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Nasa's advanced ion propulsion rocket engine has run continuously for over five and a half years, setting a new world record.
This makes it the longest test duration any kind of space propulsion system demonstration project ever.
The solar-electric propulsion thruster could be used in a wide range of science missions including intriguing journeys into deep space.
The thruster is part of the space agency's Evolutionary Xenon Thruster (NEXT) project at its Glenn Research Centre in Cleveland.
The project aims to develop a next-generation electric propulsion system, including power processing, propellant management and other components.
Despite setting a new record by operating for more than 48,000 hours, the long-running test will be shut down.
Michael J. Patterson, principal investigator for NEXT at Glenn, said: 'We will voluntarily terminate this test at the end of this month, with the thruster fully operational.
Read More Here


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The Boatyard is where local sailors, fishermen and lovers of the Chesapeake enjoy pint drinks, great crab cakes and the freshest local seafood. Specialties include smoked fish of the day (on premise), cream of crab and Maryland crab soups and an extensive list of crab and seafood specialties.
Our Address:
400 Fourth Street Annapolis, 21403
38.9712112, -76.4824582

subset: commoncrawl


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|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|"Chris Douglas (JIRA)" <j...@apache.org>
|[jira] Updated: (HADOOP-6244) Improvements to FileContext metrics output formatting
|Tue, 03 Nov 2009 02:29:59 GMT
[ https://issues.apache.org/jira/browse/HADOOP-6244?page=com.atlassian.jira.plugin.system.issuetabpanels:all-tabpanel ] Chris Douglas updated HADOOP-6244: ---------------------------------- Status: Open (was: Patch Available) While timestamps and distinguishing tags from metrics are both useful properties, changing the format of FileContext disrupts all the downstream consumers. Other metrics consumers (e.g. Chukwa) have defined different MetricsContexts to effect formatting changes, rather than modifying this class. That said, either (a) making the format configurable or (b) making FileContext more readily extensible would be welcome changes, since most alternative implementations end up copying FileContext. IIRC, there's a Log4j-based MetricsContext in Chukwa that may be a worthy, if heavyweight option for a configurable, file-based context. Other, small notes: * This seems unnecessary, as the lock is held while accessing {{updaters}}: {noformat} - private void timerEvent() throws IOException { + private synchronized void timerEvent() throws IOException { if (isMonitoring) { Collection<Updater> myUpdaters; synchronized (this) { {noformat} Either the latter synchronized block needs to be removed (with the comment justifying it) or this should be reverted. * The protected fields are part of FileContext's API and probably should not be made package-private. * {{emitNowForTests}} is a regrettable method, but then again, so is use of {{Timer}}, and the metrics have been without any unit tests for too long. Still, this makes timerEvent a public API, despite the javadoc. Adding a call to {{timerEvent}} after {{stopTimer}} in {{stopMonitoring}} is tempting, but the caller of the latter method should probably not block if the metrics update does. Since it's only required for FileContext testing at the moment, would it be reasonable to let {{emitNowForTests}} be a package-private on FileContext? * The unit test should use JUnit4 rather than JUnit3 semantics * Adding a static class to read records emitted by FileContext would be great, but I think the notion highlights how the metrics package would be better served by adding a FileContext using a standard format, like JSON, or base it on Avro. > Improvements to FileContext metrics output formatting > ----------------------------------------------------- > > Key: HADOOP-6244 > URL: https://issues.apache.org/jira/browse/HADOOP-6244 > Project: Hadoop Common > Issue Type: Improvement > Components: metrics > Affects Versions: 0.22.0 > Reporter: Todd Lipcon > Assignee: Todd Lipcon > Fix For: 0.22.0 > > Attachments: hadoop-6244.txt > > > The output of FileContext has two big issues: 1) it doesn't include a timestamp, 2) it doesn't differentiate between tags and metrics in formatting. This patch is to improve the output format to be more useful. -- This message is automatically generated by JIRA. - You can reply to this email to add a comment to the issue online.
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Date(s) - 08/11/2017
7:30 am - 7:00 pm
Highland Springs Country Club
Categories No Categories
Watch the future of the PGA Tour come through Springfield.
The Price Cutter Charity Championship presented by Dr Pepper is set for Thursday, August 10 through Sunday, August 13 at Highland Springs Country Club.
Tee times for the pros will vary but generally they begin at 8 a.m.
Other notable events:
- 7 a.m. daily — An honor guard from either the Greene County Sheriff's Department, Springfield Police Department, Army National Guard or Missouri Highway Patrol will march the U.S. flag to the first tee box.
- Bass Pro Fishing Contest after play every day Thursday through Saturday
- Go Blue for Autism Championship Sunday — 7 a.m. Sunrise Service on the 18th green and, after play, winners of the TLC Properties Charity Sweepstakes (new truck and $10,000 prize) will be announced on the 18th green. Likewise, we'll have a Volunteer Party in the Jackson Brothers of the South Ozarks Club Tent.


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1957 first printing. Nice paperback. No spine crease. Moderate wear. A little soiling to page blocks. Text is clean, unmarked. (Shelf location: F1) All items carefully packed to avoid damage from moisture and rough handling. Tracking included. Bookseller Inventory #
Title: Nine Who Survived Hiroshima and Nagasaki (...
Publisher: Tuttle
Publication Date: 1957
Binding: Paperback
Book Condition: Collectible: Good
Edition: First Edition.
Book Description E. P. Dutton, New York, 1969. Hardcover. Book Condition: Very Good. Dust Jacket Condition: Good. Sixth Edition. 8vo - over 7¾" - 9¾" tall. Covers have only light wear, dust jacket 1" chip to top of spine and small closed tear and is price-clipped, no markings and no writing to text, remains of bookplate on front endpaper, 6th printing, 148 pages, index, illustrated with photographs. Bookseller Inventory # 12311
More Information About This Seller | Ask Bookseller a Question


text:
Thomas Super Pocket Library
Written by
Illustrated by
when in stock
As soon as this book is back in stock we will send you an email.
Thomas Super Pocket Library by
About the Author
Other Formats
Book Info
Board book
48 pages
Interest Age: From 2
Egmont Books Ltd an imprint of Egmont UK Ltd
Publication date
6th July 2012
I love 'LoveReading 4 kids' because they let you read and learn things you'd never dreamed of learning before.Emily Horncastle – age 11
We love Lovereading4kids because they put books in front of us we wouldn't otherwise have read. They make us more adventurous readers!Emily Jacques
I love Lovereading4kids because I get an opportunity to put my opinion forward and to try new booksElosie Clarkson – age 11
I am so pleased to have signed my kids up as they are reading a much wider range of books and even choosing books out of their comfort zone.Angela East
I love Lovereading as it provides an honest opinion and showcases a range of fiction. Suited to both parents & kids alike, it's a must-use.Georgie Rowe – age 16
Lovereading is just a convenient way to find new books and hear others opinions on them.Sarah Murray – age 15
We love Lovereading as my 5 year old loves to read new books before anyone else has a chance, she says it makes reading exciting!Tracey Chorley
This company is amazing; not only is it is a great opportunity to get books and review them but everyone is so friendly and supportive!Jemma Rubens, age 10


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The Like A Prayer singer made a surprise appearance at the gong-fest, held at London's Television Centre, to present the special Ronnie Barker award to Borat creator Sacha Baron Cohen. But what she hadn't bargained for was a pasting from the loose-tongued host.
The television funnyman, who is hardly known for his subtlety, joked about 47-year-old Madge's recent adoption of a baby from Malawi.
Shortly before she gave the award to Ali G impersonator Cohen, Ross said to her: "Congratulations on your little lovely black baby, David. Are you stopping there, or getting more? When I went to Africa all I got was a wallet."
To which a less-than-amused Madonna replied: "You might go home with a black eye." Immediately the US superstar, who is married to British film director Guy Ritchie, went from being all smiles to having the hump - and she walked out before the after-party had even begun.
Her appearance at the annual awards was accompanied by her usual diva behaviour. While other high-profile celebrities were happy to enter via the venue's front entrance, Madge insisted on making work for event's organisers by demanding to sneak in via the back door, well away from fans outside who had heard of her impending appearance.
Our source said: "Madonna refused to enter in the usual entrance - it took a lot of work to make sure that her journey ran smoothly." Once inside, Madge had staff, and indeed her own heavies, working overtime to ensure that she wasn't pestered by other celebs.
And Heather Mills McCartney joined Madge on Ross's gag hit-list when he jibed: "Heather leaving Paul McCartney - like leaving on a limb."
Winners at last night's ceremony included Harry Hill, who picked up two, Charlotte Church, for being the best comedy newcomer, Extras actor Stephen Merchant, and Ant and Dec, who took the People's Choice Award.
- More about:
- Ali G
- Malawi
- Sacha Baron Cohen


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This B&B is located in a working farm and has a gorgeous setting. The room was nice and comfortable and clean. However, what makes us want to come back to this place is the owner Mary. She was born to be in the hospitality business:...More
Getting you more information on this room
Getting you more information on this room
"All rooms are spacious, clean and well provisioned - rear rooms overlook the farm"


text:
Configuring new E1 MFT
Unanswered Question
User Badges:
Hi all
Can you please confirm the correct configuration for a new E1 card install. Currently I have 1 30 channel E1 installed in the 3825 VG. I am assuming all I will have to do is add the controller and timeslots and I should be good to go. Then just add the translation patterns in the CUCM
Look forward to a reply
I have this problem too.
0 votes


