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Justia Patents Oxygen Single Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring SystemUS Patent Application for Progesterone receptor antagonists Patent Application (Application #20080200440)
Progesterone receptor antagonists
The present invention relates to progesterone receptor antagonists of general formula I: in which R1 can be a hydrogen atom and R2 a hydroxyl group or R1 and R2 together can be an oxo group.
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/858,955 filed Nov. 15, 2006.
The present invention relates to progesterone receptor antagonists of general formula I:
in which R1 can be a hydrogen atom and R2 a hydroxyl group or R1 and R2 together can be an oxo group, to drugs (pharmaceutical compositions) containing them and to their use in the manufacture of medicaments.
The invention relates in particular to the progesterone receptor antagonists
11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17a-pregna-4,9-dien-3-one
and its individual epimers
11β-[4-[(1R)-1,2-dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17a-pregna-4,9-dien-3-one and
11β-[4-[(1S)-1,2-dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one
20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one
and to drugs containing them and to their use in the manufacture of medicaments.
A preferred compound of this invention is 20,20,21,21,21-Pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one.
Compounds with antigestagenic activity (competitive progesterone receptor antagonists) first became known in 1982 (RU 486; EP57115) and have since been very well described. Steroids with antigestagenic activity which are different from the substances according to the invention and have a fluorinated 17α side chain were published in WO98/34947 and Fuhrmann et al., J. Med. Chem. 43, 5010-5016 (2000). The class of compounds disclosed in WO98/34947 permitted a large variety of substituents at position-11 of the steroid nucleus but did not extent to disubstituted alkylphenyl groups. EP57115 allowed a range of substituents at position 11 of the steroid nucleus but required that such substituents contained a nitrogen, phosphorus or silicon atom. There is therefore no suggestion that steroids containing a fluorine containing substituent at position 17 and a disubstituted alkylphenyl substituent at position 11 of the steroid nucleus could have desirable properties.
Substances claimed here are at least partially metabolites of a substance claimed in WO98/34947.
The object of the present invention is to provide novel competitive progesterone receptor antagonists and drugs containing them and hence to create alternative ways of treating gynecological diseases.
The object has been achieved by the synthesis of 1162 -[4-(1,2-dihydroxyethyl)phenyl]-20,20,21 ,21 ,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one and 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one. The epimers of 11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one can be specifically prepared either by means of chromatographic separation on a Chiracel OD-H column with hexane/ethanol 90:10 (v/v) as mobile phase, or by starting from chiral structural entities such as (R)- or (S)-1-(4-bromophenyl)-1,2-ethanediol.
The compounds of this invention are therefore favourable those that have been prepared by chemical processes.
Aptly the invention provides a dihydroxy compound of this invention substantially free of its isomer, that is when in at least 90%, more aptly at least 95% preferably at least 98% and most preferably 100% free from the corresponding isomer.
Since the compounds of the invention are to be used in pharmaceutical compositions it is favoured to provide then is isolated form, for example as a solid, aptly as a substantially pure solid, for example substantially free of other steroidal compounds or other biologically active agents.
Substances of general formula I are valuable pharmaceutical active ingredients. They can be used inter alia for the manufacture of pharmaceutical preparations for the treatment of myomas or endometriosis, for female contraception, for postcoital fertility control, for bringing on menstruation, for inducing labor, for hormone replacement therapy, for the treatment of symptoms associated with dysmenorrhea, for the treatment of hormonal irregularities and for the treatment of hormone-dependent tumors, e.g. a progesterone receptor-positive carcinoma of the breast. Their efficacy as progesterone receptor antagonists has been identified in the abortion test on the rat and by determination of the McPhail index on the rabbit.
The substances of general formula I exhibit a higher metabolic stability in human liver microsomes (HLM) than the progesterone receptor antagonist 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one disclosed in WO98/34947. This is indicative of enhanced oral bioavailability of the compounds of this invention so that they can be used in pharmaceutical compositions adapted for oral administration.
The drugs (pharmaceutical compositions) according to the invention can be adapted for systemic or local administration. Generally it is preferred to adapt the drugs for systemic administration, for example by injection or by oral administration. If injectable form are contemplated these may be prepared by conventional methods known in the art for formulating steroids. If orally administrable forms are contemplated these may also be prepared by conventional methods known in the pharmaceutical arts for formulating steroids.
Preferred forms of the drugs will comprise a compound of the formula 1 and a pharmaceutically acceptable carrier therefore.
The pharmaceutical composition of the invention may be provided in a form suitable for systemic or local administration of which a systemically administrable form is generally is most apt. The systemically administrable form may be adapted for administration by injection, for example as a sterile form, for example an emulsion. The systemically administrable form may be adapted for oral administration and such forms are generally most suitable. Such forms generally will be a unit dosage form containing a predetermined amount of the compound of the invention. Suitable forms include tablets, capsules, powders, granulated and the like of which tablets are generally preferred. Such dosage forms can be manufactured in conventional manner and the pharmaceutically acceptable carrier can be any suitable carrier especially a carrier known to be if use in formulation steroidal medicaments.
The unit dosage form may contain 0,01-100 mg of the claimed substances.
FIGS. 1 and 2 show CD spectra.
The Examples which follow serve to illustrate the invention without in any way implying a limitation.
EXAMPLE 1 Synthesis of 11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one
a) 11β-(4-Ethenylphenyl)-5-hydroxy-5α-estr-9-ene-3,17-dione 3-(2,2-dimethyl-propane-1,3-diyl) ketal
3.3 g of magnesium turnings are placed in 14 ml of absolute tetrahydrofuran under inert gas and one drop of 1,2-dibromoethane is added. After the reaction has started, a solution of 25 g of 4-bromostyrene in 137 ml of absolute tetrahydrofuran is slowly added dropwise so that the internal temperature remains in the range from 40 to 45° C. The reaction mixture is subsequently stirred for one hour until the magnesium has completely reacted. 2.26 g of copper(I) chloride are then added to the mixture. A solution of 8.5 g of 5,10-epoxy-5α,10α-estr-9(11)-ene-3,17-dione 3-(2,2-dimethylpropane-1,3-diyl) ketal (for preparation cf. Tetrahedron Lett. 26, 2069-2072 (1985)) in 137 ml of absolute tetrahydrofuran is slowly added dropwise. The reaction mixture is stirred for one hour at room temperature and then poured into saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate and the organic phases are combined, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The product is filtered and concentrated under vacuum. Column chromatography on silica gel with a hexane/ethyl acetate mixture gives 6.76 g of the title compound as a colorless foam.
1H-NMR (300 MHz, CDCl3): δ=7.30 d (J=9 Hz, 2H, aryl); 7.18 d (J=9 Hz, 2H, aryl); 6.66 dd (J=17 Hz+11 Hz, 1H, vinyl); 5.70 dbr (J=17 Hz, 1H, vinyl); 5.20 dbr (J=11 Hz, 1H, vinyl); 4.44 s (1H, 5-OH); 4.29 dbr (J=6.5 Hz, 1H, H-11); 3.53 m (2H, 3-ketal); 3.51 m (J=11.4 Hz, 1H, 3-ketal); 3.42 m (J=11.4 Hz, 1H, 3-ketal); 1.05 s (3H, 3-ketal); 0.85 s (3H, 3-ketal); 0.49 s (3H, H-18).
b) 11β-(4-Ethenylphenyl)-20,20,21,21,21-pentafluoro-5,17-dihydroxy-19-nor-5α,17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal
A solution of 6.76 g of the compound prepared under a) in 140 ml of absolute toluene is added at −78° C. to 27.9 g of condensed pentafluoro-iodoethane in 140 ml of absolute toluene. 66.3 ml of a 1.5 molar solution of methyllithium/lithium bromide complex in diethyl ether are added at this temperature. The reaction mixture is subsequently stirred for one hour at 0° C. It is then poured into saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. Chromatography of the resulting crude product on silica gel with a hexane/ethyl acetate mixture gives 3.73 mg of the title compound as a white foam.
11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-5,17-dihydroxy-19-nor-5α,17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal
1.68 ml of an aqueous buffer solution at pH 7.00 of potassium dihydrogen phosphate and dipotassium hydrogen phosphate and 206 mg of trimethylamine N-oxide are added to a solution of 1 g of the compound prepared according to Example 1b) in 8.4 ml of tetrahydrofuran. 4.3 ml of a solution of 250 mg of osmium tetroxide in 50 ml of butanol are added dropwise at 0° C. The reaction mixture is stirred for three hours at room temperature and then poured into saturated aqueous sodium thiosulfate solution. The product is extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. Chromatography of the resulting crude product on silica gel with a hexane/ethyl acetate mixture gives 860 mg of the title compound as a white foam. A mixture of epimers at the benzylcarbinol is obtained.
1H-NMR (300 MHz, CDCl3): δ=7.25 d (J=9 Hz, 2H, aryl); 7.20 d (J=9 Hz, 2H, aryl); 4.78 m (1H, CHOH); 4.44 s (1H, 5-OH); 4.32 dbr (J=6.5 Hz, 1H, H-11); 3.73 m (1H, CH2OH); 3.65 m (1H, CH2OH); 3.54 m (2H, 3-ketal); 3.52 m (J=11.0 Hz, 1H, 3-ketal); 3.44 m (J=11.0 Hz, 1H, 3-ketal); 1.04 s (3H, 3-ketal); 0.87 s (3H, 3-ketal); 0.51 s (3H, H-18).
d) 11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one
200 mg of the compound described under Example 1 c) are stirred in 3 ml of methanol with 141 μl of semiconcentrated aqueous sulfuric acid for one hour at room temperature. The mixture is then poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum. Column chromatography on silica gel with a hexane/ethyl acetate mixture gives 78 mg of the title compound as a colorless foam. A mixture of epimers at the benzylcarbinol is obtained.
1H-NMR (300 MHz, CDCl3): δ=7.25 d (J=9 Hz, 2H, aryl); 7.15 d (J=9 Hz, 2H, aryl); 5.77 s (1H, H-4); 4.74 m (1H, CHOH); 4.42 dbr (J=7 Hz, 1H, H-11); 3.69 m (1H, CH2OH); 3.59 m (1H, CH2OH); 0.56 s (3H, H-18).
EXAMPLE 2 Synthesis of 11β-[4-[(1R)-1,2-Dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one a) (R)-1-(4-Bromophenyl)-1,2-ethanediol:
17.0 g of potassium carbonate and 40.4 g of potassium hexacyanoferrate(III) are dissolved in a mixture of 190 ml of n-butanol and 190 ml of water. 30 mg of potassium osmate and 300 mg of (DHQD)2PHAL are then added and the solution is cooled to 0° C. 7.5 g of 4-bromostyrene are then added at 0° C. and the mixture is stirred overnight. It is worked up by the addition of 30 g of sodium sulfite. The reaction solution is extracted with 300 ml of ethyl acetate. The organic phase is dried over sodium sulfate and concentrated to give 7.3 g of a white solid.
Yield: 7.3 g=82.1% of theory
1H-NMR (300 MHz, CDCl3): δ=7.50 d (J=9 Hz, 2H, aryl); 7.25 d (J=9 Hz, 2H, aryl); 4.80 dd (J=4.4 Hz+3.6 Hz, 1 H); 3.70 m (2H); 2.50 sbr (2H, OH).
The NMR data of the product are consistent with the NMR data described in the literature (T. Barlow, A. Dipple, Chem. Res. Toxicol. 1998, 11, 44-53).
b) (R)-4-(4-Bromophenyl)-2,2-dimethyl-1,3-dioxolane:
