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|Publication number
|Publication type
|Publication date
|May 6, 1975
|Filing date
|May 3, 1974
|Priority date
|Nov 7, 1972
|Publication number
|Gerald Fagan Holland
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|Patent Citations (2), Referenced by (13), Classifications (19)
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United States Patent 1 [111 3,882,230
Holland May 6, 1975 i 1 SUBSTITUTED BENZOIC ACID [58] Field of Search 424/317 HYPOLXPEMIC AGENTS [75] Inventor: Gerald Fagan Holland. Old Lyme. [56] References Cited Conn UNITED STATES PATENTS 1594.478 7/197] Brandstrum el al, l, 260/3305 [73] Asslgnee Pfizer York N 3129.508 4mm Zzeglerel ul H 260/470 [22] Filed: May 3, 1974 Priman- Examiner-ler0me D. Goldberg 21 A I. N 466,776 l 1 PP O Aztorney. Agent, or Firm-C0nn0lly and Hutz Related US. Application Data {62] Division of Ser. No, 304,528, Nov, 7, l972 which is [57] ABSTRACT a division of Ser, No. [55,209, June 21, [97],
US. Cl. 424/317 Int. Cl A6lk 27/00 Polysubstituted benzoic acids, and their use in mam mals as hypolipemic agents.
3 Claims, N0 Drawings SUBSTITUTED BENZOIC ACID HYPOLIPEMIC AGENTS CROSS REFERENCE TO RELATED APPLICATIONS This application is a division of application Ser. No. 304,528 filed Nov. 7, 1972, which, in turn, is a division of application Ser. No. 155,209 filed June 21, l97l.
BACKGROUND OF THE INVENTION Atherosclerosis, a form of arteriosclerosis, is characterized by deposition of lipids in the aorta and in the coronary, cerebral and peripheral arteries of the lower extremities. As these masses increase in size, the risk of thrombosis and the ensuing occlusion arises,
Although the etiology of this disease is not fully understood, it has been found that those afflicted with atherosclerosis exhibit elevated levels of plasma lipoprotein, of which cholesterol and triglycerides are the major constituents. In addition to the recommendation that dietary habits leading to lower Blipoprotein levels be observed. various therapeutic agents such as estrogens, thyroxine analogs. sitosterol preparations and, more recently, Atromid-S (ethyl p-chlorophenoxyisobutyrate) have been used to lower cholesterol levels in individuals prone to the condition.
lt has now been found that benzoic acids, and more particularly a series of polysubstituted benzoic acids are effective in reducing plasma lipid levels and can be expected to be useful in the treatment of atherosclerosis and related cardiovascular diseases associated with elevated lipid levels.
Benzoic acid derivatives have been known in the chemical literature for some time and have been reported to possess varied utilities, the most common of which is as intermediates leading to more complicated and diverse chemical structure, For example, Sphenacylthiosalicylic acids are reported, Netherlands Specification 6,607,608, to be useful in the synthesis of benzothiophenes reported to be valuable because of their analgetic, antipyretic, antiinflammatory, antitus sive, local anesthetic, antispasmodic, and antihistaminic activity.
Benzoic acid derivatives are utilized in the synthesis of tricyclic dibenzlb,e]oxepines (Collect, Czech. Chem. Commun, 32, 3448, l967; CA, 68, 29677r. [968) and dibcnzo{b,f]thiepins (Collect. Czech. Chem. Commun, 33, i852, 1968', C.A,, 69, 86950u, 1968), useful as neurotropic and psychotropic agents.
Ouinuclidinyl esters, claimed in US. Pat. No. 3,405,134 as central nervous stimulants, utilizes mbenzyloxybenzoic acid in the preparation of final products.
Baker, et al., J, Med. Chem. [0, H29 l I967), has recently shown that certain phenacyloxy and acetonyloxy derivatives of benzoic acid are inhibitors of a-chymotrypsin.
Recently, m-fluorobenzoic acid has been prepared, Belgium Pat, No, 724,121, to possess analgesic, antipyretic and hypolipemic activity.
SUMMARY OF THE INVENTION The hypolipemic agents of this invention are represented by the formulae:
COZH X CO h X 02H 11 III and the pharmaceuticully acceptable basic salts thereof, where:
X is selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy and trifluoromethyl;
R is selected from the group consisting of methyl, benzyl, substituted bcnzyl where said substituent is selected from the group consisting of fluorine, chlorine,
methyl, methoxy, trifluoromethyl and 3,4-dimethoxy and acylmethyl of the formula where R is selected from the group consisting of alkyl containing from 1 to 4 carbon atoms and phenyl and substituted phenyl where said substituent is selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl and methoxy;
R is selected from the group consisting of methyl, 2-hydroxyethyl, allyl, methallyl, crotyl and acylmethyl of the formula RCCH 9 RCCHZ- where R is alkyl containing from 1 to 4 carbon atoms, and where X is trifluoromethyl and R is methyl or benzyl.
A second group of prepared compounds are those of formula ll where X is trifluoromethyl, n is O and R is allyl, methallyl. or phenacyl, and where X is chlorine, n is 0 and R is 2hydroxyethyl or phenacyl.
Also considered within the purview of this invention substituent by the requisite alcohol, R OH. or merare compounds of formula I Where R is phenyl and capto R SH. Further, it is frequently advantageous to phenyl substituted by simple substituents usually found employ, instead ofthe trifluoromethyl substituted haloon aromatic rings, i.e.. alkyl, halo. alkoxy, etc. benzoic acid, the corresponding trifluoromethyl substi- DETAILED DESCRIPTION OF THE INVENTION 5 tuted halobenzonitril e. which after the reaction is complete. can be suitably hydrolyzed to the benzoic in accordance with the process employed for syntheacid. sizing substituted benzoic acids of formulae l and II. The above-described reaction is generally carried out wherein X is fluorine, chlorine, bromine, methyl and by contacting the appropriate trifluoromethylmethoxy, n is 0 and R and R are as previously indii0 halobenzoic acid or nitrile with at least an equimolar cated, the following scheme, where Halis a suitable amount of the requisite alcohol or mercaptan, plus as halogen, is illustrative: much as a l0-50 percent excess, in an aprotic solvent x coat 1 00 a Q R -Hal X C0 E X CO H SH SR Both the above illustrated reactions are conducted such as dimethylformamide, dimethylsulfoxide or under similar conditions well known to those skilled in hexamethylphosphoramide and employing from 1 to 2 the art and comprises heating a basic salt of the phenol molar equivalents of a base such as sodium rrtethoxide OI thiophenol With at kZdSt 211'] equimolar amount Of thfi odium Such reaction is generally conapp p iate halide. i 0r Z- L in l'eactiml- 3O ducted at elevated temperatures of from 60l50 C.
inert solvent. for 2-l0 hours. The desired product is isolated by dilu- Convenience {ha basic 0f the Phfiflol Or thin' tion of the reaction mixture with water followed by adphenol, the preferred salt being sodium, is generated in jusimem f the pH to 3 i h h d hl i id Sim li l one or more of the bases Sodium In those instances wherein the nitrile is employed, the dride, sodium methoxide, sodium hydroxide or sodium 5 benzoic acid is Obtained b subsequent h d l i f carbonate. At least one equivalent of said base is used, the product employing aqufious h ii di h with much as 100 PQYCQnt eXCeSS- droxide at steam bath temperatures and reaction times The solvent can vary considerably in nature and can of i2 i0 24 hours comprise one or more of those selected from dimethyl- Those trifluommethyl benzoic acid congeners sulfoxide, dimethylformamide, hexamethylphosphora- 40 midc. acetone, ethanol, methanol and water.
ln practice, a solution or suspension of the requisite phenol or thiophenol in a reaction-inert solvent is treated with one or more of the aforementioned bases followed by the addition of the appropriate halide, R Hal or R Hal. In general, it is advantageous to conduct the reaction at elevated temperatures, the prewherein the hydroxy or mercapto are situated meta to the trifluoromethyl substituent can be alkylated directly by the aforedescribed procedure.
The requisite hydroxybenzoic acids employed as the starting materials leading to compounds of formula l are either available as commercial reagents or are well known in the chemical literature to those skilled in the ferred range being from 75l50 C. Reaction time is not critical and is dependent on temperature, concen- The Corresponding mercaptobfinloic acids used as tration and reactivity of the starting reagents. Times of the rting Compounds for the preparation of those l-l2 hours have generally been adequate to id congeners related to formula" are either commercially the desired products in good to moderate ields. available or can be synthesized either from the corre- A convenient method for isolation of the product p nding hydroxybenzoic acid employing the method comprises dilution of the cooled reaction mixture with of Newman, et al., J. Org. Chem. 3], 3980 (1966), water followed by acidification with 6N hydrochloric which teaches the acylation of a phenol with dimethylacid. The resulting precipitate is then filtered, dried thiocarbamyl chloride, thermal rearrangement to the and recrystallized from a suitable solvent. S-aryl dimethylthiocarbamate and subsequent hydroly- Starting phenols and thiophenols wherein X is trifluosis to the thiophenol; or from the corresponding aminoromethyl and the hydroxyl or mercapto group to be al benzoic acid using the procedure of Tarbell. et 211., Or kylated are ortho or para to said trifluoromethyl moiety 69 ganic Synthesis," Coll. Vol. Ill. John Wiley & Sons, represent a special case since said phenol or thiophen- I N Y k, N Y k 1955 page 809 hi h ols cannot be alkylated under the aforedescribed basic tea h th a ti fa di i lt ith potassium reaction conditions. Compounds of the present invenh l thm f ll wed by hydrolysis of the intermedition related to l and ll wherein X is trifluoromethyl and m to h ihiophenoi R,O or R-;S are ortho or para to said trifluoro- The appropriate trifluoromethyl halobenzoic acid Subsliwcm p y displacement of an and benzonitriles are compounds fully disclosed in the aromatic halogen ortho or para to the trifiuoromethyl h i literature,
Regarding the alkylating reagents employed in the process leading to Compounds of the present invention, allyl, crotyl, methallyl and certain phenacyl and benzyl halides are commercially available. Those benzyl halides not available as commercial chemicals can easily be prepared by those skilled in the art according to the methods as taught by Fuson and McKeever, Organic Reactions Vol. 1, John Wiley & Sons, Inc., New York, New York, 1954, Chapter 3; and Wagner and Zook, Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York, N.Y., 1956, Chapter 4. Phenacyl halides and a-halomethyl alkyl ketones are synthesized according to the methods as outlined by Wagner & Zook, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York, N.Y., 1956, Chapter 4.
