Compositions containing and methods employing, as the essential ingredient, anthrone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions are also disclosed. Anthrone-2-carboxylic acid and 7-methoxyanthrone-2-carboxylic acid are illustrated as representative of the class.
The present invention is directed to anthrone carboxylic acid compounds and to compositions containing and methods utilizing these compounds as the essential ingredient in the treatment of symptoms associated with allergic manifestations, for example, asthmatic conditions.
In a first aspect, the present invention relates to novel anthrone carboxylic acid compounds selected from those represented by the following formulas: ##SPC1##
And the pharmaceutically acceptable, non-toxic esters, amides and salts thereof; wherein one of R 1 and R 2 is hydrogen and the other of R 1 and R 2 is a lower alkyl group or each of R 1 and R 2 is a lower alkyl group or R 1 and R 2 taken together is ethylene, 1,3-propylene, 1,4-butylene, or 1,5-pentylene;
R 3 is lower alkyl, lower alkoxy, cycloalkyl, cycloalkoxy, hydroxy or a conventional ester thereof, mercapto, lower alkylthio, trifluoromethyl, or a group of the formulas: ##SPC2##
In which n is the integer 1 or 2, R is lower alkyl when n is 1 and R is lower alkyl, hydroxy, amino, monolower alkylamino, or dilower alkylamino when n is 2; and
R 4 is hydrogen, halo, or a group defined by R 3 .
In the above depicted formulas, "alkyl" is lower alkyl.

The acid esters of the anthrone-2-carboxylic acids hereof are prepared upon treatment of the acid with ethereal diazoalkane such as diazomethane and diszoethane or with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature or with the desired lower alkanol in the presence of a trace of sulfuric acid at reflux. The glycerol esters are prepared by treating the acid with thionyl chloride followed by treatment with a suitably protected ethylene glycol or propylene glycol (e.g., solketal) in pyridine, and hydrolyzing the protecting group of the esters thus formed with dilute acid.

The amides of the anthrone-2-carboxylic acids hereof are prepared by treatment of the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl, amine, dialkyl amine, dialkylaminoalkylamine, alkoxyalkylamine, or phenethylamine.

The salts of the anthrone-2-carboxylic acids hereof are prepared by treating the corresponding acids with pharmaceutically acceptable base. Representative salts derived from such pharmaceutically acceptable bases are sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, ferric, zinc, maganous, aluminum, manganic, the salts of trimethylamine, triethylamine, tripropylamine, β-(dimethylamino)ethanol, triethanolamine, β-(diethylamino)ethanol, arginine, lysine, histidine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl glucamine, theobromine, purines, piperazine, piperidine, polyamine resins, caffeine, procaine or the like. The reaction is conducted in an aqueous solution, alone or in combination with an inert, water miscible organic solvent, at a temperature of from about 0°C to about 100°C preferably at room temperature. Typical inert, water miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane, or tetrahydrofuran. When divalent metal salts are prepared, such as the calcium salts or magnesium salts of the acids the free acid starting material is treated with about one half molar equivalent of pharmaceutically acceptable base. When the aluminum salts of the acids are prepared, about one third molar equivalent of the pharmaceutically acceptable base are employed.
A mixture of 3.5 grams of anthrone manufacturer , 10 g. of methyl iodide, and 10 g. of lithium carbonate in 75 ml. of dimethylformamide is stirred at room temperature for a period of 18 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant precipitate is filtered off and washed to give methyl anthrone-2-carboxylate.

Lithium metal (0.56 g.) is added to a mixture of 80 ml. toluene and 15 ml. methanol. After stirring at room temperature for 2 hours, 20.2 g. of methyl anthrone-2-carboxylate are added and the mixture is then stirred at 60° for 1 hour. The solvent is evaporated and the lithium salt heated with 25 ml. methyl iodide and 0.4 ml. t-butanol at 150° for 24 hours in a sealed tube. After cooling, most of the methyl iodide is distilled off, the residue taken up in ether, washed with water and the solvent evaporated. The residue is chromatographed on alumina and recrystallized from chloroform/ethanol to give methyl 10-methylanthrone-2-carboxylate.

Methyl 10-methylanthrone-2-carboxylate (4.5 g.) is combined with 150 ml. of 5 percent potassium hydroxide in methanol. The resultant mixture is refluxed for one hour after which time it is acidified, cooled and filtered, to give 10-methyl- anthrone-2-carboxylic acid. Methyl anthrone-2-carboxylate (5.04 g.) is stirred with lithium methoxide (prepared from 0.24 g. lithium metal and 10 ml. methanol) in 80 ml. toluene at 65°C for 3 hours. After removal of the methanol, 3.8 g. 1.2-dibromoethane are added and the mixture is refluxed for 7 hours. The cooled solution is washed with water, the solvent evaporated and the residue chromatographed to give methyl 10,10-ethylene- anthrone -2-carboxylate.