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Question about Kia Sportage
Posted by atcullen45 on
The first thing that comes to thought is the timing belt Sadly there are too many posibilities to say right now you will need a shop with a scan tool to help you the Cam sensot or its wiring can be bad
The Crank sensor or its wiring can be bad Sorry Just right now it's only a guess at what can be your problem If this information is helpful please give me a good rating.
But Please be careful who you trust to diagnose your vehicle some shops are so dishonest its just rotten Ask is they have at least one ASE L-1 technician on staff he will be the most knowlegeable and if you don't feel totally comfortable there don't go there.
Posted on Aug 13, 2008
SOURCE: I have freestanding Series 8 dishwasher. Lately during the filling cycle water hammer is occurring. How can this be resolved
a 6ya expert can help you resolve that issue over the phone in a minute or two.
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the service is completely free and covers almost anything you can think of (from cars to computers, handyman, and even drones).
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Posted on Jan 02, 2017
Tips for a great answer:
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text:
Text Publishing has come up with a fantastic early cover blurb for Shimmer (out in July), which I'm busting to share. So here it is (warning – there's a spoiler if you haven't read Haze):
Gaby thought her life couldn't get more complicated.
She's almost used to the idea that she's not the nineteen-year-old backpacker she thought she was. She can just about cope with being one of the Rephaim – a 140-year-old half-angel – whose memories have been stolen. She's even coming to grips with the fact that Jude, the brother she's mourned for a year, didn't die at all.
But now Rafa—sexy, infuriating Rafa—is being held, and hurt, by Gatekeeper demons. And Gaby has to get the bitterly divided Rephaim to work together, or Rafa has no chance at all.
It's a race against time – and history. And it may already be too late.
And now, drumroll for the title of Book 4 of the Rephaim series (the last one)…
Hope you like it. 🙂


text:
Join Our San Francisco Committee!
The San Francisco Committee is a network of leaders dedicated to advancing human rights in both their communities and around the world. As ambassadors and advocates, members play an active role in a global network of philanthropists, investors, and influencers who make up the Human Rights Watch Council. If you are in the San Francisco Bay Area, please join us at one of our upcoming events!


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Day Out
Dinos Den at Comber Leisure, Castle Street, Comber, County Down, BT23 5DY
Weekdays: 9:00am - 10:00pm; Saturday 9:00am - 6:00pm; Sunday: 1:00pm - 6:00pm
Child - GBP 3.00
Suitable for:
Dino's Den has exciting activities including slides, a biffbash forest, ball juggler, climbers, roller squeeze and log ramp - a great way to thrill and amuse toddlers to ten year olds.
Dino's Den includes a seating area for parents or guardians to relax while children enjoy independent play in a safe environment.
Come and relax while the children amuse and tire themselves out.


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I'm excited to go to Chicago for a week to see family and friends. Of course I'll stop by Gramophone Records and Smart Bar but until then, here's a song to get me in the mood.
I've been to over half of the Pride events ever held in San Francisco so for me, the parade lost its luster once it passed the two hour mark – it's long because SF includes everyone if they're based in the city or not because, hey, it's their pride too…
An ever accelerating phenomenon of the SF Pride events is attendance by younger and more ethnically diverse people. While I think it's great that 20 and under kids that are too young for bars are coming out and finding a place in our community, I think there needs to more of a place for them at the event. Women outnumbered men at least 3-to-1 in every area of the festival except maybe the Faerie Village but there was so much androgyny in that space that I can't be certain.
What is certain is the organizers are out of touch with their demographics. Instead of courting alcohol vendors and airlines to underwrite the event with sponsorships, they should look to companies more in line with the folks who actually turn up.
It felt like they were selling 25-45 year-old Gay White Men to their sponsors and delivering 16-25 year-old Black, Hispanic and Asian Women.
When Ggreg Taylor and Gilbert Baker launched the Pink Saturday street party on the night before the big Freedom Day Parade & Festival, they asked me to help out with a few things. .
While I only helped produce the first three or four, I don't think I've missed more than one in this event's history. After this year's Pink Saturday event, I think it's safe to say that if I never go to another one, I'll still have a really fun and interesting life.
The Dyke March wasn't a huge priority for me this year. I love seeing the spectrum of female expression parading around the streets exuding a sense of empowerment and sometimes they take their tops off too…
The Pride Parade with the cultural events & parties built around it is like a bit of grit or sand in the LGBT community oyster. Everyone adds their own layers around it to make the biggest pearl in the same-sex calendar. As my friend Steve calls it, "The highest of the High Homo-Holidays"
This year I attended the official Pride kick-off party at the Clift Hotel. It was a festive party to present the official Pride Weekend events to the media and public at large.
Great news about this year's Bay To Breakers – Geographer is headling Footstock, the official party in the park at the end of the race!
If you're not familiar with this B2B, it's one of those "Only in SF" events where people dress up in silly costumes and get drunk in the streets. As much as the organizers try to downplay the debauchery the event will always be a sort of straight version of gay pride…
I've worked at a few Geographer shows over the last couple of years and I'm so happy for them. This gig will raise their profile considerably and I hope it introduces their music to a much wider audience coz they're really nice guys and they do make some great music.
Bay 2 Breakers Finish Line Party
Zazzle Footstock
Sunday May 15th 2011
Speedway Meadow, Golden Gate Park, San Francisco
8:30 a.m. to 1 p.m.
FREE Admission to all, courtesy of Zazzle
Every neighborhood in San Francisco has at least one street fair that reflects the area. South Of Market or SOMA hosts a number of Street Fairs throughout the year. The Howard Street Fair kicks off Street Fair season for me – officially it's called the How Weird Street Faire and it celebrates SOMA's enduring legacy as the epicenter of SF's nightlife.
Foxgluv played at one of the first How Weird events and I've seen it evolve over the years from a Rave/New Age focus to get a bit more Hippy Trippy and then a bit more Night Clubby with its move to the eastern section of Howard Street where there are a number of night clubs to host official after parties.
Because the royal family's surname is Orange-Nassau the whole country gets decked out in orange. It is also the only time of year that people are allowed to sell stuff without a retail license so the last weekend in April has something for everyone – yard sales all over the country and lots of drinking in the streets.
In one of my favorite "Only In San Francisco" events, the Sisters of Perpetual Indulgence host an Easter Sunday party in the park. They have games and activities for little kids and the Sisters set up a stage in Dolores Park and local bands like Ejector perform and the people bring blankets and picknics.
The highlight of the afternoon for me is the Easter Bonnet Contest and the Hunky Jesus Contest. Both shows allow people to exhibit exuberant displays of creativity. You can tell some of these queens spend days working their hot glue guns assembiling their elaborate hats, helmets and head ornaments.
I look forward to the Hunky Jesus Contest to see what themes people will come up with. The best need little to no explanation – like the double cross Jesus with two guys on an H shaped cross – or this year's Obviously Drunk Redneck Jesus. The video below features most of this year's contestants and the winner…


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- by oceanicmood
- 142
- 1h14m
- 6 years ago
Sufjan Stevens, School of seven bells, Apparat, Team B, Nicolas Jaar and more.
I recorded this mix in such a melancholic mood, I needed some lightness but at the same time I wasn't able to set me free from those "dark" sounds, anyway, now, after an hour phone talk with my mum (nobody is able to hold you as a Mamma)I can say that maybe this mix is not so bad...
Press play to try again.
Please update your browser or install another such as Google Chrome.
Mixcloud requires HTML5 audio with MP3 and MP4 support.


text:
I happened to find an open deluxe cabin (w a bathroom) for one night for July 4th weekend at the last minute. My best friend and I drove through Lassen Nat Park, and this was an easy place to stop off after our day in...More
Getting you more information on this room
Getting you more information on this room
"Do not stay here unless you are out of options. The Feather Falls KOA & a couple really nice OR State..."
"Mt Shasta is a natural wonderland and if you are more adventurous you can easily find many very wonderful..."


text:
Maze Gobblers
Category: Activities
Leave a Comment
Eat or be eaten!
Are you the Prince of Puzzles? Do your friends refer to you as, The Master of Mazes? Play Maze Gobblers online, and be the first to eat your way through a fruit filled labyrinth, while avoiding hungry monsters! This old-school, arcade-style, two player game will leave you craving more!
Start a Round with your favorite friend, find "Maze Gobbler's" on video chat rounds in the activities menu and click the "start" button to begin your labyrinthian journey. Your goal is to eat your way through as much of the maze as possible while avoiding obstacles! Try to outlive your opponent and eat as much point-rich fruit as you can. The highest scorer (and biggest eater) wins! Play free games online, now!
Do you like to play games together online with friends? Check out our multi-player games on Facebook!
Tags: Maze Gobbler's, multiplayer games, online games, pacman, play games online


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- Instrument:
- Format:
- Publisher:
Holy Manna
By Karen Thompson
Handbells (2-3 octaves) (5-7 ringers) - Level 2
Composed by Karen Thompson. Ring More With Less Series. Sacred. Handbell score. 8 pages. Published by Chorister's Guild (LX.CGB736).
Item Number: LX.CGB736
If your ensemble is lacking the "traditional" number of ringers and needs a flexible arrangement, take a look at our "Ring More with Less Series" for five to seven ringers. The first title in this series is the American folk tune HOLY MANNA, a popular tune utilized in conjunction with a vast number of hymn texts. This creative arrangement uses a variety of techniques and is easy enough for beginners yet satisfying enough for more experienced ringers.
About Digital Downloads
Digital Downloads are downloadable sheet music files that can be viewed directly on your computer, tablet or mobile device. Once you download your digital sheet music, you can view and print it at home, school, or anywhere you want to make music, and you don't have to be connected to the internet. Just purchase, download and play!
PLEASE NOTE: Your Digital Download will have a watermark at the bottom of each page that will include your name, purchase date and number of copies purchased. You are only authorized to print the number of copies that you have purchased. You may not digitally distribute or print more copies than purchased for use (i.e., you may not print or digitally distribute individual copies to friends or students).


