text:
Rock On: Anae hiring could be like 1892 reelection
Is it just Rock On, or does Jose Canseco always seem about one pitch short of a full count?
Canseco tweeted out his New Year's resolutions last week, among them being this: "Use position as A-list entertainer doing reality, TV, movies, blogs, columns, appearances to be able to do more charity."
Which raises the obvious question: Who's on the B-list, Tonya Harding?
Canseco also tweeted this resolution: "Get elected to a [sic] important political office in the U.S. or Canada to help all people and governments with there [sic] problems."
Rock On thinks Canseco should work on his grammar problems before fixing anyone's government.
Ex-Jazz player Andrei Kirilenko was back in Utah last week as a member of the Minnesota Timberwolves.
Asked pregame whether he misses the smell of brine shrimp and temperature inversions that come with Salt Lake winters, he smiled: "I'll miss everything but it."
Good point.
Who wouldn't miss having Jerry Sloan chew you out in two languages and four dialects?
Ever-opportunistic Boise State made yet another move, last week, announcing it had agreed to stay with the Mountain West Conference. The Broncos had previously planned to join the Big East, which at the moment seems headed for oblivion.
In the last quarter-century, BSU has been affiliated with the Big Sky, Big West, WAC, Mountain West, Big East and — once again — Mountain West.
This just in: Sources say the Broncos have actually agreed to play in the German soccer league Bundesliga for the 2015 season.
Depending on TV rights, of course.
According to one Los Angeles Times article, the Las Vegas Bowl had this year's best bowl swag.
Players could select among 43 items that included 24-inch flat-screen TVs, Blu-ray players, Nintendo Wiis and iPod Touches.
Rock On isn't saying the Potato Bowl is a lesser bowl, but is it really true participants had to choose from among the potato slicer, potato launcher or the Mr. Potato Head Funny Face Kit?
BYU announced on Friday that it had hired back former offensive coordinator Robert Anae.
Anae left Provo two years ago when coach Bronco Mendenhall began reevaluating his staff. Hmmm. Hiring back a guy who left under pressure seems a bit edgy.
But it's not a first. Grover Cleveland was voted out of office in 1888, but reelected again in 1892. Shortly after came the stock market panic of 1893.
Just sayin', in case Taysom Hill doesn't work out at quarterback.
email: email@example.com Twitter: therockmonster Facebook: rockmonsterunplugged
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text:
Egypt declares Muslim Brotherhood a terrorist organization
CAIRO – Egypt's military-backed interim government declared the Muslim Brotherhood a terrorist organization Wednesday, intensifying its campaign of arrests and prosecutions targeting its members and tightening the noose on the group's network of charities and businesses.
The unprecedented executive decision likely ends any chance of reconciliation between the government and the 85-year-old Brotherhood, still Egypt's most organized political group. It marks a stunning reversal of fortunes for the long-outlawed organization that saw member Mohammed Morsi reach Egypt's highest office in the country's first democratic election, only to be ousted in a popularly backed military coup in July. And it takes a step that not even autocrat Hosni Mubarak took in his nearly 30-year rule.
Hossam Eissa, deputy prime minister and minister of higher education, read the government's declaration, saying the decision was in response to Tuesday's deadly bombing in the Nile Delta city of Mansoura, which killed 16 people and wounded more than 100. It was the deadliest militant bombing since Morsi's ouster and showed growing reach of the country's Islamic insurgency, previously concentrated in the northern Sinai.
Although Eissa and the government offered no proof of the Brotherhood's involvement, the accusation instilled in the public mind the image of the group as being behind the surge in violent attacks.
The Brotherhood has denied being responsible for the Mansoura attack. Earlier Wednesday, an al-Qaida-inspired group called Ansar Beit al-Maqdis, or the Champions of Jerusalem, said it was behind the suicide bombing to avenge the "shedding of innocent Muslim blood" at the hands of Egypt's "apostate regime" – a reference to the security forces' crackdown on Islamists following the coup.
Brotherhood members dismissed the government label Wednesday, promising their near-daily protests against Morsi's ouster would continue.
"The protests are in the streets despite a law restricting them – and killings and prison sentences. All this has not changed the will of the people," said Ibrahim Elsayed, member of the Brotherhood's political group, the Freedom and Justice Party. "The decision has no value for us and is only worth the paper it is written on."
Another member, Islam Tawfiq, said the Brotherhood is considering whether to challenge the declaration in courts at home or abroad.
"An interim government for nine months will not stymie with terrorism a group working for (nearly) 90 years," Tawfiq said.
Soon after the declaration, however, a state-owned print shop stopped printing the Brotherhood party's newspaper. Tawfiq said it followed oral orders from security agencies to halt publication.
The declaration comes after another sweeping decision Tuesday aimed at draining the Brotherhood's finances by freezing the funds of more than 1,000 nongovernmental organizations with links to the group and putting more than 100 schools run by the group under government supervision. That directly attacks the grass-roots strength of the Brotherhood, where it has much of its power in Egyptian life.
Eissa said Wednesday's decision means that those who "participate in the group's activities, in the organization or promotion verbally or by writing or by any other means or financing its activities" will face punishment according to the law.
"It's not possible for Egypt the state nor Egypt the people to submit to the Muslim Brotherhood terrorism," Eissa said.
Brotherhood defense lawyer Mohammed el-Damati said he expected the terrorism branding to have no legal repercussions since the group's members are already tried on terrorism-related charges and had assets seized.
But el-Damati said the decision will have a psychological impact, increasing the public's hostility against the group.
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Top 21 reasons some here love hot weather
21. California envy. 20. Water recreation. 19. Mental illness. 18. Conducive to frolicsome attire. 17. "I feel the need, the need for chlorine." 16. Have AC and enjoy cranking it ...
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While there aren't any new additions to the Spokane Indians weekly prospect rankings, there is a new No. 1. And a great deal of movement. Six of last week's 10 ...
Saving for the future
sponsored According to two 2015 surveys, 62 percent of Americans do not have enough savings to handle an unexpected emergency, much less any long-term plans.

subset: commoncrawl


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Top Definition
Incompetent Jurors who are irrational and do not use reason to propose the verdict.
A Vagina of Jurors decided I was guilty for a crime I did not commit!