The thus prepared compound is hydrolyzed as described in Example 5 to give 10,10-ethyleneanthrone-2-carboxylic acid.

Likewise prepared through the respective methyl esters are 10,10-(1,3-propylene)- anthrone-2-carboxylic acid, 10,10-(1,4-butylene)- anthrone-2-carboxylic acid, and 10,10-(1,5-pentylene)- anthrone-2-carboxylic acid. A dosage of 100 mg. per kg. of body weight of anthrone-2-carboxylic acid is given intraperitoneally to guinea pigs. Other pigs are left untreated to serve as controls. After treatment, the treated pigs and the controls are exposed to an aqueous spray of 0.05 percent histamine diphosphate (calc. as base), delivered by a nebulizer, until they exhibit a loss of righting ability. During exposure they are observed for severity of reaction. This ranges from slightly deeper breathing to deep breathing to preconvulsive gasping and ataxia to collapse. The pigs which receive the anthrone products exhibit a significant resistance to the histamine aerosol challenge, whereas all control pigs collapse within the exposure time.

 

 

source:freepatentsonline

The present invention relates to a process for converting alcohols, which have heretofore found little or no utility, into ketones which are valuable Pharmaceutical Intermediates   in the preparation of compounds which display potent analgesic

Propoxyphene Propoxyphene hydrochloride is a well known and widely used analgesic. The chemical name for propoxyphene is α-d-1,2-diphenyl-2-hydroxy-3-methyl-4-dimethylaminobutane propionate.

One of the processes for the preparation of propoxyphene comprises reacting a benzyl Grignard reagent with 1-phenyl-2-methyl-3-dimethylamino-1-propanone and acylating the resulting tertiary alcohol with propionic anhydride. The Grignard reaction yields 1,2-diphenyl-2-hydroxy-3-methyl-4-dimethylaminobutane as a mixture of four diastereoisomers, occuring as two racemic pairs or racemates.
A scan of open positions on Internet job boards reveals document control positions as part of an in-house function, such as IT or Quality Assurance, or embedded in the department where specific documents are generated, such as the Legal Department, Research or Human Resources. Jobs are also found in independent firms that provide document management services to companies. Entry-level positions are typically clerical, with progression possible through management level.

Upper-level career path positions are larger in scope, with responsibility for developing and enforcing policies. These are often found in government facilities where knowledge and application of government regulations is required. Job titles include Document Control Administrator; Document Control Coordinator; Document Control Specialist and Director, Records Management.

Document Control positions are found in multiple industries, particularly regulated industries. Examples include construction, healthcare, Pharmaceutical Intermediates , technology, legal, utility, manufacturing and financial as well as government and educational institutions.
In accordance with the usual practice, the less soluble diastereoisomeric pair is designated as the α-dl racemate and the more soluble as the β-dl racemate. In the foregoing process for the preparation of propoxyphene, the α-dl racemate is obtained in about 85% yield. The remainder of the reaction product comprises about 15% of the β-dl racemate which is discarded since this racemate lacks analgesic activity. The α-dl-racemate is further separated into its α-d and α-l components. The α-d component is acylated with propionic anhydride, affording propoxyphene. Some of the α-l isomer is acylated to provide the active ingredient of an anti-tussive preparation, but such use of the α-l isomer does not equal that of the α-d isomer (propoxyhene) in terms of weight of drug used, and substantial quantities of the α-l isomer are discarded yearly.

I have now discovered a new and useful process by which these α-l and β-dl isomers may readily be converted to an Pharmaceutical Intermediate supplier which is useful in the preparation of analgesic substances, including, of course, propoxyphene.
Entry-level document control professionals generally are required to be a high school graduate or equivalent. Pharmaceutical Intermediate and senior levels may require some college or a bachelor's degree.

Acid addition salts of amines refers to the pharmaceutically acceptable nontoxic salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, and the like. Other nontoxic salts include those prepared with organic acids, for example acetic acid, maleic acid, benzoic acid, 2-naphthalenesulfonic acid, and the like.