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Apartment Features
- Air Conditioning
- Balcony
- Cable Ready
- Ceiling Fan(s)
- Dishwasher
- New/Renovated Interior
- Oversized Closets
- Some Paid Utilities
- View
- Washer & Dryer Connections
- Patio
- Refrigerator
Special Features
- Pets
Community Features
- Accepts Credit Card Payments
- Accepts Electronic Payments
- Emergency Maintenance
- On Site Maintenance
- On Site Management
- Pet Friendly
Additional Features
- FREE Cable with HBO and Showtime
- $250 pet fee. A pet interview is required. Dogs Allowed
- $250 pet fee. A pet interview is required. Cats Allowed
- $10 Monthly Pet Rent Pets Accepted
Floor Plans & Pricing
Prices and availability subject to change without notice.
Property Details
Country Living in a City Environment. If you are looking for a convenient location and a beautiful apartment home, Briarcliffe is the place for you! Hidden among towering trees, our quiet neighborhood offers the perfect end to your busy day. With easy access to I-40, you are never far from where you need to be. Our professional management team is looking forward to meeting you and helping you with all of your move-in needs. Schedule your tour today!
Lease Terms
Our lease terms are: 6-12 Months.
Cat Policy: Maximum 2 cats per apartment. $10.00 pet rent. $250 pet deposit. Restrictions: Please contact office for pet policy. A pet interview is required.
Dog Policy: Maximum 2 dogs per apartment. $10.00 pet rent. $250 pet deposit. Restrictions: Please contact office for pet policy. A pet interview is required.
Office Hours
Open Today
Ratings & Reviews
10 Reviews for Briarcliffe
Sort by:
We have been living in Briarcliffe for 6 years now and recently moved to a larger apartment within the community. They staff is always helpful and polite. They are a big part of why we have stayed so long. If we ever have an issue or concern, it is always handled quickly and efficiently. This community is also much quieter than others that we have lived in within Kernersville, which is always a positive. The location is super convenient as well.
This complex is very convenient to highways, shopping, restaurants and public services. I feel safe in the area and am very pleased with the maintenance and 24/7 on call repair.
Management is amazing. Always there to help and work with you. Maintenance is great usually on top of everything - quiet place to live with no drama. I love living here. Only think that would make it better is a pool!
I've never had any problems with anything related to the office staff or maintenance.
I have enjoyed my time at Briarcliffe and I only gave a Good rating because as impossible as it may seem I would enjoy it more if people were somehow punished for not scooping after their pet. This I understand is time consuming and costly to pursue. I run a lot and as I run along I really dislike knowing that I will be smelling that as I run through our area. I do see people all the time walking their dog from one complex to mine to let that happen. It is just stupid they cant scoop.
- 1
- 2
What is a Certified Resident?
A resident who lives at the property and has completed a resident satisfaction survey.
Advertising properties provide a list of email addresses of its residents to Kingsley Associates, a third party market research firm, who then sends out the satisfaction survey to the residents. Properties may also conduct satisfaction surveys of its residents through other third party market research firms. In those cases, we will publish those survey responses as long as the questions conform to our standard survey format.
Because reviews are from Certified Residents, and are managed by a third party, you can feel confident that the feedback provided is accurate and trustworthy.
General Directions
From Business 40, exit Hwy 66 south. Turn right on Edgewood Street (beside Shell Gas). Take 2nd left on Lee Street and take 1st right on Michael Street. Follow signs to Briarcliffe office.
Helpful Information
Fax: 3369931575
Visit the property's management website


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How to Invest in the Stock Market. Starting to think about retirement? Wondering how you...[More]
TIAA Launches TIAA Personal Portfolio: Profes
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TIAA Personal Portfolio offers active, passive and socially responsible investing. TIAA is the first major provider to offer socially responsible inve...[More]
Jean Chatzky answers, Should I be investing m
[INVESTING] 2017-06-09 05:10:52 138reading
Jean Chatzky says you don...[More]
News~ 4 Ways A Business Can Find Funding For
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Guest Contribution: Uncertainty and business
[INVESTING] 2017-06-08 17:38:51 129reading
Today, we are pleased to present a guest contribution written by Laurent Ferrara (Adjunct Professor of Economics, University Paris Nanterre, France). The views expressed here are those solely of the au...[More]
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- inquirer.com


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Shopping for someone else but not sure what to give them? Give them the gift of choice with a SOLUDE Gift Card.
Gift cards are delivered by email and contain instructions to redeem them at checkout. Our gift cards have no additional processing fees.
SOLUDE Coffee will always taste freshest if you grind it just before brewing. But we know that can be tough in our busy lives, so we are happy to grind your SOLUDE coffee for you at no extra cost. We often get asked what grind to select. Well, it all depends on how you are going to brew your SOLUDE Coffee.
Coarse Grind - works best in French Presses
Regular Grind - is best suited to percolators and regular (drip) coffee machines. You should also select regular grind if you want to use SOLUDE coffee in a reusable single serve filter machine
Fine Grind - is only for espresso machines. Do not use fine ground coffee in a French Press or drip machine