The requisite benzyl alcohols are either commercial chemicals or are prepared by a lithium aluminum hydride reduction of the corresponding alkyl benzoate according to the methods outlined by Brown, Organic Reactions," Vol. 6, John Wiley & Sons, Inc, New York, New York, 1951, Chapter 10. The requisite acylcarbinols,
RLLH OH are prepared via hydrolysis of the corresponding acylmethyl halides according to the procedure of Straus, Ann., 393, 331 (1912), while the corresponding mercaptomethyl ketones,
are synthesized from the appropriate acylmethyl halides according to the methods reported by Reid, Organic Chemistry of Bivalent Sulphur, Vol. I, Chemical Publishing Co., Inc., New York, N.Y., 1958, Chapter 4, page 390.
The sulfoxides and sulfones of formula I], wherein n l or 2, are synthesized by oxidation, employing standard oxidizing agents such as hydrogen peroxide or potassium permanganate.
The structurally novel hypolipemic compounds of the present invention comprise those of formula 1 and their pharmaceutically acceptable basic salts, wherein X is selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl and R is selected from the group consisting of benzyl and substituted benzyl wherein said substituent is selected from the group consisting of fluorine, chlorine, methyl, methoxy, trifluoromethyl and 3,4-dimethoxy and acylmethyl of the formula wherein R is selected from the group consisting of alkyl containing from 1 to 4 carbon atoms and phenyl and substituted phenyl wherein said substituent is selected from the group consisting of fluorine, chlorine, methyl, methoxy and trifluoromethyl.
Also structurally novel are hypolipemic agents of the present invention represented by formula II and their pharmaceutically acceptable basic salts, wherein Y is selected from the group consisting of fluorine, bromine and trifluoromethyl; R is selected from the group consisting of allyl, methallyl, crotyl and acylmethyl of the formula R CH wherein R is selected from the group consisting of alkyl containing from 1 to 4 carbon atoms and phenyl and substituted phenyl wherein said substituent is selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl and methoxy; and n is an integer from 0 to 2.
Compounds of the present invention of formula III and their pharmaceutically acceptable basic salts are all either commercially available or described in the chemical literature and are synthesized according to known standard procedures, for example, those outlined and reported by Moffett, et al., J. Med. Chem, 11, 1020 (1968), Karler, et al., Arch. Intern. Phar macodyn., 173, 270 (1968), Hansch, et al., Biochem. PharmacoL, 19, 2193 (1970), Muir, et al., Plant PhysioL, 26, 369 (I951), Zimmerman, et al., Contr. Boyce Thompson Inst., 12, 321 1942) and in Dictionary of Organic Compounds," Oxford University Press, New York, N.Y., 1965, Volumes 1-5.
As has been previously noted, a characteristic feature of the acidic compounds of the instant invention is their ability to form basic salts. Acid congeners of the present invention are converted to basic salts by the interaction of said acid with an appropriate base in an aqueous or non-aqueous medium. Said basic reagents suitably employed in the preparation of said salts can vary in nature, and are meant to contemplate such bases as organic amines, ammonia, alkali metal hydroxides, car bonates, bicarbonates, hydrides and alkoxides, as well as alkali earth metal hydroxides, hydrides, alkoxides and carbonates. Representative of such bases are ammonia, primary amines such as n-propylamine, nbutylamine, aniline, cyclohexylamine, benzylamine, ptoluidine, ethylamine, octylamine, tertiary amines such as diethylaniline, N-methylpyrrolidine, N- methylmorpholine and l,5-diazabicyclo-[ 4,3,0]- nonene', sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydride and barium hydroxide.
in the utilization of the chemotherapeutic activity of those compounds of the present invention which form basic salts, it is preferred, of course, to use pharmaceutically acceptable salts. Although water-insolubility, high toxicity, or lack of crystalline nature may make some salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water insoluble or toxic salts can be converted to the corresponding acids by decomposition of the salts as described above, or alternately they can be converted to any desired pharmaceutically acceptable basic salt. The said pharmaceutically acceptable salts preferred are those wherein the cation is ammonium, sodium or potassium.
As previously indicated, the benzoic acids of the present invention are all readily adapted to therapeutic use as hypolipemic agents in mammals. Outstanding for their effectiveness in this regard include the following agents: 2-benzyloxy-S-trifluoromethylbenzoic acid, 2-ben2yloxy-5-chlorobenzoic acid, 2-( 3 ,4-
dimethoxybenzyloxy )--chlorobenzoic acid, 2 acetonyloxy-5-chlorobcnzoic acid, Z-methoxy-S-tri fluoromethylbenzoic acid, 3-methoxy-5trifluoromethylbenzoic acid, Z-allylthio-S-trifluoromethylbenzoic acid, Z-methallylthio-5-trifluoromethylbenzoic acid, lphenacylthio-S-trifluoromethylbenzoic acid, 2-(2- hydroxyethylthio)-5-chlorobenzoic acid and Z-phenacylthio-5-chlorobenzoic acid.
The products of the invention are tested in vivo for hypolipemic activity in ratsv Groups, each comprising 4 animals, of normal Sprague-Dawley {Charles River) male rats weighing from 160 to 220 grams are fed rat chow containing the compound under test for two overnight feeding periods. On the morning of the third day the animals are anesthetized and bled from the abdominal aorta. The total plasma cholesterol is then determined by the method of .l. J. Carr and l. J. Drekter, reported in Clin. Chem., 2, 353 (1956). Most of the tests are conducted at a feed concentration of U. l 5 to (1.25 weight per cent of the compound under test, but lower levels, 0.0] to 0.l0 weight per cent, are em ployed in some instances where particularly high potency is anticipated. The plasma cholesterol level of the treated animals is found to be significantly reduced when compared to animals not receiving the test compound.
This pharmacological test for measuring hypocholestermic activity is a reliable indication that similar activity in humans can be expected because those compounds effective in the rat which have been tested in humans have demonstrated similar activity. p Chlorophenoxyisobutyric acid, ethyl ester, marketed as Atromid-S. a well-known and clinically effective hypocholesteremic agent, causes a -35 percent cholesterol fall in the rat test when administered at a level of 0.25 percent in the feed.
Although the use of the present invention is directed toward the treatment of mammals in general, the preferred subject is humans. In determining an efficacious dose for human therapy, results of animal testing are frequently extrapolated and a correlation is assumed between animal test behavior and proposed human dosage. When a commercially employed standard is available, the dose level of the clinical candidate in humans is frequently determined by comparison of its performance with the standard in an animal test. For example, Atromid-S is employed as a standard bypolipemic agent and is administered to humans at the rate of 2.0 g, daily in individual doses. It is assumed, then, that if compounds of the present invention have activity comparable to Atromid-S in the test assay, that similar doses will provide comparable responses in humans.
Obviously, the physician will ultimately determine the dosage which will be most suitable for a particular individual, and it will vary with the age, weight and re sponse of the particular patient as well as with the na ture and extent of the symptoms and the pharmacodynamic characteristics of the particular agent to be administered. Generally, small doses will be administered initially, with a gradual increase in the dosage until the optimum level is determined. It will often be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quantity administered parenterally.
Having full regard for the foregoing factors it is considered that an effective daily dosage of the compounds of the present invention in humans will generally range from 0.3 to 5 gv per day in single or divided doses. These values are illustrative, and there may, of course, be individual cases where higher or lower dose ranges are merited.
The benzoic acids of this invention can be administered either alone, or, preferably, in combination with a pharmaceutically acceptable carrier. They may be combined with various pharmaceutically acceptable, inert carriers in the form of tablets, capsules, troches. powders, aqueous suspensions or solutions, elixirs, syrups and the like. Suitable carriers include solid diluents or aqueous media and non-toxic organic solvents. The oral pharmaceutical compositions of this invention may be suitably sweetened and flavored by means of various agents commonly employed for such a purpose.
For parenteral administration, solutions or suspensions of the herein described benzoic acids in sesame or peanut oil or in aqueous propylene glycol solutions can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such solutions are suitable for intramuscular and subcutaneous administration. Sterile aqueous solutions are additionally useful for intravenous injection, provided that their pH is suitably adjusted and buffered, if necessary, and the liquid diluent rendered isotonic with saline or glucose.
The herein disclosed compounds may also be useful in other aspects of abnormal metabolism, the latter possibly accounting for clinical problems in diabetes, pancreatitis, coronary heart disease, and cerebrovascular disease. Hence the ability of polysubstitutedbenzoic acids of this invention to regulate lipid metabolism might find utility in the treatment of said disease.
Also considered within the scope of the present invention are compounds related to formula III wherein R is amino or amino derivative, e.g., monoand disubstituted amine, urea or acylamine; and X is as previously indicated.
The following examples are provided solely for the purpose of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the spirit or scope thereof.
EXAMPLE l 3-Benzyloxy-S-chlorobenzoic Acid To a solution of 173 mg. (l m mole) of 3-hydro-5- chlorebenzoic acid in 2 ml. of dimethylformamide is added mg. (2 moles) of 56.6 percent sodium hydride in an oil suspension. After l0 minutes, the result ing suspension is treated with 130 mg. (l m mole) of benzyl chloride and the mixture heated to C for 1 hour. The reaction mixture is then cooled, diluted with 5 ml, of water, and extracted with ether. The aqueous phase is separated, acidified with 6N hydrochloric acid and the product extracted with ether. The ether solvent is removed in vacuo and the residual product triturated with water and filtered. The dried product is sublimed at C. and 0.02 mm of pressure to provide 50 mg. of the desired product. mp l27l29 C.
Anal. Calcd. for C H O Cl: C, 64.00; H, 4.22
Found: C, (14.05; H, 4.3L
EXAMPLE 2 2-( 3.4-Dimethoxyhen7yloxy )5-chlorohen2oic Acid To a suspension resulting from 5. l5 g. (0.03 mole) of S-chlorosalicylic acid and 2.5 g. (0.006 mole] of st dium hydride (56.6 percent oil dispersion) in 50 ml. of dimethylformamide is added 1 l g. (0.065 mole} of 3.4 dimethoxybenzyl chloride and the mixture heated to ll()7 C for 40 minutes. The reaction mixture is cooled. diluted with l50 ml. of water and extracted with ether. The ether layer is washed with 1N sodium hydroxide solution. water and finally evaporated to dryness. The residual product. 3.4-dimethoxybenzyl Z-( 3.4dimethoxyhenzyloxy )-5-chlorosalicylatc is triturated with isopropanol. 7.5 g. mp. 7083 C. A small sample is recrystallized from isopropanol. m.p. 909 1 5 C.
