. Kirk and Jan talk about the legendary 85/86 Celtics and how the team was constructed and of course the decision to draft Len Bias and his tragic death.
This week we look back at the US Open.
Boston Celtics select Jaylen Brown with No. 3 overall pick in the 2016 NBA Draft.More from this show
Danny Ainge joins Glenn and Christian to explain the Celtics draft process; and he also discusses the trade rumors that permeated the night.More from this show
Who would you like to see in Dino's chair, Gary or Mut?More from this show
Jackie MacMullen talks about Jaylen Brown, the Celtics thought process, and what may happen in Free Agency.More from this show
The debate heats up as the discussion turns towards O.J. SimpsonMore from this show


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Search by location or home name below to find an Orchard Care Home that's right for you...
We are a leading provider of care homes in the UK and we set our standards high.
We like to hear from caring individuals who share our values and go the extra mile to deliver outstanding outcomes, no matter what their role.
Over 5,000 street parties were held on the weekend of The Queen's Patron's Lunch this year, and many of our homes chose to hold celebrations of their own.
Looked after in a friendly manner, nothing was too much bother for them.
Review relates to March 2016.
How likely would you be to recommend Priestley Care Home? Extremely LikelyContinue reading
We provide a wide range of specialist care services on both a long and short-term basis. This includes elderly residential and nursing care, in addition to specialist care for more complex health needs such as mental health, physical disability and young adults.


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brand manager jobs near Indianapolis, IN
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Restaurant General Manager
Steak n Shake Corporate - Indianapolis, IN
Identify, Train and Develop Trainers, Operations Supervisors, Managers and Restaurant Managers. The General Manager will partner directly with his/her District...
Restaurant Management
CMR Associates LLC / Qdoba Mexican Eats - Indianapolis, IN
Uses discretion in daily management decisions with accountability for living the Brand values and helping the brand thrive....
Restaurant Manager
Steak n Shake Corporate - Avon, IN
Field Training Manager. The Manager will partner directly with his/her Restaurant and General Manager and will receive market level support from his/her Human...
IT Business Integrator- Digital
Eli Lilly - Indianapolis, IN
Provide IT technical and industry consultation to cross-functional brand team, brand operations teams, brand agencies and global IT teams on web analytics best...
Pre-Owned Sales Manager
Tom Wood Jaguar Land Rover Volvo - Indianapolis, IN
Established experience as a pre-owned sales manager or equivalent duties. Our current candidate search is for an experienced Pre-Owned Sales Manager....
Restoration Technician
ServiceMaster by Crossroads Restoration Services - Indianapolis, IN
The Restoration Technician will report directly to the Operations Manager. Family of brands serves 10.5 million homes and businesses in the United States....
Assistant Manager
American Mattress - Indianapolis, IN
Additionally, every Assistant Manager is a Store Manager in training - one store can generate well over a million dollars in revenue and more than twelve...
Local Project & Sales Manager - Indy
The Indianapolis Star - Indianapolis, IN - Indianapolis, IN
We have an opening for a Consumer Marketing Manager. With more than 110 markets internationally, it is known for Pulitzer Prize-winning newsrooms, powerhouse...
Talent Acquisition Specialist
Koorsen Fire & Security - Indianapolis, IN
Administer pre-employment assessments, including assisting hiring managers in interpreting results. Manage full life cycle recruiting responsibilities to...
The Children's Place - Noblesville, IN
The Store Manager has a direct reporting relationship to the District Manager. The Store Manager is responsible for leading store teams in driving sales, brand...


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Daily lineup not yet announced. Artists scheduled to appear include The Offspring, Dropkick Murphys, Clueso, K.I.Z., Interpol, The Kooks, Gaslight Anthem, Floggin Molly, The Wombats, Prinz Pi, Donots, The Subways, Millencolin, Danko Jones and many more.
Frank Erwin Center, Austin, TX
Gary Miller
May 12, 2016 |
Fox Tucson Theatre, Tucson, Ariz.
Fox Tucson Theatre
May 13, 2016 |
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Cyrilla Daybed
We were taken aback when we came across Canadian company PURE and Ami McKay's beautiful and "guilt-free" furniture line. They've managed to create green furniture without sacrificing on style (something easier said than done). All of the materials used in the production of PURE's furniture are biodegradable and sustainable. We love PURE's focus on sustainability and health, but we're convinced their pieces would appeal to non-greenies as well...
What is PURE? PURE is the vision and result of interior designer Ami McKay, who is most well-known for her role on HGTV Canada's Makeover Wish. After years of working with clients who were frustrated by the lack of stylish, eco-friendly designs for their home, she set out to create her own line of elegant, sustainable furniture. PURE's mantra is "you do not have to compromise style for healthy and sustainable furniture."
Hazel Settee
Sedge Sofa
Cyrilla Banquette
The furniture designs are divided up into four categories: Water (Fluid and Sensuous), Fire (Bold and Sensual), Earth (Grounded and Welcome), and Air (Light and Free). The result is a variety of pieces, some of which have a vintage, feminine feel (think Anthropologie), and others which are more streamlined. Furniture can be custom ordered without the embroidery, although personally we love that element! The materials used include:
• Biodegradable, natural latex rubber
• FSC Certified Hardwood Frames
• Organic Cotton Batting
• Renewable jute and latex webbing
• Non-toxic adhesives
• OEKO-tex certified wool fabrics with organic dyes
• Renewable and sustainable Kirei grass and wheat boards
• Hemp and bamboo
WCS Dining Table
Hazel Lounge Chair
Keiro Coffee Table
They have a number of showrooms in Canada and the US, including Green Depot and Vivavi in New York.