3.5 g of the diol described in Example 2 a) are suspended in 100 ml of acetone. 30 ml of 2,2-dimethoxypropane and 0.3 ml of concentrated sulfuric acid are added. After 2 hours, 100 ml of saturated sodium bicarbonate solution are added to the reaction mixture and the product is extracted with three times 50 ml of ethyl acetate. The organic phases are dried over sodium sulfate and concentrated under vacuum to give 3.7 g of a white solid. FIG. 1 shows the CD spectrum of (R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane.
1H-NMR (400 MHz, CDCl3): δ=7.48 d (J=9 Hz, 2H, aryl); 7.25 d (J=9 Hz, 2H, aryl); 5.04 dd (J=9 Hz+8.2 Hz, 1H) 4.30 dd (J=9 Hz+8.2 Hz, 1H); 3.16 dd (J=9 Hz+9 Hz, 1H); 1.53 s (3H); 1.48 s (3H).
c) 20,20,21,21,21-Pentafluoro-17-hydroxy-5,10α-epoxy-19-nor-5α,17α-pregn-9(11)-en-3-one 2,2-dimethylpropane-1,3-diyl ketal
50 g of 5,10-epoxy-5α,10α-estr-9(11)-ene-3,17-dione 3-(2,2-dimethyl-propane-1,3-diyl) ketal (for preparation cf. Tetrahedron Lett. 26, 2069-2072 (1985)) are added at −70° C. to 116 g of condensed pentafluoroiodoethane in 500 ml of absolute toluene. 290 ml of a 1.5 molar solution of methyllithium/lithium bromide complex in diethyl ether are added at the same temperature. The reaction mixture is subsequently stirred for one hour at 0° C. It is then added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. The crude product is dissolved in 200 ml of acetone, and 450 ml of water are added. The product which precipitates out is filtered off and dried under vacuum.
Yield: 61.6 g (93% of theory)
1H-NMR (500 MHz, CDCl3): δ=6.04 brd (J=2.5 Hz, 1 H, vinyl); 3.60 d (J=11.3 1H); 3.46 d (J=11.3 Hz); 3.39 dd (J=11.3 Hz+9.5 Hz, 1H); 2.51 dbr (J=10.6 Hz, 1H); 1.06 s (3H); 0.93 s (3H); 0.85 s (3H).
d) 11β-{4-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]phenyl}20,20,21,21,21-penta-fluoro-5,17-dihydroxy-19-nor-5α,17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal
387 mg of magnesium turnings are suspended . . . 3 ml of THF, and 50 μl of dibromoethane are added, with stirring. A solution of 4.35 g of the ketal described in Example 2 b) in 16 ml of THF is slowly added to the suspension at 65° C. The resulting solution is cooled to 0° C. 21.5 mg of CuCl and 2.75 g of the compound prepared in Example 2 c) in 11 ml of THF are added. The reaction mixture is stirred for 2 hours at 20° C. and 28 ml of 10 percent NH4Cl solution are then added. The reaction mixture is extracted with 20 ml of MTB ether. The organic phase is concentrated and the resulting solid (5.9 g) is purified by chromatography on 120 g of silica gel, with hexane/ethyl acetate as mobile phase, to give 3.2 g of the product as a white solid.
Yield: 3.2 g=85% of theory
1H-NMR (600 MHz, CDCl3): δ=7.23 d (J=9 Hz, 2H, aryl); 7.20 d (J=9 Hz, 2H, aryl); 5.03 dd (J=9 Hz+8.4 Hz, 1H); 4.46 s (1H, OH); 4.33 dbr (J=6.5 Hz, 1H); 4.27 dd (J=9 Hz+8.4 Hz, 1H); 3.68 dd (J=9 Hz+9 Hz, 1H); 1.56 s (3H); 1.49 s (3H); 1.07 s (3H); 0.86 s (3H); 0.50 s (3H).
e) 11β-[4-[(1R)-1,2-Dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna4,9-dien-3-one
2.5 g of the compound described under Example 2 d) are dissolved in 20 ml of THF, 2.5 ml of semiconcentrated aqueous sulfuric acid are added and the reaction mixture is stirred for three hours at 20° C. It is then poured into 60 ml of saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. Purification by column chromatography on silica gel with a dichloromethane/acetone mixture gives 1.2 g of the title compound as a colorless foam. FIG. 2 shows the CD spectrum of 11β-[4-[(1R)-1,2-Dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
EXAMPLE 3a Synthesis of 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one
a) 20,20,21,21,21-Pentafluoro-11β-[4-(hydroxyacetyl)phenyl]-5,17-dihydroxy-19-nor-5α, 17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal
283 μl of tert-butyl hydroperoxide are added dropwise at room temperature to 3.6 mg of chromium trioxide in 7 ml of dichloromethane. A solution of 450 mg of the compound prepared under Example 1 c) in 7 ml of dichloromethane is then added dropwise. The mixture is stirred for three hours at room temperature. The reaction is stopped by the addition of dimethyl sulfide. The mixture is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. Chromatography of the resulting crude product on silica gel with a hexane/ethyl acetate mixture gives 87 mg of the title compound as a white foam.
1H-NMR (300 MHz, CDCl3): δ=7.83 d (J=9 Hz, 2H, aryl); 7.37 d (J=9 Hz, 2H, aryl); 4.84 m (2H, CH2OH); 4.37 dbr (J=6.5 Hz, 1H, H-11); 3.53 m (2H, 3-ketal); 3.47 m (J=11.0 Hz, 1H, 3-ketal); 3.42 m (J=11.0 Hz, 1H, 3-ketal); 1.04 s (3H, 3-ketal); 0.85 s (3H, 3-ketal); 0.49 s (3H, H-18).
b) 20,20,21,21,21-Pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one
Analogously to the process described in Example 1 d), 87 mg of the compound described under 3 a) are reacted in 1.4 ml of methanol with 62 μl of semiconcentrated aqueous sulfuric acid to give 25 mg of the title compound as a colorless foam.
1H-NMR (300 MHz, CDCl3): δ=7.86 d (J=9 Hz, 2H, aryl); 7.34 d (J=9 Hz, 2H, aryl); 5.81 s (1H, H4); 4.85 dbr (J=5 Hz, 2H, CH2OH); 4.50 dbr (J=7 Hz, 1H, H-11); 3.50 tbr (J=5 Hz, 1H, OH); 0.57 s (3H, H-18).
EXAMPLE 3b Alternative Synthesis of 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one
a) [[2-(4-Bromophenyl)-1,3-dioxolan-2-yl]methoxy](1,1-dimethylethyl)dimethylsilane
73.5 g 2-(4-Bromophenyl)-1,3-dioxolane-2-methanol are dissolved in 800 ml N,N-dimethylformamide. 38.6 g imidazole and 51.3 g tert-butyldimethylchlorosilane were added. It was stirred for 12 hours at 23° C. Afterwards, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. It was stirred for another 30 min. Then it was extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried over sodium sulphate. The crude product was purified by column chromatography. 103.21 g product was obtained (97.5% of theory).
1 H-NMR (300 MHz, CDCl3): δ=7.45 d (J=9 Hz, 2H, aryl); 7.37 d (J=9 Hz, 2H, aryl); 4.08 m (2H, ketal); 3.84 m (2H, ketal), 0.83 s (9H, t-butyl-Si); -0.05 s (6H, Me-Si).
b) 11β-[4-[2-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1,3-dioxolan-2-yl]phenyl]-20,20,21,21,21-pentafluoro-5,17-dihydroxy-19-nor-5α, 17α-preg n-9-en-3-one 2,2-d imethylpropane-1,3-diyl ketal
0.3 ml dibromoethane was added to a suspension of 6.22 g magnesium turnings in 80 ml THF. Afterwards, a solution of 95.5 g 3ba) in 900 ml THF was added slowly. The temperature was kept below 50° C. Afterwards, it was stirred at 50° C. for 1 h. Then, the reaction mixture was cooled to 0° C. and 400 mg CuCl was added. After the stirring was continued for another 10 minutes, a solution of 20 g of the compound described under 2c) in 200 ml THF was added at 0° C. The mixture was stirred for 2 hours at 0° C. and then allowed to warm up to 23° C. Stirring was continued for another 12 hours at 23° C. Then the reaction mixture was poured into a saturated solution of ammonium chloride. It was stirred for another 30 minutes and afterwards it was extracted with ethyl acetate 3 times. The combined organic layers were washed with brine and dried over sodium sulphate. The crude product was purified by column chromatography. 31 g product was obtained (97% of theory).
1H-NMR (300 MHz, CDCl3): δ=7.40 d (J=9 Hz, 2H, aryl); 7.20 d (J=9 Hz, 2H, aryl); 4.49 s (1H, OH); 4.36 dbr (J=6.5 Hz, 1H); 4.12 m (2H, ketal), 3,90 (2H, ketal), 3.79 m (4 H, ketal); 3.50 m (2H), 1.09 s (3H); 0.94 s (3H); 0.90 (9H, t-butyl-Si), 0.57 s (3H); 0.00 (6H, Me-Si).
c) 20,20,21,21,21-Pentafluoro-5,17-dihydroxy-11β-[4-[2-(hydroxymethyl)-1,3-dioxolan-2-yl]phenyl]-19-nor-5α, 17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal
Tetrabutylammonium fluoride (0.6 ml of a 1 molar solution in THF) was added to a solution of 470 mg compound 3bb) in 5 ml THF. It was stirred for 2 hours at 23° C. Then, the reaction mixture was poured into a saturated solution of ammonium chloride. It was stirred for another 30 minutes and afterwards it was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. The crude product was purified by column chromatography. 318 mg product was obtained (80% of theory).
1H-NMR (300 MHz, CDCl3): δ=7.34 d (J=9 Hz, 2H, aryl); 7.18 d (J=9 Hz, 2H, aryl); 4.44 s (1H, OH); 4.30 dbr (J=6.5 Hz, 1H, H-11); 4.10 m (2H, ketal), 3.88 m (2H, ketal); 3.70 m (4H, ketal), 3.50 m (2H); 1.02 s (3H); 0.88 s (3H); 0.50 s (3H).
dα) 20,20,21,21,21-Pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one from 3bb:
‥ml of semiconcentrated aqueous sulfuric acid were added to a solution of 15 g of the compound described under example 3bb in 150 ml THF. It was stirred for 2.5 hours at 23° C. Afterwards, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution. It was stirred for another 30 minutes and afterwards extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. The crude product was purified by column chromatography. 7.99 g product was obtained (80% of theory).
dβ) 20,21,21,21-Pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-17α-pregna-4,9-dien-3-one from 3bc:
Reaction of 300 mg 3bc with semiconcentrated aqueous sulfuric acid in THF in analogy to the procedure described under example 3dα yielded 198 mg (85% of theory) product.
EXAMPLE 4 Abortion Test on Female Rats
The antigestagenic action of the progesterone receptor antagonists according to the invention was tested on pregnant rats (6 rats per group) on days 5 to 7 post coitum under conventional housing and feeding conditions.
After successful copulation, the pregnant animals (presence of sperm in the vaginal smear on day 1 of pregnancy=d1 p.c.) were randomized and divided up into the treatment group and the control group. Each animal was then injected subcutaneously with 1.5 mg/kg of the test substance (11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one according to Example 1 or 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one according to Example 3) or 1.0 ml/kg of vehicle (benzyl benzoate/castor oil: 1+4[v/v]) daily from day 5 to day 7 (d5-d7 p.c.).
The autopsy was performed on day 9 (d9 p.c.). As the parameter of antigestagenic action, the uterus was examined for the presence of implantation sites. The complete absence of implantation sites as well as the presence of pathological, hemorrhagic or otherwise abnormal implantation sites on day 9 (d9 p.c.) were evaluated as abortions. The results of the abortion test are shown in Table 1.
Results of the abortion test
Daily dose Abortion rate Test substance [mg/kg] [%] 11β-[4-(1,2- 1.5 100 Dihydroxyethyl)phenyl]- 20,20,21,21,21-pentafluoro- 17-hydroxy-19-nor-17α- pregna-4,9-dien-3-one (Example 1) 20,20,21,21,21-Pentafluoro- 1.5 100 17-hydroxy-11β-[4- (hydroxyacetyl)phenyl]-19- nor-17α-pregna-4,9-dien-3- one (Example 3)
EXAMPLE 5 Determination of the McPhail Index on the Rabbit
The antigestagenic efficacy of the progesterone receptor antagonists according to the invention was tested on 35-day-old rabbits under conventional housing and feeding conditions.
As a preparatory measure, the animals were treated subcutaneously with 5.0 μg/kg/d with 17β-estradiol from day 1 to day 4. To determine the antigestagenic efficacy, the animals were treated subcutaneously from day 7 to day 10 with 0.2 mg/kg/d of progesterone and 3 mg/kg/d of the test substance (11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one according to Example 1 or 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one according to Example 3) simultaneously. The vehicle used was a mixture of benzyl benzoate and castor oil in a ratio of 1+4 (v/v).
The autopsy was performed on day 11 after the start of treatment. The uteri were removed and fixed for histology. The McPhail index (degree of glandular differentiation) was determined by means of light microscopy (evaluation: 1=no glandular differentiation; 4=maximum glandular differentiation) as the parameter of antigestagenic efficacy (inhibition of the glandular differentiation caused by progesterone). The resulting McPhail index is shown in Table 2.
McPhail index
Daily dose McPhail index Test substance [mg/kg] [median] 11β-[4-(1,2- 3.0 + 0.2 1.0 Dihydroxyethyl)phenyl]- 20,20,21,21,21-pentafluoro- 17-hydroxy-19-nor-17α- pregna-4,9-dien-3-one (Example 1 + progesterone) 20,20,21,21,21-Pentafluoro- 3.0 + 0.2 1.0 17-hydroxy-11β-[4- (hydroxyacetyl)phenyl]-19- nor-17α-pregna-4,9-dien-3- one (Example 3 + progesterone)