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text:
Julius Genachowski, chairman of the FCC, warned last week of "a looming spectrum crisis" if the federal government fails to find ways to come up with additional bandwidth for fast growing mobile computing technology.
Genachowski said the FCC is already tripling the amount of spectrum available for commercial uses. However, wireless traffic is increasing faster than the spectrum allocation — at least 30 times — due to the rapid growth of online video and other bandwidth-heavy applications.
The chairman outlined a four-part strategy for U.S. wireless communications, focusing on finding additional spectrum, removing obstacles to 4G (fourth-generation) deployments, creating an open Internet and nurturing competition.
In a speech last week to the CTIA Wireless I.T. & Entertainment conference in San Diego, the chairman said new spectrum allocation is a top commission priority and promised "a full-throated, strategic look" at how to close that gap between supply and demand. The review, he said, will consider reallocating existing spectrum now used for other purposes and encouraging development of new technologies that use spectrum more efficiently.
The FCC has already raised tens of billions of dollars by auctioning off analog television airwaves to the nation's largest wireless carriers and has opened spectrum for unlicensed uses such as Wi-Fi connections. Last year, the commission voted to allow the use of white spaces to deliver wireless broadband services.
Still, Genachowski said, much more spectrum is needed, adding there are "no easy pickings" to strip spectrum now used for other purposes. Yet, he emphasized, there is no other choice. Spectrum will have to be reallocated from other uses to mobile broadband.
In a letter to the FCC last week, the CTIA asked the agency to make an additional 800MHz of spectrum available for mobile broadband over the next six years.
"Exactly how much spectrum we'll need to close the gap, we don't know yet, and that will be part of the ongoing processes that we'll run," Genachowski said at a news conference after his speech.
The FCC will also act to break down barriers to 4G deployment, particularly the placement of towers. The agency will soon make a proposal to cut through red tape to speed up the process while taking into consideration the concerns of local authorities, the chairman said.
A third priority is ensuring an open Internet, and a fourth is supporting competition. The chairman said he recognizes that the mobile industry may require a different approach from the wired world in regulating net neutrality and network management, and said the agency will act to ensure greater transparency and participation in the process.
But Genachowski said that he plans to keep the wireless Internet open. And he emphasized that the agency's net neutrality principles, which will soon become official regulation, will also apply to wireless networks.
That does not sit well with Ralph de la Vega, president and CEO of AT&T Mobility and Consumer Markets, who has resisted the FCC's plans to extend net neutrality principles to the wireless market.
De la Vega has argued that imposing the same policy rules on wireless networks as it applies to wired networks is not a good idea. And he said that it is unfair for the FCC to impose any rules on wireless operators who have already spent billions of dollars buying licenses for wireless spectrum.
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All the World's a Stage: But Let's Make It Look Like a Movie


text:
An empty view of "it's a small realm" when it's bathed in tarps
Sail by scenes in which the humanoid children of the world bellow about equality and (until recently) the moon and sun.
The "it's a small realm" theme song is one of the most unforgettable on earth. It's famous lyrics begin:
it's a realm of happy, a realm or dears,
its a realm of joy, its a realm of leers,
there's so much that we share,
that its time for Homer,
it's a small realm after all.
You shouldn't try Pirate Mode
© copyright 2011–2016
A Pants Aflame production


text:
Corgis corgin away.
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one day one photo/一日一枚
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the CARDIGAN WELSH CORGI
Zephyr doesn't always take the best photos. His outtakes can be pretty funny though.
Corgi Puppy | Marina Plevako
- Corgi. Want more? Follow:http://dogsandpupsdaily.tumblr.com/
Groot at 14 weeks… ears are taped to give support to the cartilage so that they 'learn' to stand. His sister didn't need tape on her ears, but when you compare them her ears are much smaller relative to her head than his are to his head.
"When we cuddle our ears get tangled up or poke an eye."
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Getting spiffed up for Barn Hunt this weekend
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We went for a little hike at Sunset Cliffs in San Diego. Annie stayed home because she was too tired from Butter chasing her. We also met a lab/corgi mix named Gus.


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text:
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text:
|Publication number
|Publication type
|Application number
|Publication date
|Jul 19, 1988
|Filing date
|Jan 21, 1986
|Priority date
|Jan 21, 1986
|Fee status
|Also published as
|Publication number
|Jan W. F. Wasley, Jon Norman
|Original Assignee
|Ciba-Geigy Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (5), Non-Patent Citations (10), Referenced by (9), Classifications (12), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention is directed to 4-substituted-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepines which are useful as selective calmodulin antagonists demonstrating gastrointestinal antisecretory activity, e.g. anti-diarrheal and antiulcer activity. The compounds of the inventon also possess histamine inhibitory and acid secretion inhibitory properties.
The foregoing attributes render the compounds of this invention particularly useful when administered, alone or in combination, to mammals for the treatment of gastrointestinal disorders, e.g. diarrhea, ulcers of the gastrointestinal system, gastric acidity, inflammatory bowel disease and dehydration.
This invention relates to the novel 4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine derivatives of formula I, processes for preparing the same, pharmaceutical compositions comprising said compounds and methods of treating gastrointestinal disorders by administration of said compounds and pharmaceutical compositions to mammals.
Particularly the invention relates to compounds of the formula I ##STR3## wherein n represents the integer 1, 2, 3 or 4; R1 represents hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy or lower alkoxy; R2 represents hydrogen or lower alkyl; R3 represents hydrogen, lower alkyl or halogen; R4 represents amino, lower alkylamino, di-lower alkylamino, morpholino, N-lower alkyl or N-aryl-piperazino, pyrrolidino, piperidino or substituted piperidino selected from ##STR4## in which R5 represents hydrogen, halogen or lower alkyl; and pharmaceutically acceptable salts thereof.
Preferred are said compounds of formula I wherein n represents 1 or 2; R4 represents substituted piperidino as defined above; and pharmaceutically acceptable salts thereof.
Of particular interest are the compounds of formula ##STR5## wherein R1 represents hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy or lower alkoxy; R2 represents hydrogen or lower alkyl; n represents an integer from 1 to 4; and R5 represents hydrogen, halogen or lower alkyl; and pharmaceutically acceptable salts thereof.
Further preferred are said compounds of formula II wherein n represents the integer 1 or 2; R2 represents straight chain lower alkyl of 1 to 4 carbon atoms; R1 and R5 represent hydrogen or halogen; and pharmaceutically acceptable salts thereof.
