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Well, I've hit a rough patch :P I started off the week rough and I was like, "Oh, it's ok. You'll get back into it tomorrow." Then I would say it the next day, and the next, and the next, and here I am towards the end of the week and I didn't get my crap together. I felt like crap all week and it got me thinking that maybe I felt like crap since I was eating like crap. All I wanted to do was sleep. I talked myself out of every workout. I HAVE to stop this crapiness because I know if I keep this up I will gain back my hard working 12 lbs that I have lost and I DONT want that happening!! I weigh in on Saturday so I'm sure there will be a nice little gain but that's ok...that's just my reminder that that scale isn't going to go down if I keep up with my crap like lifestyle. So, here we go...time to refocus and get back on track and reach those September goals since there are only 9 more days left!!!!
Cousin's Wedding - 2 weeks
26th Birthday - 20 weeks (I want to be at my goal weight of 145 lbs)
My Wedding - 1 year and 21 days (It'll get here before I know it...)
It's almost the middle of the month so I decided to do a check in with the goals I set...
Goals for September
1. Continue to lose 0.5 - 1 lb a week - So far so good... i took a peak at the scale and it looks like i should have a loss on saturday if i keep up the good work that ive been doing
1. Log food to keep track of points...ive been slacking and what do ya know...I gained... - I'm not writing down as often as i should but I have been mentally adding the points up in my head. So still need to work on writing down my points just to be more accurate sp i dont miss something
2. Look up more new recipes and try them - I've got some new recipes off of pinterest... just need to go to the grocery and get the ingredients
1. Make workout calendar - The calendar is still sitting in my printer...not filled out... BAD!!
2. Start Ripped in 30 - Finish by the end of September - Havent started...idk why i dread it do much... just gotta make myself start
3. Zumba or Run twice a week - I think the first week I only went to zumba but this week I've already went twice... woot woot!
4. On days I work do a bodyrocktv workout or at least push ups and sit ups - work has been totally exhausting lately due to being understaffed and just the heavy patient load so by the time I get home I just want to sit on the couch lol
So far so good. I know I shouldn't be so hard on myself but even though the numbers on the scale are going down I still don't see a difference. I really need to start Ripped in 30 cause I know she gets rid of the belly fat and thats the area that i absolutely hate on my body and I know I need to get rid of the belly fat so I can look AMAZING when I try on wedding dresses or wear any kind of dress really lol Just gotta keep it up!!
The bestie and I started Weight Watchers together about 6 weeks ago and lately we have both been slacking. So yesterday we decided we have things coming up that we want to lose weight for so we are going to do it together. We also arent going to go to Weight Watchers anymore since we can't afford it. We have all the tools we need so we just have to be very disciplined with it. I suggested that we send pics of our weigh ins to each other and then at the end of the day tell each other how many points we ate for the day. I want to lose 5 lbs in a 4 week time period. And then Tasha wants to lose 10 lbs in an 8 1/2 week time period. So we decided wed do it together!! I started yesterday off by staying within my points range and I went to Zumba. I'm taking it one day at a time.
Weigh in was this morning for WW. I had a 1.6 lb gain which I wasn't surprised about at all. I ate absolutely horrible the whole week. I took a long enough "break" so it's time to refocus and remember why I'm doing this!!
- Goals for September
1. Continue to lose 0.5 - 1 lb a week
1. Log food to keep track of points...ive been slacking and what do ya know...I gained...
2. Look up more new recipes and try them
1. Make workout calendar
2. Start Ripped in 30 - Finish by the end of September
3. Zumba or Run twice a week
4. On days I work do a bodyrocktv workout or at least push ups and sit ups
so I will...
1. Look HOTT at my cousin's wedding in 5 weeks
2. Look GORGEOUS on my wedding day which is 13 months away
3. Love my body image and be CONFIDENT
4. Feel comfortable in my own skin
5. Live a healthier lifestyle
This past weekend was a very emotional and stressful weekend for me. It was the end of my 6 year enlistment with the Air Force Reserves. I decided to not reenlist because I was failing the waist measurement part on my physical fitness test and since I failled my last semester of Nursing school I made the decision that I needed to get rid of something in my crazy life. It was a great six years and I hope after things calm down and i lose some weight once and for all that I may be able to join again. I met some of the most amazing people while I was in the Air Force and being an Air Force Medic made me realize that I wanted to be a nurse. It's so weird to think that I wont get back into my uniform again for awhile.
My AMAZING wing[wo]men :]
So with that kind of weekend came a crappy weekend eating wise. Saturday we had a unit picnic. I told myself to eat in moderation but I totally pigged out. Then Sunday we had a pizza party and ice cream cake since me and another one of the troops were leaving. So, I'm trying to get back on track. It's been a little difficult since I have no groceries. I'm getting food tomorrow though!!
At the last WW weigh in I only lost 0.4 lbs. It's better than a gain but I knew the time would come where the pounds wouldn't drop as fast as they did in the beginning. I am still 2 lbs away from my 10 lb loss mark!! SO FRIGGIN CLOSE!!!! I was thinking once I hit my 10 loss mark that I won't go to WW anymore. I'm not quite sure yet. I keep going back and forth because it keep me more accountable since I'm paying $12 and weighing myself infront of a complete stranger. But then it irritates me that I'm actually paying someone just to see how much I weigh lol I haven't been able to stay for the meeting because of time conflict. I figured I got all the tools I need now and I can make my own food logs like they have. I'm just going to have to be the one that is accountable with it and actually stick with it. I guess we'll just see how things go.
Saturday our family got a new dog :] Her name is Tola. She's three years old and she's a rotty/lab mix. She's so cute and loving. Sometimes I think she doesn't realize how big she is because she just plows over our little dog and shell step on our feet and bump into us lol I think our little dog is the one having the hardest time adjusting with the change.
Abs loves her doggies
Hmmm...who do you think will win? lol
Abbie starts 3rd grade tomorrow! Just craziness...it seriously feels like I had her not too long ago. Where does the time go? She's so excited to go back to school...well see how long that excitement lasts lol She said the funniest thing to me the other day...
Abs - "Did you watch Honey I Shrunk the Kids when you were little?"
Me - "Yes. DiDi (my sister) and I used to watch it all the time."
Abs - "Was it in color then?"
Me - "Yes dear." burst out laughing
It's so funny that she thinks I am that much older than her...fyi... I am only 16 years older than her lol
I went to Zumba last night for the first time in I don't know how long!!!! It felt good to go and I'll be going tomorrow!! I've been going on walks but I need to start running. I didn't make my workout calendar but I'll get right on it for September. Gotta step things up in the workout department since I like food so much lol
Hope everyone has a great week!! End August in a BANG!! :]


text:
This glow stick shines a bright orange color when activated. The 6" glow stick attaches to a 32" lanyard, included. Perfect for adults or children. Not intended for children under 3 years of age.
" Got my morphsuit early enough to party at my office for halloween. Everyone loved it, including my boss. "

subset: commoncrawl


text:
Part of the largest of the Galapagos Islands lays directly on the Equator. What is the name of this island?
a) Ferdinand Island
b) Isabela Island
c) Catherine Island
d) Santa Cruz
Tags: money, education, entertainment
Asked by Komonika Mazumdar, 09 Mar '12 02:07 pm
Earn 10 points for answering
Answers (3)
Answer is b - isabella islandAnswered by Ataur Rahman, 09 Mar '12 02:08 pm
Isabela IslandAnswered by sanjeev, 09 Mar '12 02:08 pm
CAnswered by vikram bawa, 09 Mar '12 02:08 pm


text:
Find records of Ona Owens
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Biography & Family History Add details
Ona Owens (1913 - 1997) was born on May 12, 1913. She was born into the Owens family.
There are no known marriages or children on file for Ona. Ona died on June 5, 1997 at age 84.
Ona Owens's last known residence is at Idaho Falls, Bonneville County, Idaho.
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- Ellis Owens
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text:
Does anyone know why he would leave his stuff behind?
Okay so I was with this guy for a long time and the other night he wanted me to drink but I didn't want to. So he got mad at me, so I called him and asked if he was coming over cause it was his night off and he said he was busy and he didn't know. So I told him to come get his stuff and he came over and got his dad's stuff but left his stuff here. Does anyone know why he would leave his stuff behind?
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- Studio: Paramount Pictures
- Release Date: May 7, 2009
- Critic Score
- Most active
- Publication
- Most clicked
Paced at warp speed with spectacular action sequences rendered brilliantly and with a cast so expert that all the familiar characters are instantly identifiable.
The new Star Trek is more than a coat of paint on a space-age wagon train. It's an exciting, stellar-yet-earthy blast that successfully blends the hip and the classic.
Not only does this Star Trek proffer smart thrills and slick kicks, but it builds upon the original's history–from its very first pilot episode to Robert Wise's 1979 "Star Trek: The Motion Picture" and beyond–while creating an entirely new future.
Blasting onto the screen at warp speed and remaining there for two hours, the new and improved Star Trek will transport fans to sci-fi nirvana.
This installment has achieved a nearly impossible hat trick. It's a movie that is exegetically correct enough to appease the most hard-core buffs, while opening up the final frontier to a whole new generation of fans who have yet to appreciate Star Trek's ineffable combination of sci-fi action, campy humor and yin-yang philosophical tussle between logic and emotion.
The clever and infectious reboot of the amazingly enduring sci-fi classic, director J.J. Abrams crafts an origin myth that avoids any hint of the origin doldrums. That's because he rewires us back into the original Star Trek's primal appeal.
