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Justia Patents Oxygen Of The Saccharide Radical Bonded To A Nonsaccharide Hetero Ring By Acyclic Carbon BondingUS Patent for Pyrimidine nucleoside derivatives and salts thereof Patent (Patent # 8,076,302)
Pyrimidine nucleoside derivatives and salts thereof
Feb 15, 2007 - aRigen Pharmaceuticals, Inc.
A novel pyrimidine nucleoside derivative represented by the following formula (1) and a salt thereof, as well as a pharmaceutical composition comprising the same as an active ingredient have excellent antiviral properties and are useful as antiviral therapeutic agents: [wherein R represents a nitrogen-containing heterocyclic ring which may have any one of a C1-C3 alkyl group or a C1-C3 alkoxy group as a substituent, or a C1-C6 alkyl group which has one primary amino group as a substituent].
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This application is a 371 U.S. National Stage of International Application No. PCT/JP2007/052758, filed Feb. 15, 2007. The disclosure of the above application is entirely incorporated herein by reference.
The present invention relates to novel pyrimidine nucleoside derivatives having excellent antiviral properties and salts thereof, as well as applications of these compounds.
"Herpes virus" comes from the ancient Greek meaning "to creep or crawl while hiding itself." The feature of this virus is that once it has infected patients, the virus continues to hide in their ganglia even after symptoms have dissipated, and becomes active again upon reduction of the patients' immunity.
At present, 8 types of herpes viruses are known to infect humans: herpes simplex virus type 1 (HSV-1) which causes gingivostomatitis, keratitis, pharyngitis, herpes labialis, etc.; herpes simplex virus type 2 (HSV-2) which is responsible for genital herpes infections; varicella-zoster virus (VZV); cytomegalo virus (CMV) which causes retinitis, hepatitis, interstitial pneumonia, etc.; EB virus (EBV) which is responsible for infectious mononucleosis; human herpes virus 6 (HHV-6) which causes exanthema subitum; human herpes virus 7 (HHV-7); and human herpes virus 8 (HHV-8) which is responsible for Kaposi's sarcoma seen in AIDS patients.
Herpes virus infections are characterized by persistent infection (latent infection) in the body (mainly in ganglia) following primary infection. Except for VZV and HHV-6 cases, primary infection is often inapparent infection. After primary infection, regardless of whether it is apparent or inapparent, the viruses establish latent infection in trigeminal and/or sacral ganglia, and they further cause blisters at specific skin sites such as areas around the lips and genitals (recurrent infection) when the viruses become active again due to fatigue, pregnancy, injury, febrile diseases and other causes.
The incidence rate of herpes zoster is reported to be 300 patients per year per 100,000 adults. Herpes zoster patients are numerous particularly among the elderly (50 to 79 years old), and tend to slightly increase. In recent years, there has been an increasing number of patients who develop herpes zoster at younger ages and repeatedly. In patients whose pain persists for a month after developing the disease, the pain disappears within 3 months in half of such patients, but it persists for 3 months or longer in the remaining half of the patients, 20% of which will have pain persisting for longer than a year (postherpetic neuralgia).
DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
Many antibiotics are known for bacterial infections, whereas there are few antiviral agents effective against virus infections.
Sorivudine [i.e., 1-β-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil] has a cytostatic effect on herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV), and is also known as a compound whose cytotoxicity is extremely low because it is not phosphorylated in uninfected cells (Patent Document 1). Moreover, as an external formulation for HSV-1 infection in mice, sorivudine is also reported to be as useful as acyclovir (i.e., 9-[(2-hydroxyethoxy)methyl]guanine) which is a representative antiviral drug and is regarded as being effective for treatment of herpes virus infections and other purposes (Non-patent Document 1). Further, CVAU [i.e., 1-β-D-arabinofuranosyl-(E)-5-(2-chlorovinyl)uracil, 5-chlorovinyl-araU] is also known to have the same activity as sorivudine (Patent Document 1). However, there is still a demand for the development of antiviral therapeutic agents which are highly effective in in vivo tests and are expected to have a higher therapeutic effect.
Patent Document 1: JP 57-48160 B
Non-patent Document 1: Antiviral Research, 21, 47-57, 1993
The object of the present invention is to provide a compound useful as an antiviral therapeutic agent which has excellent antiviral properties, and a pharmaceutical agent containing the same.
Means for Solving the Problems
As a result of extensive and intensive efforts, the inventors of the present invention have found that a novel pyrimidine nucleoside derivative represented by the following formula (1) has an excellent anti-herpesvirus effect. This finding led to the completion of the present invention.
The present invention is directed to the following inventions.
1. A novel pyrimidine nucleoside derivative represented by formula (1) and a salt thereof:
[wherein R represents a nitrogen-containing heterocyclic ring which may have any one of a C1-C3 alkyl group or a C1-C3 alkoxy group as a substituent, or a C1-C6 alkyl group which has one primary amino group as a substituent].
2. A pharmaceutical composition, which comprises a compound represented by formula (1) or a salt thereof as an active ingredient together with a pharmaceutically acceptable carrier or diluent.
3. An antiviral agent, which comprises a compound represented by formula (1) or a salt thereof as an active ingredient.
4. A method for treating a virus infection, which comprises administering a therapeutically effective amount of at least one compound represented by formula (1) or salt thereof to a patient in need of treatment.
5. Use of a compound represented by formula (1) or a salt thereof in the manufacture of a pharmaceutical preparation for treating a patient with a virus infection.
Advantages of the Invention
The novel pyrimidine nucleoside derivatives of the present invention and salts thereof have excellent antiviral effects and are useful as antiviral agents (therapeutic agents for virus infections).
FIG. 1 is a graph showing the time course of changes in average lesion scores during antiviral test.
BEST MODE FOR CARRYING OUT THE INVENTION
The pyrimidine nucleoside derivatives of the present invention are novel compounds having a chemical structure represented by the above formula (1), wherein R represents a nitrogen-containing heterocyclic ring which may have any one of a C1-C3 alkyl group or a C1-C3 alkoxy group as a substituent, or a C1-C6 alkyl group which has one primary amino group as a substituent. The compounds of the present invention represented by the above formula (1) and salts thereof have various structural isomers and stereoisomers. All of these isomers also fall within the scope of the pyrimidine nucleoside derivatives of the present invention and salts thereof.
Preferred nitrogen-containing heterocyclic rings are piperidine (including positional isomers), pyridine (including positional isomers) and pyrimidine (including positional isomers), each of which may have any one of a C1-C3 alkyl group or a C1-C3 alkoxy group as a substituent.
Examples of a C1-C3 alkyl group which may be on the nitrogen-containing heterocyclic ring include a methyl group, an ethyl group, a propyl group and an isopropyl group, with a methyl group being preferred.
Examples of a C1-C3 alkoxy group which may be on the nitrogen-containing heterocyclic ring include a methoxy group, an ethoxy group, a propoxy group and an isopropoxy group, with a methoxy group being preferred.
Examples of a C1-C6 alkyl group in the C1-C6 alkyl group which has one primary amino group as a substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an isopropylmethyl group (a 2-methylpropyl group), a n-pentyl group, a cyclopentyl group, a n-hexyl group and a cyclohexyl group, with an isopropylmethyl group (a 2-methylpropyl group) being preferred.
R is more preferably a 1-amino-2-methylpropyl group, a 4-piperidyl group, a N-methylpiperidyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group or a 2-methoxy-5-pyrimidinyl group.
R is most preferably a 1-amino-2-methyl-propyl group or a 4-piperidyl group.
Salts of the pyrimidine nucleoside derivatives of the present invention may be any salts as long as they are pharmaceutically acceptable salts. Examples include mineral acid salts such as a hydrochloride salt, a hydrobromide salt, a sulfate salt, a nitrate salt and a phosphate salt, as well as organic acid salts such as an acetate salt, a propionate salt, a tartrate salt, a fumarate salt, a maleate salt, a malate salt, a citrate salt, a methanesulfonate salt, a paratoluenesulfonate salt and a trifluoroacetate salt. Moreover, the pyrimidine nucleoside derivatives of the present invention can be present in the form of solvates typified by hydrates, and such solvates typified by hydrates also fall within the scope of the present invention.
The novel pyrimidine nucleoside derivatives of the present invention and salts thereof can be prepared according to Reaction Scheme 1 or 2 shown below. In these schemes, formula (2) represents a pyrimidine nucleoside derivative of formula (1), in which the nitrogen atom(s) in the substituent R may be protected with a protecting group(s).
wherein R′ represents piperidinecarboxylic acid whose nitrogen atom may be protected, pyridinecarboxylic acid whose nitrogen atom may be protected, pyrimidinecarboxylic acid whose nitrogen atoms may be protected, or a C1-C6 alkyl group which has one primary amino group as a substituent whose nitrogen atom may be protected. Protecting groups for nitrogen atoms are not limited in any way as long as they are conventionally known protecting groups, and suitable examples are those found in T. W. Greene, "Protective groups in Organic Synthesis", A Wiley-Interscience Publication, John-Wiley & Sons, New York, 1981, p. 218-287, as exemplified by a tert-butoxycarbonyl group (Boc).
(Scheme 1)
In this scheme, (E)-5-(2-chlorovinyl)-1-β-D-arabinofuranosyluracil may be reacted through condensation reaction with, e.g., piperidinecarboxylic acid whose nitrogen atom is protected, a C1-C6 alkyl group which has one primary amino group as a substituent whose nitrogen atom is protected, pyridinecarboxylic acid, or pyrimidinecarboxylic acid to thereby prepare a compound represented by formula (2).
The condensation reaction is not limited in any way as long as it is commonly used to prepare an ester from a carboxylic acid and an alcohol, as exemplified by a mixed acid anhydride method, a method using a condensing agent, etc.
In the case of using a mixed acid anhydride method, examples of a reagent used for mixed acid anhydride formation include isobutyl chlorocarbonate, pivaloyl chloride, etc. Likewise, examples of a base available for use include organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and collidine, as well as inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate.
Examples of a reagent used as a condensing agent include 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), and diphenylphosphorylazide (DPPA). Examples of a condensation aid include 1-hydroxybenzotriazole hydrate (HOBT), N-hydroxysuccinimide (HONSu), N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB), and 4-dimethylaminopyridine (DMAP). Any solvent may be used as long as it is inert to the reaction, and examples include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran (THF), dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), which may be used either alone or in combination. The reaction temperature ranges from −30° C. to 100° C., preferably 0° C. to 30°, while the reaction time is 0.1 to 100 hours, preferably 1 to 20 hours. The compound of formula (2) prepared by this reaction may be isolated and purified as required, or may be used directly, without purification, for deprotection or salt formation described below.
In a case where the pyrimidine nucleoside derivative represented by formula (2) has a protecting group(s) on its nitrogen atom(s), a deprotecting reagent may be reacted to remove the protecting group(s) to thereby obtain a compound represented by formula (1). For example, when the protecting group is a tert-butoxycarbonyl group (Boc), any deprotecting reagent may be used as long as it is commonly used, and examples include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, as well as organic acids such as trifluoroacetic acid, acetic acid, propionic acid, formic acid, methanesulfonic acid and paratoluenesulfonic acid.