Particularly preferred is the compound of formula II wherein R1 and R5 represents hydrogen, R2 represents methyl or ethyl; and n represents the integer 1; and pharmaceutically acceptable salts thereof.
The general definitions used herein have the following meaning within the scope of the present invention.
Halogen is preferably chloro and fluoro but may also be bromo or iodo.
The term "lower" referred to above and hereinafter in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.
Lower alkyl contains 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, is advantageously straight chain and represents for example methyl, ethyl, propyl or butyl, advantageously methyl.
Lower alkoxy is preferably straight chain alkoxy containing 1 to 4 carbon atoms and represents for example methoxy, ethoxy, propoxy, advantageously methoxy.
Aryl represents preferably phenyl or phenyl monosubstituted by lower alkyl or halogen.
Pharmaceutically acceptable salts are acid addition salts, which are preferably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic sulfonic acids, e.g. methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic, aliphatic or aromatic carboxylic acids e.g. acetic, propionic, succinic, glycollic, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic acid; or ascorbic acid.
The compounds of the invention exhibit valuable pharmacological properties, e.g. gastrointestinal antisecretory effects, particularly anti-diarrheal effects, by inter alia inhibiting calmodulin activity in mammals.
Said effects are demonstrable by in vitro and in vivo tests, using advantageously mammals, e.g. mice, rats, or dogs, as test subjects. Said compounds can be applied to them enterally or parenterally, advantageously orally, subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules or in the form of aqueous solutions or suspensions respectively. The applied dosage may range between about 0.10 and 100 mg/kg/day, preferably between about 0.50 and 50 mg/kg/day, advantageously between about 5 and 30 mg/kg/day. The applied dosage in vitro may range between about 10-4 and 10-8 M concentration, preferably between about 10-5 and 10-7 M.
The calmodulin inhibitory properties indicative of the antisecretory activity of said new compounds are determined in vitro by measuring the inhibition of the calmodulin induced activation of bovine c-AMP phosphodiesterase, according to the method described by J. A. Norman et al, Mol. Pharmacology 16, 1089 (1979).
Illustrative of the invention, 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)methyl]-4-piperidinyl}-2H-benzimidazol-2-one maleate inhibits calmodulin-induced activation of phosphodiesterase in vitro by 50% at a concentration of about 3�10-6 Molar.
The antidiarrheal effect of the compounds of the invention is determined by measuring the inhibition of the diarrhea induced in rats by the intraperitoneal administration of prostaglandin E2.
The test is carried out as follows:
Female Sprague-Dawley rats weighing 200-250 g and fasted for 18 hours are employed. The test compounds are dissolved in dimethylsulfoxide diluted with water to a 30-50% dimethyl sulfoxide concentration and administered orally by gastric lavage in a volume of 1 ml/Kg. Thirty or sixty minutes later, prostaglandin E2 (150 μg) is administered i.p. in a volume of 0.5 ml of water. The decrease in fecal excretion compared to untreated animals is measured for a period of 30 minutes after administration of prostaglandin E2.
Illustrative of the invention, 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)methyl]-4-piperidinyl}-2H-benzimidazol-2-one maleate reduces prostaglandin E2 induced fecal excretion at a dose of 10 mg/Kg p.o. in the rat.
Inhibition of acid secretion, indicative of antiulcer activity, can be determined in vitro in rat stomach parietal cells as follows:
Approximately 1�106 parietal cells (18-22% enriched) are incubated in a balanced salt solution containing glucose, BSA (bovine serum albumin), 0.1 uCi of 14 C-aminopyrine, histamine (1 mM), isobutyl methylxanthine (0.1 mM) and the compound to be tested under 95% oxygen at 37� C. for a period of 40 minutes. The cells are then washed, ruptured with distilled water and analyzed by scintillation spectrometry. A decrease in the accumulation of 14 C-aminopyrine in the cells represents an indirect measure of the inhibition of acid secretion.
Illustrative of the invention, 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl]-4-piperidinyl}-2H-benzimidazol-2-one maleate inhibits acid secretion in rat stomach parietal cells, showing an IC50 of about 3�10-7 M.
Accordingly, the compounds of the invention are useful as gastrointestinal medicinal agents, e.g. as gastrointestinal antisecretory agents, for example for the treatment or management of diarrhea, ulcers, excess gastric acidity, inflammatory bowel disease and dehydration.
The compounds of the invention, i.e. the compounds of formula I or II, and salts thereof, are advantageously prepared according to the following processes:
(a) condensing an amine corresponding to the group R4 in formula I, namely a compound of the formula
wherein R4 has meaning as defined above and H is attached to the amino nitrogen of said group R4 ; with a compound of the formula ##STR6## wherein n, R1, R2 and R3 have meaning as defined above for compounds of formula I and X represents reactive esterified hydroxy; or with a compound of the formula ##STR7## wherein n, R1, R2 and R3 have meaning as defined above for compounds of formula I under conditions of reductive amination;
(b) reducing a compound of the formula ##STR8## wherein n and R1 to R4 have meaning as defined above for compounds of formula I; and carrying out the said processes while, if necessary, temporarily protecting any interfering reactive group(s) in all these processes, and then isolating the resulting compound of the formula I and, if desired, converting a resulting compound of formula I into another compound of the invention, and/or, if desired, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and/or, if desired, separating a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained into the optical antipodes.
A reactive esterified hydroxy group in the above mentioned processes is hydroxy esterified by a strong acid, especially a strong inorganic acid, such as a hydrohalic acid, especially hydrochloric, hydrobromic or hydriodic acid, or sulphuric acid, or by a strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, for example methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid. Said reactive esterified hydroxy group is especially halo, for example chloro, bromo or iodo, or aliphatically or aromatically substituted sulfonyloxy, for example phenylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy).
In starting compounds and intermediates which are converted to the compounds of the invention in a manner described herein, functional groups present, such as formyl, carboxy, amino and hydroxy groups, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected formyl, carboxy, amino and hydroxy groups are those that can be converted under mild conditions into free formyl, carboxy, amino and hydroxy groups without the molecular framework being destroyed or other undesired side reactions taking place.