Full of life, wit, smarts, thrills and sheer gratifying entertainment that it launches the mind on a stream of merry somersaults.
It's hard to imagine anyone caring much why we're plunging ahead at warp speed, when the ride is so insanely satisfying.
An affectionate, exuberant picture that seeks to bring even those who don't know Klingon from Portuguese into the embrace of a pop-culture phenomenon.
Isn't just a pleasurable rethink of your geek uncle's favorite science-fiction series. It's also a testament to television's power as mythmaker, as a source for some of the fundamental stories we tell about ourselves, who we are and where we came from.
Star Trek goes back to the legend's roots with a boldness that brings a fatigued franchise back to life.
It's not necessary to be a longtime fan of the Star Trek universe to appreciate the sheer emotional punch and swagger of this rough and randy Enterprise crew.
A burst of pure filmmaking exhilaration that manages to pay homage to the classic 1960s TV series and still boldly go where no man, William Shatner and Leonard Nimoy included, has gone before.
Vigorously played as a young man by Chris Pine, Kirk is a brilliant, sports-car driving, bar-brawling rebel who is finally shamed into joining Starfleet Academy.
The result is more exciting than the last four ST pictures put together, more fun than a barrel of Tribbles, and the most satisfying action-adventure since last year's "Iron Man."
It fulfills its promise of rebooting the series while leaving us wanting more, and it does so with style and energy to spare. Now that's an origins tale that truly delivers.
We were also glad to see they didn't ignore the humorous elements that made the original so great. Plus, the casting is spot on.
Gripping action and vulnerable heroes writ large. It boldly goes somewhere different and makes it hard to leave the film not hoping for a return voyage soon.
Star Trek is pretty damn enjoyable. By resetting the franchise to what is essentially Year One, Abrams has the luxury of...gently reshaping the core characters.
Odd-number curse be gone. The most exhilarating Trek to date marks a new future for Kirk and co. If this can boldly go on to seek out ideas to match its speed and style, a franchise is reborn.
Abrams and his writers (Roberto Orci and Alex Kurtzman) have come up with a way to make you dig the souped-up new scenery while pining for the familiar--a good thing.
Though it has its over-caffeinated aspects and its missteps, this Star Trek has in general bridged the gap between the old and the new with alacrity and purpose.
It's a real family film, relatively light on the violence and funny without being overly crude; it even has some touching moments.
There is considerable fun in discovering the hows and whys the crew of the U.S.S. Enterprise came together, and each member has at least one moment in the spotlight, including the esteemed helmsman Sulu.
At its best, the effect is like seeing life panoramically, past and future, simultaneous and magnificent.
When it comes to sheer spectacle, Star Trek, as re-imagined by J.J. Abrams, delivers.
Ultimately, when the end credits roll, we're left with the sense that Star Trek represents a good beginning. As a film tasked with getting all the characters together, re-booting a timeline, and finding a way to return a veteran actor to his beloved role, Star Trek works.
Smart and youthful, with a well-balanced package of humour, romance, crisp action and character-based drama, Star Trek gives popcorn movies a good name.
What makes this movie ultra-contemporary is the way Abrams has re-imagined Spock and Kirk as a team of rivals.
The young cast is mostly callow and TV-bland and the special effects don't quite seem worth that hefty price tag, but overall this is a presentable addition to the franchise.
This new Star Trek is nonsense, no question ("Prepare the red matter!"), but at least it's not boggy nonsense, the way most of the other movies were, and it powers along, unheeding of its own absurdity, with a drive and a confidence that the producers of the original TV series might have smiled upon.
The movie deals with narrative housekeeping. Perhaps the next one will engage these characters in a more challenging and devious story, one more about testing their personalities than re-establishing them. In the meantime, you want space opera, you got it.
The visual effects are predictably excellent -- sometimes, in the case of a three-man free fall through space, unexpectedly lyrical -- but most of the movie's dramatic conflicts feel strictly pro forma.
A relatively mindless thrill ride that would have made the old NBC execs grin from ear to ear.
User Score
Generally favorable reviews- based on 1222 Ratings
User score distribution:
Positive: 427 out of 533
Mixed: 42 out of 533
Negative: 64 out of 533
Oct 19, 2011A very enjoyable action extravaganza. I loved it pretty much from start to finish and laughed out loud in parts. Chris Pine did a great job as Captain Kirk and Simon Pegg as Scotty!!!… Full Review »
JohnJDec 2, 2009I can't believe that any Star Trek fan enjoyed this movie. It failed, in every aspect, to capture the spirit of what made Star Trek great. Even without the Star Trek grievances, it was still a bad movie. So the special effects were cool and the acting was pretty good, but the script was lame and horribly cliched and the plot was just utter nonsense. Not to mention the pacing, which was so fast it was physically draining. The only reason I watched the whole movie was so that I could make an informed criticism. Had it not been a Star Trek movie, I would have stopped watching after the first 20 minutes or so. But I'm not surprised; it did share the same writers and director as Mission Impossible 3 and I walked out of that in the second scene.… Full Review »
JCGJun 19, 2009Action? Yes, in abundance. Special FX? Obviously, being a movie about outer space and the future. Story? NO, zero story - zilch. I mean dragging out the temporal distortion alternate future time traveling episode filler is nothing new for ST, but couldn't they come up with something more original? Lot's of eyecandy but no research into the ST universe at all. And Scotty... what ludicrous ACID-snorting twit came up with the idea to make that guy scotty? sure he's a good actor (to some extent) but he aint and never will be scotty. I mean it's one thing getting used to Syler being (a very emotional) Spock (I swear at times I could hear the ticking timepieces!) And then to end the most profound meeting there could be between the two spocks ends, not with a vulcan Live Long and prosper greeting but, with a goodbye. That's not innovation. It's heresy. All REAL trekkies should band together and go put the director (or as he will from now on be known - T.A.C.) to the torch. Or the phaser or whatever.. Ps. If they insist on adapting Star Trek into an action thrill ride for the Mindless-want-it-now! generation of today... rather call it some else and let ST die a quiet and dignified death.… Full Review »


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Updated: 05/07/2014 11:09 PM
Created: 05/07/2014 11:07 PM WDIO.com
After a record-breaking winter that left several feet of ice on Lake Superior, Wednesday was supposed to be a celebration of spring with the start of saltie season.
The 453-foot Diana was scheduled to arrive Wednesday morning, but the thick ice proved to be insurmountable. The Duluth Port Authority then estimated that the Antigua and Barbuda-flagged ship would make its way under the Aerial Lift Bridge by 8 p.m. Again Wednesday night, the ice proved too thick for the ocean-going vessel.
As of 11:00 p.m., Diana was still struggling in the Harbor as tug boats, a cutter, and even a laker tried to cut her free.
The Port Authority says that even if Diana makes it before midnight, May 7 would still be the latest arrival for a saltie in Twin Port's history. May 3, 1959 had been the previous record - the very first year that the St. Lawrence Seaway opened.
Bentleyville Opening Weekend Draws Large Crowd
One of the Christmas City of the North's favorite holiday traditions, the Bentleyville Tour of Lights, officially kicked off Saturday night with more than 15,000 visitors. The man behind Bentleyville, and its unofficial "mayor" Nathan Bentley says bringing the holiday light display to Bayfront Festival Park every year is about community...
Weekend Anchor Laurie Stribling Says Goodbye
Weekend Anchor Laurie Stribling had her last show Sunday night. Before she left, we took a look at some of the highlights during her time in the Northland.
Junior League Gives Back Through Festival of Trees
The Junior League of Duluth helped give back to the community while also lending a hand to local small businesses this weekend.
Alleged Wisc. Bank Robber in St. Louis County Jail
A man was arrested in Duluth Saturday night after he allegedly robbed a bank in Eau Claire, Wisc. the night before. The Eau Claire Police Department responded to a bank robbery at Wells Fargo Bank in Eau Claire on Friday night.
Licenses, Deer Population Down for Wisconsin Deer Opener
The Wisconsin firearm deer hunting tradition got off to a safe start as Department of Natural Resources officials said they had received no reports of accidental shootings or other injuries by mid-afternoon Sunday on the opener of the state's nine-day gun deer hunt.


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Tag Archives: Lower Windsor Township
Zimmerman Center on the Susquehanna: They came by land and river to see the improvements
'By land and by boat, visitors stopped at the center Saturday to see the improvements.' So read a subhead on a York, Pa., Daily Record story about a day in which visitors could see improvements to the already vastly improved John and Kathryn Center for Heritage. Mark Platts, president of Susquehanna Gateway Heritage Area, said the revamped Lower Windsor Township site links water to land.
Posted in Archives, all posts, Events, Explanations/controversy, For photo fans, Local journalism & Web, Local landmarks, Susquehanna, waterways, Susquehannocks/Conestogas, Unsung/obscure sites Tagged Dritt House, John and Kathryn Center for Heritage, Long Level, Lower Windsor Township, Mark Platts, Native Lands County Park, Paul Nevin, Stone Mill 1792, Susquehanna River Leave a comment
John J. Snyder Jr. tall case clock exhibit: 'A simple design can tell you a lot'
John J. Snyder Jr. collected a hall-of-fame lineup of tall case clocks in his day. The works of John Fisher, Godfrey Lenhart and Jacob Hostetter, all clockmakers with York County connections, are part of that collection. Now, 14 grandfather clocks from the Snyder collection are on display at the York County Heritage Trust, 250 E. Market St. a York, Pa., Daily Record story on the exhibit noted that many dealers collect 10 to 20 such clocks. Snyder collected hundreds. The clocks are works of art and loaded with history.