Examples of a solvent available for use include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran (THF), dioxane, diethyl ether, benzene, toluene, acetone, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol and water, which may be used either alone or in combination. The reaction temperature ranges from −30° C. to 150° C., preferably 0° C. to 100° C., while the reaction time is 0.1 to 100 hours, preferably 1 to 40 hours.
In this scheme, (E)-5-(2-chlorovinyl)-1-β-D-arabinofuranosyluracil may be reacted with an acid chloride (X═Cl) derived from, e.g., pyridinecarboxylic acid or pyrimidinecarboxylic acid in the presence of a base to thereby prepare a compound represented by formula (2).
Examples of a base available for use include organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and collidine, as well as inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. Any solvent may be used as long as it is inert to the reaction, and examples include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran (THF), dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), which may be used either alone or in combination. The reaction temperature ranges from −30° C. to 100° C., preferably 0° C. to 30° C., while the reaction time is 0.1 to 100 hours, preferably 1 to 20 hours. In a case where the pyrimidine nucleoside derivative represented by formula (2) has a protecting group(s) on its nitrogen atom(s), a deprotecting reagent may be reacted to remove the protecting group(s) to thereby obtain a compound represented by formula (1), according to the procedures shown in Scheme 1.
The compound of formula (2) or (1) as obtained above according to Scheme 1 or 2 can form a salt, especially a pharmaceutically acceptable salt, in a generally known manner. Examples of a pharmaceutically acceptable salt include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, as well as salts with organic acids such as trifluoroacetic acid, acetic acid, propionic acid, formic acid, methanesulfonic acid and paratoluenesulfonic acid. The compound of formula (1) or (2) or a salt thereof can be isolated and purified using generally known separation/purification means, such as concentration, solvent extraction, filtration, recrystallization, and/or various chromatographic techniques.
For use as a pharmaceutical preparation, the compound of the present invention may be formulated into any dosage form as appropriate for prophylactic or therapeutic purposes. Examples of such a dosage form include oral formulations, injections, suppositories, creams and plasters, with creams being preferred for use. These dosage forms may each be prepared by conventional formulation techniques well known to those skilled in the art.
In the case of preparing solid formulations for oral administration, the compound of the present invention may be supplemented with excipients and, if necessary, with binders, disintegrating agents, lubricants, coloring agents, correctives and so on, followed by formulating in a routine manner into tablets, coated tablets, granules, powders, capsules, etc. Such additives may be those commonly used in the art, as exemplified by lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose and silicate for excipients; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, methylcellulose, ethylcellulose, shellac, calcium phosphate and polyvinylpyrrolidone for binders; dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride and lactose for disintegrating agents; purified talc, stearate salt, borax and polyethylene glycol for lubricants; titanium oxide and iron oxide for coloring agents; and sucrose, orange peel, citric acid and tartaric acid for correctives.
In the case of preparing liquid formulations for oral administration, the compound of the present invention may be supplemented with correctives, buffers, stabilizers and so on, followed by formulating in a routine manner into oral solutions, syrups, elixirs, etc. In this case, correctives may be those listed above. Examples of buffers include sodium citrate, while examples of stabilizers include tragacanth, gum arabic and gelatin.
In the case of preparing injections, the compound of the present invention may be supplemented with pH adjustors, buffers, stabilizers, isotonizing agents, local anesthetic agents and so on, followed by formulating in a routine manner into subcutaneous, intramuscular and intravenous injections. In this case, examples of pH adjustors and buffers include sodium citrate, sodium acetate, and sodium phosphate. Likewise, examples of stabilizers include sodium pyrosulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of local anesthetic agents include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonizing agents include sodium chloride and glucose.
In the case of preparing suppositories, the compound of the present invention may be supplemented with pharmaceutical carriers known in the art (e.g., polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride) and, if necessary, with additional ingredients such as surfactants (e.g., Tween (registered trademark)), followed by formulating in a routine manner.
In the case of preparing creams, the compound of the present invention may be combined with commonly used base materials, stabilizers, wetting agents, preservatives and so on, as appropriate for the intended purpose, followed by mixing and formulating in a routine manner. Examples of base materials include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, and paraffin. Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate.
In the case of preparing plasters, the above creams, ointments, gels, pastes or the like may be applied onto commonly used supports in a routine manner. Suitable supports are woven or nonwoven fabrics made of cotton, staple fibers or chemical fibers, as well as films or foamed sheets made of soft vinyl chloride, polyethylene, polyurethane, etc.
The amount of the compound of the present invention to be incorporated into the above dosage unit forms will vary depending on the symptom of a patient to be applied by the compound, or depending on the intended dosage form, etc. A desired amount per dosage unit form is usually about 1 to 1000 mg for oral formulations, about 0.1 to 500 mg for injections, and about 5 to 1000 mg for suppositories. Moreover, the daily dose of pharmaceutical agents having the above dosage forms will vary depending on, e.g., the symptom, body weight, age and sex of a patient, and hence should be determined for each case. However, the daily dose may generally be set to about 0.1 to 5000 mg, preferably 1 to 1000 mg per day for adult patients, preferably given as a single dose or in 2 to 4 divided doses per day.
Diseases which can be treated by administration of a pharmaceutical agent containing the compound of the present invention are human herpes infections, i.e., herpes simplex type 1 and 2 infections (HSV-1 and HSV-2 infections) including gingivostomatitis, keratitis, pharyngitis, herpes labialis, herpes encephalitis and genital herpes, as well as varicella and herpes zoster (VZV infections), EB virus infections such as infectious mononucleosis, etc.
The present invention will be further described in more detail by way of the following reference example, examples, pharmacological test examples and formulation examples, which are not intended to limit the scope of the invention.
Reference Example 1 Synthesis of 1-β-D-arabinofuranosyl-(E)-5-(2-chlorovinyl)uracil (CVAU)
This compound was synthesized according to synthesis procedures as described in JP 57-48160 B or other documents.
Example 1 Synthesis of (E)-5-(2-chlorovinyl)-1-[5′-O-(piperidine-4-carboxyl)-β-D-arabinofuranosyl]uracil hydrochloride (Compound 1)
To a solution of 1-β-D-arabinofuranosyl-(E)-5-(2-chlorovinyl)uracil (CVAU; 20.0 g), (N-Boc)piperidine-4-carboxylic acid (15.2 g), HOBT monohydrate (11.1 g) and triethylamine (7.3 g) in DMF (180 ml), EDC (11.2 g) was added dropwise at −6° C. to −3° C. After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature. The DMF was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 ml) and then washed with 5% aqueous sodium bicarbonate and saturated aqueous sodium chloride.
After drying over anhydrous magnesium sulfate, the ethyl acetate was distilled off under reduced pressure to give a light-yellow oil (33.6 g). This oil was crystallized from n-hexane and collected by filtration to give a crude product (13.6 g). This procedure was repeated twice.
The crude product thus obtained (17.1 g) was dissolved without purification in dioxane (50 ml), and a 4 N hydrogen chloride/dioxane solution (83 ml) was added dropwise thereto under ice cooling. After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature. The dioxane was distilled off under reduced pressure, and the resulting opalescent crystal (14.4 g) was washed by suspending in dioxane and ethanol, followed by filtration to give Compound 1 (12.8 g).
1H-NMR (DMSO-d6) δ 11.63 (1H, s), 8.89 (1H, br), 8.60 (1H, br), 7.65 (1H, s), 7.21 (1H, d, J=13.17 Hz), 6.66 (1H, d, J=13.17 Hz), 6.06 (1H, d, J=3.90 Hz), 5.76 (1H, d, J=4.39 Hz), 5.70 (1H, d, J=3.90 Hz), 4.58 (1H, dd, J=11.71 Hz, J=8.29 Hz), 4.22 (1H, dd, J=11.71 Hz, J=3.42 Hz), 4.03-3.95 (3H, m), 3.23-3.21 (2H, m), 2.94-2.91 (2H, m), 2.02-1.99 (2H, m), 1.80-1.74 (2H, m)
MS (FAB): m/z 450
Example 2 Synthesis of 1-[5′-0-(L-valine)-β-D-arabinofuranosyl]-(E)-5-(2-chlorovinyl)uracil hydrochloride (Compound 2)
To a solution of CVAU (20.0 g), Boc-L-valine (14.4 g), HOBT monohydrate (11.1 g) and triethylamine (7.3 g) in DMF (200 ml), EDC (11.2 g) was added dropwise at −6° C. to −3° C. After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature. The DMF was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 ml) and then washed with 5% aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the ethyl acetate was distilled off under reduced pressure to give a light-yellow oil (37.6 g). This oil was crystallized from n-hexane and chloroform, followed by filtration to give a crude product (13.5 g). The crude product thus obtained (13.5 g) was dissolved without purification in dioxane (130 ml), and a 4 N hydrogen chloride/dioxane solution (67 ml) was added dropwise thereto under ice cooling. After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature. The dioxane was distilled off under reduced pressure, and the resulting residue was crystallized from ether and collected by filtration to give Compound 2 (12.9 g).
1H-NMR (DMSO-d6) δ 11.66 (1H, s), 8.37 (3H, brs), 7.64 (1H, s), 7.23 (1H, d, J=13.17 Hz), 6.63 (1H, d, J=13.17 Hz), 6.08 (1H, d, J=3.90 Hz), 5.79 (1H, d, J=4.63 Hz), 5.72 (1H, d, J=3.90 Hz), 4.65 (1H, dd, J=11.71 Hz, J=8.54 Hz), 4.39-4.35 (1H, m), 4.05-3.99 (4H, m), 2.20-2.16 (1H, m), 1.00 (3H, d, J=6.83 Hz), 0.96 (3H, d, J=6.83 Hz)
Example 3 Synthesis of (E)-5-(2-chlorovinyl)-1-[5′-O-(pyridine-3-carboxyl)-β-D-arabinofuranosyl]uracil hydrochloride (Compound 3)
CVAU (500 mg) was dissolved in DMF (4 ml). To this solution, nicotinoyl chloride hydrochloride (427 mg) and triethylamine (648 mg) were added at room temperature and stirred for 3 hours. Nicotinoyl chloride hydrochloride (114 mg) and triethylamine (80 mg) were further added and stirred for an additional 2 hours. After addition of methanol to stop the reaction, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and then with water, followed by evaporation to dryness under reduced pressure. The residue was crystallized from methanol-chloroform to give a crude product (100 mg).
The crude product (70 mg) was dissolved in a 10% hydrochloric acid/methanol solution, and the methanol was evaporated to dryness under reduced pressure to give Compound 3 (80 mg).
1H-NMR (DMSO-d6) δ 11.60 (s, 1H), 9.16 (m, 1H), 8.86 (dd, 1H, J=5.0, 1.7 Hz), 8.41 (dt, 1H, J=8.0, 2.0 Hz), 7.65 (m, 1H), 7.65 (s, 1H), 7.15 (d, 1H, J=13.2 Hz), 6.53 (d, 1H, J=13.2 Hz), 6.07 (d, 1H, J=3.6 Hz), 4.73 (dd, 1H, J=11.5 Hz, J=7.3 Hz), 4.53 (dd, 1H, J=11.5 Hz, J=3.6 Hz), 4.07 (m, 3H)
Isonicotinic acid (689 mg), isobutyl chloroformate (764 mg) and triethylamine (566 mg) were dissolved in DMF (8 ml) and stirred for 1 hour. To the reaction mixture, CVAU (1.0 g) and triethylamine (1.0 g) were added and stirred overnight. After addition of methanol to stop the reaction, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, followed by evaporation to dryness under reduced pressure. The residue was crystallized from methanol-chloroform to give a crude product (220 mg).