See the whole line at their website and tell us what you think!


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MILLIS �The Purr-fect Cat Shelter will hold its annual Yard Sale Saturday, June 7, at the Medway Shopping Center parking lot, Rte.109, Medway, from 8 a.m. to 2 p.m. In the event of rain it will be held Sunday, June 8.
All proceeds directly benefit the homeless cats and kittens cared for by the volunteers of the shelter.
Many great items and bargains will be available. Items for sale include: Household items, dishes, glassware, jewelry, books/tapes/CD's, furniture, toys, games and much more. We regret no additional items will be accepted the day of the sale.
The Purr-fect Cat Shelter is a non-profit, no-kill, all volunteer organization caring for homeless cats and kittens in Millis, Medway, Franklin, Bellingham, Walpole, Norfolk and surrounding communities.
For more information about the Yard Sale, adopting, or volunteering call the shelter message center 508-533-5855 or visit our website at www.purrfectcatshelter.org.
Location, ST | website.com


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|Publication number
|Publication type
|Application number
|Publication date
|Nov 20, 1990
|Filing date
|May 23, 1989
|Priority date
|Nov 29, 1986
|Fee status
|Also published as
|Publication number
|Elmar Bosies, Rudi Gall
|Original Assignee
|Boehringer Mannheim Gmbh
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (11), Non-Patent Citations (4), Referenced by (32), Classifications (51), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of application Ser. No. 125,537, filed Nov. 25, 1987, now abandoned.
The present invention is concerned with new diphosphonic acid derivatives and processes for their preparation, as well as with pharmaceutical compositions which contain these compounds.
In Federal Republic of Germany Patent Specification No. 18 13 659 are described diphosphonic acid derivatives of which 1-hydroxyethane-1,1-diphosphonic acid has achieved importance as an agent for the treatment of Paget's disease. In Federal Republic of Germany Patent Specification No. 27 45 083 is described, inter alia, 1-hydroxy-1-(pyrrolidin-2-yl)-methane-1,1-diphosphonate as a complex former. In Japanese Kokai Tokkyo Koho 8098.193 are described, inter alia, pyridylmethane-diphosphonates as herbicides and in Federal Republic of Germany Patent Specification No. 34 28 524 are described heteroaromatic alkyl diphosphonates.
We have now found that analogous derivatives of these compounds, in which the heterocycle is completely or partly hydrogenated, also show this action and, furthermore, can be used as good calcium complex formers for the broader treatment of calcium metabolism disturbances. In particular, they can be well used in cases where bone formation and breakdown is disturbed, i.e. they can be used for the treatment of diseases of the skeletal system, for example osteoporosis, Paget's disease, Bechterew's disease and the like.
However, on the basis of these properties, they can also be used in the therapy of bone metastases, of urolithiasis and for the prevention of heterotopic ossification. Furthermore, due to their influencing of the calcium metabolism, they also form a basis for the treatment of rheumatoid arthritis, of osteoarthritis and of degenerative arthrosis.
Consequently, the present invention provides diphosphonates of the general formula: ##STR2## wherein Het is a hydrogenated or partly hydrogenated heterocyclic ring with one or two nitrogen atoms which, independently of one another, can optionally be substituted by lower alkyl, benzyl or cyclohexylmethyl radicals, B is a nitrogen atom or a C-H grouping, whereby the carbon atom substituted by G can also form a double bond with B, R1 and R2 are each hydrogen atoms or lower alkyl radicals or together form an alkylene chain with 3 to 5 carbon atoms, whereby this ring so annelated on Het can contain up to 3 double bonds, Y is a radical of the general formula: ##STR3## in which R3 is a hydrogen atom or a lower alkyl radical, alk is a valency bond or a straight-chained or branched alkylene chain with 1 to 6 carbon atoms which must not start from a heteroatom, X is a hydrogen atom or a hydroxyl or amino group, G is a hydrogen atom or a radical Ys and m, r or s can each be 0 or 1, whereby m+r+s must always be 1, with the proviso that, if alk is a valency bond, Het must not be a pyrrolidone ring substituted in the 2-position by Y; as well as the pharmacologically acceptable salts thereof.
The heterocyclic hydrogenated or partly hydrogenated ring is to represent a five-, six- or seven-membered ring, especially a pyrrolidine, pyrroline, pyrazolidine, pyrazoline, piperidine, tetrahydropyridine, hexahydropyrazine, tetrahydropyrazine, tetrahydropyrimidine or hexahydroazepine ring.
Lower alkyl means a hydrocarbon radical with 1 to 4 carbon atoms and preferably a methyl, ethyl or isopropyl radical.
When alk is an alkylene chain, it is preferably methylene, ethylene or propylene.
When R1 and R2, together with the heterocyclic ring, form a bicyclic moiety, they can be one of the following:
dihydroindole, octahydroindole, octahydroisoindole, tetrahydroquinoline, decahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, octahydroisoquinoline, decahydroisoquinoline, hexahydrobenzimidazole, dihydroindolizine, octahydroindolizine, dihydroazabicyclo[5,3,0]decane, octahydroaza[5,3,0]decane, octahydropyrindine, dihydropyrrolizine, hexahydropyrrolizine, tetrahydroquinolizine and octahydroquinolizine, but preferably octahydroindole, octahydroisoindole, decahydroquinoline, dihydroisoquinoline, decahydroisoquinoline, dihydroindolizine, octahydroindolizine, octahydropyrindine, dihydropyrrolizine, hexahydropyrrolizine, tetrahydroquinolizine, octahydroquinolizine and tetrahydroquinoxaline.