Posted in Antiquing & artifacts, Archives, all posts, Art & artists, Explanations/controversy, For photo fans, Genealogy/research, History video channel, Linked in/neat stuff, Local journalism & Web, Mail bag, Nostalgia & memories, People, War, Wheels of York Tagged Godfrey Lenhart, Jacob Hostetter, John Fisher, John Henry Denig, John J. Snyder Jr., jonathan Jessop, Lower Windsor Township, National Civil War Museum, trolley, trolley system, York County Law Library, Zimmerman Center Leave a comment
History mystery solved: The site of York County's Shultz one-room school
Yorkblogger Stephen H. Smith provided this Bing.com bird's-eye image the old Shultz schoolhouse, now a residence on the southeast corner of the intersection of Knights View and Trinity Church roads in Lower Windsor Township. He provided this research after a reader query.
Big snows in York County: These 8 photographs show their impact
Glen Rock, Pa., is nestled, well, within its Glen in this peaceful scene after one of the snows earlier this week. Which brings us other scenes from blizzards and heavy snows from York County's past, courtesy of the York Daily Record/Sunday News' archives. These photos, which go progressively back in time, remind us that big, bad snowfalls, however aggravating and damaging, come and go. And come again. And go again.
How two Susquehanna region farmsteads could see different fates. A story of preservation in York County
The Historic Hellam Preserve, a private restoration effort, played host to a gathering recently. A York, Pa., Daily Record/Sunday New story – 'Hellam farmhouse a treasure trove of history' – says the anonymous owner has spent five years improving the property from an old homestead to preserve. 'On Sunday, the renewal process culminated in a private opening for the owner's family and friends, who wandered among the sprawling outbuildings, took in the history and bought prints of Rob Evans' pieces,' the story states.
Posted in All politics is local, Archives, all posts, Events, Explanations/controversy, Farms & fields, For photo fans, Genealogy/research, Local journalism & Web, Local landmarks, Nostalgia & memories, People, Rob Evans, Small-town life, Unsung/obscure sites Tagged Hellam Township, Historic Hellam Preserve, Joe Kindig III, Lower Windsor Township, Native Lands County Park, Paul Nevin Leave a comment
Lauxmont from the air, in 2 different seasons, from 2 different directions
Development along the Susquehanna River has gained headlines recently. That would be at the Zimmerman Center, the old Dritt House, in Long Level, and plans to renovate the Susquehanna riverfront in Wrightsville. So, it seems appropriate to take a broader view of land near the river, specifically Lower Windsor Township's Lauxmont Farm. This land was the source of controversy about five years ago. These two aerial photographs capture the beauty of the land – and give a clue about why the preservationist v. developer battle erupted, in the first place.
Posted in All politics is local, Archives, all posts, Explanations/controversy, Farms & fields, For photo fans, Heroes, Linked in/neat stuff, Local journalism & Web, Local landmarks, School days Tagged Dritt House, Glen Rock, John Hufnagel, Lauxmont Farm, Lower Windsor Township, machete attack, mountain lion, Norina Bentzel, Oyster Festival, Wrightsville, Zimmerman Center Leave a comment
Then & Now in Lower Windsor: From 1740s Dritt House to 2013's Zimmerman Center
Structures on or around the grounds of Lower Windsor Township's Zimmerman Center have been known by many names: Cresap's Fort, Pleasant Gardens, the Dritt House.For about a decade, the beautifully remodeled stone structure along the Susquehanna in York County, Pa., has taken on the name of the philanthropists who have made it so: John and Kathryn Zimmerman. And a recent groundbreaking launched a two-fold purpose for the old property as it goes forward: public recreation and heritage.
Posted in Archives, all posts, Events, Explanations/controversy, For photo fans, History video channel, Local journalism & Web, Local landmarks, People Tagged Bill Wolf, John Zimmerman, Kathryn Zimmerman, Long Level, Lower Windsor Township, Susquehanna Gateway Heritage Area, Tom Wolf, William T. Wolf 5 Comments
Check out this gallery of York County's beautiful stained-glass windows
This stained-glass window gives natural light in the sanctuary of York, Pa.'s, old Zion Lutheran Church building, closed since the mid-1990s. Other stained-glass panels that were installed in the new church in Manchester Township in 1995. This photograph is part of series of 18 stained glass windows in York County in ydr.com's Media Center.
Posted in 1st Moravian, Archives, all posts, For photo fans, God & York County, Local landmarks, Unsung/obscure sites Tagged Dr. Eugene Segro, Irwin Goldenberg, Lower Windsor Township, Red Lion Middle School, St. Paul's United Methodist Churc, Temple Beth Israel, York Water Company, Zion Lutheran Church 2 Comments
Gettysburg 150: When Civil War generals needed info, they'd pick up a newspaper
Civil War generals would often acquire copies of newspapers published in the areas through which they were moving to add their repository of information. This is such a map showing Harrisburg at the time of the Confederate Gettysburg campaign. If Confederate Gen. Dick Ewell had secured this copy, he would have been well-briefed about the state capital he was fronting.
Posted in Archives, all posts, Civil War, Explanations/controversy, For photo fans, Local journalism & Web, Mail bag, Unsung/obscure sites, War, Wheels of York Tagged Betsy Shaw, Columbia-Wrightsville Bridge, Gettysburg 150, Jeb Stuart, John B. Gordon, Jubal Early, Lincoln Highway, Lower Windsor Township, Richard Ewell, Wrightsville Leave a comment
Frankenstorm: Check out these 10 links to stories, photos of Sandy, bad weather events
10 links tell about bad weather events in York County's past – and present – with Hurricane Sandy bearing down.


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Public Utilities Operations & Maintenance(757) 385-1400
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Society Gates
Humanity is conformity
Conformity is society
Society is this reality
The faces that saw me
And the angles that warned me
They told me to run
And dispose of the gun
I could have escaped
Be gone with no trace
Instead I just stayed
Within societies gates
Cos I can run but I can't hide
And I must justify
The way I live my life
Until the day I die
I live within these gates
I cannot go against
So I must see it through
There's nothing left to do
They said I was crazy
And they called me a fool
But words cannot change me
And my respect for the rules
I may be part of the system
But if I could rule this land
The rules would be different
But I am just one man
So I wish I was under a tree
Far away from society
Where the only truth in me
Is the soothing sound of my own entity?
While my other voice is free
It expresses words of plea
To return to a stable form of reality
But I'm inside of that tree
That tree is inside of another tree
The perplexity is infinity
So I will just chill with a spliff
I can run but I can't hide
in Education
Two National Board Certified teachers , both members of the Teacher Advisory Council of The Gates Foundation,
Cheryl Redfield and Kip Hottman
talk about their roles on the TAC and its daily impact on learning.
www.teachingquality.org @teachingquality @caredfield @kiphoffman
Director Antonio James
in Film
Antonio James was born in Memphis, TN. He was raised by his mother and step-father in Northaven, but spent most of his teenage years in Hickory Hill with his father. He attended dozens of schools by his Freshmen year at Millington Central High School in Millington Central where he graduated in 2003.
Several months after graduation James enlisted in the United States Air Force. After one term, he return to his hometown of Memphis where hardships and lack of employment opportunities led him to discover a new hobby, filmmaking.
With the help of his uncle - he begin filming music videos for Media Workz and Catina Johnson, short films and commercials. Antonio talents as a director was quickly recognized by the local community where he was hired as a contractor for the Memphis Veteran Affairs Medical Center Public Affairs Videographer. He also became the official videographer for Al Sharpton's National Action Network, Memphis Chapter under Gregory Grant.
Shortly after, James decided to quit providing video and recording services and start producing TV and Films. With help, he was able to produce and direct his first feature, Trey the Movie. After completion Antonio moved to Los Angeles, where he currently resides.
James' 2013 film debut Trey the movie received International Films Award, from IFS, Texas Black film Festival and Action on Film International Film Festival in Monrovia, California.
Since his move to Los Angeles in February 2013, Antonio James has been a background extra in Zac Efron's feature film "Neighbors" and General Hospital.
Perfecting Church & 2014 BMM Men's Conference, Bishop Lambert Gates, Sr., & more
in Religion
It's Perfecting Church & BMM Men's Conference 2014. Joining Dr. "J" as she welcomes to her show, Bishop Lambert W. Gates, Sr. - Greater Apostolic Faith Temple; Bro. Willie L. Davis - Best Man's Ministries Director and conference music guest RSVP live in studio.
Celebrating also the Inaugural "David Pop Winans Man of the Year" Award Presentation
Perfecting Prosperity & Health (III John 1:2)
Friday, November 21, 2014 @ 7:00 p.m.
U + 2 Men's Rally
Dr. Bill Winston - Living Word Christian Center
Sunday, November 23, 2014 @ 3:00 p.m.
Official Men's Day Service
Bishop Lambert W. Gates, Sr. - Greater Apostolic Faith Temple
For more information call 313.365.3787
or visit www.perfectingchurch.org
The Dark Scary Roads and Gates Show
As Halloween creeps ever closer the DCR team bring you two great interviews. First we welcome to the show for the first time author, K.M. Alexander to talk about his new book, Old Broken Road. K.M. Alexander's first novel The Stars Were Right—a thrilling Lovecraft urban fantasy—is available in paperback or as an ebook and arrived in 2013. His new novel, the sequel, Old Broken Road arrives on October 14th.
Then we will wrap up the show with our final interview with author Jonathan Ryan to talk about his book, 3 Gates of the Dead. 3Gate of the Dead skillfully blends theology, murder mystery, horror, and paranormal investigation through one man's struggle with his belief in God.