The crude product (70 mg) was dissolved in a 10% hydrochloric acid/methanol solution, and the methanol was evaporated to dryness under reduced pressure, followed by crystallization from methanol to give Compound 4 (80 mg).
1H-NMR (DMSO-d6) δ 11.60 (s, 1H), 8.90 (dd, 2H, J=4.6, 1.7 Hz), 8.04 (dd, 2H, J=4.6, 1.7 Hz), 7.67 (s, 1H), 7.16 (d, 1H, J=13.2 Hz), 6.58 (d, 1H, J=13.2 Hz), 6.07 (d, 1H, J=3.3 Hz), 4.75 (dd, 1H, J=11.9 Hz, J=7.3 Hz), 4.65 (dd, 1H, J=11.9 Hz, J=3.6 Hz), 4.11 (m, 3H)
Example 5 Synthesis of (E)-5-(2-chlorovinyl)-1-[5′-O—(N-methylpiperidine-4-carboxyl)-β-D-arabinofuranosyl]uracil hydrochloride (Compound 5)
N-Methylisonipecotic acid sodium salt (1.5 g) in DMF (14 ml) was treated with 1 N hydrochloric acid (9.1 ml) and dried to give a white solid. This solid was dissolved in isobutyl chloroformate (1.24 g) and triethylamine (1.0 g), followed by stirring for 1 hour. To the reaction mixture, CVAU (1.3 g) and triethylamine (2.7 g) were added and stirred overnight. After addition of methanol to stop the reaction, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, followed by evaporation to dryness under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform:methanol=7:1) to give a crude product. The crude product was immediately treated with a large excess of a 10% hydrochloric acid/methanol solution to give a crude hydrochloride salt. This crude product was suspended in ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and evaporated to dryness under reduced pressure. The resulting residue was purified again by NH silica gel column chromatography (chloroform:methanol=7:1), treated with about 2 molar equivalents of a 10% hydrochloric acid/methanol solution, and then lyophilized to give Compound 5 (182 mg).
1H-NMR (DMSO-d6) δ 11.60 (s, 1H), 7.63 (s, 1H), 7.20 (d, 1H, J=13.3 Hz), 6.64 (d, 1H, J=13.3 Hz), 6.04 (d, 1H, J=4.3 Hz), 5.72, 5.66 (each d, each 1H J=4.3, 3.6 Hz), 4.54 (dd, 1H, J=11.5 Hz, J=7.6 Hz), 4.19 (dd, 1H, J=11.4 Hz, J=3.0 Hz), 3.97 (m, 3H), 3.33-1.71 (m, 9H), 2.46 (s, 3H)
Example 6 Synthesis of (E)-5-(2-chlorovinyl)-1-[5′-O-(pyridine-2-carboxyl)-β-D-arabinofuranosyl]uracil (Compound 6)
CVAU (500 mg) was dissolved in DMF (4 ml). To this solution, picolinoyl chloride hydrochloride (427 mg) and triethylamine (647 mg) were added at room temperature and stirred for 3 hours. Nicotinoyl chloride hydrochloride (114 mg) and triethylamine (80 mg) were further added and stirred for an additional 2 hours. After addition of methanol to stop the reaction, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and then with water, followed by evaporation to dryness under reduced pressure. The residue was crystallized from methanol-chloroform to give Compound 6 (220 mg).
1H-NMR (DMSO-d6) δ 11.56 (s, 1H), 8.74 (d, 1H, J=4.0 Hz), 8.10 (d, 1H, J=8.0 Hz), 8.01 (dt, 1H, J=7.6, 1.7 Hz), 7.70 (s, 1H), 7.67 (m, 1H), 7.19 (d, 1H, J=13.2 Hz), 6.57 (d, 1H, J=13.2 Hz), 6.08 (d, 1H, J=4.0 Hz), 5.73, 5.69 (each d, each 1H J=4.6, 4.0 Hz), 4.73 (dd, 1H, J=11.9 Hz, J=7.3 Hz), 4.52 (dd, 1H, J=11.9 Hz, J=3.6 Hz), 4.08 (m, 3H)
Example 7 Synthesis of (E)-5-(2-chlorovinyl)-1-[5′-O-(2-methoxypyrimidin-5-yl-carboxyl)-β-D-arabinofuranosyl]uracil (Compound 7)
2-Methoxypyrimidine-5-carboxylic acid (688 mg), isobutyl chloroformate (610 mg) and triethylamine (452 mg) were dissolved in DMF (7 ml) and stirred for 1 hour. To the reaction mixture, CVAU (1.0 g) and triethylamine (730 mg) were added and stirred overnight. After addition of methanol to stop the reaction, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, followed by evaporation to dryness under reduced pressure. The residue was crystallized from methanol-chloroform to give Compound 7 (180 mg).
1H-NMR (DMSO-d6) δ 11.59 (s, 1H), 9.10 (s, 2H), 7.66 (s, 1H), 7.14 (d, 1H, J=13.2 Hz), 6.53 (d, 1H, J=13.2 Hz), 6.05 (d, 1H, J=4.0 Hz), 5.72, 5.68 (each d, each 1H, J=4.6, 4.0 Hz), 4.68 (dd, 1H, J=6.9 Hz, J=11.5 Hz), 4.51 (dd, 1H, J=3.3 Hz, J=11.5 Hz), 4.08 (m, 3H), 4.01 (s, 3H)
Pharmacological Test Example 1 In Vitro Antiviral Test
The compounds of the present invention were measured for their in vitro antiviral activity (anti-HSV-1 activity, anti-VZV activity) by using human fetal lung-derived cells in an assay for 50% plaque formation inhibition (Japanese Journal of Chemotherapy, Vol. 38, No. 3, 256-261, 1990). As a result, as shown in Table 1, the compounds of the present invention showed in vitro antiviral activity almost comparable to that of CVAU and were found to have an antiviral effect on HSV-1 and VZV.
In vitro anti-HSV-1 and anti-VZV activity of CVAU derivatives
Anti-HSV-1 activity (ED50a) Anti-VZV activity (ED50) Compound μM μM
CVAU 0.075 0.0089 Compound 1 0.40 0.046 Compound 2 0.12 0.019 Compound 3 0.49 0.052 Compound 4 0.13 0.021 Compound 5 0.56 0.047 aeffective concentration required to reduce the number of plaques to 50%
Pharmacological Test Example 2 In Vivo Antiviral Test
Creams were prepared for the compounds of the present invention according to Formulation Example 2 and tested for their therapeutic effect on HSV-1 infection in mouse skin. The incidence rate and survival rate in each treated group are shown in Table 2. Moreover, skin symptoms in the HSV-1-infected mice were scored (Antiviral Research, 17, 133-143, 1992), and the time course of changes in their average lesion scores is shown in FIG. 1. When compared to the control group treated with no drug, Compound 1 was found to reduce the incidence rate, and showed a significant increase in the survival rate and a reduction in the lesion score. Compound 2 also showed a significant increase in the survival rate and a reduction in the lesion score. These results indicated that these compounds also had an excellent in vivo antiviral effect.
Therapeutic effect of CVAU derivatives in HSV-1 mouse skin infection model
Mean survival days Drug Incidence rate Survival rate (Mean ± SE) Control 8/8 0/8 6.9 ± 0.12 Compound 1 4/8 7/8 P < 0.01a Compound 2 8/8 7/8 P < 0.01 CVAU 6/8 7/8 P < 0.01 achi-square test (Yates' correction)
Formulation Example 1 Tablets
Compound 150 mg
Corn starch 50 mg
Microcrystalline cellulose 50 mg
Hydroxypropylcellulose 15 mg
Talc 2 mg
Magnesium stearate 2 mg
Ethylcellulose 30 mg
Unsaturated glyceride 2 mg
Titanium dioxide 2 mg
According to the combination ratio indicated above, tablets (250 mg per tablet) were prepared in a routine manner.
Formulation Example 2 Creams
Compound 23.92 mg
POE (5) glyceryl monostearate 5.0 mg
Dimethylpolysiloxane 0.3 mg
Paraffin 5.0 mg
White petrolatum 9.0 mg
Glyceryl monostearate 0.5 mg
Propylene glycol 20 mg
Adjusted to 100 mg with purified water.
According to the ratio indicated above, creams were prepared in a routine manner and provided for Pharmacological Test Example 2.
Formulation Example 3 Granules
Compound 3300 mg
Lactose 540 mg
Corn starch 100 mg
Talc 10 mg
According to the combination ratio indicated above, granules (1000 mg per package) were prepared in a routine manner.
Formulation Example 4 Capsules
According to the combination ratio indicated above, capsules (193 mg per capsule) were prepared in a routine manner.
Formulation Example 5 Injections
Sodium chloride 3.5 mg
Injectable distilled water q.s.
(2 ml per ampule)
According to the combination ratio indicated above, injections were prepared in a routine manner.
Formulation Example 6 Syrups
Compound 6 200 mg
Purified sucrose 60 g
Ethyl parahydroxybenzoate 5 mg
Butyl parahydroxybenzoate 5 mg
Flavorings q.s.
Colorants q.s.
Purified water q.s.
According to the combination ratio indicated above, syrups were prepared in a routine manner.
Formulation Example 7 Suppositories
Witepsol W-35 1400 mg
(registered trademark, a mixture of mono-, di- and tri-glycerides of saturated fatty acids ranging from lauric acid to stearic acid, Dynamit Nobel)
According to the combination ratio indicated above, suppositories were prepared in a routine manner.
INDUSTRIAL APPLICABILITY
The novel pyrimidine nucleoside derivatives of the present invention and salts thereof are highly effective in in vivo tests, and hence can be expected to be used as antiviral agents (therapeutic agents for virus infections).
1. A pyrimidine nucleoside represented by the following formula (I) or a salt thereof:
wherein R represents a nitrogen-containing heterocyclic ring which may have any one of a C1-C3 alkyl group or a C1-C3 alkoxy group as a substituent, or a C1-C6 alkyl group which has one primary amino group as a substituent.
2. The pyrimidine nucleoside or salt thereof according to claim 1, wherein R is a piperidyl group which may have a C1-C3 alkyl group as a substituent, a pyridyl group which may have a C1-C3 alkyl group as a substituent, or a pyrimidinyl group which may have a C1-C3 alkoxy group as a substituent.
3. The pyrimidine nucleoside or salt thereof according to claim 1, wherein R is a 4-piperidyl group.
4. The pyrimidine nucleoside or salt thereof according to claim 1, wherein R is a 1-amino-2-methyl-propyl group.
5. An antiviral agent comprising the pyrimidine nucleoside or salt thereof according to claim 1, as an active ingredient.
7. An antiviral agent comprising the pyrimidine nucleoside or salt thereof according to claim 3 as an active ingredient.
9. The antiviral agent according to claim 5, which is used as a therapeutic agent for a herpes virus infection.
10. The antiviral agent according to claim 6, which is used as a therapeutic agent for a herpes virus infection.
13. A method for treating a herpes virus infection selected from HSV-1 and VZV, which comprises administering a therapeutically effective amount of at least one pyrimidine nucleoside represented by the following formula (1) or salt thereof to a patient in need of treatment:
4386076 May 31, 1983 Machida et al.
4542210 September 17, 1985 Sakata et al.
5446031 August 29, 1995 Sakata et al.
31128 July 1981 EP
74101 March 1983 EP
572669 December 1993 EP
56-87599 July 1981 JP
58-43993 March 1983 JP
4-505920 October 1992 JP
WO 90/15064 December 1990 WO
WO 92/19638 November 1992 WO
Razonable et al., PubMed Abstract (Herpes 10(3):60-5), Dec. 2003.
Douglas, Jr. Introduction to Viral Diseases, Cecil Textbook of Medicine, 20th Edition, vol. 2, pp. 1739-1747, 1996.
Goff, PubMed Abstract (J Gene Med. 3(6):517-28) Nov.-Dec. 2001.
Bosseray et al., PubMed Abstract (Pathol. Biol. 50(8):483-92), Oct. 2002.
Kano, F. et al., 5′-O-alkyl and acyl prodrugs of 1-β-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil, Antiviral Chemistry & Chemotherapy, 1994, vol. 5, No. 2, pp. 74-82.
Ashida, Noriyuki et al., Metabolism of 5′-ether prodrugs of 1-β-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil in rats, Biochemical Pharmacology, 1993, vol. 46, No. 12, pp. 2201-2207.
Reefschlaeger, J. et al., Antiherpes activity of (E)-5-(2-bromovinyl)- and 5-vinyl-1-β-D-arabinofuranosyluracil and some other 5-substituted uracil arabinosyl nucleosides in two different cell lines, Antiviral Research, 1983, vol. 3, No. 3, pp. 175-187.
Machida, H. et al., In vitro anti-herpesvirus activities of 5-substituted 2′-deoxy-2′ methylidene pyrimidine nucleosides, Antiviral Chemistry & Chemotherapy, 1993, vol. 4, No. 1, pp. 11-17.
Yu, Chung-Shan et al., Synthesis of (E)-5-(2-radio-iodovinyl) arabinosyl uridine analog for probing HSV-1 thymidine kinase gene, Chemistry Letters, 2005, vol. 34, No. 10, pp. 1390-1391.
Yu, Chung-Shan et al., Syntheses of 5-fluoro and (E)-5-(2-fluorovinyl) arabinosyl uridine analogues as potential probes for the HSV-1 thymidine kinase gene, Synthesis, 2006, No. 22, pp. 3835-3840.
Kulikowski, T. et al., Pyrimidine arabinofuranosyl nucleosides with 5-substituted long, branched and unsaturated chains: synthesis and antiherpes properties, Nucleic Acids Symposium Series, 1981, vol. 9, pp. 103-106.
Filed: Feb 15, 2007
Date of Patent: Dec 13, 2011
Assignee: aRigen Pharmaceuticals, Inc. (Tokyo)
Inventors: Haruhiko Machida (Tokyo), Masaichi Yamamoto (Tokyo)
Primary Examiner: Deepak Rao
Attorney: Harness, Dickey & Pierce, P.L.C.
Current U.S. Class: Oxygen Of The Saccharide Radical Bonded To A Nonsaccharide Hetero Ring By Acyclic Carbon Bonding (514/32); Chalcogen Bonded Directly To Pyrimidine At 2-position (514/274); Arabinose Is Sugar Moiety (536/27.4); At 2-position And At 4- Or 6-position (544/309); Nitrogen Attached Directly Or Indirectly To The Diazine Ring By Nonionic Bonding (544/311); 5-position Is Unsubstituted Or Alkyl Substituted Only (544/312); Additional Chalcogen Attached Directly Or Indirectly To The Diazine Ring By Nonionic Bonding (544/314)
International Classification: C07H 19/09 (20060101); A61K 31/7072 (20060101);