EXAMPLE 6a Metabolic stability of 11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one and 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)-phenyl]-19-nor-17α-pregna-4,9-dien-3-one in human liver microsomes (HLM)
Human liver microsomes (HLM) were used to assess the metabolic stability of substances of general formula I.
The incubations were carried out in duplicate with HLM and an NADPH-generating system using a shaker bath at 37° C. The incubation mixture (consisting of cofactor solution, potassium phosphate buffer and microsome preparation) was freshly prepared according to the Table below.
Buffer Potassium phosphate, 100 mM, pH 7.4
Reconstitution system in buffer: NADP 1.2 mM Glucose-6-phosphate 8.0 mM Glucose-6-phosphate dehydrogenase 1.4 units/ml MgCl2 5.0 mM KCl 38.0 mM Protein concentration (HLM) 1.0 mg/ml
The incubation volume was 0.25 ml. The incubation mixture was preincubated for three minutes at 37° C. The reaction was started by the addition of the test substance (final concentration 50 μM). The reaction was ended after an incubation time of 60 minutes by the addition of 250 μl of methanol and the mixture was then centrifuged to pellet the protein. The samples were stored at −18° C. for subsequent RP-HPLC analysis.
According to RP-HPLC analysis, about 70% of the 11β-[4-1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one used and about 80% of the 20,20,21,21,21-penta-fluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one used were recovered in the supernatant.
EXAMPLE 6b Metabolic stability of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one in human liver microsomes (HLM)
According to RP-HPLC analysis, 60% of the 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one used was recovered in the supernatant.
EXAMPLE 7 Antigestagenic action of 11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one and 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)-phenyl]-19-nor-17α-pregna-4,9-dien-3-one in stable transfectands of human neuroblastoma cells (SK-N-MC cells) with human progesterone A or progesterone B receptor and an MTV-LUC reporter construct
SK-N-MC cells (human neuroblastoma cells), stably transfected with plasmids, which express human progesterone receptor B (pRChPR-B-neo) or human progesterone receptor A (pRChPR-A-neo) and a reporter construct (pMMTV-LUC), were incubated for 24 hours, either in the absence (negative control) or in the presence of increasing amounts of 11β-[4-(1,2-dihydroxy-ethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one or 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)-phenyl]-19-nor-17α-pregna-4,9-dien-3-one (0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 μmol/l), in order to determine the agonistic efficacy. As a positive control of reporter gene induction, the cells were treated with the synthetic gestagen promegestone (0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 μmol/l). To determine the antagonistic activity, the cells were treated with 0.1 nmol/l of promegestone and additionally with increasing amounts of 11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one or 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one (0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 μmol/l). As a positive control of the inhibition of reporter gene transcription, the cells were incubated with increasing amounts of the progesterone receptor antagonist 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one (1 pmol/l, 0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l and 100 nmol/l). The activity of the LUC reporter gene (LUC=luciferase) was determined in the cell lyzates and measured as RLU (relative light units). All the measured values are given as % efficacy (relative LUC activity as mean plus/minus standard deviation (n=3experiments)) and as EC50 or IC50 concentrations.
a) Agonistic Activity:
Neither 11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one nor 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one exhibits induction of the LUC activity on PR-A or PR-B (in contrast to the promegestone positive control, which induces the reporter gene as a function of dose). Table 3 shows the agonistic activity of the two test substances and promegestone.
Agonistic activity of 11β-[4-(1,2-dihydroxyethyl)phenyl]- 20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one or 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor- 17α-pregna-4,9-dien-3-one
Progesterone receptor A Progesterone receptor B (PR-A) (PR-B)
Potency Efficacy Potency Efficacy Compound EC50 [nmol/l] [%] EC50 [nmol/l] [%] Promegestone 0.23 ± 0.03 100 0.03 ± 0.00 100 (n = 3) (n = 3) (n = 3) (n = 3) 11β-[4-(1,2-Dihydroxyethyl)phenyl]- 0 ± 0 no effect 0 ± 0 no effect 20,20,21,21,21-pentafluoro-17-hydroxy- (n = 3) (n = 3) (n = 3) (n = 3) 19-nor-17α-pregna-4,9-dien-3-one 20,20,21,21,21-Pentafluoro-17- 0 ± 0 no effect 0 ± 0 no effect hydroxy-11β-[4-(hydroxyacetyl)phenyl]- (n = 3) (n = 3) (n = 3) (n = 3) 19-nor-17α-pregna-4,9-dien-3-one
b) Antagonistic Activity:
11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna4,9-dien-3-one and 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one exhibited dose-dependent inhibition of the LUC activity induced by 0.1 nmol/l of promegestone (100%) at both progesterone receptor isoforms. Table 4 shows the agonistic activity of the two test substances compared with 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
Antagonistic activity of 11β-[4-(1,2-dihydroxyethyl)phenyl]- 20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one or 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor- 17α-pregna-4,9-dien-3-one
Progesterone Progesterone receptor A receptor B (PR-A) (PR-B)
Potency Efficacy Potency Efficacy Compound IC50 [nmol/l] [%] IC50 [nmol/l] [%] 11β-(4-Acetylphenyl)-20,20,21,21,21- 0.014 ± 0.01 100 ± 0 0.02 ± 0.01 100 ± 0 pentafluoro-17-hydroxy-19-nor-17α- (n = 2) (n = 2) (n = 3) (n = 3) pregna-4,9-dien-3-one 11β-[4-(1,2-Dihydroxyethyl)phenyl]- 1.87 ± 0.23 100 ± 0 3.47 ± 0.46 100 ± 0 20,20,21,21,21-pentafluoro-17-hydroxy- (n = 3) (n = 3) (n = 3) (n = 3) 19-nor-17α-pregna-4,9-dien-3-one 20,20,21,21,21-Pentafluoro-17- 0.18 ± 0.06 100 ± 0 0.28 ± 0.08 100 ± 0 hydroxy-11β-[4-(hydroxyacetyl)phenyl]- (n = 3) (n = 3) (n = 3) (n = 3) 19-nor-17α-pregna-4,9-dien-3-one
These data show that 11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna4,9-dien-3-one and 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one are pure antagonists of both progesterone receptor isoforms in SK-N-MC cells which stably express progesterone receptor A or progesterone receptor B. Neither compound exhibits any selectivity in respect of one progesterone receptor isoform. However, 11β-[4-(1,2-dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one is about 130 times less potent than 11β-(4-acetyl-phenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one at the progesterone receptors. 20,20,21,21,21-Pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one is about 13 times weaker than 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna4,9-dien-3-one. The stably transfected cell lines express approximately 500 fm (femtomol) of PR-A or PR-B.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 10 2006 054 535.5, filed Nov. 15, 2006, and U.S. Provisional Application Ser. No. 60/858,955, filed Nov. 15, 2006, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
1. A progesterone receptor antagonist of general formula I: in which R1 can be a hydrogen atom and R2 a hydroxyl group or R1 and R2 together can be an oxo group.
2. 11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
3. 11β-[4-[(1 R)-1,2-Dihydroxyethyl]phenyl]20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
4. 11β-[4-[(1 S)-1,2-Dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
5. 20,20,21,21,21-Pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-l9-nor-17α-pregna-4,9-dien-3-one.
6. A drug containing progesterone receptor antagonists as claimed in claim 1.
7. The drug as claimed in claim 6 containing 11β-[4-(1,2-dihydroxyethyl)-phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna4,9-dien-3-one.
8. The drug as claimed in claim 7 containing 11β-[4-[(1R)-1,2-dihydroxy-ethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
9. The drug as claimed in claim 7 containing 11β-[4-[(1S)-1,2-dihydroxy-ethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
10. The drug as claimed in claim 6 containing 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one.
11. Use of A method for the treatment of endometriosis, myomas or hormone-dependent tumors, especially a carcinoma of the breast, and of pharmaceutical preparations for female contraception comprising administering progesterone receptor antagonists as claimed in claim 1.
12. A method as claimed in claim 11 wherein said antagonist is 11β-[4-(1,2-dihydroxyethyl)phenyl]-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl) estra-4,9-dien-3-one.
13. A method as claimed in claim 11 wherein said antagonist is 11β-[4-[(1R)-1,2-dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna4,9-dien-3-one.
14. A method as claimed in claim 11 wherein said antagonist is 11β-[4-[(1S)-1,2-dihydroxyethyl]phenyl]-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one.
15. A method as claimed in claim 11 wherein said antagonist is 20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-(hydroxyacetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one.
16. A method for the preparation of the progesterone receptor antagonist of general formula I comprising employing 11β-(4-Ethenylphenyl)-20,20,21,21,21-pentafluoro-5,17-dihydroxy-19-nor-5α, 17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal as an intermediate.
17. A method for the preparation of the progesterone receptor antagonist of general formula I comprising employing 11β-[4-(1,2-Dihydroxyethyl)phenyl]-20,20,21,21,21-pentafluoro-5,17-dihydroxy-19-nor-5α,17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal as an intermediate.
18. A method for the preparation of the progesterone receptor antagonist of general formula I comprising employing 20,20,21,21,21-Pentafluoro-17-hydroxy-5,10α-epoxy-19-nor-5α, 17α-pregn-9(11)-en-3-one 2,2-dimethylpropane-1,3-diyl ketal as an intermediate.
19. A method for the preparation of the progesterone receptor antagonist of general formula I comprising employing 11β-{4-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]phenyl}20,20,21,21,21-pentafluoro-5,17-dihydroxy-19-nor-5α,17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal as an intermediate.
20. A method for the preparation of the progesterone receptor antagonist 20,20,21,21,21-Pentafluoro-17-hydroxy-11i-[4-(hydroxyacetyl)phenyl]-19-nor-17a-pregna-4,9-dien-3-one comprising employing11β-[4-[2-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1,3-dioxolan-2-yl]phenyl]-20,20,21,21,21-pentafluoro-5,17-dihydroxy-19-nor-5α,17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal as an intermediate.
21. A method for the preparation of the progesterone receptor antagonist 20,20,21,21,21 -Pentafluoro-17-hydroxy-11i-[4-(hydroxycetyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one comprising employing 20,20,21,21,21-Pentafluoro-5,17-dihydroxy-11β-[4-[2-(hydroxymethyl)-1,3-dioxolan-2-yl]phenyl]-19-nor-5α,17α-pregn-9-en-3-one 2,2-dimethylpropane-1,3-diyl ketal as an intermediate.
22. A compound as claimed in any of claim 1 in isolated form, preferably in solid form.
23. A compound as claimed in claim 3 when substantially free of the other compound of claim 3.
24. A drug as claimed in claim 6 adapted for oral administration, preferably as a unit dosage form.
25. A drug as claimed in claim 6 which contains from 0.01 mg to 100 mg of the compound.
Inventors: Ulrike Fuhrmann (Berlin), Anja Schmidt (Berlin), Arwed Cleve (Berlin), Orlin Petrov (Berlin), Gunnar Garke (Berlin), Stefan Pruehs (Neuss), Margarete Brudny-Kloeppel (Berlin), Antje Rottmann (Berlin), Rainer Hasselmann (Berlin), Marcus Schultze-Mosgau (Berlin), Carsten Moeller (Berlin)
Current U.S. Class: Oxygen Single Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring System (514/178); Oxygen Bonded Directly At The 16- Or 17-position Of The Cyclopentanohydrophenanthrene Ring System (552/650)
International Classification: A61K 31/56 (20060101); A61P 35/04 (20060101); C07J 1/00 (20060101);