A strong base refers herein to a base selected from among the group of alkali metal and alkaline earth metal lower alkoxides, aryloxides, hydroxides or hydrides. Lower alkoxides include methoxide, ethoxide, n-propoxide, isopropoxide, n-butoxide and tert-butoxide. Suitable aryloxides include phenoxide and naphthoxide. Typical bases employed in the process of this invention include sodium hydroxide, potassium tert-butoxide, sodium hydride, magnesium hydroxide, calcium hydroxide, barium hydride, sodium methoxide, lithium ethoxide and sodium phenoxide.
The document control worker should have good clerical and organizational skills. Accuracy and attention to detail and good language and reading skills are assets in this position. The successful candidate should possess good computer skills, including the ability to learn and use one or more versions of specialized software. Knowledge and understanding of document control regulations, especially in regulated industries, is required at the supervisory level. Management levels require people management skills, and the ability to develop, implement and enforce policies and procedures.

The Mitsunobu reaction in which a phosphorus compound and an azodicarboxylic acid diester are used to carry out dehydration condensation have been employed as a useful synthetic reaction for producing medical drugs and the like. The Mitsunobu reaction is known as a dehydration condensation reaction between alcohols and a variety of acidic compounds such as carboxylic acid compounds, phenolic compounds, imide compounds, phosphoric acid compounds and hydrogen azide, and it is also known that use of an optically active alcohol as a starting material can provide the desired product as a result of complete stereo inversion (see Non-patent Document 1).

However, known azodicarboxylic acid dimethyl ester, azodicarboxylic acid diethyl ester, and Diisopropyl Azodicarboxylate ester have the following disadvantages.

(1) Since these compounds are liquid at ordinary temperatures, purification by distillation must be performed. However, azo compounds are generally unstable in heat, and it is therefore dangerous to heat these compounds. In fact, it has been demonstrated that caution should be exercised when synthesizing azodicarboxylic acid dimethyl ester and azodicarboxylic acid diethyl ester (see Non-patent Document 2).

(2) For example, when a Mitsunobu reaction in which dehydration condensation is carried out in combination with a phosphorus compound, or an oxidation reaction is performed, 1,2-hydrazinedicarboxylic acid diester is produced as a by-product; this compound is insoluble in water and moderately dissolves in an organic solvent, and therefore, many processes are required to remove or separate this compound from the product.

Therefore, at present, conventional azodicarboxylic acid diester compounds are not industrially advantageous compounds due to the above-described disadvantages.
The present invention solves the above-described problems of the conventional art, and provides an industrially safe and useful azodicarboxylic acid bis(2-alkoxyethyl) ester compound that is useful for the Mitsunobu reaction in which it is used in combination with a phosphorus compound to perform dehydration condensation, and also useful as an oxidizing agent, and a starting material for various synthesis processes. The invention also provides a production intermediate of the above-described compound, and methods for producing these compounds.

As a result of extensive studies for solving the above-described problems, the present inventors found a crystalline azodicarboxylic acid bis(2-alkoxyethyl) ester compound that does not require purification by distillation, and a method for producing the compound. The inventors also found that a 1,2-hydrazinedicarboxylic acid bis(2-alkoxyethyl) ester compound produced as a by-product when using the above-described azodicarboxylic acid bis(2-alkoxyethyl) ester compound in a Mitsunobu reaction in which the azodicarboxylic acid bis(2-alkoxyethyl) ester compound is used in combination with a phosphorus compound to carry out dehydration condensation, or in an oxidation reaction, or the like, dissolves in water and thus can be easily removed, and thereby the present invention was achieved.

More specifically, the present invention provides an Diisopropyl Azodicarboxylate ester compound as shown below, a production intermediate thereof, and methods for producing these compounds.
According to the present invention, an azodicarboxylic acid bis(2-alkoxyethyl)ethyl ester compound represented by formula (1) can be produced more safely and the after-treatment therefor is easier compared with conventional azodicarboxylic acid esters, and it has a comparable reactivity and is thus an industrially highly advantageous compound.

Since conventional azodicarboxylic acid diesters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate are liquid, purification by distillation must be performed. During distillation, heat is applied, and thus there is a danger of explosion caused by thermal decomposition, for example. In contrast, the azodicarboxylic acid bis(2-alkoxyethyl)ethyl ester compound represented by formula (1) is crystalline, and thus can be produced industrially safely without the need of purification by distillation.

In addition, the azodicarboxylic acid bis(2-alkoxyethyl)ethyl ester compound represented by formula (1) falls under the category of Type 5 hazardous materials (self-reacting materials) under the Japanese Fire Service Act, and therefore may be dissolved before shipment in an organic solvent at a ratio such that the quality of the compound is not reduced, thereby increasing the safety to about the same level as that of general purpose organic solvents which fall under the category of Type 4 hazardous materials (flammable liquids) under the Japanese Fire Service Act. In this case, examples of organic solvents include ether-based solvents, ketone-based solvents, nitrile-based solvents, aliphatic solvents, aromatic solvents, and halogen-based solvents. Examples of the ether-based solvents include diethyl ether, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran, dioxane, and cyclopentyl methyl ether, examples of the ketone-based solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone, examples of the nitrile-based solvents include acetonitrile, examples of the aliphatic solvents include hexane, heptane, cyclohexane, and octane, examples of the aromatic solvents include toluene, xylene, benzene, and mesitylene, and examples of the halogen-based solvents include dichloromethane and chloroform. However, examples are not limited to these.