The alkane-diphosphonic acid group can be not only on the heterocyclic moiety but also on its annelated ring but alkane-diphosphonic acids are preferred which are linked with the heterocyclic moiety.
The compounds can be present as stereoisomeric mixtures or as pure cis- or trans-isomers.
Asymmetric carbon atoms can possess the R-, S- or R,S-configuration.
Compounds of the general formula I are prepared according to known processes.
When X (in Y) in general formula I is a hydroxyl group, the compounds are preferably prepared by:
(a) reacting a carboxylic acid of the general formula: ##STR4## in which Het, B, R1, R2, alk, m and r have the above-given meanings, G1 is a hydrogen atom or the grouping (alk-COOH)s, whereby alk and s have the above-given meanings, with a mixture of phosphorous acid or phosphoric acid and a phosphorus halide and subsequently saponifying to the free diphosphonic acid, or
(b) reacting a carboxylic acid chloride of the general formula: ##STR5## in which Het, R1, R2, alk, m and r have the above-given meanings, G2 is a hydrogen atom or the grouping (alk-COCl)3, with a trialkyl phosphite of the general formula:
in which R' is a lower alkyl radical, to give an acyl phosphonate of the general formula: ##STR6## in which Het, B, R1, R2, R', alk, m and r have the above-given meanings, G3 is a hydrogen atom or the grouping [alk-CO-P(O)(OR')2 ]s, whereby alk, R' and s have the above-given meanings, subsequently reacting with a dialkyl phosphite of the general formula: in which R' has the above-given meaning, to give a diphosphonate of the general formula: ##STR7## in which Het, B, R1, R2, R', alk, m and r have the above-given meanings and G4 is a hydrogen atom or the grouping [alk-C(OH)[P(O)(OR')2 ]2 ]s, whereby alk, R' and s have the above-given meanings, and optionally saponifying the resultant tetraester to a diester or acid of general formula I, or
(c) when X (in Y) in general formula I is an amino group optionally substituted by alkyl radicals, reacting a carboxylic acid derivative of the general formula: ##STR8## in which Het, B, R1, R2, alk, m and r have the above-given meanings, Z is a nitrile, imino ether or N,N-dialkylcarboxamido radical and G5 is a hydrogen atom or the grouping (alk-Z)s, whereby alk, Z and s have the above-given meanings, with a phosphorus compound of the general formula:
in which T is a halogen atom, OH or OR', whereby R' has the above given meaning and possibly subsequently saponifying, or
(d) when X in Y) in general formula I is a hydrogen atom, reacting a compound of the general formula: ##STR9## in which Het, B, R1, R2, alk, m and r have the above-given meanings, A is a reactive residue, for example a halogen atom or a sulphonate group, and G6 is a hydrogen atom or the grouping (alk-A)s, whereby alk, A and s have the above-given meanings, with a compound of the general formula: ##STR10## in which R' has the above-given meaning, to give a diphosphonate of the general formula: ##STR11## in which Het, B, R1, R2, R', alk, m and r have the above-given meanings and G7 is a hydrogen atom or the grouping [alk-CH[P(O)(OR')2 ]2 ]s, whereby alk, R' and s have the above-given meanings, or
(e) when Het in general formula I is a five- or six-membered ring, converting a compound of the general formula XIII ##STR12## in which B, R1, R2, G, Y, m and r have the above-given meanings and Het' is a heteroaromatic five- or six-membered ring with one or two nitrogen atoms, by hydrogenation into a compound of general formula I, and optionally saponifying the resultant tetraester into a diester or acid of general formula I or, if desired, converting the compound obtained of formula I into a pharmacologically acceptable salt.
The carboxylic acids of general formula II used in process (a) are reacted with 1 to 2 and preferably 1.5 mole of phosphorous acid or phosphoric acid and 1 to 2 and preferably 1.5 mole of phosphorus trihalide at a temperature of 80� to 130� C. and preferably of 100� to 110� C. The reaction can also be carried out in the presence of a dilution agent, such as halogenated hydrocarbon, especially chlorobenzene or tetrachloroethane, or also dioxan. The subsequent hydrolysis can take place by boiling with water but preferably with semi-concentrated hydrochloric or hydrobromic acid.
In the case of process (b), the acid chloride of general formula III is reacted with the trialkyl phosphite of general formula IV at a temperature of 0� to 60� C. and preferably of 20� to 40� C. The reaction can be carried out without a solvent or also in the presence of an inert solvent, such as diethyl ether, tetrahydrofuran, dioxan or also a halogenated hydrocarbon, for example methylene chloride. The acyl phosphonate of general formula V resulting as intermediate can be isolated or further reacted directly.
The subsequent reaction is carried out in the presence of a weak base and preferably of a secondary amine, for example dibutylamine, at a temperature of 0� to 60� C. and preferably of 10� to 30� C.
In the case of process c), the nitriles of general formula VIII are reacted with phosphorous acid at a temperature of 110� to 180� C. The reaction can be carried out without or in the presence of an aprotic solvent, for example diglycol dimethyl ether or diglycol diethyl ether.