Anal (tried for C H O CI. (I 63.49; H. 5.33. Found (163.841 H. 5.43.
The above intermediate. 7.5 g. 15.8 m moles) in 50 ml. of acetone is treated with 50 ml. of lN aqueous sosure. The aqueous solution is extracted with ether and finally acidified with 6N hydrochloric acid. The resulting precipitate is filtered and dried. 4.8 g., m.p. l0l- 105 C. The desired product is purified by recrystallization from methanol containing a small amount of methylene chloride. nip. 1 l0-l 12 C.
Anal. Calcd. for C ;H lI (I 59.54; H. 4.68, Found: C. 59.60; H. 4.86.
EXAMPLE 3 2-Benzyloxy-S-trifluoromethylhenzoic Acid To a solution of [0.8 g. (().l mole) of henzyl alcohol in 50 ml. of dimethylsulfoxide is added 4.2 g. (0.l mole) of a 56.6 percent suspension of sodium hydride in oil, and the mixture stirred until the evolution of hy drogen ceases. 4-Chloro-3-cyanohenzotrifluoride [8.6 g.; 0.09 mole) is added and the resulting mixture heated 34 temperatures. The reaction is cooled. diluted with 200 ml. of water and the resulting precipitate filtered and dried. The intermediate. 4-bcnzyloxy-3 cyanobenzotrifluoride, is recrystallized from isopropa n01. 10.8 g., m.pv 6970.5 C.
To 10 ml. of ethanol containing 4 ml. of 5N aqueous sodium hydroxide solution is added 600 mg. of the above intermediate and the resulting solution heated to 90 C. overnight. The reaction mixture is cooled. extracted with ether. and the aqueous layer acidified with 12N hydrochloric acid. The precipitate which forms is filtered. washed with water and dried. 570 mg. 92-94 C. A small sample is recrystallized for analysis from ether-hexane, mp 94.596 C.
Ana]. Calcd for H O Fm C. 608i; H. 3.74. Found: C. 60.64; H. 3.8].
EXAMPLE 5 3 Benzyloxy-S-trifluoromethylbenzoic Acid To a solution resulting from 206 mg. l m mole) of 3-hydroxy-S-trifluoromethylhcnzoic acid* and mg. (2 m moles) ot'a 56.6 percent oil suspension of sodium hydride in 2 ml. ofdimethylsulfoxide is added 127 mg. l m mole) ofbenzyl chloride and the reaction mixture heated to C. for l2 hours. The mixture is cooled to room temperature. diluted with 10 ml. of water and extracted with ether. The aqueous phase is separated and acidified with 6N hydrochloric acid. The precipitated product is filtered. dried and suhlimed at C. and 0.05 mm pressure. nip. 143l45 C.
Anal. ('aletl for -,H O E (I 60.81. H. 74 Found C. 60.30. H. 3 70 *Hauptschein. et al J Am. ('hem. Soc 76, I053 l I954).
EXAMPLE 6 Starting with the requisite reagents, and employing the procedures of Example 4 or Example 5, the following henzoic acids are prepared:
Z-Benzyloxy-S-methoxybenzoic Acid A solution of 5.0 g. (0.03 mole) of 2-hydroxy-5- methoxybenzoic acid in 50 ml. of dimethylformamide is treated with 2.5 g. (0.06 mole) of sodium hydride in a 56.6 percent oil suspension, followed by the addition of 7.6 g. (0.06 mole) of benzyl chloride. The resulting mixture is heated at 98l03 C. for 1 hour, after which the insolubles are filtered, the filtrate diluted with l ml. of water and the aqueous solution extracted with ether. The aqueous phase is discarded and the ether phase dried over sodium sulfate and evaporated to pro vide the intermediate, benzyl Z-benzyloxy-S- methoxybenzoate, as an oil, 5.0 g.
The intermediate ester is dissolved in 35 ml. of ethanol containing 30 ml. of 1N aqueous sodium hydroxide solution and the resulting solution heated for 50 minutes on a steam bath. The ethanol is removed in vacuo and the mixture diluted with ml. of water and extracted with ether. The water phase is acidified with lZN hydrochloric acid and the product extracted into ether. The ether is evaporated and the residual crude product is chromatographed over 40 g. of Silica Gel packed in ethyl acetate. The desired product is eluted with l00 ml. of ethyl acetate, 29 g., m.p. 8892 C. and is finally recrystallized from methylene chlorideether. l6 g, mp. 9394.5 C.
Anal. Czilcd. for C H O L. (19.75; H. 5.46. Found: (169.65; H. 5.59.
EXAMPLE 8 Employing the procedure oi Example 7 and starting with the appropriate chemical reagents, the following analogs are synthesized:
Anal. Calcd. for C ..H,,O,Cl: C. 52.5
Found: C. 52.84".
EXAMPLE l0 In a similar manner. employing the requisite starting materials and following the procedure of Example l l, the following compounds are prepared:
EXAMPLE ll 3-Phenacyloxy5-tritlnoromethylbenzoic Acid To 206 mg. l l m mole) of 3-hydrosy5trilluoromethylhenzoie acid dissolved in 2.5 ml. of dimethylsulfoxide is added 85 mg. (2 m moles! oi'a 56.6 percent sodium h dridc suspension in oil. When the hydrogen evolution has ceased. 199 mg. (l m mole) of cz-hromoacctophenone is added and the reaction mire ture is allowed to stir at room temperature for 2 hours. The reaction is diluted with 10 ml. of water and extracted with ether. The aqueous phase is acidified and the product extracted with ether. Removal of the ether under reduced pressure followed by sublimation at 150 C. and 0.1 mm pressure provided the pure product. mp l80 l82 C.
Anal Calcd for H Q l- C. 59.26; H. 3.42. l'ound: C. 59.26; H. 3.60.
EXAMPLE 12 The procedure of Example 1] is repeated. starting with the appropriate hydroxybenzoic acid and phenacyl halide to provide the following compounds: 2-
phenacyioxy-S-fluorobenzoic acid. 2-( 4 fluorophenacyloxy)-5-fluorobenzoic acid. 2-( 2' chlorophenacyloxy)-5-fluorobenzoic acid. 3-( 4'- methylphenacyloxy )-5-fluorobenzoic acid. 4-( 4'- methylphenacyloxy )-5-chlorobenzoic acid. 3-( 4 methoxyphenacyloxy )-5-chlorobenzoic acid. 3-( 4 methoxyphenacyloxy )-5chlorobenzoic acid. 3-( 4 fluorophenacyloxy lfi-bromohenzoic acid. 2- phenacyloxy-S-bromobenzoic acid. 3-( 2 methylphenacyloxy l-S-trifluoromethylbenzoic acid.
3-( 4'methoxyphenacyl0xy )-S-trifluoromethylbenzoie acid. 3-( 3'-trifluoromethylphenacyloxy l-5-tri fluoromethylbenzoic acid. 4-( 4'-fluorophenacyloxy )-5- methylbenzoic acid. 6-( 3 '-methoxyphenacyloxyl-5- methylbcnzoic acid. 4-(2'-methoxyphenacyloxy1-5- methylbenzoic acid. 2-(4'-fluorophenacyloxy)-5- mcthoxybenzoic acid. 3-( 3 '-chlorophenacyloxy )-5- methoxybenzoic acid. 6-(4'-methoxyphenacyloxy)-5- methoxybenzoic acid. 2-( 3 trifluoromethylphenacyloxyl-S-methoxybenzoic acid and 3-phenacyloxyfi-methoxybenzoic acid.
EXAMPLE l3 2-Methylthio-S-trit'luoromethylbenzoic Acid lnto 75 ml. otdimethylformamide containing ml. of 5N sodium hydroxide solution is bubbled methyl mercaptan until a weight increase of 6.3 g. per cent excess) is noted. followed by the addition of 20.5 g. [0.01 mole) of Lchloro-lcyanobenzotrifluoridc. At'ter allowing the reaction mixture to stir at room temperature for 2 hours. the precipitated solid is filtered and the filtrate diluted with 500 ml. of water and extracted with ether. The ether layer is separated. dried over sodium sulfate and concentrated to a semi-solid which on trituration with hexane provides the desired intermediate. 4-methylthio-3-cyanohenzotrit'luoride. as a crystalline solid. l5 g. mp. (i872 C.
Thirteen grams of the above intermediate in 150 ml. of ethanol containing 200 ml. of 20 percent aqueous sodium hydroxide solution is heated at 90 C. for l8 hours. The reaction mixture is cooled and acidified with [ZN hydrochloric acid. and the resulting precipi tate filtered and dried. 14.2 g. m.p. 198200 C. A small sample is sublimed at lZ5-l 35 C. and 0.02 mm pressure. mp. l98.5200 C.
Anal. Calcd for (I HJI SH. C. 45.76. H. 2.9). Found. C. 46.09. H. 3.10.
In a similar manner are prepared: 2-(2- hydroxyethylthio)-5-trifluoromethylbenzoic acid. mp. l53l54 C.; 2-crotylthio-S-trifluoromethylbenzoic acid. m.p. l39l4l C.'. Z-methallylthio-S-trifluoromethylbenzoic acid. m.p. l50l52 C. and Z-allylthio-S- trifluoromethylbenzoic acid. m.p. l78l90 C.
EXAMPLE l4 3-Methylthio-S-trifluoromethylbenzoic Acid Anal. Calcd. for c H o sF i C. 45.76; H. 2.99. Found: C. 45.85; H. 3.02.
EXAMPLE 15 Following the procedure of Example l3 or Example 14. and starting with the requisite chemical reagents, the following congeners are synthesized;
EXAMPLE l 6 3 Mcthylthio-5-chlorobenzoic Acid In a manner similar to procedure of Example 14. 3-mercapto5-chlorobenzoic acid is contacted with methyl iodide in methanol containing potassium hydroxide as the base to yield the desired product in percent yield. mp. l48-l50 C Anal Called. for C H O SCl: 47.4[1 H. 3.48. Found. (Y. 4755; H. 3.56.