There are Pharmaceutical Intermediates  of the azodicarboxylic acid bis(2-alkoxyethyl)ethyl ester compound represented by formula (1) as represented by the following formulae.

When a Mitsunobu reaction, which causes dehydration condensation, or oxidation reaction is performed using a phosphorus compound and an azodicarboxylic acid bis(2-alkoxyethyl)ethyl ester compound represented by formula (1), a 1,2-hydrazinedicarboxylic acid bis(2-alkoxyethyl)ethyl ester compound represented by formula (3) is generated as a by-product. This by-product dissolves in an amount of 0.55 g per mL of water (22° C.), and thus can be removed simply by washing the extraction solvent with water. Therefore, the by-product can be removed more easily than in the case of conventional azodicarboxylic acid diesters.

Accordingly, in the case of a Mitsunobu reaction product obtained in this manner, the by-product can be removed simply by washing the extraction solvent with water. Mitsunobu reaction products obtained in this manner may be applied to, for example, medical drugs, physiologically active natural products and the like.After triphenylphosphine (566 mg, 2.16 mmol), (2R,4R)-2,4-pentanediol (225 mg, 2.16 mmol), and THF (6 ml) were added to a 50 mL flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.13 mL, 2.16 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C. Subsequently, 4-nitrobenzoic acid (300 mg, 1.80 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour.

 Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 593 mg of a pale yellow solid substance. Measurement of 1H-NMR showed that 379 mg of (4S,2R)-4-(4-nitrobenzoyloxy)pentane-2-ol (yield: 83%/4-nitrobenzoic acid), and 213 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.

 

 

from:freepatentsonline

The present invention relates to an isomerisation method of vitamin D analogues, such as compounds useful for the synthesis of calcipotriol, and to and to the use of a flow-through photoreactor or continuous flow photoreactor reactor for making said vitamin D analogues. The present invention relates further to the use of Pharmaceutical Intermediates produced with said method for making calcipotriol or calcipotriol monohydrate, or pharmaceutical formulations thereof.

Nearly every large pharmaceutical company has a pharmaceutical research and development department. In addition, private laboratories work towards pharmaceutical research and development on a regular basis. The goal of this type of research is to develop newer and more effective treatments for a number of different ailments.

The present invention relates to an isomerisation method of vitamin D analogues useful for the synthesis of calcipotriol {(5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22 -tetraene-1α-3β-24-triol}, and to the use of a flow-through or continuous flow photoreactor for making said vitamin D analogues. The present invention relates further to the use of intermediates produced with said method for making calcipotriol or calcipotriol monohydrate, or Pharmaceutical Intermediates thereof.

While it's true that there are effective treatments for many illnesses, this is not the case with every condition. Some people suffer from diseases that do not have any therapeutic choices. Thus, these people must follow a drug routine that may not be beneficial. Through pharmaceutical research and development, these illnesses may have viable treatments in the future. In addition, some pharmaceutical companies also work towards creating better medications than the ones that already exist.

Often, Pharmaceutical Intermediate research and development leads to scientific breakthroughs that can mean the elimination of an illness. While this is rare, without pharmaceutical research and development, cures to ailments would never be discovered. Each laboratory works towards perfecting existing medication as well as finding a cure for incurable illnesses.
Calcipotriol or calcipotriene (structure I) [CAS 112965-21-6] shows a strong activity in inhibiting undesirable proliferation of epidermal keratinocytes [F. A. C. M. Castelijins, M. J. Gerritsen, I. M. J. J. van Vlijmen-Willems, P. J. van Erp, P. C. M. van de Kerkhof; Acta Derm. Venereol. 79, 11, 1999]. The efficiency of calcipotriol and calcipotriol monohydrate (I-hydrate) in the treatment of psoriasis was shown in a number of clinical trials [D. M. Ashcroft et al.; Brit. Med. 3. 320, 963-67, 2000] and calcipotriol is currently used in several commercial drug formulations.  embedded image