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$6,880Open House4 beds, 3 full baths2,727 sqft lot 3,654 sqftWalk Score® 55MLS NP17144203
$1,224,900Open House3 beds, 3 full baths2,072 sqft lot 2,500 sqftWalk Score® 58MLS NP17142569
$13,2004 beds, 5 full, 1 half baths4,400 sqft lot 10,137 sqftWalk Score® 3MLS PW17141230
$1,869,0004 beds, 1 full, 2 three-quarter baths2,373 sqft lot 4,250 sqftWalk Score® 19MLS OC17137164
$2,698,000Open House5 beds, 5 full, 1 half baths3,575 sqft lot 6,746 sqftWalk Score® 0MLS NP17140439
$6,190,0005 beds, 5 full, 1 half baths5,117 sqft lot 9,797 sqftWalk Score® 2MLS NP17140245
$85,0006 beds, 6 full, 2 half baths7,700 sqft lot 15,825 sqftWalk Score® 6MLS 17243460
$20,0004 beds, 4 full, 1 half baths4,000 sqft lot 6,156 sqftWalk Score® 0MLS OC17139578
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text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 5, 2006
|Filing date
|Oct 13, 2004
|Priority date
|Oct 14, 2003
|Fee status
|Also published as
|Publication number
|Kenneth M. Boy
|Original Assignee
|Bristol-Myers Squibb Company
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (8), Non-Patent Citations (1), Classifications (10), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This application claims the benefit of U.S. Provisional Application Ser. No. 60/511,016 filed Oct. 14, 2003.
The present invention is generally directed to quinolinone derivatives, and more specifically directed to 3-thia-4-arylquinolin-2-one derivatives.
Potassium channels are transmembrane proteins which are ubiquitously expressed in mammalian cells and represent one of the largest and the most diverse group of ion channels from a molecular perspective. Potassium channels play a key role in regulation of cell membrane potential and modulation of cell excitability. Potassium channels are largely regulated by voltage, cell metabolism, calcium and receptor mediated processes. [Cook, N. S., Trends in Pharmacol. Sciences 1988, 9, 21; and Quast, U., et al., Trends in Pharmacol. Sciences 1989, 10, 431]. Calcium-activated potassium (KCa) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of KCa channels is regulated by intracellular [Ca2+], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K+ solutions, KCa channels are divided into three subclasses: large conductance (BK or Maxi-K) are those having a conductance of greater than about 150 picosemens (pS); intermediate conductance are those having a conductance of about 50–150 pS; and small conductance are those having a conductance of less than about 50 pS. Large-conductance calcium-activated potassium channels are present in many excitable cells including neurons, cardiac cells and various types of smooth muscle cells. [Singer, J. et al., Pflugers Archiv. 1987, 408, 98; Baro, I., et al., Pflugers Archiv. 1989, 414 (Suppl. 1), S168; and Ahmed, F. et al., Br. J. Pharmacol. 1984, 83, 227].
Potassium ions play a dominant role in controlling the resting membrane potential in most excitable cells and maintain the transmembrane voltage near the K+ equilibrium potential (Ek) of about −90 milliVolts (mV). It has been shown that opening of potassium channels shift the cell membrane potential towards the Ek, resulting in hyperpolarization of the cell. [Cook, N. S., Trends in Pharmacol. Sciences 1988, 9, 21]. Hyperpolarized cells show a reduced response to potentially damaging depolarizing stimuli. Those BK channels which are regulated by both voltage and intracellular Ca2+ act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore cell hyperpolarization via opening of BK channels may result in protection of neuronal cells, as well as other types of cells, e.g., cardiac cells. [Xu, W., Liu, Y., Wang, S., McDonald, T., Van Eyk, J. E., Sidor, A., and O'Rourke, B. Cytoprotective Role of Ca2+-activated K+ Channels in the Cardiac Inner Mitochondrial Membrane. Science 2002, 298, 1029–1033].
BK channels have been shown to be one of two physiologically relevant potassium channels in relaxing human smooth muscle, including both intestinal and penile smooth muscle. Evidence that relaxation of smooth muscle is beneficial to irritible bowel syndrome and erectile dysfunction has been reported. See the following references: Christ, G. J. Drug News Perspect. 2000, 13, 28–36; Poynard T. et al. Alimentary Pharmacology and Therapeutics 2001, 15, 355–361; and Argentieri, T. M. U.S. patent application No. 2002/0183395.
A variety of synthetic and naturally occurring compounds with BK opening activity have been reported. 4-Aryl-3-hydroxyquinolin-2-one derivatives are disclosed in U.S. Pat. No. 5,892,045, issued Apr. 6, 1999; U.S. Pat. No. 5,922,735, issued Jul. 13, 1999; U.S. Pat. No. 6,353,119, issued Mar. 5, 2002. 4-Arylquinolin-2-one derivatives are disclosed in U.S. Pat. No. 6,184,231, published Feb. 6, 2001 and U.S. Pat. No. 5,972,961, published Oct. 26, 1999. See also Hewawasam, P. et. al. J. Med. Chem. 46 2819–2822 (2003). Other quinolinones are disclosed in U.S. Pat. No. 6,538,022; Japanese Pat. No. 2002371078; and PCT patent application WO 2002026713.
Despite advances in the art, further advances are needed for compounds capable of modulating potassium channels, in particular, large-conductance calcium-activated potassium channels. Such compounds would be useful in treating conditions arising from dysfunction of cellular membrane polarization and conductance.
This invention describes 3-thia-4-arylquinolin-2-one compounds having the general formula I or pharmaceutically acceptable salts or solvates thereof,
wherein R, R1, R2, R3, R4, R5 and R6 are as defined below.
The present invention also provides pharmaceutical compositions comprising these compounds and methods for the treatment of conditions responsive to potassium channel activity, such as ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction and urinary incontinence.
The present invention describes novel 3-thia-4-arylquinolin-2-one compounds and related derivatives of Formula (I) or pharmaceutically acceptable salts or solvates thereof
The present invention also provides a method for the treatment or alleviation of disorders associated with BK channels, such as ischemia, stroke, convulsions, epilepsy, asthma, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction, urinary incontinence and especially male erectile dysfunction and irritable bowel syndrome which comprises administering together with a conventional adjuvant, carrier or dilutent a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The term "alkyl" includes both straight and branched chain alkyl groups. "Fluoroalkyl" means alkyl groups bearing from 1 to 5 fluorine atoms. Some examples of fluoroalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and perfluoroethyl.
The term "atropisomer" refers to a stereoisomer resulting from restricted rotation about a single bond where the rotation barrier is high enough to permit isolation of the isomeric species.
The invention encompasses all stereoisomers and tautomers, including atropisomers. Examples of atropisomers and tautomers are shown below.
The terms "racemic mixture" and "racemate" refer to an equimolar or nearly equimolar mixture of two enantiomeric species. In addition, as used herein, the terms "racemic mixture" and "racemate" are intended to include equimolar mixtures of the two atropisomers.
The term "pharmaceutically acceptable salt" is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445. Suitable inorganic bases such as alkali and alkaline earth metal bases include metallic cations such as sodium, potassium, magnesium, calcium and the like. The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
The term "halogen" as used herein and in the claims is intended to include fluorine, bromine, chlorine and iodine while the term "halide" is intended to include fluoride, bromide, chloride and iodide anion.
The term "therapeutically effective amount" means the total amount of each active component that is sufficient to show a meaningful patient benefit, i.e., amelioration of acute conditions characterized by openers of large conductance calcium-activated K+ channels or increase in the rate of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
The term "compounds of the invention", and equivalent expressions, are meant to embrace compounds of Formula I and include prodrugs, pharmaceutically acceptable salts, and solvates, e.g. hydrates. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
The term "derivative" means a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for an amine.
The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, and the like.
The term "patient" includes both human and other mammals.
The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutical carrier, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Ingredients listed in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa. (1999) for example, may be used.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable risk/benefit ratio.
The term "pharmaceutically acceptable prodrugs" as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as zwitterionic forms, where possible, of the compounds of the invention.
The term "prodrugs", as the term is used herein, are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a patient. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (i.e., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the skilled artisan will appreciate that the present invention encompasses prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to form the parent compound. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a patient, it cleaves to form a free hydroxyl, free amino, or free sulfydryl group, respectively. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups can act as prodrugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p. 309–396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; "Design and Applications of Prodrugs" p. 113–191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p. 1–38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987.
One aspect of the invention are compounds of formula (I) where R is hydrogen.
Another aspect of the invention are compounds of formula (I) where R1 is hydrogen.
Another aspect of the invention are compounds of formula (I) where R2 is hydrogen, R3 is trifluoromethyl, and R4 is hydrogen.
Another aspect of the invention are compounds of formula (I) where R5 is chloro.
Some compounds of the invention include
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms including hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. The products may be true solvates, while in other cases, the products may merely retain adventitious solvent or be a mixture of solvate plus some adventitious solvent. It should be appreciated by those skilled in the art that solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of Formula I may be prepared by various procedures such as those illustrated herein in the examples and in the Reaction Schemes described in the specific embodiments and variations thereof which would be evident to those skilled in the art.
The following reaction schemes illustrate representative general procedures for the preparation of intermediates and methods for the preparation of compounds of Formula I according to this invention. It should also be evident to those skilled in the art that appropriate substitution of both the materials and methods disclosed herein will produce the examples illustrated below and those encompassed by the scope of this invention.
Reagents and conditions: (a) bromoacetyl bromide, pyridine, CH2Cl2, 0� C.; (b) NaH, p-nitrothiophenol, III, 0� C. to r.t.; (c) NaOMe, MeI, THF; (d) SnCl2, EtOH, reflux; (e) BBr3, CH2Cl2, −78� C. to r.t.
Reagents and conditions: (1) RSO2Cl, CH2Cl2, pyridine, r.t. or 80� C.
Openers of BK channels exert their cellular effects by increasing the open probability of these channels [Gribkoff, V. K., et al., Neuroscientist, 7:166–177 (2001); Gribkoff, V. K. et al., Adv. Pharmacol., 37:319–348 (1997); McKay, M. C., et al., J. Neurophysiol., 71: 1873–1882 (1994); and Olesen, S.-P., Exp. Opin. Invest. Drugs, 3: 1181–1188 (1994)]. This increase in the opening of individual BK channels collectively results in the hyperpolarization of cell membranes, particularly in depolarized cells, produced by significant increases in whole-cell BK-mediated conductance. Hyperpolarization, in turn, reduces the excitability of nerve and muscle cells, and decreases the open probability of voltage-dependent Ca2+ channels, effectively lowering intracellular concentrations of this potentially harmful cation. The effect on smooth muscle is that of relaxation.
The ability of the compounds of the invention to open BK channels and increase whole-cell outward (K+) BK-mediated currents was assessed under voltage-clamp conditions by determining their ability to increase cloned mammalian (mSlo or hSlo) BK-mediated outward current heterologously expressed in Xenopus oocytes [Butler, A., et al., Science 1993, 261, 221–224; Dworetzky, S. I., et al., Mol. Brain Res. 1994, 27, 189–193; Gribkoff, V. K., et al., Mol. Pharmacol. 1996, 50, 206–217]. The two BK constructs employed represent nearly structurally identical homologous proteins, and have proven to be pharmacologically indistinguishable in our tests. To isolate BK current from native (background, non-BK) current, the specific and potent BK channel-blocking toxin iberiotoxin (IBTX) [Galvez, A., et al., J. Biol. Chem. 1990, 265, 11083–11090] was employed at a supramaximal concentration, e.g., 50–100 nanomolar ("nM"). The relative contribution of BK channel-mediated current to total outward current was determined by subtraction of the current remaining in the presence of IBTX (non-BK current) from the current profiles obtained in all other experimental conditions (control, drug, and wash) [Gribkoff, V. K. et al., Mol. Pharmacol. 1996, 50, 206–217]. It was determined that at the tested concentrations the compounds profiled did not significantly effect non-BK native currents in the oocytes. All compounds were tested in 5–10 oocytes and are reported at the indicated concentration of 20 micromolar ("μM") (or as otherwise indicated); the effect of the selected compounds of the invention on BK current was expressed as the percent of control IBTX-sensitive current at a single transmembrane voltage (+140 mV) and is listed in Table 1. Recordings were accomplished using standard two-electrode voltage clamp techniques [Stuhmer, W., et al., Methods in Enzymology, 1992, 207, 319–339]; voltage-clamp protocols consisted of 500–750 milliseconds ("ms") duration step depolarizations, from a holding potential of −60 mV, to a final voltage up to +140 mV in 20 mV steps. The experimental media (modified Barth's solution) consisted of millimolar ("mM"): NaCl (88), NaHCO3 (2.4), KCl (1.0), HEPES (10), MgSO4 (0.82), Ca(NO3)2 (0.33), CaCl2 (0.41); pH 7.5.
The ability of the compounds of the invention to relax rat small intestine tissue as a model for the treatment of irritable bowel syndrome is described as follows. Male rats (Harlan, Sprague Dawley, 250–350 g) were sacrificed by decapitation. A portion of small intestine (ileum) was removed and the attached connective tissues and intestinal contents removed. The ileum was cut into segments of ≦1 cm in length. The segments were mounted longitudinally between fixed hooks in organ baths containing warm (37� C.) physiological salt solution (composition in mM: NaCl 118.4, KCl 4.7, KH2PO4 1.2, MgSO4 1.2, CaCl2 1.8, Glucose 10.1, NaHCO3 25; gassed with 95% O2/5% CO2, pH 7.4). A stable tension of ˜1.5 g was maintained in the tissue segments during the equilibration period of 45 minutes. Changes in muscle tension were measured with isometric force transducers (Grass, FT-03C) and recorded using AcqKnowledge data acquisition system (AcqKnowledge for MP100WS, Biopac Systems Inc., Goleta, Calif.). Compound or vehicle was added in the baths for 30 minutes. "Zero" active force was established at the end of the experiment using nifedipine (20 μM). The effects of compounds or vehicle on force was determined by measuring the integral of nifedipine-sensitive force (including resting tone and spontaneous contractions) pre- and 30 min post-compound (or vehicle) addition. Results are expressed as the percentage inhibition of force. DMSO vehicle inhibited force (integral) by −0.6�3.0% (n=25). Results are summarized in Table 1.
The ability of the compounds of the invention to relax rabbit corpus cavernosum tissue as a model for the treatment of erectile dysfunction is described as follows. New Zealand white rabbits (3.4–3.7 kg) were euthanized by sodium pentobarbital (100 mg/kg) overdose. The penis from each animal was rapidly removed and immersed in a cold oxygenated modified Krebs Henseleit bicarbonate buffer. The penis' outer tunica was removed and the corpus cavernosum smooth muscle obtained and cut into strips approximately 3–5 mm long. The strips were suspended in tissue baths containing physiological salt solution (see above), and allowed to equilibrate for at least one hour under resting tension of 1.0 gram. Isometric force was measured as described above. Tissue strips were stimulated with the (x-agonist phenylephrine (3 μM) and allowed to reach a steady level of force prior to the addition of test compounds. The results are expressed as the percentage inhibition of phenylephrine-induced force as compared to vehicle control. Results are summarized in Table 1.
of force
of force
*at 20 μM (unless otherwise indicated) expressed as percent increase over BK current in controls, voltage step to +140 mV
⋄at 1 μM.
The results of the above biological tests demonstrate that the compounds of the invention are potent openers of large-conductance calcium-activated K+ channels (BK or Maxi-K channels) and are effective at relaxing intestinal and penile smooth muscle.
The compounds of the present invention are useful for the treatment of patients for conditions arising from dysfunction of cellular membrane polarization and conductance and are indicated for the treatment of ischemia, stroke, convulsions, epilepsy, asthma, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction, urinary incontinence and especially male erectile dysfunction and irritable bowel syndrome, as well as other disorders sensitive to BK channel activity. Accordingly, in one aspect of the present invention, there is provided a method of treatment or prevention of conditions responsive to opening of potassium channels in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. In another aspect, this invention provides a method for the treatment of or protection from disorders which are mediated by opening of the large conductance calcium-activated K+ channels in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. Preferably, the compounds of Formula I are useful in the treatment of ischemia, stroke, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, urinary incontinence, irritable bowel syndrome, and sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, psychogenic etiology or any other cause) and women by improving blood flow to the genitalia, especially the corpus cavernosum, and other disorders sensitive to BK channel activating activity.
In another aspect, this invention provides pharmaceutical compositions comprising at least one compound of Formula I and a carrier.
The pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I directly in parenteral formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention.
The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that the unit dosage form would be adjusted accordingly by one skilled in the art to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
A suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.01 micrograms per kilogram (μg/kg) to 50 milligrams per kilogram (mg/kg) body weight and preferrably, from about 0.1 μg/kg to 5 mg/kg body weight for oral administration. For parenteral administration, the dose may be in the range of 0.1 μg/kg to 1 mg/kg body weight for intravenous administration. The active ingredient will preferably be administered in equal doses from one to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
The compounds of the present invention may be employed alone or in combination with other suitable therapeutic agents useful in the treatment of the dysfunction of cellular membrane polarization and conductance, e.g., sexual dysfunction such as cyclic guamine monophosphate, phosphodiaterase (cGMP PDE) inhibitors and particularly cGMP PDE V inhibitors such as sildenafil. Exemplary of the therapeutic agents are PDE V inhibitors selected from imidazo-quinazolines (see WO 98/08848), carbazoles (see WO 97/03675, WO 97/03985 and WO 95/19978), imidazopurinones (see WO 97/19947), benzimidazoles (see WO 97/24334), pyrazoloquinolines (see U.S. Pat. No. 5,488,055), anthranilic acid derivatives (see WO 95/18097), fused heterocycles (see WO 98/07430) and thienopyrimidines (see DE 19632423). Alosetron hydrochloride can be combined with the compounds of the present invention to treat irritable bowel syndrome (see, e.g., U.S. Pat. Nos. 5,360,800 and 6,284,770).
The amount of compound actually administered will be determined by a physician using sound medical judgement.
The following examples are given by way of illustration and are not to be construed as limiting the scope of the claims which follow.
In the following examples, all temperatures are given in degrees Centigrade. Melting points were recorded on a Gallenkamp capillary melting point apparatus are uncorrected. Proton magnetic resonance (1H NMR) spectra were recorded on a Bruker AC 300 or 500 megaHertz ("MHz") spectrometer. All spectra were determined in the solvents indicated and chemical shifts are reported in δ units downfield from the internal standard tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz (Hz). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublet; bd, broad doublet; dt, doublet of triplet; bs, broad singlet; dq, doublet of quartet. Infrared (IR) spectra using potassium bromide (KBr) were determined on a Perkin Elmer 781 spectrometer from 4000 cm−1 to 400 cm−1, calibrated to 1601 cm−1 absorption of a polystyrene film and reported in reciprocal centimeters (cm−1). Low resolution mass spectra (MS) and the apparent molecular weight (MH+) or (M−H)− was determined on a Finnigan TSQ 7000. LC-MS analysis were carried out on a Shimadzu instrument using one of the following methods (1) YMC ODS C18 column (4.6�33 mm) employing a 4 min linear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B (2) YMC ODS C18 column (4.6�30 mm) employing a 2 min linear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B (3) YMC ODS C18 column (3.0�50 mm) employing a 2 min linear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B (4) YMC ODS. C18 column (3.0�50 mm) employing a 4 min linear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B. In all cases solvent A: 10% methanol, 90% water, 0.1% TFA; and solvent B: 90% methanol, 10% water, 0.1% TFA with UV detector set at 220 nm. The element analyses are reported as percent by weight. Unless otherwise indicated in the Specific Embodiments, R2 and R4 are H in the descriptive title of the Examples.
2-Bromo-N-[2-(5-chloro-2-methoxy-benzoyl)-4-trifluoromethyl-phenyl]-acetamide. To a solution of (2-Amino-5-trifluoromethyl-phenyl)-(5-chloro-2-methoxy-phenyl)-methanone (IV) (14.13 g, 42.9 mmol, 1 eq) in Dichloromethane (120 mL) at 0� C. was added pyridine (4.65 mL, 57.5 mmol, 1.34 eq), then Bromoacetyl bromide (4.98 mL, 57.2 mmol, 1.33 eq). After 3 h, the reaction was quenched with Sodium bicarbonate (aq) and extracted three times into Dichloromethane. The combined organic layers were dried over Magnesium sulfate, filtered and concentrated in vacuo. The product was used without further purification.
1H NMR (300 MHz, CDCl3) δ 12.18 (s, 1H), 8.88 (d, J=8.9 Hz, 1H), 7.82 (dd, J=1.9, 8.9 Hz, 1H), 7.71 (d, J=1.9 Hz, 1H), 7.51 (dd, J=2.6, 8.9 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 4.08 (s, 2H), 3.70 (s, 3H).
4-(5-Chloro-2-methoxy-phenyl)-3-(4-nitro-phenylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one. To a solution of 4-nitrothiophenol (8.73 g, 56.3 mmol, 2.5 eq) in THF (140 mL) at 0� C. was added Sodium hydride (2.26 g, 60% dispersion in mineral oil, 56.5 mmol, 2.5 eq). After stirring for 15 min, a solution of III (10.15 g, 22.5 mmol, 1 eq) in THF (50 mL) was added rapidly dropwise to the blood-red solution. After 5 min, the ice bath was removed, and the solution stirred for 3 h at room temperature. The reaction was quenched with 1 M HCl, and extracted three times into EtOAC. The combined organic layers were dried over Magnesium sulfate, filtered, and concentrated in vacuo. Chromatography (2:1, 1:1 Hexane:EtOAc) provided pure II in quantitative yield.
1H NMR (300 MHz, CDCl3) δ 12.64 (s, 1H), 8.06 (d, J=8.9 Hz, 2H), 7.68 (d, J=7.1 Hz, 1H), 7.47 (dd, J=2.6, 8.9 Hz, 1H), 7.38–7.31 (m, 4H), 7.12 (d, J=2.6 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 3.64 (s, 3H).
4-(5-Chloro-2-methoxy-phenyl)-1-methyl-3-(4-nitro-phenylsulfanyl)-1H-quinolin-2-one. To a suspension of NaOMe (64 mg, 1.2 mmol) in THF (10 mL) was added II (R1=H) (500 mg, 0.99 mmol). The mixture was stirred for 0.5 h at room temperature, at which time methyl iodide (760 μL, 12 mmol) was added. After 18 h, the mixture was concentrated in vacuo. Brine and ethyl acetate were added, and the mixture extracted three times with ethyl acetate. The organic extracts were dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography to provide pure II (R1=Me), (350.4 mg, 68% yield).
3-[(4-Aminophenyl)thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone. To a solution of II (2.07 g, 4.09 mmol, 1 eq) in EtOH (21. mL) was added SnCl2 (4.56 g, 24.0 mmol, 5.9 eq), and the resulting suspension heated to reflux for 3 h. After cooling to room temperature, the mixture was added to ice, and Sodium bicarbonate was added. The mixture was filtered, extracted to EtOAc, and dried over Magnesium sulfate. Concentration in vacuo followed by recrystallization in EtOAc/Hexane provided Ia (1.28 g, 66%).
3-[(4-Aminophenyl)thio]-4-(5-chloro-2-hydroxyphenyl)-1-methyl-6-(trifluoromethyl)-2(1H)-quinolinone. To a solution of Ia (R=Me) (509 mg, 1.07 mmol, 1 eq) in methylene chloride (30 mL) at −78� C. was added a 1M solution of boron tribromide in methylene chloride (6 mL, 6 mmol, 5.6 eq). The solution was brought to room temperature and stirred for 60 h. The solution was cooled to −78� C. and quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo. Silica gel chromatography (ethyl acetate, then methanol/methylene chloride) provided the desired material Ia (R=H).
N-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]phenyl]ethanesulfonamide. To a solution of 3-(4-Amino-phenylsulfanyl)-4-(5-chloro-2-methoxy-phenyl)-6-trifluoromethyl-1H-quinolin-2-one or 3-(4-Amino-phenylsulfanyl)-4-(5-chloro-2-hydroxy-phenyl)-6-trifluoromethyl-1H-quinolin-2-one (49.0 mg, 103 μmol, 1 eq) in pyridine (50 μL) and methylene chloride (500 μL) was added the appropriate sulfonyl chloride (422 μmol, 4.1 eq), and the mixture stirred overnight at room temperature, or at 80� C. in the absense of methylene chloride for difficult cases. The pyridine was removed in vacuo, and 4 N NaOH was added. The suspension was diluted with water, washed with chloroform, and adjusted to pH 5 with 1 M HCl. The product was extracted into a mixture of EtOAc and methylene chloride, dried with Magnesium sulfate, and concentrated in vacuo. Final purification was effected by reverse phase HPLC to afford pure Ib. 1H NMR (300 MHz, CDCl3) δ 11.04 (s, 1H), 8.90 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.43 (s, 1H), 7.40–7.30 (m, 2H), 7.30–7.24 (m, 3H), 7.11 (d, J=2.5 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 2.99 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.4 Hz, 3H); LCMS (M+H) 555, RT=3.177 (Method 1).
Examples 4–10 were prepared by similar methods.
** (1) YMC ODS C18 column (4.6 � 33 mm) employing a 4 min linear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B (2) YMC ODS C18 column(4.6 � 30 mm) employing a 2 min linear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B (3) YMC ODS C18 column (3.0 � 50 mm) employing a 2 minlinear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B (4) YMC ODS C18 column (3.0 � 50 mm) employing a 4 min linear gradient of 0% to 100% solventB in A and a 1 min hold at 100% B. In all cases solvent A: 10% methanol, 90% water, 0.1% TFA; and solvent B: 90% methanol, 10% water, 0.1% TFA with UV detector set at 220 nm.
Although the invention has been described with respect to specific aspects, those skilled in the art will recognize that other aspects are intended to be included within the scope of the claims which follow. Other substituents substantially equivalent to the specific substituents described herein, e.g., R, R1, R2, R3, R4, R5, can be employed within the scope of the invention.
|Cited Patent
|Filing date
|Publication date
|Nov 18, 1997
|Apr 6, 1999
|Bristol-Myers Squibb Company
|4-aryl-3-hydroxyquinolin-2-one derivatives as ion channel modulators
|Oct 5, 1998
|Jul 13, 1999
|Bristol-Myers Squibb Company
|4-aryl-3-hydroxyquinolin-2-one derivatives as ion channel modulators
|Aug 24, 1998
|Oct 26, 1999
|Bristol-Myers Squibb Company
|4-aryl-3-aminoquinoline-2-one derivatives as potassium channel modulators
|Dec 1, 1999
|Feb 6, 2001
|Bristol-Myers Squibb
|3-substituted-4-arylquinolin-2-one derivatives as potassium channel modulators
|Nov 28, 2000
|Mar 5, 2002
|Bristol-Myers Squibb Company
|Preparation of 3-substituted-4-arylquinolin-2-one derivatives
|Feb 18, 1999
|Mar 25, 2003
|Orion Corporation
|Compounds for deactivating phospholamban function on Ca-ATPase (phopholamban inhibitors)
|Title not available
|Sep 28, 2001
|Apr 4, 2002
|King's College London
|Antiparasitic compounds
|Boy, Bioorganic & Medicinal Chemistry Letters, 14, pp. 5089-5093, 2004.
|U.S. Classification
|546/153, 546/157
|International Classification
|Cooperative Classification
|European Classification
|Nov 9, 2004
Owner name: BRISTOL-MYERS SQUIBB COMPANY, NEW JERSEY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BOY, KENNETH M.;REEL/FRAME:015357/0229
Effective date: 20041108
|May 7, 2010
|Fee payment
Year of fee payment: 4
|May 7, 2014
|Fee payment
Year of fee payment: 8