EXAMPLE l7 Again. the procedure of Example 14 is employed, starting with the appropriate starting reagents to provide the following analogs:
EXAMPLE l8 2-Phenacylthio-S-trilluoromethylbenzoic Acid A suspension of 14 g. (0.06 mole) of methyl 2-chloro-5-trifluorobenzoate, 9.0 g. (0.06 mole] of a-mercaptoacetophenone and 4.2 g. (0.03 mole) of potassium carbonate in 45 ml. of dimethylformamide is allowed to stir at room temperature for 3 hours after which 200 ml. of ether is added and the resulting mixture extracted with water. The ether layer is separated. dried over sodium sulfate and concentrated to an oil, which crystallizes on treatment with isopropyl ether. l .6 g.. m.p. l28.5l 30 C. The analytical sample of the intermediate. methyl Z-phenacylthio-5'trifluoromethylbenzoate, is purified by sublimation at 120 C. and 0.01 mm pressure, m.p. l27-l29 C.
The desired acid is prepared from the crude ester through mild base hydrolysis.
EXAMPLE [9 3-Phcnacylthio-5-trifluoromethylbenzoic Acid A mixture of l .33 g. (6 m moles] of3-mcrcapto5trifluoromethylhcnzoic acid, 12 ml. of l N sodium hydrox- Anal. Caled. for C H O Sli C. 56.47; H
32h. Found: Cv 56.84. H. 2.88.
EXAMPLE 20 Employing the procedure of Example l8 or Example l9, and starting with the appropriate reagents. the following benzoic acid derivatives are prepared:
l- R Position of 2 Substituent -SR2 Procedure CK ECH 3 Example 19 C H CH 3 Example 19 (CH Cl-lgCl-l 4 Example 18 3 C ll CH 4 Example 18 q r C H CCl-l 6 Example 18 4-FG H gCl-l 3 Example 19 Q 4- FC H CCH 6 Example 18 O. t 3-ClC H ECH 2 Example 18 O 4ClC H ECH 3 Yxample l9 3 4-Cil C l i LCH 3 l'xample 19 ll 3-Cll UC H CCl'l 3 Example 19 3 Example 19 4-CH 0C H @CH 6 Example 18 t-CH 0C H &CH
g 3 Example 19 3-CF C H CH2- EXAMPLE Zl Z-Phenacylthio-S-chlorobenzoic Acid A solution of 18.9 g. (0.] mole) of S-chlorothiosalicyclic acid. 15.4 g. (0.] mole) of a-chloroacetophcnone and 8 g. (0.2 mole) of sodium hydroxide in 200 ml. of ethanol containing 45 ml. of water is heated to reflux for 2 hours. After removing one-fourth the alcohol under reduced pressure, the mixture is acidified with hydrochloric acid and the resulting precipitated product filtered, 5.0 g., mp. l54l 56 C. The analytical sample has a melting point of l56l57.5 C.
Anal. Calcd. for C H ChSCl: C. 58.72; H, 3.62. Found: C. 58.59; H, 3.74.
EXAMPLE 22 In a similar manner to the procedure of Example 21, but substituting chloroacetone for chloroacetophenone, the corresponding 2-acetonylthio-5- chlorobenzoic acid is prepared, mp. l39l40 C.
Anal. Calcd. for C,,,H,,O;,SCI: C, 49.08; H, 3.7l. Found: C, 4921; H, 3.80
EXAMPLE 23 acid, 3-(4'-methoxyphenacylthio)-5-bromobenzoic acid, 4-( 3 '-trifluoromethylphenacylthio )-5- hromobenzoic acid, 2-(4'-chlorophenacylthio)-5- bromobenzoic acid, 2-acetonylthio-5-methylbenzoic acid, 2-phenacylthio-5-methylbenzoic acid, 2-( 4 fluorophenacylthio )-3-methylbenzoic acid, 2-( 4 methoxyphenacylthio )-5-methylbenzoic acid, 2-
acetonylthio-S-methoxybenzoic acid, 3-phenacylthio- S-methoxybenzoic acid, 2-(4chlorophenaeylthio)-5- methoxybenzoic acid, 2-(4-methylphenacylthio)-3- methoxybenzoic acid, and 3-( 3'- trifluoromethylphenacylthio)-5-methoxybenzoic acid EXAMPLE 24 3-Phenacylsulfinyl-S-trifluoromethylbenzoic Acid A solution of 2.6 g. (7.5 m moles) of 3-phenacylthio- S-trifluoromethylbenzoic acid and 0.75 ml. of 30 percent hydrogen peroxide in ml. of acetic acid is heated on a steam bath for 1 hour, after which the reac tion mixture is cooled and diluted with water to the turbidity point. The crystalline product which forms on standing is filtered, 1.0 g, m.p. l48-l5l C., and finally recrystallized from acetone-isopropyl ether, 850 mg, mp. lS4-l55 C.
Anal. failed. for C,,,H O,SI1,: (I 53.93; 1'.
H, ll I. Found: C, 54.l H. 3 29.
EXAMPLE 25 Z-Phenacylsulfonyl-S-chlorobenzoic Acid In a manner similar to the procedure of Example 24, 1.0 g. (3 m moles) of 2-phenacylthio-5-chlorobenzoic acid and 3 ml. of 30 percent hydrogen peroxide in 40 ml. of acetic acid yielded 800 mg. of the desired sulfone, m.p. -l7l C.
Anal. Calcd. for C,,,H O .,SCl: C. 5318; H, 3.27, Found: C, 53.16; H, 3.32.
EXAMPLE 26 The following sulfoxides and sulfones are prepared,
starting with the requisite chemicals, by repeating the procedure of Examples 24 and 25 respectively:
X 2 21 Position c1 CH3 1 2 cs BOCHZCHZ- 1 2 93 HOCPECl-lg 2 2 cs ca es-cs 1 2 cF CH 2 4 F cu 1 4 r cs -1,
F CH3CH=CHCH2- 2 3 r r H0CH2CH2- 1 3 C1 611 1 2 'c1 CH2=C(CH3)CH2 1 6 c1 CH2=C(CH3)CH2 1 3 Br CH3- 2 3 Br HOCH2CH2- 1 2 Br tidcii cii z 2 ca, CH2=C(CH3)CH2- 1 2 an cu ca=ciicn 2 2 0011 crifcii iiJ- 1 3 oca 'cn =cncii 2 3 0on5 ci =cricii 1 4 OCH OCH
c u cii HgCH J-CH C H CCH CHCCH- Position X 2 n Position 5 3 C1130 CH3 CH2 1 2 C11 c n cu 2 3 C1130 b C1C ll gCH 1 2 CH O 4 CIIC H CCH 2 2 6 EXAMPLE 27 3-Methoxy-5-trifluoromethylbenzoic Acid 2 This product is prepared according to the procedure of Example 5 and comprises contacting 3-hydroxy-5- 2 trifluorometh lbenzoic acid with meth l iodide in Y y methanol containing sodium methoxide as the base, m.p. l3ll35 C. 3
Anal. Calcd. for CQHTOJFH: C. 49.]1; H. 3.20. 2 Found: C. 49.28; H 3.30.
EXAMPLE 28 3 2-Methoxy-S-trifluoromethylbenzoic Acid 2 Starting with 4-chloro-3-cyanobenzotrifluoride and sodium methoxide and following the procedure of Example 4, the above product is prepared, m.p. 2 l05-l06.5 C. Netherlands Application 6,507,7l2 (C.A., 64, l2606g) reports a melting point of 2 l03-l05 C. for this compound.
In a similar manner are prepared 2-methoxy-3-trifluoromethylbenzoic acid and 3-trifluoromethyl-4- methoxybenzoic acid 3 EXAMPLE 29 Groups, each comprising 4 animals, of normal 3 Sprague-Dawley Charles River) male rats weighing from 160 to 220 grams are fed rat chow containing the '0 test compounds for two overnight feeding periods. On
the morning of the third day the animals are anesthe- 2 tized and bled from the abdominal aorta. The total plasma cholesterol is then determined by the method of 2 J. J. Carr and l. J. Drekter reported in Clin. Chem. 2,
353 (I956). Most of the tests are conducted at a concentration in the feed of 0.15 to 0.25 weight per cent 2 5 of the compound under test, but lower levels are employed in some instances. The total quantity of test 2 compound consumed is computed from feed consumption over the two-day period and is tabulated, in milli- 2 grams per kilogram body weight per day, along with the 0 associated per cent cholesterol fall measured:
Dal Do Compound Cholesterol Full i'rig/kg f Z-Methoxy-S-trifluorometh lbcnzoic acid 42 223 2-Bcnzyloxy-S-trifluoromet ylbenzoic acid 4] 256 2-Chloro-5-trifluoromethylbenzoic acid l9 23l 2-Benzyloxy-S-chlorobcnzoic acid l7 208 3-Bcnzyloxy-S-trifluoromethylbcnzoic acid l8 I64 Daily Dosage mgikg,
- Continued Compound 'Jl Cholestcrol Fall 2-Methoxy-5-chloroben2oic acid 28 3-Methoxyfi-lrifluoromcthylbenzoic acid 48 2-Acctonyloxy-S-chlorobenzoic acid 32 2-( -1- '-Chloroben2yloxy |--chlorobenzoic acid l4 Z-Mcthoxy-4 triiluoromcthylbenzoic acid 39 3-Benzyloxy-5-chlorobcnzoic acid Z-Benzyloxy-5-mcthoxybenzoic acid 17 2( 3 .4 '-Dimethoxyhcnzyloxy )5-chlorobenzoic acid 36 2,5-Dimcthoxybcnzoic acid 20 3-Chloro-5-trifluoromethylbcnzoic acid l3 2-Bromo-S-trifluoromcthylbenzoic acid [5 2,4-Dichlorobcnzoic acid 42 2Bromo-5-chiorobenzoic acid lb 2-Methylthio-S-trifluoromethylbcnzoic acid 27 Z-Methylsulfinyl-5-trifluoromethylbcnzoic acid 14 2AIIyIthio-S-trifluoromethylbcnzoic acid 2Phenacylthio 5-chlorobenzoic acid 3i Z-Phcnacylsull'onyhfi-chlorobenzoic acid 2| 3Phcnacylthio-S-tril'luoromethylbenzoic acid 20 3-Phenacylsulfinyl-S-trifluuromethylbenzoic acid 20 3-Mcthylsulfonyl-S-trifluoromethylbenzoic benzoic acid 22 2-( 2' Hydroxyethylthio I-S-chlorobenzoic acid 29 2-AcctonyIthio-S-chlorobenzoic acid 2! 2-Crotylthio-5-tril'luoromethylbenzoic acid l6 2-Mcthallylthio-5-trifluoromcthylbenzoic acid 25 3-Mcthylthio-5chlorobcnzoic acid 22 3-Fluorobcnzoic acid 0 5 Chloro-2-l 4-chlorophcnylureylcne )bcnzoic acid 32 S-Trifluoromcthyl-2-benzylaminobcnzoic acid I? 5 Chloro-2-( n-propylurcylene )benzoic acid It) 5-Trifluoromcthyl-2-( 3-methylpiperidino)- benzoic acid 27 5-Trifluoromcthyl-2-( 3.5-dimcthylpipcridinolbcnzoic acid I) S-Trifluoromcthyl-Zacetamidobenzoic acid 7 5-Trifluororncthyl-2-bcnzamidobenzoic acid 26 5-Trifluoromethyl-l-diethylaminobenzoic acid 6 In a similar manner, when tested by the above procedure, the following benzoic acids also lower cholesterol levels: 3,5-dil'luor0benzoic acid, 2,5-difluorobenzoic 4U acid, 2-chloro-5-fluorobenzoic acid. 3-fluoro-4- chlorobenzoic acid, 3-fluoro-4-bromobenzoic acid, 2,3-dibromobenzoic acid, Z-bromoS-fluorobenzoic acid, 3,5-dibromobenzoic acid, 3-fluoro-4- methylbenzoic acid, 2-methyl-5-fluorobenzoic acid,
EXAMPLE 30 A dry solid pharmaceutical composition is prepared by combining the following materials in the indicated weight proportions:
lhcnq lox -S-trilluoromcthylhcnzoic ucitl 5U calcium carbonate 2U 3U polyethylene glycol. average molecular weight 4000 The dry mixture is thoroughly agitated to obtain a completely uniform blend. Soft elastic and hard gelatin capsules containing this composition are then prepared. employing sufficient material to provide each capsule with I mg. of active ingredient.