In the preparation of calcipotriol, the (Z)-stereochemistry for the double bond at C-5 is necessary for full expression of the biological activity. In the previously disclosed process for making calcipotriol I, the hydroxyl protected Pharmaceutical Intermediate IIaaa with (E)-stereochemistry at C-5 is photoisomerised in an unspecified process on a laboratory scale using anthracene as a photocatalyst to give the corresponding (Z)-isomer IIIaaa followed by the removal of the silyl protecting groups to give calcipotriol I [WO 87/00834, M. J. Calverley; Tetrahedron, 43 (20), 4609-19, 1987; E. Binderup, Drugs of the Future Vol. 15, No. 1, 1990, “Calcipotriol”, M. P. Folkmann, Ph.D. Thesis, The Danish Academy of Technical Science (ATV) EF 488, 1996]. embedded image

The references above do not teach how to scale the isomerisation of IIaaa or related compounds to achieve a process applicable to large-scale production. Hence, a routine process applicable to large-scale production for the isomerisation of vitamin D analogues useful is the synthesis of calcipotriol is needed.

The problems associated with performing preparative synthetic photochemistry on large scale have been perceived as being preventive to its routine application on an industrial scale. Photochemical conversions are in general difficult to scale, if at all. The utility of a specific photochemical reaction also often depends on specific reactor and light source design, among many other variables, which are all scale-dependent.
Some of the diseases that are studied by almost every laboratory include cancer, diabetes, and cardiovascular disease. By working towards a cure or treatment for these ailments, people who suffer from any of these diseases may be able to live longer. New medications are being developed every single day across the globe. When an improved medication replaces an existing drug, scientists come one step closer to finding a cure or providing a treatment for a seemingly untreatable disease. Within the United States, billions of dollars are invested in Pharmaceutical Intermediates manufacturer research and development on a yearly basis.

An astronomical amount of substances are tested for human usage regularly. Out of all the substances tested, only a very small fraction are deemed safe for human usage. Thus, the amount of money needed to produce new drugs is vast. Only large pharmaceutical companies can afford to test new substances for a wide array of ailments. This is precisely why smaller laboratories only focus on one or two illnesses.

Pharmaceutical research and development is important, though there has also been some controversy surrounding research conducted by large corporations. Some people claim that the results provided by large pharmaceutical companies may be biased. This type of reasoning is based upon the fact that pharmaceutical companies manufacture, sell, and profit from medication. Thus, it is within the best interests of these companies to claim that their medication works better than any other. However, those companies in question largely dispute any claim of this type.

Men who drink five or more cups of green tea a day might reduce the risk of advanced prostate cancer by up to 50 percent compared to those who drink one cup a day, according to a study by researchers at Japan’s National Cancer Center. “This does not mean that people who drink green tea are guaranteed to have reduced risk of advanced prostate cancer,” said Norie Kurahashi, a scientist who took part in the study. ” But the study does point to the hope that green tea reduces the risk of advanced prostate cancer.”

Purdue University researchers Dorothy Morre and D. James Morre found that EGCg, a compound in green tea, inhibits an enzyme required for cancer cell growth and can kill cultured cancer cells with no ill effect on healthy cells. The findings offer the first scientific evidence to explain precisely how this compound works within a cell to ward off cancer. The results were presented this month at the 38th annual meeting of the American Society for Cell Biology in San Francisco.
“Our research shows that green tea leaves are rich in this anti-cancer compound, with concentrations high enough to induce anti-cancer effects in the body,” says Dorothy Morre, professor of foods and nutrition at Purdue.

The findings suggest that drinking more than four cups of green tea a day could provide enough of the active compound to slow and prevent the growth of cancer cells, she says.
Although all teas come from the same botanical source, green tea differs from black tea or other teas because of the way the tea leaves are processed after they are picked. For black tea, freshly picked leaves are “withered” indoors and allowed to oxidize. With green tea, the leaves are not oxidized, but are steamed and parched to better preserve the natural active substances of the leaf.

Morre and her husband, who is the Dow Distinguished Professor of Medicinal Chemistry and Molecular Pharmacology at Purdue, show in their study how green tea interacts with an enzyme on the surface of many types of cancer cells including breast, prostate, colon and neuroblastoma. This enzyme, called quinol oxidase, or NOX, helps carry out several functions on the cell surface and is required for growth in both normal and cancerous cells.

“Normal cells express the NOX enzyme only when they are dividing in response to growth hormone signals,” Dorothy Morre says. “In contrast, cancer cells have somehow gained the ability to express NOX activity at all times.” This overactive form of NOX, known as NOX - for tumor-associated NOX - has long been assumed to be vital for the growth of cancer cells, because drugs that inhibit NOX activity also block tumor cell growth in culture.
After hearing a researcher discuss green tea’s anti-cancer potential on a television show, the couple set out to investigate whether tea infusions — made when the compounds of tea leaves leach into hot water — would have an effect on NOX enzyme activity.