text:
Cosplay Cafe
There`s a coffee shop that attracts a lot of customers, but not because of the coffe, but because of the waitresses who are all married women wearing outfits that normal waitresses wouldn`t wear. But the story focuses more on the love life of Asahina Tomoya who`s the temporary owner of…
Futari no Tobari 3D
Our first 3D release is here and it's on a show titled "Our curtain". Not sure how this will go if people do like 3D enough, but it was requested way back so lets see how this goes, it could be fun. Have fun watching!
Hime-sama Gentei!
This is the first title by Princess Sugar. Celina is the princess of the prosperous western European country of Mellberg and came to Japan to study at a normal school while concealing her true identity. Since she is a distant relative to Yuu, she ends up living in his house….
Based on the adult game by Lune.
Natsuno Himegoto 3D
Someone requested this and I found the quality of the 3D to be amazing so we just had to do it. I know we've got a lot of request's we need to work on, no worries, we will. Have fun watching!
Onisaku Core Mix
From revenge rapey to punishment rapey, we're on a roll here. I wonder what will be next. But this is quite some old skull H here. I hope you enjoy it.
Taimanin Yukikaze
Yukikaze, a student at a ninja training academy, learns new demon-fighting techniques. One day, she and her friend Akiyama Rinko decide to infiltrate an evil organization in hopes of finding Yukikaze's mother; however, to do so, there is a great price they have to pay…