However, the nitriles can also be reacted with a phosphorus trihalide, for example phosphorus tribromide or phosphorus trichloride, in an inert solvent, for example dioxan or tetrahydrofuran, optionally with the addition of water, at a temperature of 20� to 80� C. Imino ethers of general formula VIII are preferably reacted with dialkyl phosphites in the presence of an equimolar amount of sodium in an inert solvent, for example diethyl ether, dioxan or also benzene, the reaction usually taking place at the reflux temperature of the solvent used. Acid amides of general formula VIII can be reacted in an inert solvent, for example a halogenated hydrocarbon or an ether, for example diethyl ether, with a mixture of phosphorus pentahalide/phosphorous acid or also of oxalyl chloride/trialkyl phosphite.
In the case of process d), the methylenediphosphonic acid ester of general formula XI is used in the form of its sodium or potassium salt. For this purpose, it is reacted with sodium, potassium or a corresponding hydride in an inert solvent, for example benzene, toluene or dimethylformamide, at a temperature of 0� to 40� C. and preferably at 25� C. The alkali metal salt is reacted, without isolation, with the appropriate halide or sulphonate. The temperature used is hereby 20� to 110� C.
In the case of process e), hydrogenation is carried out in the presence of a noble metal catalyst, for example palladium or platinum, preferably in acidic medium, for example, in aqueous solution, with or without the addition of an inorganic or organic acid at 1 to 100 bar and preferably 1 to 10 bar and at 20� to 80� C. and preferably at 20� to 50� C.
The tetraalkyl esters possibly obtained in the case of processes (b), (c), (d) and (e) can be saponified to diesters or free tetraacids. As a rule, the saponification to diesters takes place by treating the tetraalkyl esters with an alkali metal halide, preferably sodium iodide, in an appropriate solvent, for example acetone, at ambient temperature. There hereby results the symmetrical diester/disodium salt which can optionally be converted by an acidic ion exchanger into the diester/diacid. The saponification to free diphosphonic acids usually takes place by boiling with hydrochloric or hydrobromic acid. However, cleavage can also be carried out with a trimethylsilyl halide, preferably the bromide or iodide. On the other hand, the free diphosphonic acids can again be converted into the tetraalkyl esters by boiling with orthoformic acid alkyl esters. The free diphosphonic acids of general formula I can be isolated as free acids or in the form of their mono- or dialkali metal or ammonium salts. As a rule, the alkali metal salts can be well purified by reprecipitation from water/methanol or water/acetone.
The compounds of general formula I can, if desired, be subsequently converted into other compounds of general formula I. They can, for example, be alkylated or, by hydrogenolytic splitting off of an N-benzyl group, there can be prepared, for example, the corresponding unsubstituted compounds of general formula I.
As pharmacologically acceptable salts, there are especially used alkali metal and ammonium salts which are prepared in the usual way, for example by neutralisation of the compounds with inorganic or organic bases, for example sodium or potassium hydrogen carbonate, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous ammonia or amines, for example trimethyl or triethylamine.
The new compounds of general formula I according to the present invention and salts thereof can be administered enterally and parenterally in liquid or solid form. There are hereby used all conventional forms of administration, for example tablets, capsules, dragees, syrups, solutions, suspensions and the like. As injection medium, water is preferably used which contains the additives usual in the case of injection solutions, such as stabilising agents, solubilising agents and buffers.
Such additives include, for example, tartrate and citrate buffers, ethanol, complex formers (such as ethylene diamine-tetraacetic acid and non-toxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Liquid carrier materials for injection solutions must be sterile and are preferably filled into ampoules. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, higher molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols); compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.
The dosaging can depend upon various factors, such as the manner of administration, species, age and/or individual state. The doses to be administered daily are about 1 to 1000 mg. and preferably 10 to 200 mg. in the case of humans and can be taken once or divided up several times.
Preferred according to the present invention are, apart from the compounds mentioned in the Examples and compounds derivable by combination of all the meanings of the substituents mentioned in the claims, the following diphosphonic acids, as well as their sodium salts and methyl and ethyl esters.
1-hydroxy-2-(octahydro-1-H-2-pyridin-3-yl)-ethane-1,1-diphosphonic acid,
1-hydroxy-1-(octahydro-1-H-2-pyridin-4-yl)-methane-1,1-diphosphonic acid,
2-(3,4-dihydroisoquinolin-1-yl)-ethane-1-hydroxy-1,1-diphosphonic acid,
1-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-1-yl)-ethane-1,1-diphosphonic acid,
1-hydroxy-2-(piperidin-2-yl)-propane-1,1-diphosphonic acid,
1-hydroxy-2-(1,2,3,4,5,6,7,8-octahydroisoquinolin-1-yl)-ethane-1,1-diphosphonic acid,
2-(decahydroisoquinolin-3-yl)-ethane-1-hydroxy-1,1-diphosphonic acid,
1-hydroxy-1-(1,2,3,4-tetrahydroisoquinolin-3-yl)-methane-1,1-diphosphonic acid,
1-hydroxy-1-(1,2,3,4-tetrahydroisoquinolin-4-yl)-methane-1,1-diphosphonic acid,
1-(decahydroisoquinolin-8-yl)-methane-1-hydroxy-1,1-diphosphonic acid
1-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-4-yl)-ethane-1,1-diphosphonic acid
1-(decahydroisoquinolin-3-yl)-methane-1-hydroxy-1,1-diphosphonic acid
1-(decahydroisoquinolin-4-yl)-methane-1-hydroxy-1,1-diphosphonic acid
2-(decahydroisoquinolin-4-yl)-ethane-1-hydroxy-1,1-diphosphonic acid
1-decahydroquinolin-8-yl)-methane-1-hydroxy-1,1-diphosphonic acid
2-(decahydroquinolin-2-yl)-ethane-1-hydroxy-1,1-diphosphonic acid
2-(decahydroquinolin-3-yl)-ethane-1-hydroxy-1,1-diphosphonic acid
2-(decahydroquinolin-8-yl)-ethane-1-hydroxy-1,1-diphosphonic acid
3-(decahydroquinolin-2-yl)-propane-1-hydroxy-1,1-diphosphonic acid
1-(decahydroquinolin-4-yl)-methane-1-hydroxy-1,1-diphosphonic acid
1-hydroxy-1-(octahydro-1-H-1-pyridin-3-yl)-methane-1,1-diphosphonic acid
1-decahydro-1-methylquinolin-3-yl)-methane-1-hydroxy-1,1-diphosphonic acid.