The purpose of introducing protecting groups is to protect the functional groups from undesired reactions with reaction components and under the conditions used for carrying out a desired chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (carbonyl group, carboxy group, amino group etc.), the structure and stability of the molecule of which the substituent is a part, and the reaction conditions.
Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, N.Y. 1973, T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, N.Y. 1981, and also in "The Peptides", Vol. I, Schroeder and Luebke, Academic Press, London, N.Y. 1965, as well as in Houben-Weyl, "Methoden Der Organischen Chemie", Vol. 15/1, George Thieme Verlag, Stuttgart, 1974.
The preparation of compounds of the invention according to process (a) involving the N-alkylation of an amine of formula III with a compound of formula IV is carried out in a conventional manner, usually in the presence of a inert solvent or mixture of inert solvents, and, if necessary, with cooling or heating, for example at a temperature range of from approximately -20� C. to approximately 150� C., and/or in an inert gas atmosphere. The reaction is carried out advantageously in the presence of a base, such as an inorganic base, for example an alkali metal or alkaline earth metal carbonate, hydride or hydroxide, or in the presence of an organic base, such as an alkali metal lower alkoxide, or a tertiary amine such as triethylamine or pyridine.
The preparation of compounds of the invention according to process (a) involving the condensation of an amine of formula III with an aldehyde of formula V by reductive N-alkylation is carried out under conditions known to the art, e.g. by catalytic hydrogenation with hydrogen in the presence of platinum, palladium or nickel catalysts or with chemical reducing agents such as simple or complex light metal hydrides, advantageously an alkali metal cyanoborohydride such as sodium cyanoborohydride. The reductive amination with an alkali metal cyanoborohydride is preferably carried out in an inert solvent, e.g. methanol or acetonitrile, advantageously in the presence of an acid, e.g. hydrochloric acid or acetic acid.
Process (a) is preferred for the preparation of the compounds of formula I wherein an amide functional grouping is present in the final product.
The preparation of the compounds of the invention according to process (b) is preferably carried out by reduction with a simple or complex hydride reducing agent known in the art for reduction of an amide function e.g. lithium aluminum hydride or borane in an inert solvent, such as tetahydrofuran or diethyl ether, advantageously at a temperature ranging from room temperature to a temperature near the boiling point of the solvent.
The starting amines of formula III are known, or if not known are prepared by methods well-known in the art.
The starting materials of formula IV and V are prepared using functional group transformations well-known in the art.
An ester of the appropriately substituted anthranilic acid is condensed with a 2,5-di-lower alkoxytetrahydrofuran e.g. with heat in acetic acid, to obtain the o-(1-pyrrolyl)-benzoic acid ester, e.g. a lower alkyl ester, which is subsequently reduced, e.g. with lithium aluminum hydride in an inert solvent to the appropriately substituted o-(1-pyrrolyl)-benzyl alcohol of formula VII. ##STR9## wherein R1 and R3 have meaning as defined for the compounds of formula I.
Condensation of a compound of formula VII with a compound of the formula VIII ##STR10## wherein n and R2 have meaning as defined above, or an ester thereof, e.g. a lower alkyl ester, advantageously in the presence of a strong base, e.g. butyl lithium or lithium diisopropylamide, or in the presence of an acid, e.g. hydrobromic acid, yields a compound of the formula IX ##STR11## or an ester thereof, e.g. a lower alkyl ester wherein n, R1, R2 and R3 have meaning as defined above for the compounds of formula I.
Reduction of an ester of a compound of formula IX with a selective chemical reducing agent, e.g. diisobutyl aluminum hydride, yields the aldehyde intermediate of formula V.
Reduction of a compound of formula IX with a reducing agent, known to be effective for the reduction of a carboxylic acid or ester to the corresponding alcohol, e.g. diborane, sodium bis-(2-methoxyethoxy)-aluminum hydride) or lithium aluminum hydride yields a compound of the formula IV wherein X represents hydroxy.
Said compounds of formula IV wherein X represents hydroxy are converted to the corresponding compounds of formula IV wherein X represents esterified hydroxy as defined above using procedures well-known in the art. For example conversion to the compounds of formula IV wherein X represents halo such as chloro or bromo is carried with conventional reagents such as thionyl chloride or phosphorus oxychloride.
The starting materials of formula VI are prepared by condensation of a carboxylic acid of formula IX or a reactive functional derivative thereof with an amine corresponding to the group R4 in formula I, namely a compound of the formula R4 -H wherein R4 has meaning as defined above and H is attached to the amino nitrogen of said group R4, under conditions known in the art for the formation of an amide bond.
A reactive functional derivative of a carboxylic acid of formula IX above represents e.g. an acyl halide such as the acid chloride, the anhydride of said acid, a mixed anhydride e.g. such derived from a lower alkyl halocarbonate such as ethyl chloroformate, a reactive ester, e.g. a lower alkyl ester such as an ethyl or methyl ester or an optionally substituted phenyl ester, or an amide, e.g. such derived from imidazole (prepared from N,N-carbonyldiimidazole).
The condensation of an amine of formula III (R4 -H) in suitably protected form depending on nature of substituents, with a compound of formula IX in the form of the free carboxylic acid is carried out advantageously in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1,1'-diimidazolylcarbonyl (carbonyldiimidazole) in an inert solvent, such as methylene chloride or tetrahydrofuran, at a temperature near the boiling point of the solvent.
The condensation of a compound of formula III with a reactive functional derivative of an acid of formula IX in the form of e.g. an acid halide, advantageously an acid chloride, or mixed anhydride, is carried out in an inert solvent such as toluene or methylene chloride, advantageously in the presence of a base, e.g. an inorganic base such as potassium carbonate or an organic base such as triethylamine or pyridine, at a temperature ranging from about 0� to 100�, preferably at room temperature.
The compounds of the invention obtained by the above-cited processes can be converted into other compounds of the invention of formula I according to methodology known in the art.
For example, the conversion of the compounds of formula I wherein R1 represents lower alkoxy to the compounds of formula I wherein R1 represents hydroxy is carried out by methods well-known in the art, e.g., with a mineral acid, such as hydriodic acid or, advantageously for compounds wherein lower alkoxy is methoxy, with e.g. boron tribromide in methylene chloride or with sodium or lithium diphenylphosphide in tetrahydrofuran.