text:
John Holdren (John P. Holdren; * 1. März 1944 in Sewickley, Pennsylvania) ist ein US-amerikanischer Physiker. Er war unter US-Präsident Barack Obama von 2009 bis 2017 der Berater für Wissenschaft und Technologie.

Am 19. März 2009 wurde er durch einstimmiges Votum im Senat der Vereinigten Staaten als Direktor des Office of Science and Technology Policy (OSTP) bestätigt. Zuvor war er Teresa und John Heinz Professor für Umweltpolitik an der Kennedy School of Government der Harvard University sowie Leiter des ebenfalls an der Harvard University angesiedelten Science, Technology, and Public Policy Program am Belfer Center for Science and International Affairs.

Holdren ist Vorsitzender des Gremiums von Innovations: Technology | Governance | Globalization, eines vierteljährlich erscheinenden Magazins von MIT Press über unternehmerische Lösungen für globale Probleme.

Leben und Wirken
Holdren erwarb 1965 am Massachusetts Institute of Technology (MIT) den Bachelorgrad. 1970 schloss er ein Studium an der Stanford University mit dem Grad eines Ph.D. ab. Holdren unterrichtete über 20 Jahre an der University of California, Berkeley. Schwerpunkte seiner Arbeit sind globaler Umweltwandel, Energietechnologie, Energiepolitik, Atomwaffenrüstungskontrolle, Wissenschafts- und Technologiepolitik.

Holdren verfasste über 300 Artikel und fungierte als Mitautor und Mitherausgeber von Büchern und Berichten. Unter seiner Mitwirkung entstanden unter anderem die Bücher: Energy (1971), Human Ecology (1973), Ecoscience (1977), Energy in Transition (1980), Earth and the Human Future (1986), Strategic Defences and the Future of the Arms Race (1987), Building Global Security Through Cooperation (1990), Conversion of Military R&D (1998) und Ending the Energy Stalemate (2004).

Von Februar 2007 bis Februar 2008 war Holdren als Vorstandsvorsitzender der American Association for the Advancement of Science (AAAS) tätig.

Nach seiner Nominierung wurde Holdren Ziel einer öffentlichen Kampagne von Abtreibungsgegnern und Gegnern von Klimaschutzpolitik. Die Angriffe gegen Holdren stützen sich vor allem auf Stellen in seinem Beitrag zu einem 1977 erschienenen Buch, worin mögliche Maßnahmen zur Kontrolle von Übervölkerung der Erde erörtert werden, darunter verbesserte Familienplanung und leichterer Zugang zu Verhütungsmitteln und Abtreibungen, aber auch erzwungene Abtreibungen und Sterilisierungen von Frauen, nachdem diese eine bestimmte Zahl von Kindern geboren haben.

Holdren lehnt den Einsatz von Atomwaffen als Reaktion auf Angriffe mit biologischen und chemischen Waffen ab. Er zeigt sich offen dafür, die Frage wissenschaftlich zu untersuchen, ob notfalls die drohende Erderwärmung mit dem Einsatz verfügbarer technischer Mittel ("Geo-Engineering") verhindert werden könnte.
Holdren wurde zusammen mit Steven Chu von Foreign Policy auf Platz 34 der Top Hundert Globalen Vordenker 2009 gestellt; ihr Verdienst: Sie haben der Spitzenwissenschaft wieder politischen Einfluss verschafft.

Holdren nimmt zudem aktiv an der öffentlichen Debatte zur Klimakrise teil. So sagte er einmal über das Verhältnis von Klimaschutz, Anpassung an die globale Erwärmung und dem Leid aus der globalen Erwärmung: "Wir haben im Grunde drei Möglichkeiten: Schutz, Anpassung und Leid. Wir werden von jedem einen Teil haben. Es stellt sich die Frage, wie die Mischung aussehen wird. Je mehr Schutz wir betreiben, desto weniger Anpassung wird erforderlich sein und desto weniger Leid wird es geben." Den Klima-Problemen galt auch sein erfolgreiches Agieren für den Beitritt der USA zum 2016 ratifizierten Übereinkommen von Paris.