 

from:timepharm|anti-cancer

HIV is a member of the genus Lentivirus, part of the family of Retroviridae. Lentiviruses have many common morphologies and biological properties. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry of the target cell, the viral RNA genome is converted to double-stranded DNA by a virally encoded reverse transcriptase that is present in the virus particle. This viral DNA is then integrated into the cellular DNA by a virally encoded integrase, along with host cellular co-factors, so that the genome can be transcribed. After the virus has infected the cell, two pathways are possible: either the virus becomes latent and the infected cell continues to function or the virus becomes active and replicates, and a large number of virus particles that can then infect other cells are liberated.

There are two species of HIV known to exist: HIV-1 and HIV-2 . HIV-1 is the virus that was initially discovered and termed LAV. It is more virulent, more infective, and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.

Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load. The stage of infection can be determined by measuring the patient's CD4+ T cell count, and the level of HIV in the blood.

HIV infection has basically four stages: incubation period, acute infection, latency stage and AIDS. The initial incubation period upon infection is asymptomatic and usually lasts between two and four weeks. The second stage, acute infection, which lasts an average of 28 days and can include symptoms such as fever, lymphadenopathy (swollen lymph nodes), pharyngitis (sore throat), rash, myalgia (muscle pain), malaise, and mouth and esophageal sores. The latency stage, which occurs third, shows few or no symptoms and can last anywhere from two weeks to twenty years and beyond. AIDS, the fourth and final stage of HIV infection shows as symptoms of various opportunistic infections.

A study of French hospital patients found that approximately 0.5% of HIV-1 infected individuals retain high levels of CD4 T-Cells and a low or clinically undetectable viral load without anti-retroviral treatment. These individuals are classified as HIV controllers or Long-term nonprogressors.

The initial infection with HIV generally occurs after transfer of body fluids from an infected person to an uninfected one. The first stage of infection, the primary, or acute infection, is a period of rapid viral replication that immediately follows the individual's exposure to HIV leading to an abundance of virus in the peripheral blood with levels of HIV commonly approaching several million viruses per mL. This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viremia is associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts rebound to around 800 cells per µL (the normal blood value is 1200 cells per µL ). A good CD8+ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.

During this period (usually 2–4 weeks post-exposure) most individuals (80 to 90%) develop an influenza or mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophagal sores, and may also include, but less commonly, headache, nausea and vomiting, enlarged liver/spleen, weight loss, thrush, and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week. Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. As a consequence, these primary symptoms are not used to diagnose HIV infection, as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.

A strong immune defense reduces the number of viral particles in the blood stream, marking the start of the infection's clinical latency stage. Clinical latency can vary between two weeks and 20 years. During this early phase of infection, HIV is active within lymphoid organs, where large amounts of virus become trapped in the follicular dendritic cells (FDC) network. The surrounding tissues that are rich in CD4+ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4+ CD45RO+ T cells carry most of the proviral load.

When CD4+ T cell numbers decline below a critical level of 200 cells per µL, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis),prostatitis, skin rashes, and oral ulcerations. Common opportunistic infections and tumors, most of which are normally controlled by robust CD4+ T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis(thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma. Pneumonia caused by the fungus Pneumocystis jirovecii is common and often fatal. In the final stages of AIDS , infection with cytomegalovirus (another herpes virus) or Mycobacterium avium complex is more prominent. Not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant.

α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) was prepared and purified according to the previously reported procedure .Briefly it was prepared by reaction of a polysuccinimide (PSI), obtained by thermal polycondensation of d,l-aspartic acid, with ethanolamine in DMF solution and purified by dialysis. Spectroscopic data (FT-IR and 1H NMR) were in agreement with attributed structure .

1H NMR [D2O]: δ 2.82 (m, 2H, –CH–CH2–CO–NH–), 3.36 (t, 2H, –NH–CH2–CH2–OH), 3.66 (t, 2H,–CH2–CH2–OH), 4.72 (m, 1H, –NH–CH–CO–CH2–).

Average molecular weight of PHEA and of all its copolymers were measured by Size Exclusion Chromatography (SEC). The standard aqueous SEC protocol involved the use of two Ultrahydrogel columns from Water (500 and 200 Å) (Milord, MA, USA) connected to a Water 2410 refractive index detector. Phosphate buffer solution at pH 8 was used as eluent at 37 °C with a flux of 0.6 mL/min and Poly(ethylene oxide) standards (range 145–1.5 kDa) were used for calibration. Weight average molecular weight of PHEA was 51.1 kDa (Mw/Mn=1.7).