text:
Home ›
Caxias-do-sul Champagne Gifts
30 items found
You can send Champagne Gifts to Brazil in the following locations.
What our Customers Say about our Service
"I am extremely happy ! The order I placed was delivered today to my family in Tuscany ! This was the first time I dealt with Giftbasketoverseas.com so I was a little reluctant, but very hopeful it will work. They delivered it promptly, just as requested, today, at the right address of my brother's house. I think they were too thrilled about it and decided to check it later so they did not notice my card, I will check again with them tomorrow, for it's got its rightful place: under the Christmas tree along with the rest of the gifts ! :)
Mara B. - Canada - Dec 23, 2014
"Thank you for doing such fine work! I appreciate what you have done. It allowed me to send my love and aloha to my beloved friend more than half way across the world. She was very surprised and happy to receive her special favorite flower, white roses, in perfect condition. Thank you for making that possible !!!"
Fred G - Hawaii, USA - Sep 1, 2015
"Thank you for the wonderful service you provided in sending the flower gift basket that I ordered. Not only did the flowers arrive at the time requested, but I also learned that they were absolutely Gorgeous."
Shirley B. - Shreveport LA, USA - May 9, 2009
"I would like to thank you for the gift that surprisingly over-shocked my fiancee when he came into his room, it was already there... he was even so boastful taking picture and sending it to me thinking it was from the hotel like a giveaways since Chinese new year was just over, and a told him to go over if there was a note... he was even more shocked when he saw the line 'Hi babe' and made him curios how could it be from the hotel? Later he just knew, it was from me..so cute and I'm really happy he was so surprised and really making his day even when I am away ;)..thanks gift baskets overseas, thanks for making our valentines day & our upcoming 2nd yr anniversary possible for us... it was really great indeed.. Warm greetings, Elvira"
Elvira G - Qatar - Feb 15, 2013
See other testimonials or leave your feedback here.