Auszeichnungen
 Fellow, American Academy of Arts and Sciences
 Fellow, American Physical Society, 1988
 Member, National Academy of Engineering
 Member, National Academy of Sciences
 Member, American Philosophical Society, 2015
 MacArthur Foundation Prize Fellowship, 1981
 Member of President Clinton's Committee of Advisors on Science and Technology (PCAST), 1994–2001
 Chair of the Committee on International Security and Arms Control of the U.S. National Academy of Sciences, 1993–2004
 Volvo Environment Prize, 1993 (mit Paul R. Ehrlich)
 Nobel Peace Prize acceptance lecture on behalf of the Pugwash Conferences on Science and World Affairs, December 1995
 Chair of the Executive Committee of the Pugwash Conferences on Science and World Affairs, 1987–1997
 Kaul Foundation Award in Science and Environmental Policy, 1999
 Tyler Prize for Environmental Achievement, 2000
 7th Heinz Award in Public Policy, 2001
 Präsident der American Association for the Advancement of Science, 2007
 Public Welfare Medal der National Academy of Sciences, 2022

Weblinks
 John P. Holdren auf der Website des Belfer Center for Science and International Affairs
 John Holdren auf der Website der Harvard Kennedy School
 Curriculum Vitae auf der Website des Woods Hole Research Center
 The New Team of the 44th President: John P. Holdren, Profil der New York Times

Fußnoten

Person im Executive Office
Hochschullehrer (Harvard University)
Präsident der American Association for the Advancement of Science
Mitglied der National Academy of Sciences
Mitglied der American Academy of Arts and Sciences
Mitglied der American Philosophical Society
Fellow der American Physical Society
Physiker (20. Jahrhundert)
US-Amerikaner
MacArthur Fellow
Geboren 1944
Mann

redpajama_set_name: RedPajamaWikipedia


text:
Praise The Process, Not The Person, When Giving Feedback
Published 7 years ago: October 29, 2013 at 4:00 pm -
Filed to:feedback
When offering criticism, it's important not to attack the recipient on an individual level — focus on actions, not attributes. 99u points out that you should take a similar approach when you're offering positive feedback as well.
Photo by nfusionsoft
When you're in a team and motivating people, 99u recommends shying away from direct praise of a person's abilities. While the post talks about about how managers should act, it's really applicable to anyone working in a team:
[P]raise aspects of your employee's performance that were under his control. Talk about his creative approach, his careful planning, his persistence and effort, his collaborative attitude. Praise the process, not the person. That way, when he runs into trouble later on, he'll remember the process that helped him to succeed in the past, and put that knowledge to good use.
It's a solid piece of advice that makes giving praise to co-workers a lot easier. Head over to 99u for a few more tips on giving better feedback.
The Key to Great Feedback? Praise the Process, Not the Person [99U]

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Did you know that our bones continue to grow until we're about 30 years old? When you reach this age, your bones will likely be the strongest and densest they'll ever be. Bone density loss becomes a concern for many as we age because it can lead to the brittle bone condition osteoporosis. This May is National Osteoporosis Month, and it's the perfect excuse to prioritize bone health. Learn the risk factors for osteoporosis and ways you can maintain bone density as you age. Care for your bones!
Osteoporosis is a condition in which loss of tissue leads to fragile and brittle bones. It's often referred to as 'the silent disease' because of its gradual onset overtime that presents no symptoms. The condition affects roughly 55% of Americans aged 50 and older, and it is also the most common cause of fractures.
Regular exercise and a healthy diet are the recommended prevention methods for a number of health conditions, and the prevention of osteoporosis is no exception. Focus on getting active and eating the right foods this month and every month to both benefit your waistline and your bones.
Exercise – Add both weight-bearing and muscle-strengthening exercises to your workout routine to promote better bone health. Running, walking, and using the elliptical are great ways to keep bones strong. To strengthen all the major muscle groups that support your bones, use free weights, resistance bands, or even your own bodyweight during your workouts.
Healthy diet – Many Americans eat a diet high in fat and salt, and these poor habits lead us to far exceed our daily recommended sodium intake. Many of us know that sodium can lead to high blood pressure and heart problems, but it also causes calcium loss and makes our bones fragile over time. Better bone health calls for us to eat a balanced diet and foods rich in calcium and vitamin D. Limit your sodium intake to less than 2,300mg daily, and reach for foods like fruits, vegetables, and whole grains. If you're looking for a healthy recipe that's quick and easy, try these flourless egg pancakes that will give you the vitamin D you need to care for your bones. Also, consider taking a calcium and vitamin D supplement with vitamin K.
Invokana – This SGLT2 Inhibitor helps type 2 diabetics by regulating their blood glucose levels. Although it has been proven effective at treating the chronic condition, recent lawsuits have been filed because the medication has also been linked to a higher risk of below-the-knee amputations and bone fractures.
Corticosteroids – This class of medications is used as a form of pain relief and a means of preventing severe inflammation for those who are living with rheumatologic conditions. Despite the drugs' effectiveness at helping those with chronic conditions like rheumatoid arthritis and lupus, the popular medication has also been shown to cause osteoporosis, glaucoma, and high blood pressure.
These are two risk factors. They're out of our control, but understanding your predisposed risk for osteoporosis can be the encouragement you need to actively care for your bones.
10 million Americans live with osteoporosis, and women make up 80% of those affected. In general, women are at a greater risk of developing the disease because they have smaller bones than men. During menopause, women also experience a decrease in estrogen production, a hormone that also helps protect our bones.
The older we get, the greater our risk is of developing osteoporosis. Our bones naturally deteriorate during the aging process, making those in their older years more susceptible to the condition and more prone to severe injuries. A wrist that was once able to withstand the pressure of a fall could easily fracture as a result of old age and poor bone health.
National Osteoporosis Month isn't the only time that you can prioritize bone health. Remember to exercise often, eat a well-balanced diet, and talk to your doctor if you have any concerns about your medications. By making an effort each and every day of the year, you can strive to prevent the onset of brittle bones and live a healthy life.


Kane suffered injury in Tottenham's 1-0 defeat to Manchester United on January 13, and he is yet to play for the club since.
He was ruled out by his club until March, but, after undergoing a spell of warm weather training, Kane is hoping to be back sooner than expected.
He said: "I can not tell you if he is ahead of schedule or not".
"He is showing on social media that he looks very strong and very fit and very well, running and doing some exercises".
"He's determined to try and recover as soon as possible and be available as soon as possible". It's going well so far, but we have just got to take our time with it and make sure we get it right.
"You know him, Harry would want to play tomorrow".
'I think it is so important for him to feel so important.
'I never put a time on any of my injuries.
"I am disappointed because we are in a very good position and maybe, with a little more help, we could not have an excuse not to be a real contender".
"Reality - if you see the table of course we are there". The key players of the game are Rondon, Matt Ritchie.
Tottenham are now third in the Premier League, just five points off current leaders Liverpool, while the only other competition Maurico Pochettino's side are still in is the Champions League, where they've been handed a hard last 16 tie against current Bundesliga leaders Borussia Dortmund. "But the dream is the dream, my dream is to win the Premier League or Champions League, to win the FA Cup or the Carabao Cup".


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The first an element of the Vassar-Yale research unearthed that many pupils felt just like Vassar students.
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In its comparisons of other coordinated university systems, particularly the Douglass-Rutgers, Barnard-Columbia, and Sophie Newcomb-Tulane co-ordinations, the Joint Committee unearthed that the many effective systems were the ones that offered few limitations on cross-registration and incorporated the 2 universities since closely as you possibly can. Schools that attempted to keep specific identities and split intercourse classrooms fostered dissatisfaction one of the pupils and jealousies amongst the two characteristics. This an element of the research concluded that should a merger that is vassar-Yale, the main focus should always be on assisting simple relationship involving the two schools and assimilating the particular divisions whenever you can without threatening Vassar's autonomy. Joseph Lieberman, the advisor that is legal the research and from now on a Senator from Connecticut, noted that the plans for department relationship will have to be because certain as you are able to entering any merger to allow the change to go efficiently.
The part that is second of research desired to give you the groundwork for anyone plans. Both schools come up with data on admissions data, tuition and space and board costs, faculty pay scales, advantages, and then leave policies, teaching lots, tenure policies, requirements for advertising and visit, graduation needs, course and lab usage, etc. Vassar computed the worth of their present facilities as well as the anticipated costs of creating a full campus in brand new Haven. The proposed plant in brand new Haven would consist of a library, classrooms, dorms, and a student center all for Vassar use within addition to your current brand new Haven campus. The proposed site because of this complex that is new on Prospect Street, in which the Culinary Institute of America was previously found before it relocated to its current house in Hyde Park, NY. As the site, in a single Vassar agent's evaluation, had been "more appealing than anticipated," a factory nearby marred the horizon and a planned highway underneath or overpass threatened to cut the location removed from the primary Yale campus. Mini-bus solution might have been necessary to reach the Yale Sterling Library, since it had been a 25 minute walk from Prospect Street. Nevertheless, the data-based region of the research did not address desirability, but rather displayed facts and sought to offer a blueprint for producing a distinct location for Vassar in brand new Haven, split from Yale, if the move happen.
The third an element of the research proved probably the most controversial. Vassar faculty, already cautious with the scholarly research and stressed concerning the discrepancy in capital between your Yale-Vassar research and also the Committee on New Dimensions, felt that the educational areas of the move had been underrepresented in the 1st stages of this research. Increasing numbers of people started to start to see the Vassar-Yale merger a concern of academic philosophy in place of just concerns that are logistical. Within the springtime of '67, in between administering and grading exams for the conclusion of the institution 12 months, two representatives of each and every Vassar Department came across with two representatives through the corresponding Yale Department for 2 times to talk about the methods when the two traits would communicate at on a campus that is vassar-Yale. In those two times, talks ranged from possible graduate training at Yale by Vassar teachers, evaluations needless to say listings and structures, pedagogical obligations and philosophy, as well as class facilities. Both edges then reported the total results of the conference to your study. Lots of the reports talked of shared respect and compromises, just a few included caustic remarks that are personal one other college's division together with to be modified before last book regarding the study. The conferences solidified the Vassar faculty's opposition towards the move, and many concluded within their reports that the move wouldn't be into the desires of the division.
The faculty opposition reflected when you look at the 3rd the main research included gas towards the dissent that is already aggressive the alumnae. All the ladies in the Alumnae Association thought Vassar ought to remain in Poughkeepsie and explore its possibilities at its historic house. Letters from mad alumnae contrasted the "squalor" of the latest Haven to your tranquility that is"pastoral of Vassar's Poughkeepsie location. Other people pointed from what they regarded as inadequate focus on undergraduates at Yale https://datingranking.net/es/senior-friend-finder-review/ and feared that a Vassar in brand new Haven would no longer carry on its tradition of undergraduate excellence. Nevertheless other people pointed to your Radcliffe-Harvard merger as evidence that no "royal wedding" will allow autonomy for Vassar, despite good luck motives. In 1967, an article by a Vassar alumnae entitled "How Dare They Do It" appeared in Time magazine october. This article referenced rumors of a conspiracy between your two Presidents and stated Vassar have been Yale's 2nd option for a "dancing partner" after Connecticut university turned it straight down. President Brewster of Yale had written a letter that is private enough time editors doubting the rumors, and both the Vassar and Yale pupil newspapers responded with scathing reviews associated with the article within their editorial columns. Nonetheless, this article reflected the attitudes of a tremendously vocal part of this Vassar alumnae populace who have been so aggravated in the chance of a merger it move to New Haven that they threatened to pull their support, financial and otherwise, from the school should.
By the end of October, the trustees, that would finally decide in the Vassar-Yale proposal, had unofficially refused the offer. Proposals had been designed for cooperation lacking moving, but Yale desired Vassar as the resident female university or otherwise not after all. On November 20, 1967, the Vassar Trustees rejected the Vassar-Yale plan and declared that alternatively that Vassar research the integration of males by itself campus, whether in a graduate or undergraduate institution built nearby for that function or in coeducation from the current campus. Almost all of the work for the Vassar-Yale research, particularly components two and three, had been inapplicable to your choices dealing with Vassar after it chosen to stay in Poughkeepsie. Nevertheless, the info about other college that is female experiences with co-operative systems plus the wider academic concerns raised by the Vassar-Yale study both highly affected the faculty's decisions within the next 2 yrs. Both the option to make usage of coeducation from the university as opposed to producing a men that are cooperative university as well as the Comprehensive Arrange that radically changed Vassar's curriculum stemmed straight from talks about Vassar's feasible invest brand new Haven. The Vassar-Yale research, though beaten, forced the college to reevaluate its traditions and reform to mirror this new expectations of liberal arts universities within the years in the future.
"Coeducation File" assembled by Clyde Griffen, personal assortment of Elizabeth Daniels
Chesler, Ellen, Steven Weisman, and Michael Winger. "Vassar and Yale: the complete Sad Story, This new Journal, vol. 1, no. 12 (April 28, 1968): 1-9, 16.
Daniels, Elizabeth and Griffen, Clyde. Comprehensive Steam Ahead in Poughkeepsie. Poughkeepsie: Vassar University, 2000.
Foote, Barbara A. "A Royal Marriage," The Alumnae/I Quarterly, vol. 101, issue 1 (wintertime 2004).
Tchat bouteflika mimolette Dixit Hollande, ! Bouteflika pГЁte la forme !