text:
Otis has become Plymouth's favorite dog
Big white dog who befriended the police department has some health concerns and is undergoing tests
Otis has become Plymouth's favorite dog Big white dog who befriended the police department has some health concerns and is undergoing tests Check out this story on mansfieldnewsjournal.com: http://ohne.ws/1S1OH7T
Lou Whitmire, Reporter Published 6:16 p.m. ET July 25, 2015
Otis is known in law enforcement circles in Richland County and beyond. He's a frequent visitor at the Plymouth Police Department. Video by Lou Whitmire
Otis is Plymouth police Chief Charlie Doan's dog and known and loved by many people in the village. The 130-pouond American bull dog is having some health concerns.(Photo: Lou Whitmire/News Journal)Buy Photo
PLYMOUTH – Otis is known in law enforcement circles in Richland County and beyond for being the big white dog who hangs out at the Plymouth Police Department.
"Around town people don't know my name but they say, 'You have Otis? How's Otis?' They know Otis," said Plymouth police Chief Charlie Doan this week as Otis quietly roamed the halls of the police station.
Otis, a 130-pound American bull dog, initially put himself at night in a kennel crate in the police department's classroom after he was taken in when someone had to get rid of him, thus his namesake from the town drunk in the "The Andy Griffith Show."
The show happens to be Doan's favorite.
With almost 40 years in law enforcement, Doan said the long-running TV show lets people see what law enforcement is about: Helping people.
Active in teaching at police academies, Doan said he tells students when they go on the street to work that a law enforcement officer's job is to serve.
"Ultimately the best service is to take somebody to jail when they're not smart enough to take care of themselves," Doan said. "It's certainly not my first choice. ... We're here to help people and if you watch Andy that's what he was really about. If you look at Barney, he's the young cop that everything is by the rule.... He's a legalistic nut."
Doan said the first time he took Otis home, he was timid and growled. "I had a friend there who said, 'Why would you bring a dog home who hates you?' We got past that."
Otis comes to the station regularly and rides with the chief in his cruiser. He does not do police work but is known for announcing guests who come in the front door with his bark.
Doan said everyone at the department became attached to the dog. Doan took him to a veterinarian to get shots and then took him home, where he gets along with a Shitzu named Barney.
Velveeta cheese is Otis's favorite people food treat. He also likes toast, but only if it has butter, and corn on the cob.
"I got some plain Jane (Velveeta-like) cheese, he wouldn't eat it. I have to get Velveeta," Doan said.
Otis also used to eat a lot of jalapenos but Doan said the results were too unpleasant for he and his wife.
"He was so bad that Jackie McKinney, the owner of JJ Pizza here in town, would send a cup of jalapenos with every pizza we ordered. But, as I pointed out, the results were disastrous to the atmosphere," chief said.
Plymouth clerk of courts Hope Adams, whose office is at the police station, said Otis is her protector.
When someone comes to the front door, he barks loudly behind the glass-enclosed window office.
"I was afraid of him when I first met him," she said as she gave him a dog treat. "He's my buddy. I wouldn't have it any other way."
This month Otis is having some health concerns and Doan recently posted on Facebook updates about Otis being anemic, having low red and white blood cell counts and suffering from dehydration even though he drinks plenty of water.
Otis received lots of social media posts, words of encouragement from village residents and others.
A Willard veterinarian has told Doan the dog could have leukemia; he may have to go to a veterinarian who specializes in oncology.
The gentle giant is eating well and is up and about, but not his usual spunky self, Doan said.
Doan will continue to post updates on his condition on social media. Otis on Friday was at the veterinarian getting more tests done.
whitmir@nncogannett.com
Twitter: @LWhitmir
Read or Share this story: http://ohne.ws/1S1OH7T
One shot on Walker Lake Road
ATV victims drove off 39-foot cliff, onto US 30
Two killed in ATV crash on U.S. 30
Man charged after he refused to give up drone
Prosecutor: Officer-involved shooting justified
Three children die in Jeromesville fire