1-hydroxy-3-(1H-octahydroindol-2-yl)-propane-1,1-diphosphonic acid
1-hydroxy-1-(1H-octahydroindol-3-yl)-methane-1,1-diphosphonic acid
1-hydroxy-1-(1-propyloctahydroindol-3-yl)-methane-1,1-diphosphonic acid
1-hydroxy-2-(1H-octahydroindol-2-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-2-(1-methyloctahydroindol-2-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-2-(1H-octahydroindol-3-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-1-(1H-octahydroindol-7-yl)-methane-1,1-diphosphonic acid
1-hydroxy-2-(1H-octahydroindol-7-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-2-(2H-octahydroisoindol-1-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-2-(pyrrolidin-2-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-2-(1-methylpyrrolidin-2-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-1-(octahydro-1-H-1-pyridin-4-yl)-methane-1,1-diphosphonic acid
1-hydroxy-2-(pyrrolidin-3-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-2-(1-propylpyrrolidin-3-yl)-ethane-1,1-diphosphonic acid
3-(1-cyclohexylmethylpyrrolidin-2-yl)-propane-1-hydroxy-1,1-diphosphonic acid
1-hydroxy-1-(octahydro-1-H-1-pyridin-7-yl)-methane-1,1-diphosphonic acid
1-hydroxy-2-(octahydro-1-H-1-pyridin-2-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-2-(tetrahydroquinoxalin-2-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-3-(piperidin-2-yl)-butane-1,1-diphosphonic acid
1-hydroxy-5-(piperidin-2-yl)-pentane-1,1-diphosphonic acid
1-hydroxy-2-(piperidin-3-yl)-ethane-1,1-diphosphonic acid
1-hydroxy-3-(piperidin-3-yl)-butane-1,1-diphosphonic acid
2-(1H-hexahydroazepin-2-yl)-ethane-1-hydroxy-1,1-diphosphonic acid
1-(1H-hexahydroazepin-3-yl)-methane-1-hydroxy-1,1-diphosphonic acid
1-hydroxy-1-(3-pyrrolin-2-yl)-methane-1,1-diphosphonic acid
1-hydroxy-1-octahydroindolizin-8a-yl-methane-1,1-diphosphonic acid
1-hydroxy-1-[2,5,6,7-tetrahydro(3H)pyrrolizin-1-yl)-methane-1,1-diphosphonic acid
1-hydroxy-1-[5,6,7,7a-tetrahydro(3H)pyrrolizin-1-yl]-methane-1,1-diphosphonic acid
1-[hexahydro(3H)pyrrolizin-7a-yl]-methane-1-hydroxy-1,1-diphosphonic acid
2-[1,2-dihydro(3H)pyrrolizin-3-yl]-ethane-1-hydroxy-1,1-diphosphonic acid
2-[1,2-dihydro(3H)pyrrolizin-5-yl]-ethane-1-hydroxy-1,1-diphosphonic acid
2-[hexahydro(3H)pyrrolizin-7a-yl]-ethane-1-hydroxy-1,1-diphosphonic acid
1-hydroxy-2-(octahydro-1-H-2-pyridin-1-yl)-ethane-1,1-diphosphonic acid
1-[1,2-dihydro(3H)pyrrolizin-6-yl]-methane-1-hydroxy-1,1-diphosphonic acid
1-[1,2-dihydro(3H)pyrrolizin-7-yl]-methane-1-hydroxy-1,1-diphosphonic acid
1-hydroxy-1-[octahydro(4H)quinolizin-1-yl]-methane-1,1-diphosphonic acid
1-hydroxy-1-[octahydro(4H)quinolizin-2-yl]-methane-1,1-dihosphonic acid
1-[3,6,7,8,9,9a-hexahydro(4H)quinolizin-1-yl]-methane-1-hydroxy-1,1-diphosphonic acid
1-hydroxy-2-[octahydro(4H)quinolizin-1-yl]-ethane-1,1-diphosphonic acid
1-hydroxy-2-[octahydro(4H)quinolizin-2-yl]-ethane-1,1-diphosphonic acid.