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Google Unveils White Nexus 7 Tablet
Google is now selling a white version of its Nexus 7 tablet, available via the Google Play store in the U.S., U.K., and Japan.
By Stephanie Mlot
https://www.pcmag.com/news/google-unveils-white-nexus-7-tablet
The new model comes with 32GB of memory and Wi-Fi connectivity only, unlike its all-black sibling, which is also available in 16GB, with LTE Unlocked options.
The slate's coloring is about all that has changed, though. Priced at the same $269 as the original Nexus 7 model, the white version also sports a 1,920-by-1,200 HD Corning glass display, a 1.2-megapixel front camera and 5-megapixel rear shooter, Bluetooth 4.0, 2GB of RAM, and a quad-core Qualcomm Snapdragon S4 Pro processor.
According to Google's product page, it also comes with Android 4.3 Jelly Bean, though customers can expect a quick update to 4.4 KitKat, which rolled out to the Nexus 7 a month ago.
There's one sort-of catch, though: While the search giant is marketing its new slate as an alabaster beauty, it is in fact only half white. The front covering keeps its black color, while only the back and sides are a milky white. Add a protective case, and your white Nexus 7 will look like nothing more than an ordinary black Android tablet.
Still, those hoping to wrap the new device in time for Christmas should order it online by noon on Dec. 16 to ensure ground delivery by Dec. 25.
The original all-black Nexus 7 tablet is also available in Canada, Germany, Spain, France, Korea, and Australia, with more countries to follow.
For more, see PCMag's review of the Google Nexus 7 and the slideshow above.
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Phase formation and photophysical properties of bismuth doped sodium tantalum oxide (perovskite, defect pyrochlore) nanoparticles prepared by a hydrothermal method were studied in detail. It was revealed that the synthesis conditions like NaOH concentration and bismuth precursor (NaBiO3·2H2O) markedly affect the crystal structure of sodium tantalum oxide. At low NaOH concentration and high bismuth precursor (NaBiO3·2H2O) content, Bi doped Na2Ta2O6 (defect pyrochlore) phase was predominantly formed, while at higher NaOH concentration, Bi doped NaTaO3 (perovskite) phase was formed. It was observed that the defect pyrochlore (Bi doped Na2Ta2O6) phase was formed and stabilized by the presence of dopant precursor (NaBiO3·2H2O). The chemical analysis of the samples confirmed the doping of Bi3+ cations in both phases. Doping of bismuth enabled visible light absorption up to 500 nm in perovskite and defect pyrochlore type sodium tantalum oxide. Bi doped NaTaO3 samples showed better performance for the photocatalytic degradation of rhodamine B than that of Bi doped Na2Ta2O6, under visible light irritation (λ>420 nm). The present results shed light on phase formation of sodium tantalate and these results are useful in understanding properties of NaTaO3 based compounds, synthesized by the hydrothermal method.


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Home » Articles » Live Review
Pianist Toru Dodo and Trio at Cleopatra's Needle, NYC
BY AAJ STAFF
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He finds tremendous inspiration in Art Tatum. 'He had such advanced harmony... he was so modern.'
Japanese pianist Toru Dodo and his trio are the featured act on Sunday nights at Cleopatra's Needle, 92nd and Broadway, New York City. Dodo plays a full set, then hosts the Sunday night jam. His trio usually has bassist Joseph Lapore, but on this occasion there was a new face on bass, Yoshi Waki, along with regular drummer Rodney Green. Dodo has a very interesting style, with sometimes spiky right hand figures and full, occasionally dissonant chords in the left hand. He's also a performer who's conscious of a group's visual appearance on stage: he wore a brown pullover and black jacket, and the drummer, joining him in dispensing with a shirt, wore a brown sweater.
The trio's first number was a long version of John Lennon's "Julia" from The Beatles White Album (EMI, 1968). Next was "Aruba Bura," slightly classical-sounding with some wide melodic leaps. The tune is named for the club Aruba in Manhattan where Dodo sometimes plays. The third tune was entitled "My Love Song": there was a lengthy bass solo supported by piano chords, the bassist reading sheet music and playing with long, precise fingers. Dodo frequently played a rush of notes that would then wind up leading to a single clear point.
"All The Things You Are" followed—the Jerome Kern classic. The piano stated the melody over dissonant chords with "open"-sounding voicings. At the drums, Green is a dramatic performer, hitting the skins in a deliberate manner. There was a high flurry of piano notes in the right hand, then the bassist came in like Mingus on the same tune at the famous Massey Hall concert also featuring Charlie Parker, Dizzy Gillespie, Bud Powell, and Max Roach, once released as The Greatest Jazz Concert of All Time and more recently as Jazz At Massey Hall (Debut/OJC, 1953/1991) and Complete Jazz at Massey Hall (Jazz Factory, 2004). Some classical decoration from Dodo led to the next tune of the set, appropriately enough, given the season, Vernon Duke's "Autumn In New York," which is also a track on Dodo's second album, Dodo2 (Jazz City Spirit, 2002).
Green began the tune by playing on only cymbals, then quietly introduced brushes and snare. (Meanwhile the owner of the restaurant came up from the back room carrying the double-bass case, and stuffed the offending material under the piano! Must make room for more customers!)
It was time to close the set: "The last piece is my latest composition. I hope you enjoy it," the pianist announced. A catchy melodic figure launched the piece, and Dodo began to sound like no less than a cross between Bud Powell and Dave Brubeck. That was the set, but the variety of music presented meant that here was essentially a complete formal performance by the trio, plus a jam session still to come.
Before taking the stand once again, Dodo generously shared some personal information. Talking about his influences, the pianist says that classical music is "my home," citing classical pianist Maurizio Pollini as his hero. Concerning jazz pianists, he finds tremendous inspiration in Art Tatum: "He had such advanced harmony. He was so modern," says Dodo. He also likes Oscar Petersen.
There are signs of the classical influence in his interpretations. Note clusters and precise figures proliferate, as for example in "My Love Song." In addition, some of the titles of Dodo's tunes indicate that classical music is not far from his thoughts: his most recent American album release Dodo 3 (Jazz City Spirit, 2007) has a track entitled "Arabesque," and another called "Giacomo Swing"—the Giacomo is opera composer Giacomo Puccini. And yet, Puccini, who died in 1924, has a place in jazz in any event, as a melody he wrote was adopted by a Tin Pan Alley songwriter to write the popular jazz hit "Avalon" (recorded by Al Jolson and later Benny Goodman, etc): Puccini sued and won!
As for "Arabesque," French composer Debussy is the composer of the well-known "Deux Arabesques"; this writer, on hearing it for the very first time, noticed that a brief portion seemed identical to the sound of Oscar Petersen (who was yet to record for another fifty years!) It's an eye-opener to find a jazz pianist so in touch with this heritage. Dodo's music is usually presented in a trio context, though a Berklee orchestra can be seen playing an interesting version (see below) of the title track from Dodo's first album Melancholy Cats (Jazz City Spirit, 1999).
The title "Melancholy Cats" itself indicates a different take on music in general. On occasion, Dodo also employs word play in the titles to the tunes. For example, the first track on Dodo's album Toru Dodo 3 is "R Or B." I asked whether the title was a pun on "R and B. "Yes!" He likes to experiment with the sound of language, and does so with obvious humor. It's clearly an extra source of inspiration for his writing, a further example of his invention. Another example is a track on Dodo 3 called "Brush Pitch": how can a brush have pitch? Presumably it is a drummer's brush, but you don't play the brush itself: it can't have a pitch of itself. Maybe if you struck the brush with the drum!
Further invention and word play by a creative performer with a Zen-like sense of humor and paradox. His latest (and fourth) album, Do You Like Capuccino? (Jazz City Spirit, 1999), has just been released in Japan. An album with a provocative title usually indicates thought-provoking music: those who are fortunate enough to catch him live will no doubt discover one of the more engaging music-makers on today's jazz scene.
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This statistic shows the states with the highest wages for taxi drivers and chauffeurs in the United States as of May 2018. In the District of Colombia, taxi drivers and chauffeurs were paid a mean annual wage of 37,760 U.S. dollars as of May 2018.
* Including hearse drivers, but excluding ambulance drivers and bus drivers.