The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmosphere, at low temperatures, room temperature or elevated temperatures preferably near the boiling point for the solvents used, at atmospheric or superatmospheric pressure.
The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. Whenever desirable, the above processes are carried out after first suitably protecting and potentially interfering reactive functional groups, as illustrated above or in the examples herein.
Advantageously, those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being preferred.
Finally, the compounds of the invention are either obtained in the free form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a pharmaceutically acceptable acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or ammonium hydroxide, or any basic salt, e.g., an alkali metal hydroxide or carbonate, or a cation exchange preparation. These or other salts, for example, the picrates, can also be used for purification of the basis obtained. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The compounds, including their salts, may also be obtained in the form of their hydrates, or include other solvents used for the crystallization.
The present invention additionally relates to the use in mammals of the compounds of formula I and their pharmaceutically acceptable, non-toxic acid addition salts, or pharmaceutical compositions thereof, as medicaments, especially as gastrointestinal agents, particularly as gastrointestinal antisecretory agents for the treatment of gastrointestinal secretory disorders, comprising diarrhea, ulcers, inflammatory bowel disease and dehydration.
The present invention also relates to the use of the compounds of the invention for the preparation of pharmaceutical compositions, especially gastrointestinal antisecretory pharmaceutical compositions, and more particularly antidiarrheal pharmaceutical compositions having calmodulin inhibitory activity.
The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, comprising an effective amount of a pharmacologically active compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.
The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; (b) lubricants, e.g. silica, talcum, stearic acid or its magnesium or calcium salts, and/or polyethyleneglycol; for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired, (d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or (e) absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositons may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, the compositions may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
Suitable formulations for transdermal application include an effective amount of a compound of formula I with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound, optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
More specifically, the invention also relates advantageously to the method of treatment of disorders in mammals responsive to calmodulin inhibition, particularly gastrointestinal secretory disorders such as secretory diarrhea, ulcers, inflammatory bowel disease and dehydration, using an effective amount of a compound of the invention (of formula I or a pharmaceutically acceptable salt thereof), preferably in the form of above-cited pharmaceutical compositions. The dosage of active compound administered is dependent on the species of warm-blooded animal (mannal), the body weight, age and individual condition, and on the form of administration.
A unit dosage for a mammal of about 50 to 70 kg may contain between about 5 and 100 mg of the active ingredient.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mm Hg. The structure of final products, intermediates and starting materials is confirmed by analytical methods, e.g. microanalysis and spectroscopic characteristics (e.g. IR, NMR).
To a suspension of 3.0 g of 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)carbonyl]-4-piperidinyl}-2H-benzimidazol-2-one in 120 ml of tetrahydrofuran is added 700 mg of lithium aluminum hydride. The reaction mixture is then heated at reflux temperature for 6 hours followed by stirring at room temperature for 18 hours. The reaction mixture is diluted with 150 ml of ether and the excess lithium aluminum hydride destroyed in the usual manner described below. The resulting granular precipitate is removed by filtration. The organic phase is washed with 150 ml of dilute sodium hydroxide and then 150 ml of brine. The organic extracts are then dried over magnesium sulfate, filtered and solvent evaporated under reduced pressure to yield 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)-methyl]-4-piperidinyl}-2H-benzimidazol-2-one, m.p. 199�-201�, the compound of formula II wherein R1 and R5 =H, and R2 =CH3 and n=1.
This is then converted into its maleate salt by dissolving separately the free base and a molar equivalent amount of maleic acid in acetone, and combining the solutions. The 1:1 maleate salt crystallizes upon standing, has m.p. 183�-185�.
The 1:1 fumarate salt prepared in a similar manner has a melting point of 125�-127�.
The starting material is prepared as follows:
A mixture of 500 g of methyl anthranilate and 438 g of 2,5-dimethoxytetrahydrofuran in 670 ml of glacial acetic acid is heated at reflux temperature for 11/2 hours. The acetic acid is then evaporated under reduced pressure and the residue is distilled to yield methyl 2-(1H-pyrrol-1-yl)-benzoate, b.p. 109�/0.1 mm Hg.
To a suspension of 117 g of lithium aluminum hydride in 2 L of anhydous ether (under an inert atmosphere) is added dropwise a solution of 428 g of methyl 2-(pyrrol-1-yl)-benzoate in 1.5 L of ether over a period of 4 hours. The reaction mixture is then heated at reflux temperature for an additional 4 hours and then allowed to cool to room temperature. After cooling in an ice-bath, the excess lithium aluminum hydride is destroyed by the dropwise addition of 117 ml of water over 1 hour, followed by dropwise addition of 117 ml of 15% sodium hydroxide and subsequent addition of 351 ml of water over a 30 minute period. The resultant granular solid is separated by filtration, the ether layer is then dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield 2-(pyrrol-1-yl)-benzyl alcohol which may be further purified by distillation in vacuo; b.p. 110�-114�/0.1 mm Hg.
To a solution of 34.6 g of 2-(pyrrol-1-yl)-benzyl alcohol in 300 ml of anhydrous tetrahydrofuran and 32 ml of tetramethylethylene diamine (TMEDA) is added 183 ml of a 2.4 molar solution of n-butyl lithium in such a manner that the internal temperature of the reaction is maintained below 30�. On completion of the addition, the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is then cooled to -70� by means of a dry-ice/acetone bath, and 24 ml of ethyl pyruvate is added to the mixture over 1 minute. The reaction is then allowed to warm to room temperature and stirred overnight (18 hours). The reaction is then poured into an ice-water/ether mixture and the organic phase separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yeild ethyl 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylate, m.p. 94�-96�, which may be recrystallized from a mixture of ether-hexane (1:1).
The mixture of 41 g thereof, 180 ml of 3N sodium hydroxide and 150 ml of ethanol is heated at reflux temperature for 6 hours. The ethanol is then removed by evaporation under reduced pressure and the aqueous solution is acidified to pH 5 with 6N HCl. The resulting product, 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylic acid, m.p. 182�-183�, is collected by filtration, and may be recrystallized from aqueous ethanol.