The following Examples describe one of the process variants which can be used for the synthesis of the compounds according to the present invention but this is not to represent a limitation of the subject matter of the present invention. As a rule, the compounds are obtained as high melting solid products (mono- or disodium salt), the structure of which was verified by H, P and possibly by 13 C NMR spectroscopy. The purity of the substances was determined by means of C, H, N, P, S, Na analysis, as well as by thin layer electrophoresis (cellulose, oxalate buffer of pH=4.0). For the characterisation of the individual compounds, there are given the Mrel values (=relative mobility), referred to pyrophosphate (Mrel =1).
5.6 g. Decahydroquinoline-3-carboxylic acid (prepared by saponification of the corresponding ethyl ester which, in turn, was prepared by hydrogenation of ethyl 4-chloroquinoline-3-carboxylate with palladium on charcoal in glacial acetic acid at 5 bar and 60� C.) are suspended in 40 ml. chlorobenzene and mixed with 2.9 g. phosphorous acid. The reaction mixture is heated for 10 minutes to 120� C., then 3.8 ml. phosphorus trichloride are added dropwise and the mixture stirred for 8 hours at 120� C. After cooling, a yellow, amorphous mass is filtered off and washed with diethyl ether and the residue is heated for 5 hours under reflux with 60 ml. semi-concentrated hydrochloric acid. After cooling, the reaction mixture is filtered off with suction and the filtrate evaporated. The residue is dried and stirred with acetone. After 1 hour, the acetone is decanted off and the residue is dissolved in 16 ml. water and filtered. The filtrate is brought to a pH ≈5 with 2N aqueous sodium hydroxide solution and mixed with 150 ml. methanol. The precipitated product is filtered off with suction and dried. There are thus obtained 3.1 g. (26% of theory) of the disodium salt x 1 mole water; m.p. 270�-280� C., Mrel : 0.40.
In analogous way, there are obtained by the use of
(a) 1-ethoxycarbonylpiperidin-2-ylacetic acid (m.p.: 58�-60� C.), 1-hydroxy-2-(piperidin-2-yl)-ethane-1,1-diphosphonic acid as monosodium salt x 1 mole water in a yield of 23% of theory; m.p.: 250�-255� C., Mrel : 0.40
(b) 1-methylpiperidin-2-ylacetic acid hydrochloride (m.p.: 178�-179� C.), 1-hydroxy-2-(1-methylpiperidin-2-yl)-ethane-1,1-diphosphonic acid as monosodium salt x 1 mole water in a yield of 28% of theory; m.p. 155�-160� C., Mrel : 0.40
(c) 3-(pyrrolidin-2-yl)-propionic acid (Can. J. Chem., 57, 1977), 1-hydroxy-3-(pyrrolidin-2-yl)-propane-1,1-diphosphonic acid as monosodium salt x 1 mole water in a yield of 39% of theory; m.p. 275�-280� C., Mrel : 0.50
(d) 1-benzylpyrrolidine-3-carboxylic acid (J. Chem.Soc., 1959, 852), 1-(1-benzylpyrrolidin-3-yl)-methane-1-hydroxy-1,1-diphosphonic acid, the purification of which was carried out over an ion exchanger IR 120/H form; the compound was eluted with ammonia from the exchanger and obtained as an amorphous ammonium salt x 1 mole water in a yield of 12% of theory; Mrel : 0.40.
1.5 g. 3-(Piperidin-2-yl)-propionic acid hydrochloride (m.p.: 193�-195� C., prepared by hydrogenation of 3-(2-pyridyl)-propionic acid in hydrochloric acid medium in the presence of platinum oxide) and 1.3 g. phosphorous acid are melted together at 80� C. After allowing to cool, 1.4 ml. phosphorus trichloride is added dropwise and further heated for 20 hours to 90� C. After cooling, 20 ml. water are carefully added thereto and heated under reflux for 7 hours. The cooled solution is treated with charcoal, filtered and the filtrate evaporated. After drying, the residue is stirred up several times with acetone, then taken up in water, the solution brought with 2N aqueous sodium hydroxide solution to a pH ≈5 and mixed with methanol. After stirring for some time with ice cooling, the precipitate is filtered off with suction and dried. There is obtained 1.05 g. (37% of theory) of the monosodium salt x 2 mole water; m.p. 270�-274� C.; Mrel : 0.41.
0.88 g. Ammonium salt of 1-(1-benzylpyrrolidin-3-yl)-methane-1,1-diphosphonic acid (see Example 1 e) is dissolved in 30 ml. water and hydrogenated in the presence of 0.7 g. palladium on charcoal at ambient temperature and normal pressure. After ending of the hydrogen take up, the catalyst is filtered off with suction, the filtrate is evaporated and the residue is treated with acetone. After suction filtration, there is obtained 0.44 g. (65% of theory) of the amorphous ammonium salt x 1 mole water, Mrel : 0.47.
1-Hydroxy-1-(4-piperidinyl)-methane-1,1-diphosphonic acid
12.9 g. Piperidine-4-carboxylic acid and 12.3 g. phosphorous acid are suspended in 130 ml. chlorobenzene, brought to 100� C. and mixed dropwise with 26.1 ml. phosphorus trichloride. The reaction is then continued at 130� C. After 25 hours, the chlorobenzene is distilled off and the residue is mixed with 170 ml. 6N hydrochloric acid and boiled for 13 hours. After filtering, the filtrate is concentrated and poured into 2 liters acetone. The greasy precipitate obtained becomes crystalline with isopropanol (7.7 g.=28% of theory). After recrystallisation from water, there are obtained 3.6 g. (13% of theory) as monohydrate of m.p. 238� C. sinters/246�-248� C. Mrel : 0.41.