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Home News Community Internet Witch Hunts and Social Media's Tenuous Footing On a Morality-Based High...
Internet Witch Hunts and Social Media's Tenuous Footing On a Morality-Based High Ground
Kristin Iversen
Christmas is on a Wednesday this year. If we were all still in high school or middle school or elementary school—if we were all still children—this would be really exciting, because it would mean an extended vacation, an extra few days with no responsibilities, scholastic or familial. But we're not children, are we? We're adults. And so we work, some of us, even though there isn't really all that much to do. And for those of who write for the Internet? Once we've exhausted our year-end recaps and holiday gift guides and best of-lists, what is left for us to do? Other than, you know, engaging in that most morally slippery of past times, "trial by social media." Even then, once the career of a racist idiot is rather gleefully destroyed, what next? What is there to write about? Rent prices in north Brooklyn? Something related to hipsters? Wait. What's that, New York Times Styles section? There's an intra-generational millennial war brewing? Wow. It's like Christmas came early for bloggers this year. Thanks, New York Times.
Except, wait. No. I refuse to take the bait, Styles section. I will be better than that. Let's go back a minute to that whole "trial by social media"/Internet witch hunt thing, because, really, anything is more interesting than talking about millennials fighting with millennials, especially when they're not even really fighting. Sorry, New York Times, but this is one blogger who is not reaching for that particular piece of low-hanging fruit. At least, not today. I'm not that desperate today. Possibly tomorrow. If there's one thing I've learned about myself, it's that desperation is never all that far away. Professionally, I mean. Obviously. Anyway, the Internet.
Last Friday, the senior director of communications at IAC, Justine Sacco, sent an incredibly offensive, inexplicably stupid tweet before boarding a flight to South Africa. Sacco wrote: "Going to Africa. Hope I don't get AIDS. Just kidding. I'm white!" Sacco then boarded her 11-hour-long, WiFi-free flight having no idea that her tweet was going viral (aided by BuzzFeed and Valley Wag and, well, thousands and thousands of people on Twitter) or that she had lost her job while she was up in the air. Sacco has since apologized for the tweet in question (although not for her many, MANY other offensive tweets, including ones reading "I had a sex dream about an autistic kid last night. #fml" and "Someone get the rape kit ready for Tom Brady. Go Giants! #SuperBowl") and has deleted her Twitter and Instagram accounts. And so we can all just move along now, secure in the knowledge that a racist twit was brought down by the immense power of the blogosphere/social media machine, and that good has persevered. Yay.
The problem with that, though, as many are pointing out today, is that there are much more problematic things in the whole Justine Sacco affair than just the idiocy of the origin tweet. In an essay on Flavorwire, Tom Hawking questions whether or not anything was actually accomplished by the Internet's outrage at Sacco, and how—even if the anger at the tweet was justified, and even if her termination from her job is a reasonable response—nothing much has changed following this whole thing, except that a lot of people online feel morally superior to one, rather insignificant woman. Which, what kind of victory is that? A pretty hollow one when it comes right down to it. Part of the reason that Sacco's tweet was so outrageous was because she is someone whose whole job is public relations, yet she has little to no comprehension of how best to, you know, relate to the public. Even so, there's little doubt that this particular Internet pile-on was disproportionate to what Sacco actually tweeted. After all, the Internet is constantly bringing us all news of prominent people who advocate segregating the homeless or those who are totally blind to their white privilege, and instead think of it as "life hacking." And, for that matter, Twitter is constantly bringing us borderline (and not even all that borderline) offensive and racially sensitive tweets by people who, as blogger Padraig Reddy points out, are not so different from Justine Sacco when it comes to their sense of humor, they're just more famous, and therefore protected by their celebrity.
The thing about Sacco, though, is that she's a nobody. And so it's extremely easy to vilify her and think of her as just a bad person, allowing all of us, collectively, to think of ourselves as different from her, as good. But what makes us good? That we have the ability to identify something idiotic? That we haven't done anything comparably bad ourselves? Or that we just haven't done anything that bad in public? Internet witch hunts such as this one tend to thrive on a problematic (and false) dichotomy that presumes that everyone can be divided into categories of good and bad. When it's put so simply as that, the lack of nuance inherent in this type of duality is so plain as to seem almost insulting, and yet so many otherwise intelligent and thoughtful people are tempted to join in on attacking people like Sacco because…why? They're eager to prove that they're different? They're eager to solidify their footing on a moral high ground built on the incredibly tenuous foundation of other people's terrible behavior on social media? Unfortunately, it seems like that's exactly the case. Many people do gravitate toward social media scandals like this so that they can jump on the finger-wagging bandwagon and—however briefly—feel better about themselves and perhaps even elevate their own sense of self-worth. But just like the Sacco uproar will prove to be a fleeting one that perhaps blew-up because it came during a slow news cycle, that newfound sense of self-worth that everyone has will also soon disappear. Until that is, some other idiot comes along saying some other idiotic thing, and we obsess over it, ignoring anything more complicated and interesting going on in the world, because at least when things are this simple and reductive, we can feel good about ourselves…if only for the brief span of a news cycle.
Follow Kristin Iversen on twitter @kmiversen
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Sundarbans & Forest
Tiger Temple to face charges over dead tigers
Thu Jun 2, 2016 12:07 PM Last update on: Thu Jun 2, 2016 12:11 PM
Thailand has long been a hub for the illegal trafficking of wildlife and forest products. Photo: AFP
Wildlife authorities in Thailand have said they will press charges against a Buddhist temple where the bodies of 40 dead tiger cubs were found.
The discovery came during a week-long effort to relocate 137 tigers from the tourist site in Kanchanaburi province.
The "Tiger Temple" operators have been accused of wildlife trafficking, animal abuse and illegally possessing carcasses and endangered species.
They deny all allegations and resisted previous attempts to remove the tigers.
The tiger cub corpses were found in a freezer at the Wat Pha Luang Ta Bua temple complex on Wednesday, along with body parts from other animals.
Police Col Bandith Meungsukhum told AFP the cubs would have been one or two days old, but it was not clear how long they had been dead.
They will be DNA tested to see whether they were related to other tigers at the site.
National parks official Adisorn Noochdumrong said a keeper had been "told to place the carcasses when they died in cold storage".
He told AFP the temple operators could be charged with keeping the carcasses without permission.
The temple has previously said it decided in 2010 to stop cremating cubs which died soon after birth. It has always denied trafficking allegations.
Authorities started the operation to remove all 137 living tigers from the temple on Monday. Dozens have already been removed.
The site, west of Bangkok, is a popular tourist attraction, with visitors able to post for photos with the animals for a fee.
It has been closed to the public since the raid.
Animal activists and former workers have claimed the tigers are mistreated and kept in small concrete cages.
Wildlife authorities in Thailand / buddhist temple / 40 dead tiger cubs / Thailand Tiger temple
2012 Ramu Violence: High Court yet to act on probe reports
Tiger Temple monk held 'for smuggling'
Main accused held in Dhaka


Here it is - the ultimate list of resources, references and tools to help you customize your Shopify theme! There are many that you can use directly in your store and there also quite a few to help inspire the process overall.
Frustrated with the 14-day Shopify trial period?
Let's start with your logo!
Although this article is aimed at logo designers, there's a lot of good pointers for us all.
This is a great article in Smashing Magazine that outlines ten mistakes to be avoided in logo design - well worth reading.
A beautifully designed book on logo design. You can read a free chapter here.
Although they seem to have gone way overboard with advertising, this gallery of logos is worth a browse for those seeking inspiration.
This article features links to more than sixty brand identity guides - a fascinating resource that shows how the big companies manage their identities.
How about a bit of color?
Searching for a color-combination (or palette) for your store. Browse through millions of color palettes on this immensely useful site. Note not all palettes are available for commercial use.
This excellent app provides some great ways to create your own color palettes.
A great online tool from Adobe with some similar features to the Spectrum App plus the option to browse through thousands of downloadable color themes (or palettes).
Create color palettes on your iPhone or iPad based on a website or photo of your choice.
Behance is full of amazing creative work. With this tool, you can browse the network based on a pantone color and find great artists and inspiration.
And a background or pattern?
If you're looking for a low-key pattern to use as a background on your store, this site provides hundreds of great subtle patterns to download. Also check out this bookmarklet that allows you to visualize the patterns direct on your store.
For another variation on subtle patterns, use this tool to create textures with noise.
This great site also offers a huge selection of patterns. Note not all patterns are available for commercial use.
If you're looking for something a whole lot less subtle, take a look at this site for some attractive repeating patterns.
Another option is to go with a high resolution blurred image for a background.
You'll find a nice selection of paid patterns in this marketplace.
Some excellent and free design resources from Shopify Expert, John Rawsterne. You'll find some great patterns for your store here!
This photo sharing website is an excellent source for photos. You can only use photos shared under the creative commons attribution license for free. Use the advanced search and check the "only search within creative commons-licensed content" checkbox. You will also have to credit the photographer with a link back to their photograph - some good guidelines here.
On this site you can buy individual stock images. So many stock photos are horribly overused and clichéd so if you have to use stock photos, spend time to find good ones.
You can use this useful app to find a great filter to your photos. You can also adjust the filter intensity to control the effect of the filter.
While viewing a product, click the edit icon on a product image and you can carry out a whole host of adjustments to the image including applying filters. Useful!
And pretty fonts are always good!
An excellent service by Google that provides access to more than six hundred free web fonts. Integration into your theme will require some knowledge of HTML and CSS.
Another excellent service providing hundreds of high-quality commercial fonts for use in your store. There are a number of different pricing plans including one for free. Integration into your theme will also require some knowledge of HTML and CSS.
A great tool for visualizing and experimenting with over 23,000 font combinations available for the web.
A great showcase for some of the best Google web fonts.
An amazing archive of hundreds of free icons. If you need icons - check it out!
A project to build a global visual language of symbols featuring hundreds of downloadable icons.
More than 250 carefully-crafted pictograms available for free for use in your store.
More than 170 icons are included in this high-quality icon set.
Or maybe you need to learn about editing your theme?
A set of lessons covering from beginner to advanced levels. If you want to delve into HTML and CSS, this is a great place to start!
The official Shopify wiki covers the basics for store owners, designers and developers.
A good overview article written in .net magazine covering the basics of liquid for Shopify.
A beautifully designed tutorial that brings you through developing a Shopify theme from scratch. Great for understanding how it all fits together.
The cheatsheet provides a complete list of the variables used in the Liquid template language used in Shopify themes.
If you are used to one of these desktop editors then this is the best way to edit and update theme files you're developing.
Extending the idea of the textmate bundle a little further, with this app for Mac you can edit and update files from your favourite code editor on your desktop.
Evernote is an brilliant research tool for filing and cataloguing designs or design elements that you find interesting. It can be used for saving interesting articles you find online. It has many other uses also. Well worth checking out.
A vast source of inspiration - try a search on any subject in this content sharing service.
Not only is this a good place to market your design-conscious products, it's also a place that you can research how other stores present their products and stores online. They have a really beautiful iOS app too.
On a similar note to Svpply, Fancy describes itself as part store, blog, magazine and wish list. Plenty of research and marketing opportunities here.
If you want to see the latest trends in web design, Awwwards is certainly one of the best places to visit.
Describing itself as "a showcase of the finest web and interactive design" - there's plenty of great web design here.
An excellent gallery of all types of inspiring websites. It also features a large selection of premium themes for Wordpress just in case you're thinking of starting a blog.
Dribbble is a community of designers sharing their work in progress. With Benchwarmer installed, each time you open up a new tab in Chrome, you get an overview of what's happening on Dribbble. There's always something to catch the eye!
Great new articles every week and a huge archive of comprehensive articles. It's well worth digging in!
As well as providing a deep archive of questions and answers, the forums are also a great place to post your questions.
Or perhaps you want to hire a professional to customize your store? Enter Shopify experts, a directory of designers, developers, marketers and photographers that are all Shopify-approved, the best of the best!
This lively group on Facebook had around 15 thousand members: store owners, Shopify experts but above all entrepreneurs. You'll have to request membership. It also now has a spin-off discussion forum.
Naturally the list couldn't be complete without my ebook on Shopify. An easy-to-use, step-by-step ebook that covers everything you need to know about designing, setting up and running a truly awesome online store with Shopify.
That's it! Or at least that's the first attempt at this list of resources. If you have any essentials that you think should be added to the list, please let me know in the comments.
Please share this list with relevant friends and co-workers!