EXAMPLE 3i A dry solid pharmaceutical composition is prepared by blending the following materials together in the specified weight proportions:
3-methoxy-S-lrifluoromethylbenzoic acid 50 sodium citrate 25 alginic acid 10 polyvinylpyrrolidone l0 magnesium stearate 5 After the dried composition is thoroughly blended, tablets are punched from the mixture, each tablet being of such size as to contain mg. of the active ingredient. Tablets are also prepared containing, respectively, 5, l0, 25 and 50 mg. of the active ingredient, by employing the appropriate proportions of 3-methoxy-5- triiluoromethylbenzoic acid and excipient blend in each case.
EXAMPLE 32 2-Benzyloxy-5-trifluoromethylbenzoic Acid Sodium Salt To a solution of 400 mg. (0.01 mole) of sodium hydroxide in 30 ml. of water is added, in portions and with stirring, 2.96 g. (00] mole) of Z-benzyl-oxy-S-trifluoromethylbenzoic acid. The slightly hazy solution is and the pharmaceutically acceptable salts thereof wherein X is selected from the group consisting of fluorine, chlorine, bromine, methyl and trifluoromethyl and R is selected from the group consisting of fluorine,
chlorine, bromine and methyl. 2. The method of claim 1, wherein X is trifluoromethyl and R is chlorine.
3. The method of claim 2, wherein said compound is of the formula:
|Cited Patent
|Filing date
|Publication date
|Nov 24, 1969
|Jul 20, 1971
|Haessle Ab
|Pharmaceutical compositions containing benzothiophene derivatives
|Nov 20, 1969
|Apr 24, 1973
|Merck & Co Inc
|Sulfonylbenzoic acids
|Citing Patent
|Filing date
|Publication date
|Mar 3, 1975
|Mar 29, 1977
|Sandoz, Inc.
|Alkanoyl substituted benzoic acids and esters
|Nov 19, 1982
|Apr 17, 1984
|Frank Scieri
|Hydro electric generating system
|Mar 20, 1996
|Mar 23, 1999
|Smithkline Beecham Corporation
|IL-8 receptor antagonists
|Jun 24, 1997
|Oct 17, 2000
|Smithkline Beecham Corporation
|IL-8 receptor antagonists
|Jan 29, 1999
|Jan 30, 2001
|Smithkline Beecham Corporation
|IL-8 receptor antagonists
|Jul 8, 1998
|Apr 3, 2001
|Smithkline Beecham Corporation
|Phenyl urea antagonists of the IL-8 receptor
|Aug 21, 1996
|Jul 17, 2001
|Smithkline Beecham Corporation
|IL-8 receptor antagonists
|Jun 24, 1997
|Aug 7, 2001
|Smithkline Beecham Corporation
|IL-8 receptor antagonists
|Nov 19, 1999
|Oct 28, 2003
|Corvas International, Inc.
|Plasminogen activator inhibitor antagonists
|Nov 17, 2000
|Jan 13, 2004
|Corvas International Inc
|Plasminogen activator inhibitor antagonists
|Aug 20, 2003
|May 26, 2005
|Atli Thorarensen
|Antibacterial agents
|Nov 17, 2000
|May 25, 2001
|Corvas International, Inc.
|Plasminogen activator inhibitor antagonists related applications
|Nov 17, 2000
|Jul 11, 2002
|Corvas Int Inc
|Plasminogen activator inhibitor antagonists related applications
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification


text:
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couldn't understand the question....could u plz elaborate it?...what is four tier hierarchy?
guys dnt get confused between ICPS n ICDS....both sound similar so plz read abt ICDS also
awesome question...:P
@jothiraj yes you have to submit the original rent agreement....and it's not included in your salary.
@ashishbharti88 it depends on your BM. My BM says that finish your work n go home...so i leave arnd 6:30 or 7....bt max to max it'll b 8....n even in rural branches CM is there so there is nothing like that u'll never get rural postings after reaching to Scale 4....if you can complete your mandatory assignment (rural n semi urban) in initial 4-5 yrs then it'll b an advantage for you. foreign postings will b only after you complete your assignments n 3 years of service...there will b an exam n interview...n it's purely merit based
@sakmn me b kaafi tym raha hu jaipur...pahle malviya nagar tha n uske baad mansarover shift ho gaya tha.....posting kahan mili hai?
@coresplit - 2. Do not expect anything big here...nobody will give you credit profile on very first day....so b ready to do anything assigned to you (i really mean it :P)...basically you'll be opening accounts n doing general operational things in first few months n then it depends on your caliber.
3. Yes casual hairstyle is ok. Dont think too much abt it but i'll suggest you not to do that coz AGMs n other authorities visit branches very frequently n it dosent look good.
4. No direct marketing. n even if it'll b there dnt worry it'll b fun....coz even i did it as a part of my training..
5. Lease amount is min. 8500 in rural n max. is 29500 (metro). Do not worry about it.. Trust me you'll b staying in one of the best colonies in your area coz the lease amount is more than sufficient. For ex. in Somnath it's 8500, in Gandhinagar ut's 20000, in vadodara it's 15000.
I hope I have cleared all the doubts. All the best
@coresplit - 1. Place of posting depends on LHO...nobody can say anything but one thing is for sure that if u'll get remote areas initially then after first transfer you can expect better postings. working hours depend on your BM...I was lucky that all my BMs were very friendly so i used to work till 6.

subset: commoncrawl


text:
Things to see and do - Saas Fee
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1 Hotel The Larix
Gletscherstrasse 14 CH - 3906 Saas-Fee
Prix from : 110 CHF
Hotel The Larix is a charming family-run hotel located in Saas-Fee, near the forest and offers 25 comfort and family rooms. The cable-cars, ski school, skating and curling rink are within 2 minutes' walk. You can taste the culinary Switzerland delig..
2 Hotel Alpin Superior
Mischistrasse 18 CH - 3906 Saas-Fee
Prix from : 115 CHF
Situated on a quiet site in Saas-Fee, near the station of the Alpin Express the Hotel Alpin offers you great wellness facilities and fine cuisine. You can ski right down to the hotel's door. Choose from spacious double rooms, that are at least 25 m²..
3 Hotel Ambiente
Saas-Fee CH - 3906 Saas-Fee
Prix from : 125 CHF
Enjoying a ski-to-door position in the centre of car-free Saas-Fee, the peacefully located 3-star Hotel Ambiente offers a typical Alpine ambience, comfortable rooms and an elegant wood-panelled restaurant. All of the rooms at Ambiente feature a sout..
4 Hotel Garni Condor
Mischistrasse 40 CH - 3906 Saas-Fee
Prix from : 98 CHF
Located 150 metres from the Saas Fee cable cars, Hotel Garni Corndor is set in a quiet area of the ski resort Saas Fee. It offers a breakfast buffet. All comfortably furnished rooms provide a balcony, free Wi-Fi access, cable TV and a private bathro..
5 Hotel Mistral Superior
Gletscherstrasse 1 CH - 3906 Saas-Fee
Located only 100 metres from the cable cars in Saas Fee, Hotel Mistral Superior offers free WiFi access. All rooms have a balcony with views of the mountains and glaciers. A shuttle service from and to the train station is provided free of charge. R..
6 Hotel Derby
Gletscherstrasse 4 CH - 3906 Saas-Fee
Prix from : 136 CHF
The Hotel Derby enjoys a quiet location next to the ski school and ski lift and close to the cable car station in Saas Fee. From December to April you can ski right down to the hotel's front door. From most rooms you can enjoy views of the mountains..
7 Hotel Annahof
Gletscherstrasse 2 CH - 3906 Saas-Fee
Featuring free WiFi, a restaurant and a seasonal outdoor pool, Hotel Annahof offers pet-friendly accommodation in Saas-Fee. The hotel has a hot tub and ski-to-door access, and guests can enjoy a drink at the bar. The rooms are fitted with a flat-scr..
8 Hotel Bristol
Hotel Bristol CH - 3906 Saas-Fee
Offering panoramic views of the surrounding mountains, Hotel Bristol in Saas Fee offers ski-to-door access just 20 metres from the lifts and 300 metres from the cable car. It is opposite the golf course, the football field, and the tennis, volleyball..
9 Hotel Burgener
Dorfstrasse 43 CH - 3906 Saas-Fee
Prix from : 55 CHF
Built in typical Valais style, Hotel Burgener is located next to the Alpin Express and Spielboden-Platt Cable Cars and to a 9-hole golf course, and just 300 metres from the centre of Saas Fee. Free WiFi is available. All rooms feature a flat-screen ..