(4a) In analogous way, from 3-(4-piperidinyl)-propionic acid (Biochem. J. 46, 192), there is obtained 1-hydroxy-3-(4-piperidinyl)-propane-1,1-diphosphonic acid as hydrochloride; yield 35% of theory; m.p. 230� C. sinters/234�-238� C. bubble formation (from aqueous methanol); Mrel : 0.40.
10 1-Hydroxy-3-(1,4,5 6-tetrahydropyrimidin-2-yl)-propane-1,1-diphosphonic acid
To 6 g. 3-(1,4,5,6-tetrahydropyrimidin-2-yl)propionic acid hydrochloride and 3.9 g. phosphorous acid, suspended in 60 ml. chlorobenzene, are added dropwise at 100� C. 8.3 ml. phosphorus trichloride and subsequently further stirred for 10 hours at the same temperature.
The chlorobenzene is then poured off, 120 ml. 6N hydrochloric acid are added thereto and boiled for 1 day. Subsequently, the hydrolysis solution is concentrated, poured into 600 ml. acetone and the separated oil brought to crystallisation with methanol. There are thus obtained 2.8 g. (29% of theory) of the desired diphosphonic acid (Mrel : 0.36) which is obtained as the monhydrate; m.p. 219�-226� C. (decomp.). The final purification takes place column chromatographically on Amberlite IR 120-H+.
The starting compound is obtained by hydrogenation, in the presence of palladium-charcoal, of the known 3-(2-pyrimidinyl)-acrylic acid, m.p. 214�-218� C., decomp. (JACS 72, 3541).
In a manner analogous to that described in Example 1, there are obtained by the reaction of phosphorous acid and phosphorus trichloride with
(a) decahydroisoquinolin-1-ylacetic acid (m.p. 224�-229� C.; prepared by hydrogenation of 1,2,3,4,5,6,7,8-octahydroisoquinolin-1-ylacetic acid (synthesised according to Helv. Chim. Acta, 41, 129) in the presence of platinum oxide), 2-(decahydroisoquinolin-1-yl)-ethane-1-hydroxy-1,1-diphosphonic acid which, after purification over an ion exchanger IR 120/H form, was isolated as the free acid; yield 53% of theory; m.p. 219�-224� C. (decomp.); Mrel : 0.35
(b) octahydro(4H)quinolizine-3-carboxylic acid (m.p. 258�-261� C.; prepared by alkaline saponification of the ethyl ester which was synthesised according to Chem. Pharm. Bull., 27, 1454), 1-hydroxy-1-[octahydro(4H)quinolizin-3-yl]-methane-1,1-diphosphonic acid which was isolated as the disodium salt x 2 mole water in a yield of 22% theory; m.p. 285�-290� C. (decomp.); Mrel : 0.45.
(c) 1-methyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (m.p. 90�-95� C.; preparation: ethyl 4-chloroquinoline-3-carboxylate is reacted with trimethyloxonium borofluorate to give the 1-methylquinolinium salt (m.p. 143�-146� C.); from this, by hydrogenation in the presence of platinum oxide, there is obtained ethyl 1-methyl-1,2,3,4-tetrahydroquinoline-3-carboxylate in the form of an oil which is then saponified under alkaline conditions to the corresponding acid), 1-hydroxy-1-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)methane-1,1-diphosphonic acid which was isolated analogously to Example 1 e) as the ammonium salt; yield 25% of theory; m.p. 210�-220� C. (decomp.); Mrel : 0.40.
(d) 1-ethoxycarbonylpiperidine-3-carboxylic acid (oil; prepared by the reaction of piperidine-3-carboxylic acid hydrochloride with ethyl chloroformate at pH 9), 1-hydroxy-1-(piperidin-3-yl)-methane-1,1-diphosphonic acid which, after purification over an ion exchanger IR 120/H form, was isolated as the free acid x 1 mole water; yield 19% of theory. The hydrolysis with hydrochloric acid was hereby carried out over 10 hours in order to split off the carbethoxy group quantitatively; m.p. 260�-264� C. (decomp.); Mrel : 0.50
(e) 1-methylpiperidine-3-carboxylic acid hydrochloride (m.p. 166�-168� C.; preparation: methyl nicotinate is reacted with methyl iodide to give N-methylpyridinium iodide (m.p. 128�-130� C.), hydrogenated in the presence of platinum oxide to give methyl 1-methylpiperidine-3-carboxylate hydroiodide (m.p. 104�-105� C.) and subsequently, after alkaline saponification, isolated as the hydrochloride of the desired acid), 1-(1-methylpiperidin-3-yl)-methane-1-hydroxy-1,1-diphosphonic acid which, after purification over an ion exchanger IR 120/H form, was isolated as the free acid x 1 mole water; yield 18% of theory; m.p. 265�-270� C. (decomp.); Mrel : 0.50.
(f) hexahydro(3H)pyrrolizine-1-carboxylic acid (amorphous substance; prepared according to Arch. Pharm., 310, 179), 1-hexahydro(3)pyrrolizin-1-yl)-methane-1-hydroxy-1,1-diphosphonic acid as disodium salt x 2 mole water; yield 32% of theory; m.p. >300� C.; Mrel : 0.55.