3-(carboxypropyl)trimethyl-ammonium chloride (CPTA), N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), hydroxybenzotriazole (HOBT), sodium dextran sulphate (Mw=500,000), albumin from bovine serum, lambda DNA HindIII, calf thymus DNA sodium salt, deoxyribonuclease II, glutathione reduced form were purchased from Sigma-Aldrich (Milan). Ethylenediamine, Bis(4-nitrophenyl) carbonate HPLC 99%   (4-NPBC), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC-HCl), 1,4-dithiothreitol (DTT) and all the other chemicals were purchased from Fluka (Switzerland).

1H NMR spectra were recorded in D2O (Aldrich) using a Bruker AC-250 spectrometer operating at 250.13 MHz.

UV Spectroscopy was performed by Shimadzu UV160U spectrophotometer. Linear PEI with an average molecular weight of 22 kDa (L-PEI) is available from Euromedex (Exgen 500; Euromedex, Souffelweyersheim, France).

Plasmid pCMVLuc (Photinus pyralis luciferase under control of the cytomegalovirus (CMV) enhancer/promoter was produced endotoxin-free by Elim Biopharmaceuticals (San Francisco, CA, USA) or Aldevron (Fargo, ND, USA).

Cell culture media and fetal calf serum (FCS) were purchased from Invitrogen GmbH (Karlsruhe, Germany). All cultured cells were grown at 37 °C in 5% CO2 humidified atmosphere. B16-F10 murine melanoma cells (kindly provided by I. J. Fidler, Texas Medical Center, Houston, TX, USA) and Neuro2A (murine neuroblastoma) (ATCC CCl-131) were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FCS, 100U/ml penicillin, 100U/ml streptomycin and 4 mM glutamine.

The synthesis of PHEA-EDA derivative was performed as previously reported .

Briefly a solution of PHEA in anhydrous DMF was added dropwise and under stirring to a solution of bis(4-nitrophenyl) carbonate (4-NPBC ) in anhydrous DMF, so that the molar ratio between 4-NPBC and repeating units of PHEA was equal to 1. The mixture was then kept for 4 h at 40±0.1 °C under argon. After this time the reaction was added dropwise and very slowly to ethylenediamine and the mixture was kept under stirring for 4 h at 25±0.1 °C. After this period the reaction mixture was precipitated into acetone, the obtained suspension was centrifuged and the residue was washed several times with the same solvent. The obtained solid residue was dried and then solubilized in distilled water to be purified by exhaustive dialysis in Visking Dialysis Tubing 18/32″ with 12,000–14,000 molecular weight cut-off.

After dialysis the solution was freeze-dried from water; the obtained pure product (90% yield, w/w, based on starting PHEA) was characterized by 1H NMR analysis in D2O. 1H NMR of PHEA-EDA (D2O) reveals peaks at δ 2.82 (m, 2H, –CO–CH–CH2–CO–NH–), 3.09 (m, 2HEDA, –NH–CH2–CH2–NH2), 3.37 (m, 2H, –NH–CH2–CH2–OH), 3.42 (m, 2HEDA, –NH–CH2–CH2–NH2), 3.67 (m, 2H, –NH–CH2–CH2–OH), 4.15 (m, 2HEDA, –NH–CH2–CH2–O(CO)NH–CH2–CH2–NH2) 4.74 (m, 1H, –NH–CH(CO)CH2) where the subscript word (EDA) means that the proton integration is related to derivatizing group (EDA) and corresponding to the fraction of polymeric repeating units that are derivatized. SEC chromatogram showed a single peak (data not showed) corresponding to 42 kDa; no additional peak was found, confirming that the reaction between PHEA and EDA occurred without crosslinking of polymer chains.

 

from:surguy.net

Adding the drug cetuximab to neoadjuvant chemotherapy can shrink tumors and boost the odds of successful surgery in colorectal cancer patients with inoperable metastatic liver lesions, new research suggests.
Tumors spread to other parts of the body in more than half of patients with colorectal cancer. Most commonly, the cancer spreads to the liver. Removing the tumors in the liver can cure patients, but about 80 percent have inoperable disease and a poor prognosis when they see doctors, the researchers explain in the Nov. 24 online edition of The Lancet Oncology.

Previous research suggests that neoadjuvant treatment with irinotecan- or oxaliplatin-based chemotherapy can make surgery more likely to succeed. The new study aimed to see if addition of the drug cetuximab, also known as Erbitux, would help patients even more.

The study authors, Gunnar Folprecht, from University Hospital Carl Gustav Carus in Dresden, Germany, and colleagues from Germany and Austria found that treatment with cetuximab boosted the proportion of tumors that could be treated with surgery. The treatment, in general, didn’t have serious side effects.
“Our data suggest that treatment with cetuximab and chemotherapy results in high confirmed tumor response rates … leading to … increased respectability,” Folprecht and colleagues wrote. “In the light of recent studies in metastatic colorectal cancer, the value of further Anti liver cancer treatment intensification will be investigated.”