text:
|Brand :
The mask containing ginseng can effectively offer your skin with elasticity to make your face smooth. In addition, the product can also provide rich nutrition and moisture to your skin to help you get healthy and silky skin. More importantly, the mask containing snail extract's chondroitin with mucin has an effect on making your skin soft and vital.
Size: 25 g
How to use:
- Apply toner to your face after cleaning
- Apply the mask to the entire face evenly, avoiding your eyes and lips
- Remove the mask after 10-20 minutes and gently pat your face to absorb the rest of the serum into skin.
Special Note:
- Do not use the product around your eyes and lips
- Avoid applying it on wounds or the inflammatory skin
- Avoid extremely high or low temperature and direct sunlight
- Keep it out of the reach of children.


text:
Hales Corners Historical Society
5885 South 116th Street, Hales Corners, Wisconsin 53130
Current Events
Your Calendar: June 24th Fundraiser!
Is there anything more fun in summer than the smell and taste of grilled brats, hot dogs, and all the fixings -- especially when they raise funds for the Historical Society? Society members will be grilling and serving at the Hales Corners Pick 'n Save (located at 5800 S. 108th Street) on Saturday, June 24, 2017 from 9:00 a.m. to 2:00 p.m.
Please make a point to stop by and satisfy your craving for summertime fare. Seneca and William Hale will be there, too; they say they'll offer their support in the "wurst" way.
News! Historical Society newsletters are now available on our
website. Click here for the
2017 Historical Society Programs
Programs are held in the Ben Hunt room on the lower level of the Hales Corners Library (5885 S. 116th Street in Hales Corners). They are free and open to the public. All are welcome. Please join us!
|Wednesday, August 2,
7:00 p.m. Milwaukee: City of
Presented by Ben Barbera, Curator, Milwaukee County Historical Society.
While most people now think of the festivals held at Henry Maier Festival Park, the origins of the city's passion for festivals goes back to the mid-19th century—from the earliest Sangerfests and Turnfest to the major festivals of today. An ice cream social will follow the presentation.
|Wednesday, October
4, 7:00 p.m.
The History of the Bosch Tavern
Presented by Al Strekow, President, Hales Corners Historical Society.
The Bosch Hotel and Tavern has been a fixture at the corner of Hwy. 100 and Janesville Rd. since 1904. Come hear about the number of names and owners it has had through those years, and how it has survived while other businesses all around it have disappeared. Refreshments will follow the presentation.
2017 Open House at the Ben Hunt Cabin and Hale Summer Kitchen
The Hunt Cabin is open from 1-3 p.m. on the first Saturday of the month from May through November, except in July the open house is on July 4th from noon to 3 p.m. Additionally, the Hunt Cabin is open in December during the Village of Hales Corners tree lighting event from 5:30 to 7 p.m. The Hale Summer Kitchen will be open July 4th from noon to 3 p.m.
Would you like to be a Guide at the Hunt Cabin?
Volunteer guides are needed at the W. Ben Hunt Cabin. Guides help at the open houses on the first Saturday of the month from 1-3 pm, and help with tours throughout the year. Being a guide is a GREAT way to learn more about Ben Hunt and the artifacts in the cabin. If you can help, please contact the guide coordinator at (262) 349-4208 (e-mail).
Hales Corners Wisconsin a History of the Village Since 1837
A publication of the Hales Corners Historical Society, January 2015. 340 pages with over 475 photos, illustrations and maps. Soft cover. Learn about the entertaining history of Hales Corners from its frontier roots in 1837 to the community it is today. To enlarge the image, click on it (jpg file).
The book is available at the Hales Corners Library, 5885 S. 116th St. in Hales Corners. The price is $25.00 ($20.00 for current members of the Historical Society go to Membership ).
Mail orders: the shipping charge for mail orders is $6.00 (go to Publications for order form).
|Summer Kitchen
|Farm & Village
|Ben Hunt Cabin
|Current Events
|Historical Links


text:
Did last winter's unusual froideur lead to more amour in the bedroom? There has been speculation that the savagely cold temperatures of earlier this year are going to result in a mini baby boom this autumn.
The evidence is, admittedly, rather threadbare. Apparently, Portsmouth midwives are preparing for an infant surge after conducting an unusually large number of 12-week scans this spring. And Marks & Spencer's sales of maternity clothes are up.
Births normally peak in September anyway (and not just in Britain but across the Christian world). But will the cold exacerbate the trend, making this an especially fecund year? We shall simply have to wait and see. But let's hope not, though. After all, we are having enough trouble dealing with the social, financial, demographic and psychological consequences of the last baby boom.
- More about:
- Children
- Christian Monastery
- Marks & Spencer
- Pregnancy


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CANADA: Beef fat does not raise blood cholesterol levels
Beef fat does not raise blood cholesterol levels, according to a study produced by Canada's Department of Agricultural, Food and Nutritional Science (DAFN). Presenting the study's findings at a conference in the Canadian Institute of Food Science and Technology , chemical technologist Margaret French: "There's a strong public perception that beef raises blood cholesterol levels because some of [its] fatty acids are saturated [but] with this, and earlier studies, we have scientifically tested this hypothesis.
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With Instructables you can share what you make with the world, and tap into an ever-growing community of creative experts.
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text:
|Reviews for Sly Smiles and Stuttering Hints
| Ema chapter 1 . 11/30/2013
This is like a sequel to Vanila Twilight huh. I loved it awsome idea and the way you wrote it is simply impecable. Lol im getting all fancy. To say the least, I realy liked it. So more like it. :)
| TheFifthCharmedOne chapter 1 . 7/15/2013
Very cute! :)
| LionDreamerAKAfan chapter 1 . 9/14/2012
i'll be ur friend, i like having new buddies to talk to :D
| BlatantBookworm chapter 1 . 5/13/2012
You can NEVER have too much fluff! Adorable!
| LunarFay chapter 1 . 8/21/2011
that was very cute!
you are one of the few writers I've seen that remembered that raven has to keep her powers in check
& if you have written/write a chapter fanfic on the paring that would be awesome~!
| black rose-raven angel chapter 1 . 8/13/2011
Who knew Raven had a playful side? _ Aww... I wanna be Raven at this moment... (one of bb's many fangirls) Tee hee! Love it!
| Evil.VS.Waffles chapter 1 . 8/11/2011
Again, epic. I loved it. I personally think that it's supposed to be rated "T" for teen, but I'm also very strict about that. :) I so will have to read your other fics!
| teentitangirl25 chapter 1 . 8/10/2011
i loved it!
| Guest chapter 1 . 8/9/2011
Awww a veeery cute and adorable ending! i wonder how was BeastBoy's drawing, and how Raven drew so fast.
great job, just they were a lityle OOC you know Raven wouldn't let him kiss her twice that fast but uh yeah well done :D
| crazynerd chapter 1 . 8/9/2011
Super cute. I love fluff.
| stormygirl335 chapter 1 . 8/9/2011
Aww! it was awsome! loved it! i really think your storys are amazing, and i love the charicters, they wernt oc :D
| LoversForeverTogether chapter 1 . 8/9/2011
I love the fluff! It's what makes the world go round! :D
| sinomin chapter 1 . 8/9/2011
Aww, cute! I love BBRae:) Great fic! It was very well written, and in my opinion they stayed in character for the majority of the story. The only thing I didn't think was very clear was if Raven wrote the "Catch me if you can" message, or if that's what Beast Boy wrote. Other than that, it was awesome! keep on writing:D
| nightstar99 chapter 1 . 8/9/2011
Aaaawww, such a cute one-shot. I like the way you portrayed Beastboy as nervous and frantic about telling Raven.
Have a nice day!


text:
DJR Architects
333 Washington Ave N Ste 210 Minneapolis, MN 55401-1353
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New York • The stock market was closing slightly lower led by declines in phone companies, banks and health care providers.
Verizon slumped 2.3 percent Friday, while Bank of America lost 1.6 percent.
In earnings news, Mattel nosedived 13.6 percent after the struggling toy maker reported a big drop in sales.
As of 2 p.m. Mountain time, the Standard & Poor's 500 index hads fallen 7 points, or 0.3 percent, to 2,348.
The Dow Jones industrial average slipped 30 points, or 0.2 percent, to 20,547. The Nasdaq composite gave up 6 points, or 0.1 percent, to close at 5,910.