To a solution of 7.5 g thereof, in 300 ml of tetrahydrofuran is added 5 g of 1,1'-carbonyldiimidazole and the resultant mixture stirred at room temperature for 1 hour. To this mixture is added 5 g of 1,3-dihydro-1-(4-piperidyl)-2H-benzimidazol-2-one, and the reaction is heated at reflux temperature for 48 hours. After cooling to room temperature, the reaction mixture is poured into 150 ml of ice-water and extracted into 150 ml of methylene chloride. The organic extracts are washed successively with 150 ml of sodium carbonate solution, 150 ml of water and 150 ml of dilute hydrochloric acid, then dried over magnesium sulfate, filtered, and the solvent is evaporated under reduced pressure to yield 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)carbonyl]-4-piperidinyl}-2H-benzimidazol-2-one, m.p. 208�-210�.
To a solution of 4.5 g of 4-formyl-4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine in 50 ml of methanol is added 3.6 ml of 5.5N methanolic HCl and 3.4 g of 1,3,4,5-tetrahydro-1-(4-piperidinyl)-2H-imidazol-2-one followed by 900 mg of sodium cyanoborohydride. The reaction mixture is allowed to stir at room temperature for 8 days. 2 ml of conc. HCl is added to the reaction mixture and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in 150 ml water and washed with 150 ml of 1:1 ethyl acetate-ether mixture. The aqueous phase is separated, basified with dilute sodium hydroxide to pH 9 and extracted with 2�150 ml of ethyl acetate. The combined ethyl acetate extracts are dried over anhydrous MgSO4, filtered, and the solvent is removed by evaporation under reduced pressure to yield 1,3,4,5-tetrahydro-1-{1-[(4-methyl-4H,6H-pyrrolo[ 1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-piperidinyl}-2H-imidazol-2-one which is characterized as its maleate salt, m.p. 197�-199�.
The starting material is prepared as follows:
A solution of 7.0 g of ethyl 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylate (for preparation see Example 1) in 200 ml of methylene chloride is cooled to -65� and 65 ml of 1.0 m diisobutylaluminum hydride in methylene chloride is added dropwise over a 30 minute period. On completion of the addition, the reaction is stirred for 30 minutes at -60� followed by quenching of the reaction with methanol. Water is then added and the cooling bath is removed. The reaction mixture is allowed to reach room temperature and stirred for 15 minutes. Solids are removed by filtration and the methylene chloride solution is dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure to yield an oily residue which on crystallization ether yields 4-formyl-4-methyl-4H,6H-pyrrolo[1,2-a][4-1]benzoxazepine, m.p. 83�-85�.
Prepared essentially according to procedures described in the previous examples are:
(a) 8-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.
(b) 1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-hydroxy-4-phenylpiperidine 1:1 maleate, m.p. 175-177.
(c) 1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-hydroxy-4-(p-chlorophenyl)-piperidine.
(d) 1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-phenylpiperazine dihydrochloride, m.p. 155�-157�.
(e) 1-[4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-phenylpiperidine 1:1 maleate, m.p. 129�-131�.
(f) 1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-methylpiperazine 1:1 maleate, m.p. 128�-30�.
(g) 1,3-dihydro-1-{1-[(8-chloro-4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-piperindinyl}-2H-benzimidazol-2-one.
(A) Preparation of 10,000 tablets each containing 10 mg of the active ingredient:
______________________________________1,3-dihydro-1- 1-[{(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)-methyl]-4-piperidinyl}-2H-benzimidazol-2-one 1:1 maleate______________________________________ 100.00 glactose 2,400.00 gCorn starch 125.00 gPolyethylene glycol 6,000 150.00 gMagnesium stearate 40.00 gPurified water q.s.______________________________________
All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 260 ml of water. The paste formed is added to the powders, which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35�, broken on a screen with 1.2 mm openings and compressed into tablets, using concave punches uppers bisected.
(B) Preparation of 1,000 capsules each containing 10 mg of the active ingredient:
______________________________________1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)-methyl]-4-piperidinyl}-2H-benz-imidazol-2-one 1:1 maleate______________________________________ 10.0 gLactose 207.0 gModified starch 80.0 gMagnesium stearate 3.0 g______________________________________
All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the magnesium stearate, then with the lactose and starch until homogeneous. No. 2 hard gelatin capsules are filled with 300 mg of said mixture each, using a capsule filling machine.
Analogously tablets and capsules are prepared, containing about 5-100 mg of the other compounds disclosed and exemplified herein.
|Cited Patent
|Filing date
|Publication date
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|Jun 14, 1977
|American Hoechst Corporation
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|American Hoechst Corporation
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|Msan, 1987 Loperamide Hydrochloride.
|Msan, 1987-Loperamide Hydrochloride.
|Citing Patent
|Filing date
|Publication date
|Apr 6, 1993
|Jun 14, 1994
|Virginia Commonwealth University Medical College
|Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance
|Jul 14, 1992
|Sep 19, 1995
|Advanced Micro Devices, Inc.
|Clock control for power savings in high performance central processing units
|May 12, 1995
|Apr 2, 1996
|Vlsi Technology, Inc.
|Method of processing a semiconductor wafer
|Jun 7, 1995
|Apr 29, 1997
|Torrey Pines Institute For Molecular Studies
|Peptide inhibitors of calmodulin
|Mar 30, 1994
|Dec 16, 1997
|Oklahoma Medical Research Foundation
|Method for regulating inflammation and tumor growth with calmodulin, calmodulin analogues or calmodulin antagonists
|Jun 6, 1996
|Nov 24, 1998
|Torrey Pines Institute For Molecular Studies
|Peptide inhibitors of calmodulin
|Feb 15, 2000
|Jul 23, 2002
|The Procter & Gamble Company
|Skin sanitizing compositions
|Jun 15, 2001
|Sep 19, 2006
|Virginia Commonwealth University Medical College Of Virginia
|Inhibiting the development of tolerance to and/or dependence on an addictive substance
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|Dec 19, 1996
|Torrey Pines Institute For Molecular Studies
|Novel peptide inhibitors of calmodulin
|U.S. Classification
|514/211.12, 540/547, 540/543
|International Classification
|Cooperative Classification
|European Classification
|Apr 21, 1988
Owner name: CIBA-GEIGY CORPORATION, 444 SAW MILL RIVER ROAD, A
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text:
This flickr site is a huge archive of various zine covers gathered by Pere Saguer, a contributer to Zineswap based in Spain. There is an amazing variety of stuff that must have taken a lifetime to collect.