This episode of Dungeon Crawlers Radio has been brought to you by Audible. Visit http://www.audibletrial.com/DungeonCrawlersRadio for a free trial membership*.
Audible® Free Trial Details
* Get your first 30 days of the AudibleListener® Gold membership plan free, which includes one credit. In almost all cases, one credit equals one audiobook. After your 30 day trial, your membership will automatically renew each month for just $14.95, billed to the credit card you used when you registered with Audible. With your membership, you will receive one credit per month plus members-only discounts on all audio purchases. If you cancel your membership before your free trial period is up, you will not be charged. Thereafter, cancel anytime, effective the next billing cycle. See the complete terms and policy applicable to Audible memberships.
The Gates Are Ours
in Prayer
Gates in the Word are extremely significant. The represent places of authority and decision. The gates werer the place that the elders of the city sat and made decisions for the city. Join us for prayer over the gates of our lives. Dial 714.459.3963 at 6:00 Am Mon. -Fri.
Gennady Golovkin vs Marco Antonio Rubio Recap
in Sports
How far would you travel to see a boxer you enjoyed watching ply his craft? This past Saturday, attending Gennady Golovkin's easy destruction of Marco Antonio Rubio in Carson, CA, I heard everything from Northern California, to Iowa, to Connecticut. If there were any question as to the budding stardom of "GGG," many remarked that this past weekend's success was the answer. This week on TQBR Radio, James Foley of Bad Left Hook and The Queensberry Rules' Patrick Connor pour accolades all over the Killer from Kazakhstan. But also on the agenda: Nicholas' Walters handling of Nonito Donaire on the undercard, as well as various other news pickings and musings. Thanks for tuning in!
(Photos: Alex Gallardo/AP/Top Rank)
Antonio Baldovinos: Unlock a Lifetyle of Intimate Encounters with God
in Art
- Are you tired of living out a boring and unfulfilling faith?
- Has Christianity become a dull religion of rules instead of a passionate relationship with Jesus?
- Have you traded in powerful divine encounters for a lifestyle of just going through the spiritual motions and rituals?
We've all been there! Join Larry Sparks as he interviews Prayer Leader and author, Antonio Baldovinos about how you can move beyond a dry, lifeless faith and start living from the inside out.
Life will always throw its share of twists and turns your way; the One Thing you should be able to rely on is Jesus! Discover how you can live passionately in love with God... all the time.
About Antonio Baldovinos
Marked by boldness and passion, Antonio Baldovinos has an uncompromising message of calling the Church to a wholehearted pursuit after God. Since 2000 Antonio has traveled to many nations seeing tens of thousands respond to the gospel. In 2008 God expanded his vision to call people to a lifestyle of prayer and intimacy with God. It is this passion that brought him and his wife to establish the Global Prayer House Missions Base, which includes the Pursuit Conference, the Pursuit Internship, and the Pursuit Worship, all flowing out of the place of prayer and worship. Antonio and his beautiful wife, Christelle, live in Alberta, Canada and love raising their five children: Michael, Gabriel, Elijah, Isabella, and Justice. To connect with Antonio go to www.antoniobaldovinos.org. Twitter @Antoniobaldov
Purchase Living From the Inside Out on Amazon!
The Zodiac Hour: With Dorothea Baker-Gates
in Science
The Journey of a Thousand Miles, begins with the first step. ~ Lao Tzu
Where are you in your journey into this thing that we call life? Sometimes we become weary on our journey, and we need the help of our brother or sister to see clearly. Join us Sunday night with our Guest, "Mrs. Dorothea Baker-Gates" as she Consult the Stars Concerning YOU, and your situation.
Dorothea is the Confirmation of what you already know and feel. She is just here to confirm that. Dorothea believe that "Insight Without Change Is Meaningless." Dorothea is a Certified Reiki and Universal Life Force Healer, Certified Practitioner, Licensed and Certified Palmist, she has a Teacher Certification from the Atlantian Mystery School, and she also received her Certified Staff Palmist from the Atlantian Mystery School.
Dorothea offer services in Clairvoyant Readings, Reiki Healing, Health & Wellbeing, Past Life Analysis, Personality Astrology Forecast, Numerology Reports, and Couple Synergy Charts.
You can learn more about Dorothea by going to her website at www.dorotheaonline.com
Gennady Golovkin vs Marco Antonio Rubio Preview
in Sports
It's happening again. Gennady Golovkin has vowed to rid the world of evil, and the only man standing in his way is "El Veneno" Marco Antonio Rubio. Okay, so there are a lot of men standing in his way aside from Rubio, but the Mexican veteran is the only heart pure enough, the only balls big enough, to accept the GGG Challenge. (That's hyperbole.) James Foley of Bad Left Hook and The Queensberry Rules' Patrick Connor are proud to be overly kind to Golovkin once more while previewing a fight of his. Also up this week: recaps of Jermain Taylor vs Sam Soliman and Cornelius Bundrage vs Carlos Molina, and a preview of Nonito Donaire vs Nicholas Walters, plus other stuff. Thanks for tuning in!
(Photos: Desde El Ring; USA Today)
An Evening With Antonio Paris
in Paranormal
Antonio, the Founder and Director of Aerial Phenomena, is a former US Army Counterintelligence Officer and Department of Defense Counterintelligence Special Agent. He was awarded a Bronze Star for combat operations in Iraq during Operation Iraqi Freedom.
Antonio is also the Director and Founder of the Center for Planetary Science – a science outreach program bringing astronomy, planetary science, and astrophysics to the next generation of space explorers. He has a Bachelor of Science in Computer Information Systems from The City University of New York and a Master's of Science in Planetary Science from the American Public University.
Antonio, moreover, is a member of the Washington Academy of Sciences, the National Capital Astronomers; is a graduate of the S2 Institute's Florida Private Investigator Course; and has appeared in dozens of radio shows, webcasts, and cable TV interviews, including consulting work for the popular TV series Unsealed: The Alien Files. He is the author of two books: Aerial Phenomena: Reviving Ufology for the 21st Century; and Space Science: Challenges for the Extraterrestrial Hypothesis of UFO Phenomena. He is also the director and producer for the documentary Area 51: A History of this Reclusive Base.
Currently, Antonio is an Adjunct Professor of Astronomy at St. Petersburg College, FL. On his spare time, Antonio enjoys hunting, SCUBA diving, rock climbing, mountaineering, and sailing.
Lets Talk Kingdom w/Catrina-Interview w/Dove Award winner Antonio Neal
Multiple Dove Award recipient, as well as Grammy and Stellar Award-nominated recording artist, Antonio Neal has set off on a new adventure with Madison Line Records.
The color of the instrument doesn't determine what it will compose.
-antonio neal
- ...
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text:
|James Madison beat UNC Wilmington 79-73
|Written by Admin
|Saturday, 31 January 2009 17:45
James Madison (14-9, 6-5 Colonial Athletic Association) trailed 41-32 at halftime. The Dukes took their first lead of the game at 68-66 on a jump shot by Semenov with 3:49 left to play.
James Madison then hit all eight of its free throw attempts in the final 1:10 to seal the win.
Semenov, who made all eight of his second-half field goal attempts, and 7 of 12 in the game, led three Dukes in double figures. Devon Moore scored 14 points and Julius Wells added 10 for James Madison.
The Seahawks (5-18, 2-9) were led by Dominique Lacy's 15 points. Kevon Moore added 13 points, Johnny Wolf tallied 12 and Chad Tomko scored 11.