text:
I'm back after Christmas with another skincare post but this time it's a little bit different because it's about a product range that's completely new to me. The Daily Care Bundle* by the Korean skincare brand IASO includes definitely one of the most intriguing products I've personally come across & it turns out it's also one of the brand's bestsellers! But let me tell you more about the company IASO.
The IASO brand began back in 2001 to address skincare needs based on the research and expertise of leading dermatologists.With their luxurious ingredients and evolved technologies, IASO wants to deliver youthful glow and timeless beauty to skin. IASO is domestically expanding both online and offline nationwide. The brand has been clearly becoming a global brand, starting with expansion of its market into New Zealand, China, Vietnam, USA, Singapore and Indonesia. + IASO has never – nor will it ever – test its products on animals!
The Daily Care Bundle set includes the Ghassoul Black Cleansing Oil*, the Purifying Emulsion* and the Purifying Toner*. As my skin is oily to combination, this set is a good option for my skin. You can get the whole set for $106 which is totally fine as you get a lot of the product within the set (Purifying Toner & Emulsion are each 180 ml).
I use the Purifying Toner in the morning and before I go to bed on my face. It's super refreshing (especially in the morning and in summer!), lightweight and not sticky. The texture of the serum is clear and liquid, it's really easy to apply. It feels a little like water on your face. If you read my October favorites you know that I already mentioned this toner as a BIG LOVE (:
The toner contains botanical extracts (picture below) but also Alcohol which is really not necessary ...
180 ml - $39 USD
★★★★★★ 6/5 (:
The Purifying Emulsion can be used day or night. I prefer applying it in the morning as the consistency is milky gel-like and for the night I love a rich cream. The emulsion moisturizes pretty good, works amazing as a foundation base but is a little to light for the cold winter. It really hydrates my skin without the feeling of applying a heavy cream.
Did you know? Oily skin needs moisture just as much as dry skin. Oil is not moisture and oily skin does not make the skin smooth. Oily skin can also be sensitive. That's why IASO recommends using water-based moisturizers on your oily skin.
The botanical extracts in this emulsion are derived from Shiso or Aloe Vera gel:
180 ml -$42 USD
★★★★ 4/5
Toner and Emulsion feel quite luxurious on my skin. Also the packaging looks really elegant. I can definitely recommend trying IASO skincare products.
You can use the coupon code ARTDICTED to get a discount of 15% when you're making a purchase on their website www.go-iaso.com!
You can use the coupon code ARTDICTED to get a discount of 15% when you're making a purchase on their website www.go-iaso.com!
I hope you're looking forward to read my thoughts on their Ghassoul Black Cleansing Oil!
*PR sample


text:
Horse Greeley, winner of the 2006 Del Mar Futurity (gr. II), is preparing for a return to the races and could start in the Malibu Stakes (gr. I) on Dec. 26, opening day of the Santa Anita meeting.
"He's doing really well," trainer Richard Mandella said on Nov. 24 at Hollywood Park. "He could possibly return around Christmas, either at the end of the Hollywood meet or the first of Santa Anita."
Mandella mentioned the seven-furlong Malibu as a possibility, though he added "it's too early to say" whether Horse Greeley will be ready in time.
Horse Greeley broke his maiden in his second start and then captured the seven-furlong Del Mar Futurity. Following a seventh in the Norfolk Breeders' Cup Stakes (gr. II), he underwent surgery to remove a bone chip in his left ankle. He returned on May 6 at Hollywood Park, finishing fourth in an allowance race, but strained a ligament. Mandella gave Horse Greeley more time off, with his current work pattern beginning in late October.
Ray and Martha Parfet own and bred the 3-year-old son of Mister Greeley--Chili Chatte, by Storm Cat.
In an unrelated note, Mandella says that the popular The Tin Man is doing well while recovering from a knee injury and that they have had him out of his Santa Anita stall walking a little the last couple of days.
The 9-year-old The Tin Man fractured his right knee coming out of surgery Oct. 25. The Affirmed gelding had undergone a bone scan and exploratory surgery of his left front ankle when he broke the intermediate carpal bone coming out of the anesthesia.
The four-time grade I winner has been retired.
Malibu Possible for Horse Greeley
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this was the 2nd time that I have stayed at the Shangri-la Bangkok, in a deluxe balcony room. i love the hotel, the service is impeccable and it is a great area to stay. close to the bts, exciting street life, great silver shops and other shops selling excellent stainless steel products. took a two hour day boat trip of the canals, the site being very near to the Shangri-la. great massage places, tailors, luggage shops and much much more.
- Official Description (provided by the hotel):
- The Shangri-La Hotel, Bangkok, is a 5-star luxury hotel in Silom district, Bangkok. The design and appointments express the welcoming warmth and richness of Thai culture throughout the hotel, from traditional teak dining pavilions to the most up-to-date room features.The hotel has a total of 802 rooms including 72 suites in two wings, Shangri-La and Krungthep, and is adjacent to the Saphan Taksin station of the Skytrain, Bangkok's elevated metro system.The hotel also offers fully-serviced apartments for guests wishing a longer stay. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Booking.com, Expedia, Southall Travel, Hotels.com, Agoda, Ctrip TA, Odigeo, Ebookers, Nozio Netplan srl, Priceline, Shangri-La Hotels and Resorts, TravelUp, Travelbag, TripOnline SA, Traveltool, S.L.U., HotelsClick, HRS, Evoline ltd, getaroom.com and HotelQuickly so you can book your Shangri-La Hotel,Bangkok reservations with confidence. We help millions of travellers each month to find the perfect hotel for both holiday and business trips, always with the best discounts and special offers.
- Also Known As:
- Shangri-La Hotel, Bangkok Hotel Bangkok
- Shangri La Bangkok


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Donations will be accepted Friday until 11 a.m. for the 13th annual Community Clothing Exchange.
Organizers will set out all clothing by size on different tables in the gym. All sizes of clothing are needed, all they ask is that they are recently cleaned.
Fall/winter clothing is especially needed, but spring/summer clothing will be gladly appreciated as well.
The exchange will held from 9 a.m.-noon Saturday, Oct. 13. Donations will also be accepted that day until 11 a.m.
"If you are in need of clothing, we are asking that you please come and take what has been donated," organizer Anna Parks said. "You can leave clothing that your children have outgrown and get something that will fit now. Winter coats are always great items to exchange. All clothing left over at the end of the day will be donated to a community organization in need of the specific sizes and types of clothing that are left."
To help, or volunteer, call Parks at 532-3995, Shae Caldwell at 539-6323 or Shelly Stiffler at 650-2028.
Flatrock Publishing, Inc.
1300 E 4th St., Suite F
North Platte, NE 69101


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I like the little rectangles. I'm not sure at this point if I will further embellish them or not. I would also like to add some red or orange or hot color to the whole composition. One idea is to hand stitch a long basting (kantha) stitch through the background.
Lots of yellow and blue greens; interesting how the texture shows differently on the various fabrics.


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Atlanta is a big city and should you be buying good piano lessons, either for yourself or even for your youngster, then you will have a tough time making up your mind about the class. However, when you bear in mind certain things about what good Atlanta piano lessons should include, then you will be capable of restrict your quest.
First, check out classes in your area. Atlanta is definitely the third-largest city in the United States and the most populated city in the country. Considering the classical music scene of this city is rich and vibrant, with all the Atlanta Symphony Orchestra, the Atlanta Opera, Atlanta Ballet and a lot of other cultural organizations, you will have a good amount of potential for anyone to show off their piano playing skills once ready.
The Atlanta Area Suzuki Piano Association (AASPA) can be quite a good organization that are able to provide you with good information on Piano Classes Atlanta. You can also think about joining this group simply because they provide good resources, workshops as well as allow members to participate in recitals. Using a good support group with teachers and students is vital since learning to play the piano can be hard.
Permanently piano lessons in Atlanta, another organization to talk about will be the Atlanta Music Teachers Association (AMTA). In reality, some individuals this organization have been instrumental in founding several chamber music groups including the Inman Piano Trio. They have also founded the Atlanta MusicFest to give music students an opportunity to perform live. Also you can contact the Chopin Society of Atlanta to discover good piano lessons.
Atlanta piano lessons that utilize the Alfred method use visuals and graphics to train the youngsters keys and in addition relies heavily on position playing as opposed to teaching the children how you can play in the piano by reading piano music notes. Eventually, children would find this a handicap since many competitions and recitals use notes as reference for playing. This is basically the primary reason this technique is not really use too much.
If you find Atlanta piano lessons offering courses that may have your child playing the piano 'like a pro' quickly in any way, it will be good never to patronize such classes! They are gimmicks as no one can learn to play the piano overnight or in some weeks. To start with, just finding out how to browse the notes is going to take many months of reading, practicing and learning. There is each of the theoretical information one should experience, following which the practicals would include actually sitting on and playing the piano.