redpajama_set_name: RedPajamaCommonCrawl


Finally! Sherwood now has its own band camp for young musicians entering grade levels 7, 8, and 9. The Sherwood Youth Band Camp is a great place for you to play your instrument over the summer, develop your musicianship, have fun with others, and put on a summer concert! Students will receive small group instrument specific master classes from our experienced staff. All Camp members will refine their small ensemble and concert ensemble skills. Camp members will also have the opportunity/option to perform in the Parade Band in the Robinhood Festival Parade here in Sherwood. The 2015 SYCB Camp will be held July 13-17 at Sherwood High School. Please let current middle school students know about this. There is a price break for early registrants. Turn in your registration forms!


A letter sent Monday by the federal government to state court administrators makes clear that judges should consider alternatives to jail, such as community service, for poor defendants who don't pay their fines. It also says judges must consider whether defendants have the ability to pay, and should not turn to incarceration without first establishing that a missed payment was willful.
The memo arose of a December meeting convened by the Obama administration that brought together judges, court administrators, prosecutors and others to discuss improvements in how court fees and fines are assessed. The new guidance comes amid concerns that some local courts across the country are effectively punishing poor people for their poverty by imposing crippling fines and fees that, when unpaid, can result in jail time.
Though the state court system operates independently of the Justice Department, the memo is intended to put state judges on notice that ordering jail time for unpaid fines can violate federal law, open the door to constitutional challenges and trap residents in a cycle of escalating debt, unnecessary incarceration and unemployment.
Lauren-Brooke Eisen, senior counsel in the Brennan Center's Justice Program, said the guidance was aimed at correcting a "financial incentive that fuels mass incarceration."
"These charges are often levied against people who can least afford to pay them," she said. "The subsequent punishment for unpaid debts helps spin the revolving door of the criminal justice system."
Also Monday, the Justice Department announced $2.5 million in competitive grants to state and local governments that want to explore changes in how court fees and fines are assessed and enforced.


text:
Der Lotus 22 war ein Formel-Junior-Rennwagen, 1962 gebaut vom britischen Motorsportteam Lotus.

Der Lotus 22 wurde 1962 auf der Londoner Motor-Racing-Show vorgestellt. Die Londoner Automobilausstellung war in den 1960er Jahren ein bedeutendes Ereignis für den Motorsport und die Teamführung von Lotus nützte die Veranstaltung zur Bewerbung neuer Lotus-Rennwagen-Modelle für die finanzstarken Privatiers.

Der neue Wagen, 77 Stück wurden gebaut, war eine Weiterentwicklung des Lotus 20, der ein Jahr davor in London präsentiert wurde. Als Antrieb diente wie im Vorgängermodell ein Motor von Cosworth. Nur Gerhard Mitter, der seinen Lotus 20 durch einen 22 ersetzte, baute wie in seinen 20er einen DKW-Motor ein.

Erneut beherrschte Lotus die britische Meisterschaft. Peter Arundell startete bei 25 Rennen, beendete 22 und gewann 18 davon. Der Südafrikaner Brausch Niemann fuhr einen 22 mit einem aufgebohrten Cosworth-Motor in der südafrikanischen Meisterschaft im Winter 1963/1964 als Formel-1-Wagen.

Literatur

 David Hodges: Rennwagen von A–Z nach 1945. Motorbuch-Verlag, Stuttgart 1994, ISBN 3-613-01477-7.

Weblinks

022
Lotus 022
Formel-Junior-Rennwagen

redpajama_set_name: RedPajamaWikipedia


To truly indulge and take advantage of Miami's luxurious and trendy lifestyle, consider Tahiti Beach in Cocoplum. This restricted gated island community features over twenty lavish homes that brilliantly overlook the pristine and quiescent Biscayne Bay. Residents of Tahiti Beach also have access to secluded unspoiled beaches, a nature reserve and a private park, perfect for recreation with close friends and family.
Fusing several architectural styles throughout each of its homes, Tahiti Beach's residences feature intercom systems, expansive foyers, boat docks and sparking heated swimming pools, a perfect match for the sultry South Florida sunshine. For about $9 million, privileged residents receive an extensive lot reaching more than 40,000 square feet in size with four bedrooms and three bathrooms.
Tahiti Beach is an excellent complement to its neighbor Cocoplum as well as the Coral Gables Waterway, one of several sapphire bodies of water that surround this posh and highly coveted community. Acclaimed, highly rated schools and universities surround all of the neighborhoods or are nearby such as Coral Gables Elementary, the University of Miami and Northwestern University.
Please contact CORAL GABLES luxury home Realtor Brian Smith for help buying, selling or renting a Tahiti Beach luxury property.


text:
REIT Podcasts
REIT Industry Veteran Expects More Public-to-Private M&A Transactions
6/19/2019 | By Sarah Borchersen-Keto
Marty Cicco, senior managing director at Evercore Partners, spoke with Nareit's REIT Report podcast in New York at REITweek: 2019 Investor Conference.
Cicco assessed the state of the commercial real estate market at mid-year. "It ranges from healthy, to beyond healthy, to unbelievable in some cases, but there are still a few sectors that have some challenges," he said.
At the same time, the business cycle—while clearly in the later stages—is breaking all records, according to Cicco.
"You're in an extraordinary time with low interest rates, the economy in the U.S. appears healthy, but we're obviously in the midst of a growing trade war with China…[and] you've got issue like North Korea and Iran out there that could jolt the markets," Cicco said.
Turning to the IPO outlook, Cicco said he expects most future IPOs to be part of a recycling process for large private equity firms that bought businesses privately and are looking to exit. "That cycle will ebb and flow. There'll be one or two more probably in 2019, but beyond that I don't see a huge amount of IPO activity as you look forward," Cicco said.
As for M&A activity, Cicco said he anticipates more public-to-private market transactions. He pointed to the "huge amount of private equity firepower" that is concentrated among a few key players. An additional factor favoring the private market is its greater tolerance toward leverage. "That's a big distinction because, on the private side, the leverage factor can be pushed and in this interest rate environment it creates positive leverage to a lot of transactions," he explained.
Cicco also said a dramatic shift is occurring in fund flow patterns.
Actively managed funds have seen a fund flow that's been negative to REIT-dedicated funds but positive to generalist funds. At the same time, passive funds have grown to be significant shareholders, on the order of 40 to 60%, of some of the the larger REITs, he said.
MGM Growth Properties, BREIT Agree to Form $4.6 Billion Joint Venture
Commercial Real Estate Market in 'Mature Recovery' Stage at Start of 2020


Primary responsibilities consist of providing support and analysis of storage solutions, including best practices for storage engineering and architectural design in an enterprise environment. Install and configure new storage solutions, including CommVault and EMC products and display knowledge of virtualization products. Work at the enterprise level with systems administrators, and database administrators in determining disk storage allocation, backup and restore requirements, and redundancy needs. Evaluate new hardware and software management solutions.
Knowledge of EMC storage solutions and the ways to store, protect, and optimize information.
Familiar with the design and deployment of large scale storage environments.
Microsoft Exchange and Active Directory skills.
CompTIA Security + or equivalent (no exceptions).