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Tyndall Glacier is a small cirque glacier in Rocky Mountain National Park in the U.S. state of Colorado. Tyndall Glacier is on the east side of the Continental Divide and in a cirque to the north of Hallett Peak. Tyndall Glacier is both an ice and a rock glacier, with the lower portions of the glacier being composed primarily of rock debris and a small portion of ice.

Tyndall Glacier is named after John Tyndall, an Irish scientist and Alpine mountaineer who in 1861 first ascended the Weisshorn and made an early attempt on the Matterhorn prior to its first ascent. In 1861 Tyndall identified carbon dioxide as a heat-trapping greenhouse gas; the glacier that bears his name appears to be retreating.

See also
List of glaciers in the United States

References

Glaciers of Rocky Mountain National Park
Landforms of Larimer County, Colorado


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Никола́й Петро́вич Майо́ров (род. 15 февраля 1958, деревня Высоково, Ивановская область, РСФСР, СССР) — Герой Российской Федерации, гвардии полковник запаса, командир 331-го гвардейского парашютно-десантного полка 98-й гвардейской Свирской воздушно-десантной дивизии (1997—2000).

Биография
Родился 15 февраля 1958 года.

В 1975 году после окончания школы поступил в Рязанское высшее воздушно-десантное командное училище, которое окончил в 1979 году. После этого служил в различных частях ВДВ. В 1990 году окончил Военную академию имени М. В. Фрунзе. С 1991 года был командиром 3 батальона 331-го пдп, с июля по ноябрь 1992 года командовал сводным батальоном 331-го полка в Приднестровье. В 1998 году был назначен командиром 331-го гвардейского парашютно-десантного полка 98-й гвардейской воздушно-десантной дивизии. С 17 сентября 1999 по 20 марта 2000 года руководил действиями 331-го полка в ходе Второй чеченской войны. Кроме этого под руководством полковника Майорова, в июне 1999 года был сформирован и отправлен в Косово 2-й парашютно-десантный батальон для участия в составе многонациональных миротворческих сил. В 2000 году полковник Майоров возглавлял пешую коробку 331 полка на параде в честь 55-й годовщины Победы.

Указом Президента Российской Федерации от 16 марта 2000 года полковнику Майорову Николаю Петровичу было присвоено звание Героя Российской Федерации.

После возвращения из Чечни Николай Майоров продолжил службу в ВДВ, занимал должность заместителя командира 98-й дивизии.

В начале 2000-х годов был уволен в запас. После увольнения работал в администрации Костромской области.

Поддержал вторжение России на Украину

Награды
 Герой Российской Федерации (16.03.2000, медаль «Золотая звезда» № 595).
 Орден Мужества (22.01.2000).
 Орден «За службу Родине в Вооружённых Силах СССР» 3-й степени.
 Медали.

Примечания

Ссылки

Выпускники Рязанского высшего воздушно-десантного командного училища
Выпускники Военной академии имени М. В. Фрунзе
Участники Второй чеченской войны


Inexpensive to build and effortless to maintain, tiny houses come in a lot of diverse types and floor plans. From Craftsman bungalows to small in-law suites, modest house programs are targeted on living huge with open floor ideas, generous porches, and versatile residing spaces. Remain on price range without having sacrificing style by selecting a tiny house plan with lots of curb appeal, from front porches to massive windows. The actual definition of modest varies from area to spot and particular person to particular person, but most of the houses in this group are under two,000 square feet (some as tiny as 300 square feet!) Whether or not you want a simple house that's low-cost to construct, an auxiliary dwelling unit for an in-law, or a charming nation cottage, you'll find what you're hunting for in our assortment of small house ideas.


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Kate Gosselin Bio, Wiki, Age, Family, Husband, Kids, Net Worth, and House
Kate Gosselin is an American television personality who is best known for starring on the US reality TV show Jon & Kate Plus 8.
Kate Gosselin Biography
Kate Gosselin is an American television personality who is best known for starring on the US reality TV show Jon & Kate Plus 8. The show was about her and Jon Gosselin as they raised their atypical family of sextuplets and twins.
Kate Gosselin Age
Kate was born Katie Irene Kreider on 28 March 1975 in Philadelphia, Pennsylvania, United States. She is 47 years old.
Kate Gosselin Height
Gosselin stands at a height of 5 feet 4 inches (163 cm) tall.
Kate Gosselin Family
Kate was born in Philadelphia, Pennsylvania to Charlene and Kenton Kreider, a pastor. She has five siblings; three sisters, Kendra, Christen, and Clairissa, and one brother, Kevin.
Kate Gosselin Husband
Kate was married to Jon Gosselin on June 12, 1999, whom she had met at a company picnic on October 5, 1997. The two announced that they were separating on June 22, 2009. Their divorce was finalized on December 16, 2009, and Kate was granted the ownership of the family home and primary custody of the children.
Kate Gosselin Kids / Kate Gosselin Children
Gosselin has eight children. Her firstborn are twin girls, Cara Nicole and Madelyn "Mady" Kate, who were born on October 8, 2000, at 35 weeks gestation, five weeks premature. In the spring of 2004, she gave birth to sextuplets: sons Aaden Jonathan, Collin Thomas, and Joel Kevin, and daughters Alexis Faith, Hannah Joy, and Leah Hope who were born 10 weeks premature.
Kate Gosselin Photo
Kate Gosselin Net Worth
Kate has an estimated net worth of $500 thousand dollars.
Kate Gosselin Education
Gosselin studied at the Reading Hospital and Medical Center, where she earned her nursing degree. She became a registered nurse after completing her diploma program at the Reading Hospital and Medical Center in Reading, Pennsylvania where worked as a labor and delivery nurse in Wyomissing, Pennsylvania.
Kate Gosselin Career
After the birth of the sextuplets, Kate's family of 10 was featured in NBC's reality show Home Delivery. Their home in Wyomissing was even renovated to accommodate the new family.
The family was then featured in Discovery Health as "Surviving Sextuplets and Twins" a show aired in the year 2005. In 2016, they were featured in another special entitled Sextuplets and Twins: One Year Later.
Due to the high ratings from the viewers, Discovery Health signed the couple to a reality series that aired beginning in April 2007, called Jon & Kate Plus 8, which documented their lives. The show's first two seasons aired on Discovery Health Channel and then moved to The Learning Channel (TLC). The reality show aired its series finale that same year because Jon made the decision to stop filming altogether.
Gosselin continued appearing on television, occasionally co-hosting 'The View' and appeared as a contestant on the reality show "Dancing with the Stars" in the year 2010. In April 2018, Gosselin announced she would star in a new TLC series, Kate Plus Date, showing her efforts to get back into the dating pool. She has written 3 non-fiction books; "Multiple Blessing", "Eight Little Faces", and "I just want you to know"
Kate Gosselin House
Kate bought a $750,000 house in North Carolina in April 2018. The 3,562 square-foot home has four bedrooms, five bathrooms, a private pier, a pool, and more relaxing amenities.
Kate Gosselin Movies
2005 Surviving Sextuplets and Twins Herself One-hour special
2006 Sextuplets and Twins: One Year Later
2007–present Jon & Kate Plus 8 / Kate Plus 8 Reality series
2008 Say Yes to the Dress One episode
2010 Dancing with the Stars Competitive reality series
2013 Celebrity Wife Swap One episode
2014 Kate Plus Eight: Sextuplets Turn 10 2 One-hour specials
2014 The Apprentice (U.S. season 14) Competitive reality series
Kate Gosselin Facebook


We are currently seeking an enthusiastic and highly organised Library Technician to support the Learning Resource Leader and Learning Resource Centre to improve the quality of staff and student learning.
All staff are expected to support the College Mission, vision and goals as a learning community and participate in ongoing professional development and learning.
Applications close 9.00 am Friday 22 March 2019.
Please see the Position Description for further details and selection criteria.
All applications must contain a resume, cover letter, including a statement addressing the selection criteria and a completed online application form (employment.marcellin.vic.edu.au).
Please note only online applications via the Marcellin website will be accepted.