text:
AJOT Digital Edition
Issue #591
Terminal Operators
Air Cargo Quarterly
|2014 Media Kit
International Trade
Page 4 of 256 pages ‹ First < 2 3 4 5 6 > Last ›
Nissan expands US recall for faulty Takata air bags to 52,738 vehicles
| November 10, 2014 | International Trade
Nissan Motor Co is expanding the number of vehicles recalled in the United States for passenger air bags that could explode with too much force and spray metal shrapnel at occupants. Read More »
US rules out major Trans-Pacific trade announcement at APEC
| November 10, 2014 | International Trade
There will be no "major announcement" on a Washington-backed Asia-Pacific free trade deal during a meeting of leaders from the region in Beijing this week, U.S. Trade Representative Michael Froman said. Read More »
UK trade deficit widens in September on higher oil imports, EU exports sluggish
| November 10, 2014 | International Trade
Britain's goods trade deficit widened by more than expected in September, hit by a jump in oil imports and by weak export growth to the European Union, official data showed. Read More »
Unclear if China ready to sign IT agreement
| November 10, 2014 | International Trade
China is part of "intensive" talks on a global trade pact regarding information technology products, the World Trade Organization's chief said, but it is unclear if a deal will be made at a meeting of Asia-Pacific leaders underway in Beijing. Read More »
China's Silk Road challenges US dominance in Asia
| November 10, 2014 | International Trade
"The Silk Road, no longer just a concept in history books, has evolved into a story of modern logistics and Sino-European cooperation," Yang Jiechi, China's top diplomat, told a conference this month. Read More »
Putin says China, Russia to settle more trade in yuan
| November 10, 2014 | International Trade
Russia and China intend to increase the amount of trade settled in the yuan, President Vladimir Putin said in remarks that would be welcomed by Chinese authorities who want the currency to be used more widely around the world. Read More »
China, South Korea sign 'substantial conclusion' of free trade deal
| November 10, 2014 | International Trade
Chinese and South Korean leaders signed a "substantial conclusion" of a free trade agreement that will sharply reduce barriers to commerce between the two trading giants, but leaves in place those on rice and automobiles. Read More »
China October trade data shows signs of manipulation, hot money inflows
| November 10, 2014 | International Trade
China's exports and large trade surplus in October pointed to signs of manipulation and inflows of speculative hot money, the official Shanghai Securities News said, suggesting that firms continue to over-invoice trade deals to avoid capital controls. Read More »
Yuan hub in Canada will increase trade
| November 10, 2014 | International Trade
The establishment of a clearing hub for the yuan in Toronto is an important development for Canada that will help accelerate increased trade with China, Canada's Finance Minister Joe Oliver said. Read More »
Annual China trade growth slows in October in further sign of fragility
| November 10, 2014 | International Trade
Annual growth in China's exports and imports slowed in October, data showed on Saturday, reinforcing signs of fragility in the world's second-largest economy that could prompt policymakers to roll out more stimulus measures. Read More »
Qualcomm sees more China trouble, faces probes in US, Europe
| November 09, 2014 | International Trade
Qualcomm Inc warned that an antitrust investigation and problems collecting royalties could harm its business in China next year and it also disclosed new regulatory investigations in the United States and Europe. Read More »
India's Ranbaxy loses six months exclusivity on Roche's antiviral drug
| November 09, 2014 | International Trade
Indian drugmaker Ranbaxy Laboratories Ltd said the U.S. Food and Drug Administration has revoked the previously granted tentative approvals to the company for launching the first cheaper generic forms of AstraZeneca's heartburn drug Nexium and Roche's antiviral Valcyte. Read More »
Honda Canada to invest C$857 million in Ontario plants
| November 09, 2014 | International Trade
Honda Motor Co Ltd's Canadian division said it will invest C$857 million ($749.98 million) over three years to upgrade manufacturing plants in Alliston, Ontario, which will be the global lead for production of the next-generation Honda Civic. Read More »
APEC set to launch study on China-backed free trade area
| November 09, 2014 | International Trade
Leaders will agree to launch a study on a China-backed free trade area at next week's Asia-Pacific Economic Cooperation meeting in Beijing, an APEC official said, amid controversy over competing U.S. and Chinese visions for regional trade. Read More »
Apple blocks malware targeting products in China
| November 06, 2014 | International Trade
Apple Inc said it has identified and blocked malicious software applications targeting users in China. Read More »
Pfizer's India unit reports Q2 loss on plant lockout costs
| November 06, 2014 | International Trade
Pfizer Ltd, the Indian unit of U.S. drugmaker Pfizer Inc, reported a quarterly loss, due to expenses related to a lockout at its manufacturing plant in Mumbai. Read More »
China issues detailed measures to support imports
| November 06, 2014 | International Trade
China's cabinet issued detailed measures to support imports via encouraging imports of high-tech equipment, key components and consumer goods, in its latest measures to support the cooling Chinese economy. Read More »
Mexico could seek hefty damages against US over meat laws
| November 06, 2014 | International Trade
Mexico would seek "hundreds of millions" of dollars in trade retaliation against the United States if Washington does not change meat labeling laws, a Mexican official said, as Mexico and Canada kept up pressure on the United States to act. Read More »
Pakistan takes EU to WTO over PET trade
| November 05, 2014 | International Trade
Pakistan launched a trade dispute at the World Trade Organization to challenge the European Union's punitive duties on Pakistani exports of polyethylene terephthalate (PET), the WTO said in a statement. Read More »
India, isolated, toughs it out in WTO food-stockpiling row
| November 05, 2014 | International Trade
India defied the world in a row over food stockpiling that has crippled attempts to reach a global trade agreement, raising doubts that backroom talks can reach a compromise before a Group of 20 summit this month. Read More »


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This is a gluten free version of Budgiegirl's 6 Grain Breakfast in the Crock Pot #158624. A hot, delicious and nutritious gluten free breakfast cereal!!
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Make this season merry, bright and manageable with our easy ideas.


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Three-ring circus
Jeff Smith noon, Nov. 24
Author Silvia Sommer signs her new memoir, in which she sheds "light and understanding" for "anyone who has ever struggled with a difficult relationship." 760-703-3889.
757 North Twin Oaks Valley Road #3, San Marcos, 92069
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Tunisian wins Muslim beauty pageant, calls for free Palestine23 Nov 2014 | 01:24
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Sport - Other Sport - ATHLETICS
My best is yet to come, says superstar Usain Bolt
Posted Jul 24th 2014, 10:18pm by Reuters
... Reuters in Kingston, Jamaica Sprinter says he can run faster next year and at Rio Olympics if he stays injury free My best days are still ahead of me: Bolt Six-times Olympic gold medallist Usain Bolt and his coach Glen Mills believe the Jamaican sprinter can run even faster as he targets the 2015 world championships and the 2016 Summer Games in Rio de Janeiro. It has been five ...http://www.scmp.com/sport/other-sport/article/1558347/my-best-yet-come-says-superstar-usain-bolt
Sport - Other Sport - ATHLETICS
Anti-doping row in Jamaica costing me money, says Usain Bolt
Posted Nov 17th 2013, 11:07pm by Reuters
... Reuters 'Anti-doping storms costs me money' Olympic sprint champion Usain Bolt says controversy over Jamaica's anti-doping programme is scaring off potential sponsors and costing him money. "There is a lot going on with this drug thing that I really feel they need to be clear [about] and clarify because now it is causing problems for me when it comes to making ...http://www.scmp.com/sport/other-sport/article/1358669/anti-doping-row-jamaica-costing-me-money-says-usain-bolt
Sport - Other Sport - ATHLETICS
US sprint star Tyson Gay banned for doping
Posted May 03rd 2014, 02:21pm by Reuters
... Reuters American handed one-year suspension for steroid positive, returns Olympic medal Former world double sprint champion Tyson Gay has been suspended for one year after testing positive in 2013 for a banned anabolic steroid, the U.S. Anti-Doping Agency (Usada) said on Friday. Gay has also returned the silver medal he won with the U.S. 4x100 metres relay team at the 2012 London ...http://www.scmp.com/sport/other-sport/article/1503360/us-sprint-star-tyson-gay-banned-doping
Sport - Other Sport - ATHLETICS
Jamaican anti-doping panel bans Asafa Powell
Posted Apr 10th 2014, 11:51pm
... Reuters IAAF declines to comment as former 100 metres world record holder's 18-month suspension is back-dated to June last year Former 100 metres world record holder Asafa Powell was banned for 18 months by a Jamaican anti-doping disciplinary panel yesterday after he tested positive for a banned substance last year. The Jamaican sprinter, 31, tested positive for the stimulant ...http://www.scmp.com/sport/other-sport/article/1474713/jamaican-anti-doping-panel-bans-asafa-powell
Sport - Other Sport - ATHLETICS
Respect the distance
Posted Apr 12th 2014, 09:28pm by Reuters
... is a risk for me," he said. "I've gone straight in at the deep end- but that's what champions do." Reuters ...http://www.scmp.com/sport/other-sport/article/1478938/respect-distance
Sport - Other Sport - ATHLETICS
Mo Farah insists 'it's no big deal' after race collapse in New York
Posted Mar 17th 2014, 09:33pm by Reuters
... Reuters in New York World track champion recovers from fall in half-marathon to finish second I'm fine, Olympic ace insists after race collapse Double Olympic and world track champion Mo Farah collapsed after crossing the finish line in the New York half-marathon on Sunday, having recovered from a fall earlier in the race to finish second to Kenyan Geoffrey Mutai. Farah ...http://www.scmp.com/sport/other-sport/article/1450909/mo-farah-insists-its-no-big-deal-after-race-collapse-new-york
Sport - Other Sport - ATHLETICS
South Africa's Pistorius back on track for 'low-key' training
Posted Jun 28th 2013, 04:29pm by Reuters in Johannesburg
... Reuters in Johannesburg South African Paralympic and Olympic athletics star Oscar Pistorius has returned to the track for "low-key" training, just weeks before he is due to appear in court for the latest hearing in his murder trial. Pistorius, a double amputee who ran the 400 metres at the last year Olympics and Paralympics, was not preparing for a return to competition but the training ...http://www.scmp.com/sport/other-sport/article/1271059/south-africas-pistorius-back-track-low-key-training
Sport - ATHLETICS
Anti-doping chief blasts 'stone-walling' Jamaicans
Posted Oct 22nd 2013, 10:05am
... Reuters 'We're not going to take it lying down, their suggestion that they'll talk to us next year,' says Fahey World Anti-Doping Agency chief John Fahey has slammed Jamaican authorities for failing to accommodate an independent audit of their anti-doping regime until next year. Wada said last week Jamaican Prime Minister Portia Simpson-Miller had invited a special team ...http://www.scmp.com/sport/article/1337066/anti-doping-chief-blasts-stone-walling-jamaicans
Sport - Other Sport - ATHLETICS
Kenyans sweep Chicago Marathon amid high security
Posted Oct 14th 2013, 11:47am
... Reuters in Chicago Dennis Kimetto edges out compatriot in record time, while Rita Jeptoo strolls to victory Dennis Kimetto and Rita Jeptoo led a Kenyan sweep in contrasting styles at the Chicago Marathon on Sunday in a race staged amid heightened security after the Boston Marathon bombings in April which killed three people. Kimetto won the men's race after a gripping duel ...http://www.scmp.com/sport/other-sport/article/1331368/kenyans-sweep-chicago-marathon-amid-high-security
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Bolt grabs 200m gold at a canter
Posted Aug 18th 2013, 12:00am by AP, Reuters, AFP
... in 12.50, while Tiffany Porter of Britain earned bronze in 12.55. Reuters, Agence France-Presse, Associated Press ...http://www.scmp.com/sport/other-sport/article/1297512/bolt-grabs-200m-gold-canter
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Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein R1 is a halogen, or an oxygen linked leaving group including an aromatic ether, an alkyl sulfonate, an aryl sulfonate, an alkyl phosphonate, an aryl phosphonate, an alkyl phosphate or aryl phosphate;
R2 is COOR5, C(═O)NH(CHR5)m --COOR5, NH(CHR5)m CON(R5)R6, C(═O)N(R5)R6 or NH(CHR5)m OH;
R3 is H or alkyl;
R4 is H, substituted or unsubstituted aryl, heteroaryl or alkyl;
R5 and R6 are independently H, lower alkyl, aryl, hydroxy alkyl, amino alkyl, heteroaryl, lower alkylene-aryl, lower alkylene-heteroaryl or lower cycloalkyl; and m=0-6; pharmaceutical compositions containing the compounds; and a method for inhibiting interleukin-1β protease activity in a mammal utilizing the compounds and compositions.