10 Hotel Saaserhof
Lehn CH - 3906 Saas-Fee
Prix from : 165 CHF
This hotel with a modern spa area and a children's playroom is located next to the ski slopes, 200 metres from the cable cars and the centre of Saas Fee. Upon request, guests will be brought free of charge to the hotel. All guest rooms in the Golfh..
11 Feehof
Hotel Feehof Garni CH - 3906 Saas-Fee
Prix from : 112 CHF
The Feehof Hotel enjoys a sunny and central location in car-free Saas Fee, close to the ski school, the sport facilities and lifts. It offers free wired internet in all rooms. The Feehof's cosy lounge with a fireplace and a small bar invites you to ..
12 Hotel Christiania
Dorfstrasse 19 CH - 3906 Saas-Fee
Prix from : 57 CHF
Only a 3-minute walk from the ski slopes, the Christiania Hotel in Saas-Fee offers a sauna and a steam bath in its wellness area. Free Wi-Fi is available. Guests can start their day with a rich breakfast buffet. Half-board is available in winter and..
13 Hotel du Glacier – The Dom Collection
Blomattenstrasse 2 CH - 3906 Saas-Fee
Prix from : 120 CHF
Located in the centre of the car-free village of Saas-Fee, Hotel du Glacier - The Dom Collection offers panoramic views of the Swiss Alps and a spa area with 2 saunas and a steam bath. The rooms at the Hotel du Glacier offer cable TV, a seating area..
14 The Dom Hotel - The Dom Collection
Dorfplatz 2 CH - 3906 Saas-Fee
Set just 500 metres from the ski lifts of Saas-Fee, The Dom Hotel offers rustic style and futuristic elegance in the Swiss Alps. Each room is equipped with a private balcony, free WiFi, and an iPod docking station and an iPad loaded with daily newspa..
15 Hotel Metropol
Untere Dorfstrasse 35 CH - 3906 Saas-Fee
Prix from : 126.50 CHF
The Metropol Hotel is surrounded by the highest Swiss mountains in the glacier village of Saas-Fee and offers first-class cuisine, cosy rooms and a spacious spa area. A wellness area features different types of saunas, and an indoor pool with a hot ..
16 Hotel Ferienart Resort & Spa
Postfach CH - 3906 Saas-Fee
Prix from : 190 CHF
The 5-star chalet-style Hotel Ferienart Resort & Spa in Saas-Fee features 3 restaurants and an exclusive spa area with a pool and a hot tub. The spacious rooms all have a balcony. All rooms at the Ferienart Hotel are furnished in an elegant Alpine s..
17 Art Hotel
Dorfweg 1 CH - 3906 Saas-Fee
Prix from : 189 CHF
Offering an indoor pool and a spa and wellness centre, the Art Hotel is located in the centre of Saas Fee, 200 metres from the Hannig Cable Car. Free WiFi is available. The spacious, elegantly furnished rooms all feature a balcony with mountain view..
18 Schweizerhof Gourmet & Spa
Saas-Fee CH - 3906 Saas-Fee
Enjoying a quiet yet central location in Saas Fee, with superb views of the Saas mountains, the Schweizerhof Gourmet & Spa Hotel also offers you a great spa area and free Wi-Fi. The 1000 m² wellness area The Wave features an outdoor panorama sauna, ..
19 Britannia
Obere Dorfstrasse 44 CH - 3906 Saas-Fee
Prix from : 75 CHF
The Britannia Hotel is situated in the centre of Saas Fee, about a 5-minute walk from the ski lifts, and offers traditional Swiss cuisine and nicely furnished rooms with a flat-screen TV. Free WiFi is available in the entire hotel. You can enjoy sup..
20 Elite Alpine Lodge - Apart & Breakfast
Haltenstrasse 21 CH - 3906 Saas-Fee
Prix from : 216 CHF
Newly-renovated in December 2013, Elite Alpine Lodge (Apart & Breakfast) is located in 200 metres from Saas-Fee centre and a 5-minute walk from the LSF Cable Car. It offers free WiFi and free ski storage. The alpine-style units at the Lodge come wit..


text:
Ministry Of Water Resources Recruitment
A career oriented Job advertisement has been disclosed for Ministry Of Water Resources Recruitment. The reputed organization invites applications from qualified & skilled candidates for filling up 25 Skilled Works Assistant Posts. Interested job appliers, who are willing to apply for Ministry Of Water Resources Recruitment 2016, can submit their application form in prescribed format before last date should be reached.
|Post Name
|Skilled Works Assistant
|Total Vacancies
|Last Date Of Receipt Of Application Form
|With-In 30 Days
Candidates, who want to apply for this Current Openings in Government Sector, must have full information regarding this advertisement. So, here on this page of recruitmentresult.com we are providing you entire details related to Ministry of Water Resources Recruitment 2016 such as qualification, age limit, process to apply, mode of selection, salary package etc.
Essential Qualification and Experience:
Aspirants, who wish to apply for above stated posts at Ministry Of Water Resources Vacancies, should have passed Matriculation from a recognized board and having / ITI or equivalent certificate from repudiated institutions and knowledge of Swimming and playing of boat.
Age Limit:
- Candidates' minimum age should be 18 years and maximum age is 30 years.
- Relaxation in age will be given to reserved category appliers as per GOI rules.
Salary Package:
Selected job finders for Skilled Works Assistant posts will receive pay scale of Rs. 5200 – 20200/- with gross pay of Rs. 1800/- per month.
Mode of Selection:
Selection of aspirants will be based on test or their appearance in personal interview which will be conducted by selection panel of reputed organization.
|Preparation Tips for Written Exam
|More Details
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|More Details
Process to Apply for Ministry Of Water Resources Recruitment:
- First of all, applicants who are applying against Ministry Of Water Resources Recruitment need to visit on official website that is www.wrmin.nic.in
- On home page, hit on "vacancies" tab.
- Then, choose appropriate link as per the notification.
- Read all details and download application form in prescribed format.
- Fill it carefully and correctly with entire details.
- Application should be super scribed as "application for the post of _______ in central ground water board" on left hand corner of envelope.
- At last, send complete application form along with attested photocopies of all documents related to your qualification, age proof, caste certificate etc through post to the following postal address which is equipped below on this page.
Postal Address:
To The Director,
Monitoring Directorate,
Central Water Commission, 177-B,
Shri Krishpuri, Patna – 800 001
Important Date:
Last Date Of Receipt Of Application Form: With-In 30 Days
Check Official Link, to collect further details regarding Ministry Of Water Resources Recruitment 2016.
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Northrop Grumman Appoints Robert Hosozawa Vice President Business Management For Integrated Logistics And Modernization Division
HERNDON, Va., Aug. 29, 2013 /PRNewswire/ -- Northrop Grumman Corporation (NYSE: NOC) has appointed Robert Hosozawa vice president, business management, for the Integrated Logistics and Modernization Division (ILMD), of the company's Technical Services sector, effective Sept. 7. (Logo: http://photos.prnewswire.com/prnh/20121024/LA98563LOGO)A photo accompanying this release is available at http://media.globenewswire.com/noc/mediagallery.html?pkgid=20711. Hosozawa will be responsible for all business matters within ILMD including developing and executing business strategies to meet division and sector business objectives. "Robert's extensive business management experience, which includes a superb track record of negotiating multibillion dollar contracts and executing major programs, will be a tremendous benefit to the division and sector," said Nimish Doshi, chief financial officer, Northrop Grumman Technical Services. Hosozawa most recently served as director of business management for the B-2 Spirit program at Northrop Grumman Aerospace Systems. His experience includes a variety of business management positions in contracts, pricing, cost and schedule management, financial planning, and capital asset management. He earned a bachelor's degree in business administration from California State University, Los Angeles, and completed executive programs at the Darden School of Business, University of Virginia, and the program management course at Defense Systems Management College. Northrop Grumman is a leading global security company providing innovative systems, products and solutions in unmanned systems, cyber, C4ISR, and logistics and modernization to government and commercial customers worldwide. Please visit www.northropgrumman.com for more information. SOURCE Northrop Grumman Corporation
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Top Teachers: Janet Givens
Echo Lake E.S., first grade
Officially, Janet Givens teaches first grade at Echo Lake Elementary School. Unofficially, she teaches creativity.
Givens' classroom is a wonderland of ingenuity, a place where students learn the same lessons in a multitude of different ways. Students often lead their peers in lessons on her classroom Promethean board or create scrapbooks from field trip experiences. Mind-bender games challenge their knowledge.
During a popular lesson about the solar system, Givens takes her students outside to draw a 15-foot sun in chalk on the pavement, then uses a golf ball to represent the size of Earth.
"The visual perception of the concept will forever be embedded in my son's head," wrote one woman who nominated Givens.
Givens – who gave up a career in interior design and retail merchandising to become a teacher 15 years ago – traces the roots of her own creativity to her great aunt, an art teacher who instilled much of it in her at a young age.
"I like thinking of news ways to do things, or unusual ways – ways the kids relate to," she said. "I just really try to be me in my classroom, and part of me is, a lot of times, doing things a little bit differently."
Givens earned National Board Certified Teacher status in 2004 – an involved process that requires teachers to develop an extensive portfolio and complete several assessment exercises. She has taught first grade at Echo Lake since the school opened in 1999. She works to develop a personal connection with each student, believing that in turn they'll open up to her and be more eager to learn.
"I like to try to find that one little special thing that makes a child unique or challenging or special," she said.
Her efforts haven't gone unnoticed among parents.
"She recognizes the wide ability range of children in her class and manages to incorporate the advanced essentials of curriculum yet still meet the needs of those requiring a 'second helping,' one nominator wrote.
Givens is a regular participant in recess – "I'm usually the pitcher for kickball," she admitted – and considers one of her most meaningful teaching moments to be one that came outside the classroom. A student had earned the reward of running a mile with her after school, but he had difficulty convincing himself he could finish.
"That whole time I kept telling him, 'One foot in front of the other, you can do this – we're not going to stop, you can do this' – and he did," he recalled. "It was the best mile I ever ran with him. It's something that I carry with me."
Richmond Solar Co-op sign ups end April 30
Citizen Staff Reports 04/25/2016
The sign up period for the Richmond Community Solar Co-op will close on April 30. Nearly 150 homeowners and businesses have joined the group to save money and make going solar easier. The group has started installations and is working with VA SUN to learn about solar technology and the process of going solar.