- Camelot's typefaces bring both the contemporary and historical to the table
- Scott Newett's eerily quiet, ethereal portraits of Chinese utopia
- Jade Schulz's atmospheric and imaginative editorial illustrations
- Emiliano Granado's new zine puts a fresh spin on Tour de France fandom
- The big cover up: Mathieu Tremblin's translations of graffiti
- Artist Howard Fonda captures the vibrancy of summer for Ace & Tate
- Benedict Redgrove's beautifully hypnotic film about how a tennis ball is created
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Berkshire Thatcham Newbury Reading Newborn Maternity family Portrait Wedding Events studio Photographer
Dan Newberry Photography
8 Titan House
Calleva Park
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Dan Newberry Photography is a professional photography studio in Thatcham located in West Berkshire. Capturing special celebrations and moments in peoples lives. This is all achieved in a fun and friendly environment resulting in natural and real lifetime memories.
Newborn Photographer, Wedding Photographer Newbury Thatcham and Reading, Photographer Berkshire, Childrens portraits, Parties, Event photographer, Photo shoots, Professional photographer, Thatcham studio, Newbury photographer, Reading Photographer, Family portraits, Engagement shoots, Maternity photography, Bump to Baby
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Nice simple peaceful newborn image
Mummy's cup of tea
First family photo and precious memories
Wishing this little man a Happy 1st Birthday. Great cake smash this morning.
Big congrats to the new Mr and Mrs Yapp. A Great relaxed and enjoyable wedding. Big thanks for allowing me to capture your special day. Thanks..
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Great and speedy service! I had service and they got me taken care of right away. Very personable staff as well!
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Broken niceties and skewerings
Ruthless at Moxie Theatre
Jeff Smith 10 a.m., July 21
This sixth annual Valentine's art show features all new work by El Baby Boy, Keith Stone, Lord Zep, and Rob Benavides. Live set by DJ Beto. Refreshments and pizza by Luigi's.
2323 Broadway, suite 101, San Diego, 92102
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Looking for the best vendors for your Palm Springs wedding? We've got them right here. How do we know? We ask. And ask. And ask. The wedding photographers, caterers, wedding planners and so on that you find here have all been Certified By The Guide. That means we've asked dozens of people (other professionals who've worked with them and brides and grooms and mothers of the bride, etc.) for feedback on each one of them…and they passed with flying colors.
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|52 Reviews
|Property type
|Minimum Stay
|7 nights
When you book through the HomeAway checkout, your booking is backed by our Book with Confidence Guarantee™ offering comprehensive payment protection.Learn more
Dolphin Lookout(TM) is like a 'ship on land,' anchored and secluded on the southeast tip of this tropical out island coral atoll. This wonderful newer hand-crafted Bahamian cottage, is perched on a bluff, providing spectacular views of the gorgeous Bahamian turquoise ocean and breath taking vistas across Scotland Bay to the beautiful little private coral island of Scotland Cay.
Guana's beaches are 'Fodor's choice' for the best beaches in the Bahamas. Just a few minutes from Dolphin Lookout, begin miles of white powdery sand beaches, where you may only see your foot prints in the sand. A magnificent outer reef, which is the 3rd largest in the world, runs the entire length of Guana Cay. Within a 'stones throw' from this very special oceanfront cottage are numerous inner reefs and coral gardens teaming with colorful marine life. Extraordinary white sand beaches, reefs, coral gardens, snorkeling, swimming, diving, kayaking are accessible by foot or golf cart and are only a few minutes from Dolphin Lookout.
About 2 miles west of Dolphin Lookout(TM) is a quaint, picturesque settlement, home to 100-125 permanent residences, descendants of loyalists, who migrated to the Bahamas from the Carolinas, Virginia and New York during the revolutionary war.
Here in the settlement, you will find Guana Harbour grocery store, several great restaurants, Donna's golf cart rentals, the upscale Orchid Bay Yacht club and Marina, a dive shop, boat rentals, and Milos fresh fruit and vegetable stand. Yes, this out island experience may be the closest thing to 'heaven on earth' for ocean lovers. To us it continues to be a fairy tale experience. Dolphin Lookout may well be that vacation or retirement home away from home you have been dreaming about. Sound and look to good to be true? Please note the comments by Dolphin Lookout guests, our photos, and then you decide.
Keywords: Cottage
Hello Ben,
We had a tremendous time celebrating our 25th anniversary on Guana Cay at Dolphin Lookout. What a unique place. We can't wait to return. We would like to share some of our favorite things about our trip:
+Coffee every morning on the Adirondack chairs under "perfectly placed" palm trees overlooking the ocean and Scotland Bay.
+Sunsets every evening from the dock on the Sea of Abaco. "Bob" the barracuda seemed to enjoy hanging out under the dock just before sunset.
+Caysera Beach. The whitest sand and clearest water that we have ever seen. Our beach umbrella was the only umbrella on the beach. Our footprints were the only footprints in the sand.
+The cool pathways from Dolphin Lookout to the ocean and bay.
+The Views! "WOW"
+We had a great time kayaking around the dock and in Scotland Bay.
+The golf cart rides to and from the cottage added an additional sense of adventure to the trip.
+Good fresh fish at Kidds Cove in the settlement on the harbor. We actually watched the boat come into the harbor with the catch of the day. We had to wait until the fish were cleaned, but the dinner was well worth the wait(grouper and wahu).
+Good dinner at Fishtails on the harbor. Neat sports bar atmosphere.
+Sunsets at Graebbers.
+Dolphin Lookout cottage was good in every way. We don't know anything we would change.
+Gina & Ronald, Caretakers. Gina met us at the dock upon our arrival and had our golf cart ready for us. We simply loaded our bags and were off. Gina and Ronald did a great job.
+The Knowles taxi service in Marsh Harbour(Joe & Susan). Per the recommendation provided in your guide, we called Joe and let him know our flight information. When we arrived, he was waiting for us at Marsh Harbour Airport. Joe's wife Susan greeted us with a hug. Joe took us to Maxwells for shopping and then returned an hour later to take us to the ferry. He kept our bags while we shopped. Only charged $25. We called Joe the day before our departure and let him know our flight information. Susan met our ferry at the dock and took us back to the airport. Only charged $15.
+Orchid Bay. Gated community. We felt very safe.