Although, there has always been, some degree of partisanship, when it comes to American politics, in recent times, we have to wonder, and consider, why has our politics, become, so progressively, PARTISAN? In the past, politicians disagreed, contended, and perceived things differently, however, in the huge majority of cases, hunted, to seek, a meeting – of – the – minds, for the common good, which seems lacking, these days! Chris Matthews' first book discussed, how, Speaker of the House, O'Neill, and President Reagan, who had been on nearly opposite poles of the political spectrum, stayed, friends, despite those differences, which allowed the possibility of making a deal, for the sake of the country. We appear to be witnessing, now, a period, where this debate, has become private, as well as political, and, instead of the typical empty rhetoric and claims, has brought with it, a polarizing, negative, vitriol, which seems to make common ground, almost unachievable. With that in mind, this article will try to briefly, consider, analyze, review, and discuss, using the mnemonic strategy, how this affects us, and why we want a return, to open discussions, and some possibility of bi – partisan, compromise.
1. Priorities; coverage; public: Although many will always disagree, there should be certain, fundamental priorities, which they can agree on. These should be based on strengthening the freedoms, rights, and liberties, mentioned, implied, and, supposedly, ensured, by our Constitution. Unfortunately, even in these areas, the unprecedented, vitriol, and appeal to the, them, mindset, has made, attaining necessary, quality public policy, nearly unachievable!
2. Attitude; ability; attention: We want leader, with a true, positive, can – do, mindset, who seek solutions, as opposed to making empty promises! Our President, is reported, to be reluctant, and not ready to, develop the aptitude, and skill – set, which might make him better equipped! Beware of, where a politician dedicates all his attention!
3. Relevant; realistic; rationale/ rationale: We should be concerned, when over one – third of the American people, supports somebody, who proceeds, with the motto, Make America Great Again, rather than seeking a relevant, realistic approach, and workable solution! Examine someone's rationale, in explaining their rationale, and focus upon, whether it is in the best interests of all Americans!
4. Timely; true; tendencies: Beware of the good old days, approach, because times change, and we need leaders, ready to evolve, with an open – mind, and the strength to introduce timely plans, and proposals! When fact – checkers proclaim, our President has made significant misstatements, over six times, per day, rather than articulating a true, focused message, and taking advantage of significant trends, our system needs fixing!
5. Ideas; ideology; creativity; Alamo Heights Wildlife Removal, integrity: This is the time for quality ideas, which align with the core ideology, which America has ever represented! As opposed to electing the same – old, same – old, politicians, we will need to be led, by individuals, with relevant imagination, and a commitment to absolute integrity!
6. Service; system; sustainable solutions: Unless/ untilour leaders emphasize service to those they represent, rather than only, their own personal/ political agenda, and self – interest, we will challenged, to proceed, using a system, which will bring forth, a truly, sustainable solution!
Enough of the PARTISAN bickering, and let's try, to see the perspective of those we disagree with, and seek, a meeting – of – the – minds, for the common good!


Atal pension yojana with an objective of providing monthly pension to the citizens from unorganized sector of India was declared during the union budget of 2015-2016. The condition is that the citizen should not have any other formal pension benefits. The scheme aims to generate corpus for retirement.
Once all the details are entered correctly, you need to mention – date, place and provide signature/thumb impression. If you are a male, provide left thumb impression. If female, provide right thumb impression.
Keep this acknowledgement slip with proper care as you might need it any time in the future. Best is to take a picture and store it as a soft copy. Read more about the features of APY.
If someone is a subscriber of Swavalamban scheme then that individual would be automatically migrated to Atal Pension Yojana unless they opt out.
I would like to ask you My age is 14th April 1974 can I join this scheme ?
great job by modi & his company, it is useful for future for downtrodden people.
If subscriber death occure during contribution period and if after 60 year then will nominee get insurance?


Remember when we used to rent movies at the video store? Ah, the eighties and nineties were a fun time.
I laughed, but the really funny thing is that Blockbuster Video is alive and well here in Alaska. I'm not kidding.
I took the twins there last Friday. Really.
They've never been to a video store, so they were very excited.
It's almost like going back in time.
Then there's the fact that about half of the radio stations here are playing "classic" 80's rock. I can close my eyes and be back in the middle of 1990.


Sterling Silver Wide Buckle Hoop Earrings!
Sterling Silver Wide Buckle Hoop Earrings with click latch!
Please be aware that the actual product might have slight variations in color. This is due to the light and monitor resolution.


I am so glad that the Lord is not complex. He keeps it simple! Rest in this: there is simplicity in Christ.
Sometimes, we are tempted to think that if we don't understand all of the Greek, Hebrew, theological arguments, historical context and every hermeneutical law of Biblical interpretation, we won't be able to understand the deep things of God. But, that's not the case. In fact, Jesus did not intend to be confusing. The religious people of His day, the doctors of the Law, the Pharisees and Sadducees tried to muddy the waters and make God formal, religious and mystifying, but we know Jesus ruined that whole philosophy. He keeps it simple. God always meets us right where we are at.
When you start to get worked up about how much you know or how deep you can go, remember this -- Jesus is a Person, not a subject. He's personal, not a research project.
The beauty of the Lord is that He makes the most wisdom-laden realities – simple! Take redemption, for example, when you study God's eternal plan for man it's absolutely amazing. But, even if you don't fully understand all the mechanics of your Great Salvation, you can still enjoy the experience of all that redemption means. You can have a personal, life-filled relationship with the Lord God Almighty. Jesus is our Redeemer. We know Him and that's enough!
Think about it this way. Perhaps, you don't understand all the inner workings of the engine in your car. You might think that pistons, carburetors and mufflers sound like a great new salad. Good news – you don't need to know all the mechanics, just enjoy the simplicity of putting your key in the ignition and driving to your desired destination!
If you've tried to make the whole Christian thing too complex and confusing, I hope you can take a deep breath and relax in this revelation a little bit today. You don't have to impress anyone with deep theological speak; just take pleasure in the reality of your personal relationship with the Lord – in all of its simplicity!
Say This: "Father, I am so glad that You've made it simple. Jesus, today I am not going to worry about all the things I don't know or understand -- instead, I am going to focus on enjoying the simplicity of just knowing You as my Lord and very best friend. In Jesus' Name. Amen."


Lexmark PRESCRIBE Emulation Card for Lexmark MX711, MX810 Printers.
Install this Lexmark Card and enable printing of the Kyocera PRESCRIBE data stream on you Lexmark network printer. This Lexmark PRESCRIBE Emulation Card is designed to be a substitution for a Kyocera printer where the Kyocera PRESCRIBE printer language is used.


text:
GENRE | Jennifer Lawrence's Nightmare – 'Mother!'
"I'm just going to start the apocalypse."
Idiosyncratic filmmaker Darren Aronofsky returns to female-focused, horror-tinged psychological thrillers (sort of) with actress Jennifer Lawrence in the totally batsh*t crazy Mother! Aronofsky's film is nearly indescribable, if often exhilarating in its audaciousness. It's essentially a sort of fever dream allegory of creation involving biblical themes as the writer/director constructs his latest as a series of madcap sequences centred on one woman's descent into complete nightmarish destruction inside her doomed home.
Javier Bardem co-stars as possibly the world's worst husband. He's a frustrated, self-obsessed poet desperate for adoration who welcomes the presence of a series of mysterious and increasingly unwelcome houseguests. Their May/December relationship and Lawrence's seemingly blind, undying love and devotion play into the intriguing thematic tension of the characters.
A very off-putting Ed Harris and truly devilish Michelle Pfeiffer put Lawrence's unnamed protagonist through a series rude situations as said guests exasperate her and the audience to no end. The carefree tension and breaking down of social norms is almost as frightening as the later acts of defiant violence.
It's almost unbelievable this film was made by a major studio in today's age. Lawrence's performance is both restrained and passive yet bravely visceral as the absurd destruction around her escalates. The religious plot points and bizarrely brazen references to Christ, Eden, Cain and Able, plagues, and sacrifice are incredibly audacious. You have to see it to believe it despite the extreme discomfort many will no doubt feel.
Regular cinematographer Matthew Libatique frames most of the film in closeup shots, many following Lawrence, as an intimate portrait of maddening isolation even when she's surrounded by throngs of people doing all sorts of crazy things. We get to know the intimate horrors of every inch of the isolated house which the film never leaves.
Mother! puts all of Aronofsky's talents and artistry to use and is an extreme encapsulation of his entire body of work. It uses the surreal and his sometimes frustrating yet dazzling style to execute a contemporary epic set in a single location from one character's point-of-view. Lawrence is game but almost left bare with the insane material she's given. It's a film that begs endless discussion but likely to infuriate most audiences.
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Tags | 2017, movie review, movies, review


R. and Usha Sundar have transport their family's love of basketball to India!
The couple, who hail from San Francisco, California, have developed a basketball program in villages to help underprivileged children through their Hi 5 Youth Foundation. Their work is making such an impact that the NBA just featured the couple and their non-profit on their platform.
Sports like cricket, hockey, and badminton have immense popularity in India, but basketball has yet to leave its mark on the nation. The Sundar's were inspired by their sons' passion for the sport and how it brought them together as a family when they watched games together. One of the core goals of their foundation is to increase socialization among children.
The non-profit foundation's motto, "hopes through hoops," has proven to be a powerful message. In tribal areas, girls often drop out of school early and marry while boys take on menial labor jobs to help run their home. The skills the children obtain through basketball includes how to work together, to be goal-oriented, to be motivated, to work hard and it has built their self-confidence.
The Sundar's team of coaches and teachers report that the children in their schools are doing better academically and working faster than the children in city schools. Currently, the school is attended by 1200 students across 13 schools, 1 YMCA center, and 1 residential school. Each center has its own full-time coach training the students from beginner to elite levels. The program even brings on talented interns from India and America to coach, as well.
They all follow a structured curriculum that teaches children equality, confidence, social skills, and leadership skills along with the logistics of the game. The students are also tested periodically and tournaments are held to measure their skills.
When Hi5 interns do sessions at our basketball center the Hi5 children are energized much more. Our interns Akhila Ramgiri from California and Shaan Navani from ASB(American School Bombay) are totally involved. The smiles and energy of the children are always Hi5.
Click here to learn more about this phenomenal foundation and find out how you can help the cause!