1. A method of inhibiting interleukin-1β protease activity in a mammal in need of such treatment comprising administering to said mammal an effective inhibitory amount of a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR27## wherein: R1 is halogen;
R2 is OR5, NH(CHR5)m --COOR5, NH(CHR5)m CON(R5)R6, N(R5)R6 or NH(CHR5)m OH;
R3 is H or alkyl;
R4 is H; substituted or unsubstituted aryl, heteroaryl, or alkyl;
R5 and R6 are independently H, lower alkyl, aryl, hydroxy alkyl, amino alkyl, heteroaryl, lower alkylene-aryl, lower alkylene-heteroaryl or lower cycloalkyl; and
m is 0-6
in a pharmaceutically acceptable carrier.
2. The method of claim 1 wherein said compound is selected from the group consisting of: 3-Chloro-4-carboethoxy-6-(4-pyridyl)pyridazine, 3-Chloro-4-carboxamido-6-(3-pyridyl)pyridazine, 3-Chloro-4-carboxamido-6-(4-bromophenyl))pyridazine and 3-Chloro-4-carboxamido-6-(4-trifluoromethylphenyl)pyridazine.
3. The method of claim 1 wherein said compound is selected from the group consisting of: 3-Chloro-4-carboxamido-6-(3,5-dichlorophenylpyridazine, 3-Chloro-4-carboxamido-6-(4-nitrophenyl)-pyridazine, 3-Chloro-4-carboxamido-6-(4-cyanophenyl)-pyridazine and 3-Chloro-4-carboxamido-6-(2-pyrazyl)pyridazine.
4. The method of claim 1 wherein said compound is selected from the group consisting of: 3-Chloro-4-carboxamido-5-methyl-6-(4-chlorophenyl)pyridazine, 3-Chloro-4-(2,4-dichlorobenzyl-aminocarbonyl)-6-(4-pyridyl)pyridazine, 3-Chloro-4-[(C-ethoxy)glycyl]-carbonyl)-6-(4-pyridyl)pyridazine, 3-Chloro-4-(2,4-dichlorobenzyl-aminocarbonyl)-6-[4-(3-chloro)pyridyl]-pyridazine and 3-Chloro-4-carboxamido-6-[4-(p-toluenesulfonamido)phenyl]-pyridazine.
5. The method of claim 1 wherein said compound is selected from the group consisting of: 3-Chloro-4-carboxamido-6-(4-quinolyl)pyridazine, 3-Chloro-4-carboxamido-6-(4-methoxyphenyl)-pyridazine, 3-Chloro-4-carboxamido-6-[3,5-difluoro-4(methylsulfonyl)phenyl]pyridazine, 3-Chloro-4-carboxamido-6-[3-fluoro-4(methylsulfonyl)-5-(methoxy)-phenyl]-pyridazine, 3-Chloro-4[(phenylalanylcarbamido)-carbonyl]-6-(4-chlorophenyl)pyridazine and 3-Chloro-4-carboxamido-6-(3-chloro-4-fluorophenyl)pyridazine.
6. A method for treating a disease or disorder selected from infectious disease, respiratory disease, inflammatory disease, an immune-based disease, auto-immune disease, bone disease, or tumors in a mammal in need of such treatment comprising administering to said mammal an effective amount a pharmaceutical composition comprising:
1) a compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR28## wherein: R1 is halogen;
R2 is OR5, NH(CHR5)m --COOR5, NH(CHR5)m CON(R5)R6, N(R5)R6 or NH(CHR5)m OH;
R3 is H or alkyl;
R4 is H; substituted or unsubstituted aryl or heteroaryl or alkyl;
R5 and R6 are independently H, lower alkyl, aryl, hydroxy alkyl, amino alkyl, heteroaryl, lower alkylene-aryl, lower alkylene-heteroaryl or lower cycloalkyl; and
m is 0-6; and
2) a pharmaceutically acceptable carrier.
7. A method for treating a disease or disorder selected from meningitis, salpingitis, septic shock, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis, reperfusion injury, hypersensitivity, or multiple sclerosis in a mammal in need of such treatment comprising administering to said mammal an effective amount a pharmaceutical composition comprising:
1) a compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR29## wherein: R1 is halogen;
R2 is OR5, NH(CHR5)m --COOR5, NH(CHR5)m CON(R5)R6, N(R5)R6 or NH(CHR5)m OH;
R3 is H or alkyl;
R4 is H; substituted or unsubstituted aryl or heteroaryl or alkyl;
R5 and R6 are independently H, lower alkyl, aryl, hydroxy alkyl, amino alkyl, heteroaryl, lower alkylene-aryl, lower alkylene-heteroaryl or lower cycloalkyl; and
m is 0-6; and
2) a pharmaceutically acceptable carrier.
8. The method according to claim 7, wherein the disease or disorder is septic shock, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, or pancreatitis.
This application is a division of application Ser. No. 08/073,914, filed on Jun. 8, 1993, now abandoned.
1. Field of the Invention
This invention relates to a series of novel pyridazine analogs which exhibit selective inhibition of interleukin-1β converting enzyme, to compositions containing the novel pyridazine analogs and methods for therapeutic utility. More particularly, the interleukin-1β converting enzyme inhibitors described in this invention comprise novel pyridazine analogs which possess particular utility in the treatment of inflammatory, immune-based diseases and cancer.
2. Reported Developments
Interleukin-1β protease (also known as interleukin-1β converting enzyme or ICE) is the enzyme responsible for processing of the biologically inactive 31 kD precursor IL-1β to the biologically active 17 kD form (Kostura, M. J.; Tocci, M. J.; Limjuco, G.; Chin, J.; Cameron, P.; Hillman, A. G.; Chartrain, N. A.; Schmidt, J. A. Proc. Nat. Acad. Sci., 1989, 86, 5227-5231 and Black, R. A.; Kronheim, S. R.; Sleath, P. R. FEBS Let., 1989, 247, 386-391). In addition to acting as one of the body's early responses to injury and infection, IL-1β has also been proposed to act as a mediator of a wide variety of diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, and acute and chronic myelogenous leukemia (Dinarello, C. A.; Wolff, S. M., New Engl. J. Med., 1993, 328, 106). The naturally occurring IL-1β receptor antagonist has been used to demonstrate the intermediacy of IL-1β in a number of human diseases and animal models (Hannum, C. H.; Wilcox, C. J.; Arend, W. P.; Joslin, G. G.; Dripps, D. J.; Heimdal, P. L.; Armes, L. G.; Sommer, A.; Eisenberg, S. P.; Thompson, R. C., Nature, 1990, 343, 336-340; Eisenberg, S. P.; Evans, R. J.; Arend, W. P.; Verderber, E.; Brewer, M. T.; Hannum, C. H.; Thompson, R. C., Nature 1990, 343, 341-346; Ohlsson, K.; Bjork, P.; Bergenfeldt, M.; Hageman, R.; Thompson, R. C., Nature, 1990, 348, 550-552; and Wakabayashi, G., FASEB, 1991, 338-343). The specific role of IL-1β in inflammation and immunomodulation is supported by the recent observation that the cowpox virus employs an inhibitor of ICE to suppress the inflammatory response of its host (Ray, C. A. et al, Cell, 1992, 69, 597-604).
The present invention also relates to the modulation of processing of IL-1β for the treatment of rheumatoid arthritis. Levels of IL-1β are known to be elevated in the synovial fluid of patients with the disease. Additionally, IL-1β stimulates the synthesis of enzymes believed to be involved in inflammation, such as collagenase and PLA2, and produces joint destruction which is very similar to rheumatoid arthritis following intraarticular injection in animals.
ICE is believed to be a cysteine protease (Thornbury, N. A. et al, Nature, 1992, 356-768). Peptidyl methyl ketone analogs constitute a well-known class of compounds having cysteine protease inhibitory activity. (D. Rich in Chapter 4 of "Proteinase Inhibitors", Barrett, A. J. and Salvensen, G., eds., Elsevier, 1986). However, there has never been a reported example of a non-peptide heterocyclic inhibitor of a cysteine protease. Hence, the inhibitory activity displayed by the pyridazine analogs described herein against ICE is unique.
An effective therapy has yet to be developed for the treatment of IL-1β mediated inflammatory diseases. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.