 

Such as:

 

Molecular formula: C14H10O Molecular weight: 194.23 Properties: colorless needle-like crystals. Melting point 156 ?. Soluble in acetone, benzene, most organic solvents, does not produce fluorescence, slightly soluble in water. Do not dissolve in cold caustic soda solution, when heated formed anthralin dissolved alkali metal salts. Colorless needle-like crystals.

Uses: Determination of body fluids, sugar, starch, animal liver tissue. Organic synthesis, for the preparation of benzo-Anthrone  and dyes, but also for the colorimetric determination of carbohydrates. By the anthraquinone with tin and hydrochloric acid or sodium hydrosulfite to restore the system.

 

 

from:timepharm

Expert opinion 2: Select Advantage Variety

Chloroformic acid is an unstable chemical compound with the formula ClCO2H. It is the single acyl-halide derivative of carbonic acid (phosgene is the double acyl-halide derivative). Chloroformic acid is also structurally related to formic acid, which has a hydrogen instead of the chlorine.

Chloroformic acid itself is too unstable to be handled for chemical reactions. However, many esters of this carboxylic acid are stable and these chloroformates are important reagents in organic chemistry. They are used to prepare mixed carboxylic acid anhydrides used in peptide synthesis. Like other related halocarbons, it is a potentially dangerous alkylating agent.

Important chloroformate esters include 4-nitrophenyl chloroformate , fluorenylmethyloxycarbonylchloride, benzyl chloroformate and ethyl chloroformate.

 

The reactions of a homogeneous series of phenols with bis(4-nitrophenyl) carbonate (BNPC), bis(4-nitrophenyl) thionocarbonate (BNPTOC), and methyl 4-nitrophenyl thionocarbonate (MNPTOC) are subjected to a kinetic investigation in water, at 25.0 degrees C and ionic strength of 0.2 M (KCl). Under excess of phenol over the substrate, all the reactions obey pseudo-first-order kinetics and are first order in phenoxide anion.

 

The reactions of BNPC show a linear Brönsted-type plot with slope beta = 0.66, consistent with a concerted mechanism (one step). In contrast, those of BNPTOC and MNPTOC show biphasic Brönsted-type plots with slopes beta = 0.30 and 0.44, respectively, at high pK(a), and beta = 1.25 and 1.60, respectively, at low pK(a), consistent with stepwise mechanisms. For the reactions of both thionocarbonates, the pK(a) value at the center of the Brönsted plot (pK(a)(0)) is 7.1, which corresponds to the pK(a) of 4-nitrophenol. This confirms that the phenolyses of the thionocarbonates are stepwise processes, with the formation of an anionic tetrahedral intermediate. By the comparison of the kinetics and mechanisms of the title reactions with similar reactions, the following conclusions can be drawn:

(i) Substitution of S(-) by O(-) in an anionic tetrahedral intermediate (T(-)) destabilizes it.

(ii) The change of MeO by 4-nitrophenoxy in T(-) results in an increase of both the rate constant and equilibrium constant, for the formation of T(-), and also in an enlargement of the rate coefficient for the expulsion of 4-nitrophenoxide from T(-).

(iii) Substitution of an amino group in a tetrahedral intermediate by ArO destabilizes it.

(iv) Secondary alicyclic amines and other amines show greater reactivity toward MNPTOC than isobasic phenoxide anions.

FIGHT FOR HEALTH, THINKING GOES FIRST

Time-chem & The Global Economy

China is leading the way forward as global trade rebounds. China’s GDP is estimated to have risen by a seasonally adjusted annual rate of 14% in the second quarter, OECD says. “The economic stimulus package implemented by the Chinese government has had a clear and positive impact on the national economy, and it is already evident that both demand and pricing of petroleum and petrochemical products are recovering,” Sinopec said late last month. The global petchem sector needs recovery to continue as Sinopec and joint venture partners are set to increase ethylene capacity by nearly 3 million m.t./year through next year, with plants at Fujian and Tianjin coming onstream in the second half, and another unit at Ningbo starting up in 2010.
Spring may be arriving about six months late for the global economy and chemical makers. Late summer economic news has been mostly favorable, and indicators point to continued improvement in demand. Inventory depletion is no longer dragging down demand, and restocking could provide some lift in late 2009.Time-chem will continue to work hard,, our Pharmaceutical Intermediates products, Electronic Chemicals products and Fine Chemicals products will give clients high quality ones, we will provide our best products and services to better display Time-Chem.

http://www.blogigo.com/timephram