"If you've ever thought about going solar, this is a great opportunity to do so," said Sekar Veerappan Co-op member and the group's first installation. "Working with the group helps members learn about going solar and make an informed decision." > Read more.
YMCA branches to host 'Healthy Kids Day' Apr. 29-30
Citizen Staff Reports 04/22/2016
The YMCA of Greater Richmond will host its "Healthy Kids Day" April 29-30 at all local branches.
The event is part of the Y's national initiative to improve families' health and well-being.
Each event features games, healthy snacks, arts and crafts and physical activities, among other events. Its goal is to motivate and teach families how to develop healthy routines at home. > Read more.
Weekend Top 10
Another great weekend of outdoor activities awaits you in Henrico! Walk MS, an annual charity run for multiple sclerosis, and the third annual Movin' & Shakin' 5K, to benefit the VCU Parkinson's and Movement Disorders Center, both take place in Innsbrook tomorrow. Another charity event, the CASA Superhero Run, will be held at St. Joseph's Villa. On Sunday, live music can be found at Belmont Recreation Center, featuring the John Winn Quartet, and at Shady Grove United Methodist Church, where pianist Sylvia Cooper will be performing. For all our top picks this weekend, click here! > Read more.
Henrico DPU flushing lines in Lakeside to clear discolored water
Henrico Public Schools to offer parenting workshops
Glen Allen teens' project fights cyberbullying
Challa to receive 'Outstanding Women Award'
Highland Springs HS teacher earns national award
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Apr. 21, 2016Click here to read the print edition.
Weekend Top 10
Henrico students star in 'The Enchanted Toy Shop'
Weekend Top 10
Weekend Top 10
Reynolds CC hosting student art show
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Obituary – Albert H. Buccini
Obituary – Rebecca Hagadorn Clarke
Obituary – David Allen Luebke
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Richmond Solar Co-op sign ups end April 30
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Of character and parenting
Opinion: Rename school for late Henrico officer
Of car chats and grocery games
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CalendarThe Henrico County and Chesterfield County Court Appointed Special Advocates (CASA) organizations will hold the seventh annual Superhero Run to support local programs for abused and neglected children. The event,… Full text


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for the weekend 7/23
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18th st lounge
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Cantina Marina
Outdoor bar
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outdoor bar to try
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Visualizing Time - Statistics and Computing (Hardback)Graham Wills
Hardback Published: 15/12/2011
- Not in our warehouse
Art, or Science? Which of these is the right way to think of the field of visualization? This is not an easy question to answer, even for those who have many years experience in making graphical depictions of data with a view to help people understand it and take action. In this book, Graham Wills bridges the gap between the art and the science of visually representing data. He does not simply give rules and advice, but bases these on general principles and provide a clear path between them This book is concerned with the graphical representation of time data and is written to cover a range of different users. A visualization expert designing tools for displaying time will find it valuable, but so also should a financier assembling a report in a spreadsheet, or a medical researcher trying to display gene sequences using a commercial statistical package.
Publisher: Springer-Verlag New York Inc.
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With the lead in the West Central Conference baseball standings on the line over two nights, round one went resoundingly to North Putnam Monday night. The Cougars beat county rival South Putnam 19-5 Monday afternoon on the Eagles' home field.
The second-inning run was the hard luck sort for South, as Cougar David Church hit a ball to the South Putnam left fielder, only to have the ball bounce out of his glove and over the fence.
However, the game got really out of hand in the third when Kyle Rooker and Kyle Alcorn led off the inning with back-to-back home runs. The next four batters all reached base, with Brock Jones finishing off South starter Brice Steinbaker's night with a three-run homer.
Steinbaker took the loss, allowing 10 runs on eight hits, two walks and four home runs.
Reliever Grant Zimmerman fared no better, allowing two more hits and issuing six walks before the inning was over.
All told, the Cougars scored 11 times in the inning, extending a 3-1 lead to a 15-1 lead.
North coach Norm Fish was very happy with the way his team is hitting the ball.
"I think we're playing with some confidence right now offensively, and that's what it takes. Hitting is 99 percent mental," Fish said.
For South Putnam coach Harold Campbell, the game turned into a teaching opportunity after the ugly third inning.
"We're a young team and we're learning every day. Sometimes you take a game like this and you have to use it as a learning experience," Campbell said. "One of the things we're looking for in our team is that they never give up. Some of our kids are starting to do that. Some still have yet to do that so we just have to keep pounding that home."
The Cougars added two runs in the fourth and two in the fifth, with Jordan Berry hitting a two-run shot in the fourth and Kyle Rooker adding a two-run homer in the fifth.
These two seniors led the potent Cougar attack on the evening. Berry was 5-for-5 with three doubles, a home run and five RBIs. Rooker was 2-for-3 with a pair of home runs and thee RBIs.
Sophomore Brock Jones has been on a tear of late, having hit four home runs in four games.
The Eagles, on the other hand, could not keep up with the Cougar output. Brayden Freeman drove in Steinbaker with a second-inning double. Cameron Chestnut scored on a wild pitch in the fifth.
The main bright spot for South came in the bottom of the fifth, when two straight players reached on errors before Noah Boswell hit a monster three-run shot that reached the infield of the softball diamond.
"You want to finish on a good note," Fish said "We played good offense for five innings, but we finished the game on kind of a sour note defensively. We just gotta keep playing."
However, Berry kept the Eagle hitters off balance most of the night. He allowed five runs on six hits and a walk while fanning nine Eagle batters.
"Jordan's a competitor and he really likes being out there. He works hard at it and he throws hard. That just carries over at the plate. He's staying focused and doing his job right now. You can't ask much more out of him," Fish said.
For both coaches, the challenge is now getting their players to forget about Monday and get ready for Tuesday's rematch at North Putnam. Campbell reminded his team that, in spite of Monday's score, the teams are still tied for the WCC lead.
"We're still excited. We know we still control our own destiny, as far as this next game. They've evened things up with us in terms of one loss in the conference," Campbell said.
"We're confident with what we're bringing tomorrow," he continued. "North Putnam probably feels like right now we're a team they can walk all over. We've just got to come out ready to fight and show them we're going give it everything we've got."
Fish is fighting hard against that kind of attitude from his team.
"We just have to keep that focus and not take anybody lightly. This score didn't mean anything because South is a good baseball team. They had young pitchers on the mound," Fish said. "I told our kids, 'Don't let that score do anything to you because we were facing young pitchers and we had a senior on the mound.'
"That's not really an indication of how close these teams are," Fish went on. "Tomorrow's gonna be a battle and we expect one. And we hope we'll be ready for it."
Noah Boswell will be on the hill today for South, matched up with the Cougars' Griffen Dahlstrom.
"We have a challenge against Noah Boswell tomorrow and we're excited about that," Fish said. "Our boys are wanting to play and we're excited about playing right now. We're having fun, but we're staying focused."
For the Eagles, their goal of a split with North Putnam is still within reach.
"We didn't get this first one, but that goal is still achievable if we do what we need to do tomorrow," Campbell said. "We expect to play great baseball and get that win tomorrow."
At South Putnam
North Putnam 31(11) 22 -- 19 15 2
South Putnam 01 1 02 -- 5 6 3
Berry and Dahlstrom; Steinbaker, Zimmerman (3), Freeman (7) and Dean.
WP -- Berry.
LP -- Steinbaker.
2B -- Berry 3 (NP), Freeman (SP).
HR -- Rooker 2, Church, Alcorn, Jones, Berry (NP), Boswell (SP).
Next game -- South Putnam (8-3, 6-1 WCC) visits North Putnam (10-2, 6-1 WCC) at 4:30 p.m. today.


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Sep 02, 2014
ANKARA [MENL] -- Turkey, fresh from the election of President Recep Erdogan,has resumed its purge of police linked to the opposition.
Aug 20, 2014
LONDON [MENL] -- The Saudi royal family was said to have been engaged inregional bribery.
Jul 11, 2014
LONDON [MENL] -- Britain has again been investigating an aerospacecorruption scandal in Saudi Arabia.
Aug 13, 2013
CAIRO [MENL] -- Algeria has issued a warrant for its former energy ministerlinked to a massive bribery scheme of the nation's energy industry.


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I know this isn't a new idea but how about a variant involving something like the Doubling Cube in Backgammon?
The usual idea is that if there is an offer to double the stakes/points, a refusal results in a win for the offerer, and an acceptance doubles the stakes/points, leaves the option for the next double in the game for the accepter, and, different for Chess, the accepter gets Draw Odds. Therefore, the offerer MUST win to not lose. The reason for this is that in a match, one player could get ahead by one point, then double every game and play for a draw, hastening the end and a win.
Anyone have any other ideas for this variant?
I'm not sure what level of player you're thinking of?
Any level.
Hmmm, could you imagine a Top (2700+) player cubing without seeing the win? Or do you think they would be speculative?
I certainly wouldn't accept if Carlsen doubles me, lol.
Good questions.
In BG, you Double with anything over 50% winning chances, and you accept if you have at least 25%, so very often, both sides are doing the correct thing, and more importantly, it is always at least partially speculative, if not wholly so.
I haven't worked out the math for Chess with the Draw odds, but despite what the numbers will be, I think it'll be less of who can calculate deeper and take advantage of that, and more a case of position evaluation.
I'll work out the math after I've had caffeine.
Caffeine's good....
I'd like to make this work, but I have issues.
In Backgammon, you basically cube to protect yourself against bad dice. You often dont cube in totally won positions, because if your opponent declines you take away the posssibility of double or triple games.
If you cube in BG, (except against BG patzers :)) you generally WANT you opponent to decline, and pay for your current advantage. A BG advantage is much more volatile than a chess one.
How do you feel when you lose against a FEMALE?
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aprilbloedow's Mom Answers Activity
Seizures in utero
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I am 30 weeks pregnant, and my baby boy has been doing that for about the past 2 weeks as well!!! It feels really freaky, and I thought h...posted by aprilbloedow


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This place is one of the most popular restaurants in Cape Town, so it is recommended to reserve well in advance. Locals visit this restaurant, but it is more a tourist thing. What you get is exotic dishes in a nice atmosphere. Live music is often played at the restaurant, in that case a small charge will be added to your table. Food mostly consists of exotic meat like crocodile or kudu, but "normal" meat as well as vegetarian dishes are served too. If you are looking for a place to spend a nice evening, get a somewhat stereotypical african experience and eat things you have never eaten before, then that's the right place. Mama Africa is mentioned in many guides as a kind of "must do" when in Cape Town and there's no reason to disagree.