In accordance with the present invention, novel non-peptidic pyridazines are provided having the formula (I) and a pharmaceutically acceptable salt thereof ##STR2## wherein R1 is a halogen, or an oxygen linked leaving group including an aromatic ether, an aromatic ester, an alkyl sulfonate, an aryl sulfonate, an alkyl phosphonate, an aryl phosphonate, an alkyl phosphate or aryl phosphate;
R2 is OR5, NH(CHR5)m --COOR5, NH(CHR5)m CON(R5)R6, N(R5)R6 or NH(CHR5)n OH;
R3 is H or alkyl;
R4 is H, substituted or unsubstituted aryl, heteroaryl or alkyl;
R5 and R6 are independently H, lower alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or lower cycloalkyl;
m=1-6; and
As used herein, the term pharmaceutically acceptable salts includes the acid and base addition salts.
The term acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxilic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
the term base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaines, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.
"Alkyl" is defined as a saturated or unsaturated aliphatic hydrocarbon which may be either straight- or branched-chain. Preferred groups have no more than about 12 carbon atoms and may be methyl, ethyl and structural isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
"Lower alky" is defined as an alkyl group as above, having 1 to 4 carbon atoms. Suitable lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and n-heptyl.
"Lower cycloalkyl" is defined as a carbocyclic ring of 3-8 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"Aryl" is defined as phenyl, naphthyl and substituted phenyl.
"Substituted phenyl" is defined as a phenyl group in which one or more of the hydrogens has been replaced by the the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, alkyl sulfonyl, arylsulfonamido, trifluoromethyl, morpholinoethoxy and morpholino-sulfonyl, and carbobenzoxy-methyl sulfamoyl.
"Halogen" is defined as chloride, fluoride, bromide or iodide.
"Heteroaryl" is defined as pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, triazinyl, quinolyl and isoquinolyl.
"Substituted heteroaryl" means a heteroaryl group in which one or more of the hydrogens has been replaced by the the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, lower alkoxy, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholino-sulfonyl, carbobenzoxy-methylsulfamoyl.
"Aralkyl" is defined as an alkyl group susbstituted by an aryl ring. For example, benzyl, phenethyl and 4-chlorobenzyl.
The present invention concerns a method for inhibiting ICE in a mammal by administering a therapeutically effective amount of a compound of the Formula (I) or a pharmaceutical composition containing a compound of the Formula (I) in a pharmaceutically acceptable carrier. The method of inhibition is directed for the treatment of IL-1β mediated disease states or disorders which include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, immune-based diseass, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain tumors.
The pharmaceutical composition of the present invention comprises an active ingredient of the compound of formula (I) in admixture with a pharmaceutically acceptable, non-toxic carrier. Such compositions may be prepared for use for parenteral (subcutaneous, intraarticular, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops or aerosols.
When administered orally (or rectally) the compounds will usually be formulated into a unit dosage form such as a tablet, capsule, suppository or cachet. Such formulations typically include a solid, semi-solid or liquid carrier or diluent. Exemplary diluents and vehicles are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup, methylcellulose, polyoxyethylene sorbitan monolaurate, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, and magnesium stearate.
The compositions may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985. Formulations for parenteral administration may contain as common excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Examples of vehicles for parenteral administration include water, aqueous vehicles such as saline, Ringer's solution, dextrose solution, and Hank's solution and nonaqueous vehicles such as fixed oils (such as corn, cottonseed, peanut, and sesame), ethyl oleate, and isopropyl myristate. Sterile saline is a preferred vehicle and the compounds are sufficiently water soluble to be made up as a solution for all foreseeable needs. The vehicle may contain minor amounts of additives such as substances that enhance solubility, isotonicity, and chemical stability, e.g., antioxidants, buffers, and preservatives. For oral administration, the formula can be enhanced by the addition of bile salts and also by the addition acylcarnitines (Am. J. Physiol. 251:3332 (1986). Formulations for nasal administration may be solid and contain as excipients, for example, lactose or dextran, or may be aqueous or oily solutions for administration in the form of nasal drops or metered spray. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
When formulated for nasal administration the absorption across the nasal mucous membrane is enhanced by surfactant acids, such as for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, desoxycholic acid, chenodesoxycholic acid, dehydrocholic acid, glycodeoxycholic acid, and the like (See, B. H. Vickery, "LHRH and its Analogs-Contraception and Therapeutic Applications", Pt.2, B. H. Vickery and J. S. Nester, Eds., MTP Press, Lancaster, UK, 1987).
In general, for the uses as described in the present invention, it is expedient to administer the active ingredient in amounts between about 0.1 and 100 mg/kg body weight, most preferably from about 0.1 to 30 mg/kg body weight for human therapy, the active ingredient will be administered preferably in the range of from about 0.1 to about 20-50 mg/kg/day. This administration may be accomplished by a single administration, by distribution over several applications or by slow release in order to achieve the most effective results. When administered as a single dose, administration will most preferably be in the range of from about 0.1 to 10 mg/kg of body weight.
The exact dose and regimen for administration of these compounds and compositions will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment, and the degree of affliction or need. In general, parenteral administration requires lower dosage than other methods of administration which are more dependent upon absorption.
Compounds of the present invention are prepared according to Schemes I, II and III. ##STR3## wherein R2 and R3 are defined previously.
Referring to Scheme I, the condensation of a-keto esters with aryl ketones to provide 6-aryl-3-hydroxypyridazines has been previously described [Druey, J. and von Schmidt, P. (1954) Helv. Chim. Acta., Vol. 37, 134]. Diethyl ketomalonate (1) and the aryl ketone (2) are heated together neat to approximately 120� C. for 15 hours to provide the condensation product (3). The keto-diester (3) is then treated with hydrazine in ethanol at reflux to form the 6-aryl-3-hydroxypyridazine (4), as crystalline solids. Saponification with aqueous alkali followed by neutralization provides the 3-hydroxy-carboxy-6-aryl-pyridazines (5). The conversion of 3-hydroxy-4-carboxy-6-aryl-pyridazines to their dichlorides (6) has been previously described in U.S. Pat. No. 4,590,194 and is performed by heating the pyridazines (5) with a halogenating agent (phosphorus oxychloride being the preferred agent) at reflux temperature (80� C.) for 4 hours. The halogenating agent may be used neat or with inert solvent such as dioxane or toluene. The addition of a catalytic amount of DMF accelerates the reaction. Other suitable halogenating agents include phenylphosphinic dichloride and phorphorus trichloride.
The corresponding 3-bromopyridazines are prepared similarly by heating (5) with phosphorous oxybromide or phosphorus tribromide. The dichlorides (6) are isolated from the reaction mixture by removing excess halogenating agent and solvent in vacuo and rdissolving the residue in hot acetonitrile or other polar inert solvent. The reaction of the dichlorides (6) in acetonitrile with alcohols or amines yield the desired esters or amides (7).
Referring to Scheme II, intermediate ketomalonate addition products (2) can be prepared by deprotonatoin of the acetophenones (1) with lithium diisopropylamine (LDA) followed by the addition of ketomatonate. This procedure was generally used for electron-rich aryl methyl ketones. ##STR4## wherein R is phenyl, substituted aryl or heteroaryl. ##STR5##
Referring to Scheme III, the intermediate 3,5-difluoro-4-(methylsulfonyl)-acetophenone (6) was prepared from commercially available 2,6-difluoroaniline. Bromination of the aniline (1) in acetic acid followed by diazotization and treatment of the diazonium salt with dimethylsulfide provides the thiomethyl derivative (3). Palladium catalyzed coupling reaction of (3) with trimethylsilyacetylene yield arylacetylene (4).
Alkaline hydrolysis of the silyl group followed by mercuration and acidic solvolysis affords ketone (5). Oxidation of the ketone with Oxone provides the desired 3,5-difluoro-4-(methylsulfonyl)-acetophenone (6).
The following examples further illustrate the invention and are not to be construed as limiting of the specification and claims in any way.
Diethyl ketomalonate (17.4 g, 0.1 mol) was heated with 4-acetylpyridine (12.1 g, 0.1 mol) at 120� C. for 15 h under nitrogen to provide diethyl 2-hydroxy-2-(4-pyridyl)cabonylmethyl-malonate as a crystalline solid. The diester was refluxed in ethanol with a slight excess of hydrazine hydrate hydrochloride for 15 h to provide 3-hydroxy-6-(4-pyridyl)-4-carbethoxy-pyridazine (4, Scheme 1). The above ester was recrystallized from ethanol, hydrolyzed with aqueous sodium hydroxide followed by careful neutralization with hydrochloric acid to afford 3-hydroxy-6-(4-pyridyl)-pyridazine-4-carboxylic acid (5, Scheme 1). The acid was dissolved in phosphorous oxychloride containing a catalytic amount of DMF and the mixture was allowed to react at 80� C. for 4 h to provide 3-chloro-4-chlorocarbonyl-6-(4-pyridyl)pyridazine (6, Scheme 1) as a dark oil The above dichloride was treated with gaseous ammonia in acetonitrile to afford the title compound as a tan solid. The above dichloride was treated with excess gaseous ammonia to afford the title compound as a tan solid: 1 H NMR (DMSO-d6) δ 8.80 (d, J=6 Hz, 2H), 8.59 (s, 1H), 8.20 (s, 1H), 8.17 (d, 6 Hz, 1H).
Utilizing appropriate starting materials and respects, and following the procedures described in the Schemes and Example 1, the following compounds were prepared.
The title compound was prepared by treating pyridazine dichloride with anhydrous ethanol and a slight excess of triethylamine. The title compound was purified via silica gel chromatography (20% ethyl acetate/hexane). Anal. Calcd. for C12 H10 ClN3 O2 : C, 54.66; H, 3.82; N, 15.94. Found: C, 54.07; H, 3.80; N, 15.83.