(g) octahydro(4H)quinolizin-9a-ylacetic acid (amorphous substance; prepared by alkaline saponification of the ethyl ester which was synthesised according to Chem. Pharm. Bull., 23, 2387), 1-hydroxy-2-[octahydro(4H)-quinolizin-9a-yl]-ethane-1,1-diphosphonic acid which, after purification over an ion exchanger IR 120/H form, was isolated as the free acid x 1 mole water; yield 27% of theory; m.p. 200�-205� C.; Mrel : 0.45.
(h) 1,2-dihydro(3H)pyrrolizin-2-ylacetic acid (m.p. 65�-67� C.; prepared according to J. Org. Chem., 42, 3955), 1-[1,2-dihydro(3H)pyrrolizin-2-yl]-methane-1,1-diphosphonic acid as the disodium salt x 1 mole water; yield 19% of theory; m.p. >300� C.; Mrel : 0.55
(i) hexahydro(3H)pyrrolizin-2-ylacetic acid hydrochloride (m.p. 186�-188� C.; prepared by hydrogenation of the dihydro compound of Example 6 h) in the presence of platinum oxide as catalyst, 1-[hexahydro(3H)-pyrrolizin-2-yl]-methane-1-hydroxy-1,1-diphosphonic acid as the sodium salt x 1 mole water; yield 24% of theory; m.p. >300� C.; Mrel : 0.50.
Male Wistar rats from our own breeding weighing about 160 g were thyroparathyroidectcmized on day 1. On day 5, the success of the operation was controlled by measuring calcemia after a night fasting. From that day on, all the animals were group-fed, that means all of them ate the same quantity of food. Furthermore, the animals received then daily for 3 days 2 subcutaneous injections, on containing 25 μg of a synthetic retinoid, the other one the bisphonsphonate to be tested. Additionally, all animals were given 2 μg of thyroxine the first and last day of treatment 24 h after the last injection of the retinoid and the biphosphonate and after one night fasting, blood was taken by retroorbital puncture under ether anesthesia. Plasma calcium was then analyzed by means of atomic absorption.
The bisphosphonate were given first at a dose of 1 mg P/kg in a volume of 2 ml/kg. Thereupon, the compounds were given in a dose of 0,1 ; 0,01 and if high active in a dose of 0,001 mg P/kg.
TABLE______________________________________ mg P/kgExample 0.001 0.01 0.1 1______________________________________1b (+) +++ +++ +++1c (+) +++ +++ +++1d 0 + +++2 + +++______________________________________ 0 = Depression of Hypercalcaemie -0.99 to +0.99 mg % (+) = Depression of Hypercalcaemie 1.0 to 1.99 mg % + = Depression of Hypercalcaemie 2.0 to 2.99 mg % ++ = Depression of Hypercalcaemie 3.0 to 3.99 mg % +++ = Depression of Hypercalcaemie >4.0%
It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
|Cited Patent
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|Citing Patent
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|Jul 28, 1992
|Ciba-Geigy Corporation
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|Boehringer Mannheim Gmbh
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|Procter & Gamble Pharmaceuticals, Inc.
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|The Procter & Gamble Company
|Quaternary nitrogen containing phosphonate compounds, pharmaceutical compostions, and methods for treating abnormal calcium and phosphate metabolism
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|The Procter & Gamble Company
|Thio-substituted cyclic phosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
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|Quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism amd methods of treating and preventing dental calculus and plaque
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|Dry mix formulation for bisphosphonic acids
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|Warner Chilcott Company, Llc
|Bisphosphonate compounds
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|Apr 29, 2014
|Warner Chilcott Company, Llc
|Bisphosphonate compounds
|Dec 3, 2012
|Jun 10, 2014
|President And Fellows Of Harvard College
|Identification of agents for treating calcium disorders and uses thereof
|Mar 12, 2014
|Sep 2, 2014
|Warner Chilcott Company, Llc
|Bisphosphonate compounds
|May 6, 2003
|Dec 4, 2003
|Frieder Bauss
|Method of treatment using bisphosphonic acid
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|Jun 24, 2004
|Hans-G Kaestle
|High dose oral formulation of bisphosphonate and a process for making thereof
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|Barr Laboratories, Inc.
|Bisphosphonate composition and process for the preparation thereof
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|Frieder Bauss
|Method of treatment using bisphosphonic acid
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|The Procter & Gamble Company
|Method for the treatment of bone disorders
|Jun 16, 2008
|Oct 9, 2008
|Frieder Bauss
|Method of treatment using bisphosphonic acid
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|Bisphosphonate compounds
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|F. Hoffmann-La Roche AG
|Risedronic acid for treatment and prevention of bone resorption diseases
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|Wrocławskie Centrum Badań Eit+ Sp. Z O.O.
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|U.S. Classification
|514/89, 514/91, 514/87, 987/91, 548/113, 514/80, 546/22, 548/414, 514/81, 514/94, 987/367, 987/366, 987/94, 987/96, 987/95, 548/413, 514/86, 514/85, 514/88, 514/82, 548/112, 987/104, 544/232
|International Classification
|Cooperative Classification
|European Classification
|Jun 8, 1993
|Certificate of correction
|May 2, 1994
|Fee payment
Year of fee payment: 4
|May 11, 1998
|Fee payment
Year of fee payment: 8
|Jun 4, 2002
|Maintenance fee reminder mailed
|Nov 20, 2002
|Lapse for failure to pay maintenance fees
|Jan 14, 2003
|Expired due to failure to pay maintenance fee
Effective date: 20021120


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