NICOLE MITCHELL (contralto) is a proud native of Brooklyn, NY. She has performed regularly with American Opera Projects and The Walt Whitman Project promoting the works of new composers. She has performed at Carnegie Hall's Zankel Hall, Avery Fisher Hall and with New York City Opera, Sarasota Opera, Piedmont Opera, Lincoln Center Festival and abroad in Teatro di San Carlo, Landestheater in Linz, Austria and at the Festival de Wiltz in Luxemburg. Earlier this year, Nicole appeared in the world premiere of Stefan Weisman's opera The Scarlet Ibis as part of the Beth Morrison Projects' and HERE ARTS CENTER production at the PROTOTYPE Festival. Last year she sang the role of the Old Woman in David Lang's The Difficulty of Crossing a Field (Beth Morrison Production)and recorded the role, released in June on iTunes and Amazon. Her concert work as alto soloist includes Verdi's Requiem, Brahms' Alto Rhapsody, Mozart's Requiem, Beethoven's Ninth Symphony and Choral Fantasy, Handel's Messiah and Rossini's Stabat Mater. Nicole has enjoyed the past four seasons as part of the acclaimed Riverside Choir. Nicole is THRILLED to return to Ojai Youth Opera for her fourth season as a guest teaching artist where she has delighted in passing on her love and passion for performing classical music to a younger generation.


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Sasha Czack Agr, Bio, Married, Son, Ex-wife, Husband, Profession, Affair, Height, Net Worth
Sasha Czack
Sasha Czack net worth: $4 million
Sasha Czack Height: 4 feet 11 inches
Sasha Czack Weight: 52kg
Sasha Czack was born on Sasha Czack in Chester, Pennsylvania, United States of America. Her complete name is Alexandra Jane Czack but she is more famous as Sasha Czack and Stitch. She graduated in media studies from the University of Notre Dame du Lac. She was interested in photography and acting from her childhood that's why she precedes her career in this field. She is famous for her Photography and acting skills, she is also working as a talented director in Hollywood. She married twice in her life but it went the wrong t as she got divorced after a few years twice. She has two children naming Sage Stallone and Seargeoh Stallone.
Complete Name: Alexandra Jane Czack
Nick Name: Sasha Czack, Stitch
Born At: Chester, Pennsylvania, United States of America
Height: 04 feet 11 inches
Marital Status: Divorced from Sylvester Stallone in 1985 and Richard Ash in 1999
Kids: Two (Sage Stallone and Seargeoh Stallone)
Education: University of Notre Dame du Lac
Ethnic background: North American
Profession: Actress, Director, Photographer
Source of wealth: Photography, Acting
Sasha was born to a North American family and her ethnicity is Caucasian. She has not revealed about her parents and siblings but she told that her childhood was beautiful and her parents supported her in every matter. She got early education from the community school Chester and later she moved to St John's senior high school for her higher studies. From here college age she was interested in acting and chose to pursue her studies in media studies. She graduated in media studies from the University of Notre Dame du Lac.
Sasha was passionate about acting from her college-age and after graduating from the University of Notre Dame du Lac in media studies she started her career in acting. She is a professional photographer too and she has also started photography as her professional career. Apart from acting and photography, Sasha is a well-known director as well, she as directed many famous Hollywood movies.
Sasha was a very slim and beautiful lady when she was young, she still is beautiful but when she was young she was a Barbie. He had many offers but she chose Sylvester Stallone as her husband in 1974. The couple remained a happy couple for a long time but they also had severe issues later. The couple had two sons Sage Stallone and Seargeoh Stallone, Sage died in his teenage and his death is a mystery, there are rumors about his death some people say he died due to over dose of drugs but his family claimed that he had suffered from heart disease. Sasha and Sylvester divorced in 1985 and she again tied the knot with Richard Ash in 1997 but after a couple of years, the couple divorced.
Sasha is a fancy woman from her teens she has lived her life with style. She lived with Sylvester who has a net worth of over $250 million. She lives in a Villa and owns different luxury cars.
Sasha is a small, slim and beautiful woman. Due to her small appearance, people use to call her Barbie. Her height is 4 feet and 11 inches and she weighs 52 kg. The color of her hairs is a natural blonde and her eyes are brown naturally.
Sasha Czack net worth is $4 million. She has earned money from her acting career, directing movies and her photography skills.
Sasha Czack was born on Sasha Czack in Chester, Pennsylvania, United States of America. Her complete name is Alexandra Jane Czack but she is more famous as Sasha Czack and Stitch.


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Small Business | USAGov
Generally, a smaller enterprise is extra versatile, whereas bigger businesses, or these with wider possession or more formal constructions, will often tend to be organized as firms or (much less often) partnerships. In addition, a business that needs to lift cash on a inventory market or to be owned by a wide range of individuals will typically be required to undertake a selected authorized type to do so. The term is also often used colloquially (but not by lawyers or by public officials) to discuss with a company. A firm, on the other hand, is a separate legal entity and provides for restricted liability, in addition to corporate tax rates. A company structure is more sophisticated and costly to arrange, however offers more protection and benefits for the proprietor.
The definition of a father or mother company differs by jurisdiction, with the definition usually being outlined by means of laws coping with firms in that jurisdiction. Coronavirus outbreak hits Beijing small businessesThe BBC's Stephen McDonell visits buying areas in Beijing to see if the virus is having an effect. A move-through entity is a authorized enterprise entity that passes revenue on to the house owners and/or investors of the enterprise. Businesses that have gone public are subject to rules regarding their internal governance, corresponding to how govt officers' compensation is determined, and when and the way data is disclosed to shareholders and to the general public. In the United States, these laws are primarily carried out and enforced by the United States Securities and Exchange Commission (SEC).
Accounting is the measurement, processing, and communication of economic details about economic entities corresponding to businesses and companies. The fashionable subject was established by the Italian mathematician Luca Pacioli in 1494. Accounting, which has been known as the "language of business", measures the results of a company's economic actions and conveys this info to a wide range of customers, including investors, creditors, administration, and regulators. The phrases "accounting" and "monetary reporting" are sometimes used as synonyms. A mother or father firm is an organization that owns enough voting stock in one other firm to manage management and operations by influencing or electing its board of directors; the second firm being deemed as a subsidiary of the father or mother firm.
Local jurisdictions may require special licenses and taxes simply to function a business. In most countries, there are legal guidelines which deal with small firms in a different way from massive ones.
Many international locations are signatories to worldwide treaties concerning intellectual property, and thus firms registered in these countries are topic to national legal guidelines bound by these treaties. In order to protect trade secrets and techniques, firms could require employees to sign noncompete clauses which can impose limitations on an employee's interactions with stakeholders, and opponents. General partners in a partnership (aside from a restricted legal responsibility partnership), plus anybody who personally owns and operates a enterprise with out making a separate authorized entity, are personally responsible for the debts and obligations of the enterprise. Business sizes vary from small proprietor-operated companies, similar to household eating places, to multinational conglomerates similar to General Electric. In this case, the company is publicly traded and has reporting and operating restrictions.
The Morning Risk Report: Supreme Court Justices Indicate They May Narrow SEC's Enforcement Authority
Service companies supply intangible goods or companies and sometimes charge for labor or other services provided to government, to shoppers, or to different companies. Interior decorators, beauticians, hair stylists, make-up artists, tanning salons, laundromats, dry cleaners, and pest controllers are service companies.
UN agency: Iran practically triples stockpile of enriched uranium
Many businesses are operated via a separate entity similar to a corporation or a partnership (both formed with or without limited liability). Most authorized jurisdictions allow folks to prepare such an entity by submitting sure charter documents with the related Secretary of State or equivalent and complying with certain different ongoing obligations. The relationships and legal rights of shareholders, restricted partners, or members are ruled partly by the constitution paperwork and partly by the legislation of the jurisdiction the place the entity is organized.
It is also essential to determine the legal construction of the enterprise. Depending on the kind of business, it could have to safe permits, adhere to registration requirements, and procure licenses to legally function. In many countries, companies are considered to be juridical individuals, that means that the business can personal property, take on debt, and be sued in court docket. A business is outlined as an organization or enterprising entity engaged in industrial, industrial, or professional activities.
In latest many years, states modeled some of their assets and enterprises after business enterprises. In 2003, for instance, the People's Republic of China modeled 80% of its state-owned enterprises on a company-sort management system. Many state establishments and enterprises in China and Russia have remodeled into joint-inventory firms, with a part of their shares being listed on public inventory markets.
It just isn't exceptional for certain kinds of company transactions to require a team of five to ten attorneys as a result of sprawling regulation. Some companies are topic to ongoing special regulation, for example, public utilities, investment securities, banking, insurance, broadcasting, aviation, and health care providers.
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Moms share their highs and lows for World Breastfeeding Week
Whether your baby latches easily, or pumping is difficult, or you find formula is the way to go, moms agree: nursing is different for everyone.
July 31, 2019, 9:05 PM UTC / Updated July 31, 2020, 8:38 PM UTC / Source: TODAY
August is National Breastfeeding Awareness Month, and each mom has a unique story. For some lucky women it's a breeze and for others, it feels like an insurmountable challenge. To kick off the yearly event, TODAY Parents profiled the journeys of six spectacular mamas.
I breastfed and I loved it!
Micol Zimmerman-Burkeman was blessed with a healthy milk supply and both of her kids latched easily. "I loved the intimacy of breastfeeding," the Massachusetts-based education consultant told TODAY Parents. "During the daily grind of parenting, especially with a newborn, it is easy to fall into auto-pilot simply trying to get through the day. But that time with them, especially at night, allowed me to be fully present with them."
Micol Zimmerman-BurkemanCourtesy of Micol Zimmerman-Burk
Aura SkigenCourtesy of Rick Skigen
Aura Skigen of Arlington, Virginia, had a similar experience. The physical therapist and influencer for EVER Skincare exclusively breastfed her two sons until they were 17 months.
"I loved the chance to bond with my babies," Skigen, 40, said. It was also a chance for Skigen to forget about grocery lists, chores and exercise. "As a new mom, I tried to do it all," she said. "Breastfeeding allowed me to really enjoy one-on-one time with my boys."
Watch TODAY All Day! Get the best news, information and inspiration from TODAY, all day long.
Breastfeeding was hard — but I persevered!
Jen Saxton, CEO and founder of Tot Squad, overflowed a bottle the first time she pumped. "The nurses at the hospital said I had enough milk to feed the whole world!"
Saxton's oversupply has led to multiple clogged ducts and a painful case of mastitis. "I remember at Mommy and Me class how everybody would describe their beautiful baby staring into their eyes while breastfeeding, and Charlotte was literally choking with my fast letdown."
Though breastfeeding is "all consuming" and the LA.-based mom loathes pumping, she is proud of what her body can do. "I love that we can go anywhere and forget everything and as long as we have each other, we're good to go," Saxton, 36, said.
Jen SaxtonCourtesy of Kern Saxton
Colleen Kurson.Colleen Kurson
While Saxton has an overabundance of milk, Colleen Kurson had the opposite problem. When Kurson's first child was born in 2012, she struggled with production despite pumping between feeds.
"I hated that my body wasn't doing what I was thought it was 'supposed' to do," the licensed mental health counselor told TODAY Parents. Things got easier when Kurson began supplementing with formula and her baby began gaining weight. "I saw it as vital to my newborn's health and and was glad to take some of the pressure off," she explained.
Parents'I thought it would be easy': When breastfeeding is the hardest thing ever
Though breastfeeding was "never a great experience" for Kurson, and she dreaded nursing in public, all three of her girls received breast milk for at least four months. "I stuck with it because I wanted to," she said. "But I'm so glad it's behind me."
I didn't breastfeed and I don't feel bad about it (and you shouldn't either)!
Breastfeeding may be natural, but it doesn't always come naturally. Just ask Kristen Barry. "I simply did not enjoy having another human being stuck on my nipples until they bled. It was uncomfortable and I dreaded every feeding," the freelance editor from Long Island, New York, told TODAY Parents. "I began to resent my son for wanting to eat. All I did was cry.
Kristen BarryCourtesy of Kristen Barry
Joey BartolomeoCourtesy of Joey Bartolomeo
Ten days into motherhood, Barry, 37, mixed a bottle of formula and never looked back. "When I told my husband, 'I can't do this anymore,' he was beyond relieved," she recalled. "He saw what the pressure was doing to me. I don't know who was more relieved — him or me."
She did not even attempt to breastfeed her second child.
Joey Bartolomeo can relate to what Barry went through. Bartolomeo broke down in a pediatrician's office after her son, Tully, was born in 2014.
"She asked how feeding was going and I started crying," the Manhattan-based writer told TODAY Parents. Bartolomeo's milk had not yet come in and Tully was having issues latching.
"I felt a bit like a failure right off the bat," she revealed.
ParentsBreastfeeding isn't always easy: Here are answers to commonly asked questions
At the suggestion of Tully's doctor, Bartolomeo rented a hospital grade pump, loaded up on breast shields and enlisted the help of a lactation consultant. But nothing seemed to work.
"Feeding times were very stressful for me, the baby and everyone who was around," Bartolomeo, 45, said.
Bartolomeo stopped breastfeeding after a week and gave up pumping soon after. "There are so many of us who can't do it, and that's OK. We need to tell each other that. Our babies are being fed and that's what matters," she told TODAY Parents. "That is the message I like to pass on to all of my friends when they become new moms."
Modern Motherhood: What nobody tells you about breastfeeding
April 30, 201910:31