Favorite Dish: I had kudu with a couple of vegetables and mealiepap. A mix of exotic meat and typical south african food.
Address: 128 Long Street
Price Comparison: more expensive than average
Directions: In the heart of Cape Town, on one of the lifeliest streets of the city
Phone: (+27) 021 426 1017
Price: US$21-30
Rating: 5
Theme: African
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Problemi di "terrorismo"?
Ecco la soluzione…
700 tonnellate di cianuro di sodio. Circa 70 volte il limite consentito dalle norme di sicurezza hanno causato un'esplosione avvertita a 160km di distanza.
Il cianuro di sodio è usato industrialmente per estrarre le tracce d'oro dalla pirite.
Oltre al controvalore di quasi 700 milioni di dollari in auto nuove andate in fumo, chi patirà il danno più importante è l'industria estrattiva "underground".
A Tianjin c'è un ComEx:
Il deposito era vicino al porto di Tianjin. Le principali miniere cinesi sono distandi decine di ore di treno da Tianjin, difficile che vi si lavorassero terre di pirite provnienti dalla Cina. Più probabile che venissero raffinate terre importate i cui prodotti venivano poi commercializzati tramite il ComEx di Tianjin.
Il tutto con un certo Chinese-Twist… visto che il depostio di cianuro di sodio era clandestino.
The Chinese sense for gold:
Ci sono cascato, lo ammetto.
Ma oggi ho capito due cose. Perché e a cosa serve Renzi.
È in realtà molto semplice, forse talmente evidente che mi era sfuggito. Cercavo qualcosa di più complesso ma ora mi è chiaro.
There isn't.
Sorry if I disappointed you. There is no such thing.
I could link here hundreds if not thousands of such pieces – and I won't – in short, whenever and where ever you find an article or a book titled like «The one secret that…whatever» that-sold-million-copies-but-it's-a-secret, I can assure you, it's pure junk.
When and if you are job hunting, there's just one thing to be aware of:«there are no tricks», full-stop.
Determined to give Windows8 family a serious go about 18 months ago I sold on eBay my midrange Android smartphone – of which I was completely satisfied – to buy the first NOKIA with WindowsPhone8.
Shortly afterwards I set my iPad aside to switch over an ASUS T-100 Transformer Book powered by Windows8.
I have never returned to Android neither iOS so fascinated I am with the challenge that Microsoft had undertaken.
I soon realized that Windows8 was – and still is – by far the most innovative and in many ways truly new OS platform on the market. It was, and largely is, immune to all the monkeying that had characterized the growth of iOS and Android and beside a few hints gathered from the other OS it has its own "vision" and path. Plus MSFT has learned the lesson. A hard learned lesson, far too late – it took MSFT nearly seven years to do the homework – but the outcome is great. Therefore, for an absolute geek technologist like me, it is definitely an unmissable journey to see how MSFT gets out of the corner and I was anxiously waiting foran announcement like this:
We will streamline the next version of Windows from three operating systems into one single converged operating system for screens of all sizes
But then the recent disquieting announcement of massive layoffs came. I then tried to put everything into perspective. Continue reading
Foreword: the role and the limits of government scope and influence in surveillance and security is an extraordinarily complex and wide topic, I don't have the goal to unfold all of its implications. What urges me is point out a few interconnected factors and unintended effects of the current immaturity of the legal framework ruling on data ownership and data collection.
At minute 26 of this fascinating debate, moderator Thomas Friedman asks Satya Nadella what he thinks the US Govern should do to help the business of companies like Microsoft (HP and Intel). Nadella's answer is "reform of the surveillance regime". Or "scale down spying" as he stated elsewhere.
Satya Nadella believes that Continue reading
I had moved in my partially furnished new home less than a month before, and, on July the 2nd, the old TV set I found in it, ceased working.
At that time I didn't have any money. Dried up by the expenses, decided to postone the purchase of e a new TV set.
In my to-do-list the entry "Buy a new TV" was classified:"NTM", Not-This-Month.
No panic. Relax. Went to sleep early & quiet. Continue reading
"most people die at 25 but are buried at 75."
Benjamin Franklin


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My baby is currenlty being watched by a babysitter, but unfortunatly we are not very happy with this situation because my daughter still cries for an average of 2 or more hours a day with the babysitter and the babysitter is unable to calm her. Ā I have only 6 more weeks of school and I am most likely not working this summer, so we are going to stick it out with this babysitter until the end of the school year and then look into something else for september. ĀI chose a babysitter because I was worried that my baby wouldn't get eough one on one attention with a daycare, but it seems from most of your posts here that most of you are thrilled with your daycares....So what is your childcare situation and are you happy with it??
What is your childcare arrangement and are you happy with it?
D + A = M 12/4/10 and A 3/9/13
Platinum ( . )( . ) Award!!!!
Joe goes to a daycare only a mile and a half from my office.┬Ā I am very pleased with the arrangement.┬Ā They encourage me to stop by whenever I want.┬Ā I go every day at lunch to nurse Joe if it works out schedule wise or just visit.┬Ā They can only have 4 infants to one adult.┬Ā At first this seemed like alot to me but it seems for the most part that one or more is usually napping.┬Ā Joe seems very happy where he is.
Tammy and John 10/4/2008
Joseph Henderson born 11/27/2010
My LO is in an in-home daycare... I think we really lucked out, I love the sitter and I think my LO does too- she doesnt show signs of unhappiness and always eats/sleeps well there which I assume are signs she is adjusted to being there.
There are 6 kids allowed in her home a day and she has 9 that rotate some of the days. Kaylah and 2 other children are there every day. She is the only baby, the next youngest are 18mo. I beleive. The kids love my LO and I really think she learns alot from being around them, she is always trying to talk and she gets excited when she sees kids when we are out and about lol.
I was so scared to leave her when I came back to work but its not as bad as I thought it would be, especially b/c I am not stressing about what is going on at Daycare.
That being said, it was HARD to find one we liked, we interviewed 4 places I think and I had called probably 15 and just didnt like some of their policies (one was right by our house but she would have had to drive with my LO every single day to take her kids to school, not okay with us in Michigan in winter especially!) or just thier demeanor on the phone.
If you go with an in-home, I would try your state's government website first, you can look up if any of them have violations (at least on Michigan.gov) so I started there with a list of homes in my area, or on my way to work... I called some and also decided to drive by BEFORE calling in case the home was something I DID NOT even want to waste time walking into lol! Which tehre were quite a few...
The only abbreviation I care about is STTN! :) OMG.
Payton goes to my MIL's who runs a home daycare. It has its ups & downs because it's my MIL, but I'm happy she is so close to home. She lives about 5 minutes from me & hubs picks her up before I get home.
cLisa (37) married Y to fDH (38) 10/13/2007
sts ePayton Faye 11/11/10 ~ Gold b( . Y . )ies sts
sts aTaylor Marie 7/9/12 ~ Gold b( . Y . )iessts
Mikko is currently with a friend of the family. DH has known her since HS. She is pregnant, so we have had to find alternative care a couple of times. It hasn't been too bad though. My grandma lives a few blocks away and just stays at the house with him. I'm a teacher with 3.5 weeks left. So he will stay with her until summer.
In the fall, he is going to an inhome-daycare down the street from my school. I have interviewed her, visited her house announced and unannounced (to drop off the deposit). I have loved everything so far. SHe has been doing it for 25+ years and really cares about the kids. She only takes teacher's kids from my district and we don't have to pay for the school's breaks. I got tons of recomendations from other teachers in the building.
For with God nothing shall be impossible. -Luke 1:37
Mikko 11/15/10
Zeke 12/23/12
Collin goes to an in-home daycare less about a mile from our home. It can have up to 12 kids at a time, but usually has 6-9 during the day (some are only there before and after school). Collin seems to really like it there, and loves watching the other kids play. She has been doing this for 26 years, and her 6 kids all have degrees (even a doctor and lawyer) so at least I know she values education. ┬ĀThere is one other infant that is there 3 days a week, and we are there all 5. i really like it there and don't stress about him being there during the day.
My only concern is that since it is in-home and her other staff is her husband (and recently graduated son as the back-up) that there may not be enough supervision at times (needs to be 2 for 12 kids, one infant per adult). I worry that there may be times when it is just her watching more than 6 kids (her husband in in another room or outside). I don't worry about them being off the property. However, with all my worries, I have not once stopped in, dropped my son off late or picked him up early and not seen enough supervision. I keep trying to catch them ┬Ā, but haven't. I just worry. On a positive note, that is my only concern with the place. I love the people, and the husband loves to take care of my son.┬Ā
Overall I am very happy with the place I chose, like ccyph11, I whent on Michigan's site of registered daycares, called 15-20 in my area and got info, drove by about 5-6 and visited another 6 or so. I was very happy with my choice when the daycare lady showed up at my sons baptism in January (before we even started going there) and brought him a Christmas gift and a baptism gift. She is very thoughtful, and gives them gifts at every holliday.
ccyph11 - You live in Michigan! Me too! I am in the Lansing region of the state.
Kim (38) and DH (42)^mmc 10/2009^, DS1 10/26/10, ^Vanishing twin 4/2013^, DS2 12/11/13, Baby girl due 6/8/16
(.)(.) Diamond
Thats crazy! I work in Lansing, live in Jackson :)
The only abbreviation I care about is STTN! :) OMG.
We have a nanny and LOVE her - she loves Matteo and he loves her too!┬Ā It's great because she also does a lot of stuff around the house for him (washes laundry and bottles, prepares pumping packets for me, cleans the kitchen too!).┬Ā We used to do daycare a few days a week but we just kept getting sick, it wasn't worth it to us.
Jeannette, married to my best friend 8.12.06
Big Brother born 11.19.10
Little Brother born 1.14.14
Serene, DH Carlos, DD Liana 11-18-10
Lucia 4/8/13
I work in East Lansing at MSU and live in St. Johns! (sorry to post non-questions related items).


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Biodiversity Teacher Resources
Find Biodiversity educational ideas and activities
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So You Think the World Evolves Around You?
Students examine the topic of evolution as it relates to biodiversity in various remote areas of the world. They watch videos, conduct Internet research, and in small groups create a digital video report to illustrate common evolution in...
7th - 9th Science