We are already thinking of our return trip.
Thanks again,
Doug and Becky
Dear Ben and Cathy,
What a wonderful two week vacation we enjoyed at Dolphin Lookout. Unarguably, the most perfect two weeks we ever could have imagined. Not using the internet service for the first two days, literally forced us to appreciate that we were on vacation in paradise, and to enjoy the infinite beauty and peace.
We used the beach chairs and umbrella every day for 12 days straight! We enjoyed going to the beach early in the day. We packed our lunch and stayed all day. We were timid about the reefs at first, but got more and more adventurous as we made discoveries like the precious coral nurseries and all of the colorful parrot fish and charismatic barracuda.
We were patrons of the local island restaurants most evenings, but twice got some nice steaks for the grill. When dining the at Dolphin Lookout, we ate out on the porch using the lovely polished rail for our table. We savored our meals while mesmerized by the picturesque cove.
We can hardly wait until the next time we visit Abaco and stay at Dolphin Lookout. With the stunning views and the nautical charm.....we were comfortable and felt right at home.
Thanks for the lovely two weeks. Best to you always,
Bryan & Sheryl
My husband and I just returned from Dolphin Lookout. It was spectacular! It would be a perfect honeymoon location! You can see gorgeous views of the water all around you and the breezes were just heavenly! Every day, I did my morning yoga out in the yard, right on the edge overlooking Scotland Cay. Then we'd listen to the marine forecast...(same beautiful weather every day) and head to the beach. We were there before the "season" I think because we almost had the beach to ourselves every day. I've never seen such beautiful beaches! Crystal clear turquoise water and powdery white sand. We didn't leave the island or even use the kayaks so, next time, we'd probably rent a boat and explore the other cays. We bought our groceries in Marsh Harbour and ferried them over. I was glad we did it that way. The market on the island carries a lot but the store in Marsh Harbour is more of a "full on" grocery store so we were able to mostly cover our week. We also lucked out and got some fresh grouper at the dock. There is nothing like fresh grouper! Can't wait to return!!
Hi Ben,
We want to thank you for the opportunity to stay and experience the splendor of Dolphin Lookout. The detailed description and photos online do not do it justice. The only way one could understand would be to experience a stay. Dolphin Lookout was an ideal place to celebrate our anniversary. We loved the outback experience, exploring the trails and walking the beach. Everyday was a new experience on you covered porch. We will not forget the amazing sunrises which began our days at DL. We visited in October which is a pretty slow time in the Abacos....but we always had fun exploring, snorkeling, reading, and just soaking up God's beautiful vistas from your covered porch. We frequented Nippers and Fish Tales Sports Bar, rode up to the north end, and then always enjoyed our off road golf cart ride back to Dolphin Lookout. We hope to come back soon.
Terry and Kathy,
Hi Ben,
Dolphin Lookout was fabulous. We couldn't have made a better choice and already plan on coming back. We loved the cottage, workmanship, foliage around the cottage, privacy, and of course the views. We did the suggested excursions and snorkeling trips. Also, we rented a boat through Dive Guana which occupied a lot of our time. Dolphin Lookout spoiled us to consider any other place.
Nick & Donna
Dear Ben & Cathy,
Thank you so much for opening Dolphin Lookout to us to celebrate our 30th anniversary. It was everything we could have dreamed of for a private get-away. The scenery from every view was breathtaking. We spent most of our time on the nearby beaches and snorkeling. We saw a small shark and stingray by the dock. Gina and Ronald were so friendly and had everything in top condition. We helped ourselves to some of the fresh berries and a coconut fresh off of one of your coconut trees. The trails were easy to find and grounds looked like the cover shot for an Abaco island brochure. This place is like no other-its beauty takes your breath. Thanks again.
Steve & Beth
Guana Cay is conveniently accessible by ferry and is about 8 miles north of Marsh Harbour, Abaco. Dolphin Lookout is OCEANFRONT AND BAYFRONT and is located on the eastern most tip of Guana Cay. It is a PARADISE for ocean lovers; honeymooners; anniversaries; sports enthusiasts; star gazers; writers; readers and romantics with a spirit for adventure; unforgettable sunrises and sunsets.
Other Activities: boating, kayaking, wildlife viewing, deep sea fishing, world class bone fishing
|Rate Period
|Weekend Night
High season
Apr 1 2016 - Sep 30 2016
7 night minimum stay
Low season
Oct 1 2016 - Mar 31 2017
7 night minimum stay
My Standard Rate
7 night minimum stay
|cleaning fee
Rates subject to change without notice. Please contact owner for stays longer than two weeks and for 2017 rates. Min. stay requirement is 7 nights. Depending on the season, you can check in or check out any day of the week. Subject to a refundable $250 security deposit. Occupancy limited to a maximum of two adults. No pets allowed. No smoking.
Both Kayaks rent for $150 for the duration of your stay.


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the first game grumps on ng and its still FUNNY, thnx binkles bro
btw, r u workin on another, and if so, which one?
fucking loved it.
Jons face after the spider in spider thing made my day though XD
Interesting points told here...
Awww the part just after that was the funny part. Good animation though.


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Video Premiere: Mariah Carey's 'Bye Bye'
The highly anticipated music video for Mariah Carey's single "Bye Bye" finally gets its official premiere on May 5. The video was directed by her rumored to be husband Nick Cannon, who also played as Mariah's lover on the video.
The pop singer has also planned to make a sequel for the "Bye Bye" music video, which will be her next single "Love Story". Report also said that the shooting for the next video has already been started.
The single, which was taken from her latest album "E=MC²", has been released through the radio on April 7, 2008. It was also being set as the second single from her new album after releasing "Touch My Body" as the first single on February 19.
As for her album, "E=MC²" has got its official release on April 25 and also become a major hit. The album debuted at #1 at the Billboard 200 Chart and sold about 463,000 copies in its first week.
Mariah Carey's "Bye Bye":
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Home > News > VLSI symposium eyes 65-nm logic
May 28th, 2003
VLSI symposium eyes 65-nm logic
Though 90-nanometer designs are not expected to move into early commercial production until late this year, about a dozen papers at the 2003 VLSI Technology Symposium will target 65-nm design rules. Full-blown 65-nm technology demonstrations are expected at the symposium-planned for June 10-12 in Kyoto, Japan.
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