Transit Systems is pleased to become a member of Hydrogen Mobility Australia. Hydrogen Mobility Australia's vision is a hydrogen society built upon clean and renewable energy technology, including hydrogen powered transport. We are pleased to join a collection of vehicle manufacturers, oil & gas companies, infrastructure providers, research organisations, financial institutions and governments with a mission to make this hydrogen vision a reality.


Watch Running on Empty (1988) : Full Movie on FMovies The Popes are a family who haven't been able to use their real identity for years. In the late sixties, the parents set a weapons lab afire in an effort to hinder the government's Vietnam war campaign. Ever since then, the Popes have been on the run with the authorities never far behind.


Join Lynn Langit for an in-depth discussion in this video About using cloud services, part of AWS for DevOps: High Availability and Elasticity.
- [Instructor] As we're getting started with this course, I want to add a caveat that I add to all of my Cloud courses. We are going to be working with live AWS accounts and services, and although my demonstrations will use services at levels that will incur little or no cost, depending on whether and how you replicate the exercises that I show in this course, there is a potential that you could incur service costs. So it's very, very important that when you're working with any Cloud vendor and learning that you remember that when you're done with services to shut them off and/or delete them so that you don't get a surprise bill at the end of learning.


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Home » Poem of the Pillow and Other Stories By Utamaro, Hokusai, Kuniyoshi, and Other Artists of the Floating World (Hardcover)
Poem of the Pillow and Other Stories By Utamaro, Hokusai, Kuniyoshi, and Other Artists of the Floating World (Hardcover)
By Gian Carlo Calza
Gian Carlo Calza is Professor of East Asian Art History and Director of the International Hokusai Research Centre at the University of Venice. A distinguished authority on Japanese art, he has published many books and articles on several artists, including Phaidon's monograph Hokusai (2003), as well as Phaidon's Ukiyo-e (2005) and Japan Style (2007).
Publisher: Phaidon Press
Publication Date: September 22nd, 2010
Art / Subjects & Themes / Erotica


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Time to Revise America's Cuban Immigration Policy
January 21, 2015 Topic: ImmigrationInternational LawForeign Policy Region: CubaUnited States
"To encourage Cuba to improve its human-rights record and commitment to the rule of law, the United States must lead the way by bringing its own policies toward asylum-seekers into compliance with international law."
by Jill Goldenziel
As a high-level U.S. delegation travels to Havana for talks on migration today, the United States must revisit its outdated policies regarding migrants from Cuba. U.S. Coast Guard interceptions of Cuban migrants have risen by 117 percent since the two countries announced that they would normalize relations last month. The United States must revise its policies to both discourage migration and comply with international human-rights law. To do otherwise would be both a human-rights travesty and tremendous hypocrisy by a nation that wants Cuba to improve its commitment to human rights.
Since 1995, the U.S. has maintained a "wet foot, dry foot" policy toward Cuban migrants. Any Cuban intercepted by the U.S. Coast Guard in the waters between the two countries may be returned to Cuba. Cubans who make it to U.S. shores, and therefore have "dry feet," are expedited for permanent resident status in the United States. Cubans who can cite a specific fear of persecution on the basis of political opinion or other grounds specified in U.S. and international law will be brought to the United States for further evaluation of their asylum claims. This policy was adopted after the Balseros crisis of 1994, when Fidel Castro lifted restrictions on those leaving the island and thousands of Cubans attempted to sail to Florida. The United States claims that this policy discourages Cuban migration, while the Cuban government says that it does just the opposite.
U.S. policy, however, may violate international law. International law requires that refugees may not be sent back to a place where his or her life will be endangered. This principle of international law is so strong that it is considered a peremptory norm that no nation can violate. Despite this, the U.S. Supreme Court has held that Caribbean migrants intercepted at sea may be returned to their countries of origin without determination of whether they have legitimate fear of persecution. Presidents from Clinton to Obama have intermittently directed the Coast Guard accordingly. U.S. policies toward Caribbean migrants have been heavily criticized by other countries and are widely viewed as incompatible with international human-rights law and the practices of other civilized nations.
Sending migrants back to Cuba would violate international law if they will be endangered at home. Illegal immigration remains a crime under Cuban law. Since 1994, Cuba has agreed not to take legal action against those who attempt to emigrate, so long as they do not face other criminal charges. In practice, the U.S. State department has found that many of those who attempt to leave the island experience harassment and discrimination by the Cuban government.
How can the Washington both discourage Cubans from migrating to the United States and comply with its obligations under international law? First, the United States must screen any Cuban who it intercepts in the Caribbean and who claims to have a specific fear of persecution based on her political opinion. If the migrant is found to have left Cuba for purely economic reasons, he may be legally returned to Cuba, so long as he will not be endangered there. Second, the United States must receive guarantees from Cuba that it will not persecute Cuban citizens who try to leave the island. If the United States cannot receive appropriate guarantees, or if Cuba mistreats those who attempt to leave, the United States must find a way to ensure the safety of any migrants that it intercepts. These migrants must be accommodated inside the United States or in a third country until the Washington can ensure that they can be safely returned to Cuba or given legal protection elsewhere. The United States need not give these Cubans a path to citizenship, but it must ensure that they are not sent to a place where they will be harmed.
Clarifying U.S. policy on Cuban migration will discourage Cubans from migrating for purely economic reasons. It will also ensure that the U.S. government complies with international law. To encourage Cuba to improve its human-rights record and commitment to the rule of law, the United States must lead the way by bringing its own policies toward asylum-seekers into compliance with international law.
Jill Goldenziel is a Lecturer in Government at Harvard University and a Research Fellow in the International Security Program at the Belfer Center for Science and International Affairs at Harvard Kennedy School. She is also a Visiting Assistant Professor of Law at the Boston University School of Law.