The title compound was prepared from 3-acetylpyridine. Anal. Calcd. for C10 H7 ClN4 O2 : C, 51.18; H, 3.09; N, 23.88. Found: C, 51.11; H, 3.09; N, 23.98.
The title compound was prepared from 4-trifluoromethylacetophenone. Anal. Calcd. for C12 H7 ClF3 N3 O: C, 47.78; H, 2.34; N, 13.92. Found: C, 48.13; H, 2.14; N, 13.88.
The title compound was prepared from 3,5-dichloroacetophenone. DCI-MS m/z 301.
The title compound was prepared from 2-acetonaphthone. DCI-MS m/z 283 (M+).
The title compound was prepared from 4-nitroacetophenone. FAB-MS m/z 279 (M+H+).
The title compound was prepared from 3-chloro-4-cyanoacetophenone. DCI-MS m/z 292.
The title compound was prepared from 2-acetylpyrazine. DCI-MS m/z 236 (M+H).
The title compound was prepared from 4-chloropropiophenone. DCI-MS m/z 282 (m+H+). 1 H NMR (MeOD) δ 7.33 (s, 4H), 2.12 (s, 3H). Anal. Calcd. for C12 H9 Cl2 N3 O: C, 51.09; H, 3.22; N, 14.89. Found: C, 50.98; H, 3.34; N, 14.48.
The title compound was prepared by treating the dichloride (6) with 2,4-dichlorobenzylamine according to Scheme I. DCI-MS m/z 392 (m+H+). 1 H NMR (CDCl3) δ 8.83 (d, J=6 Hz, 2H), 8.33 (a, 1H), 8.00 (d, J=6 Hz, 2H), 7.5 (m, 2H), 7.3 (m, 3H), 4.76 (d, J=6 Hz, 2H).
The title compound was prepared by treating the dichloride (6) with glycyl-ethyl ester according to Scheme I. DCI-MS m/z 320 (M+H). 1 H NMR (DMSO-d6) δ 8.80 (d, J=6 Hz, 2H), 8.52 (s, 1H), 8.16 (d, J=6 Hz, 2H), 4.13 (m, 4H), 1.22 (t, J=7.1 Hz, m, 3H).
The title compound was prepared by reacting the dichloride (6) with 2,4-dichlorobenzylamine according to Scheme I. Anal. Calcd. for C17 H10 Cl4 N4 O: C, 47.7; H, 2.35; N, 13.09. Found: C, 47.61; H, 2.25; N, 13.06.
The title compound was prepared via catalytic hydrogenation of the p-nitrophenyl analog (5) of pyridazine followed by toluenesulftonylation and steps 4-5 according to Scheme I. DCI-MS m/z 402 (M+), 403 (mM+H).
The title compound was prepared from 4-acetylquinoline. 1 H NMR (MeOD) δ 4.65 (s, 3H), 7.45 (m, 2H), δ 8.80 (d, J=6 Hz, 2H), 7.64 (m, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 8.79 (d, J=4.45 Hz, 1H). The intermediate 4-acetylquinoline was prepared by treatment of commercially available 4-quinolinecarboxaldehyde with methyl magnesium chloride in ether followed by oxidation of the resulting secondary alcohol with manganese dioxide.
A solution of acetophenone in THF at -70� C. was treated with a solution of lithium diisopropylamide in THF (Scheme II). After 15 min diethyl ketomalonate was added and the reaction was allowed to warm to room temperature. The resulting condensation product 2 (Scheme II) was used following the procedure of Scheme I. DCI-MS m/z 233 (M+), 234 (M+H).
The title compound was prepared from p-methoxyacetophenone in a manner analogous to Example 17. DCI-MS m/z 263 (M+), 264 (M+H).
The title compound was prepared from 3,5-difluoro-4-(methylsulfonyl)-acetophenone according to Scheme I. Anal. Calcd. for C12 H8 ClF2 N3 O3 : C, 41.45; H, 2.32; N, 12.08. Found: C, 41.19; H, 32.26; N, 12.03.
The intermediate 3,5-difluoro-4-(methylsulfonyl)acetophenone was prepared from commercially available 2,6-difluoroaniline according to Scheme III.
The title compound was prepared by refluxing 3-chloro-4-carboxamido-6-[3,5-difluoro-4(methyisulfonyl)phenyl]pyridazine made in Example 19 in methanol. DCI-MS m/z 359 (M+), 360 (M+H).
The title compound was prepared by treating the dichloride (6) with phenylalanine amide according to Scheme I. DCI-MS m/z 414 (M+), 415 (M+H).
The title compound was prepared from 3-chloro-4-fluoroacetophenone. DCI-MS m/z 286 (M+H+).
Compounds of the present invention were tested for IL-1β protease inhibition activity according to the following protocol:
Partially purified IL-1β protease is stored at -80� C., thawed on ice, and preincubated for 10 minutes at 37� C. with 2.5 mM dithiothreitol in a buffer solution containing 10 mM Tris-HCl (pH 8.0) and 25% (v/v) glycerol. Inhibitors are prepared as stock solutions in dimethyl sulfoxide (DMSO). The protease is preincubated with inhibitor in a volume of 20 μL in a 1.5 mL polypropylene microcentrifuge tube for 15 minutes at 37� C. The volume of compound added to the assay is adjusted to yield a DMSO concentration in the preincubation of <15% (v/v). The enzyme assay is then initiated by the addition of substrate (TRITC-AYVHDAPVRS-NH2) to yield a final concentration of 67 μM in a final volume of 30 μL. The reactions are carried out for 60 minutes at 37� C. in the dark and are terminated by the addition of 10 μL of 10% trifluoroacetic acid (TFA). Following the addition of 115 μL of 0.1% TFA, the samples are analyzed by high pressure liquid chromatography using a reverse phase (C18) column and elution with an acetonitrile/water/TFA gradient. Substrate and product are monitored by their absorbance at 550 nm and elute at 4.2 and 5.2 minutes, respectively.
The IL-1β protease inhibitory activity (IC50) for the pyridazine was <100 μM.
Although the invention has been described in the context of particular embodiments, it is intended that the scope of coverage of the patent not be limited to those particular embodiments, but be determined by reference to the following claims.
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Swedish word for "chav, townie", directly translates to snotkid.. pretty appropriate
ÖJJ stick från min bil snorungar
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("Oy you snotkid, get away from my car"
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$22 for a French and Asian fusion meal for two (up to a $46.65 total value)
- One appetizer (up to a $6.80 value)
- Two entrees (up to a $14.95 value each)
- One soufflé (a $9.95 value)
$42 for a French and Asian fusion meal for four or more (up to a $93.30 total value)
- Two appetizers (up to a $6.80 value each)
- Four entrees (up to a $14.95 value each)
- Two soufflés (a $9.95 value each)
See the menu, which is served Monday through Thursday from 3:30 p.m. to 2 a.m., and Friday and Saturday from 3:30 p.m. to 3 a.m.
Souffle Cafe
More than 10 flavors—among them, key lime, coffee, green tea, and red bean-coconut—compose the core of the decadent desserts that lend Souffle Cafe its name. Pastries, ice cream, cannoli, and smoothies made with real fruit also can sweetly cap one of the café's French and Asian fusion meals. To lead diners dessert-ward, cooks assemble classic sushi rolls such as spicy tuna and philadelphia, slather grilled chicken in housemade curry, and sizzle chicken, salmon, and beef in the Japanese teriyaki style.
I loved their white chocolate souffle! It was sooo soft and delicious!Racehl K., Yelp, 10/5/12
Great friendly place for soufflees, and smoothies. owners are really nice. Food was good and it is open late at night on week ends.Thierry H., Yelp, 11/15/11
Tips from Groupon Customers
"Great first time experience..."
"Environment and menu are a bit eclectic, but the souffles are great! "
"Please make it warmer inside - close the front door!"
North Beach
1401 Powell St.
San Francisco, California 94133
415-399-1687Get Directions


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Miller Std. 18" Spot Welder Tongs with 1 Set of Tips (040199)
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If Neils Miller doesn't have a statue in Appleton, Wisconsin, he should. You'll be hard pressed to find someone who has had a larger impact on the welding industry than Mr. Miller. Back in 1929, he saw a need for a small, affordable arc welder that would operate on the type of electricity readily available in rural Wisconsin. Using American ingenuity, he cobbled together scrap metal, core and coil materials and hammered out that first welder in his basement. Six short years later, Miller Electric Mfg. Co. produced an industry-changing industrial welder and the rest is history.
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- Thursday, 6 February 2014
- New York (New York)
The Fillmore New York at Irving Plaza
- 17 Irving Place Map
- 5gig.com always recommends to go to official sources to confirm the date, time and venue of the concert.
AER's latest setlist
The Theatre of Living Arts (Philadelphia) 21-03-2014
Whatever We Want, She'll Miss It, (If You Want) Trees, Come & Go, Suck My Kiss, Stars, Pretty Lady (Around Me), Floats My Boat, I'm With It, What You Need, Shout, Says She Loves Me, Songbird, Like the Way, Wonderin' Why, Spades, Clubs & DiamondsAER setlist on setlist.fm
Past AER gigs in New York
Latest AER news
AER latest news, rumors and lineup confirmations.
Oct 04, 2012
Aerosmith Extend 2012 Global Warming Tour. Ready to Release New Album November 6th.
Quite some time ago, we posted that Aerosmith was hoping to finalize an album and have it out by May of 2012. While, that time has obviously come and gone, and fans were only treated to the release of new single "Legendary Child" (listen below). However, the official word is out – an...
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