DOCSLIB.ORG

Ester of Metronidazole with N,N-Dimethylglycine and Acid Addition Sait Thereof

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ester of Metronidazole with N,N-Dimethylglycine and Acid Addition Sait Thereof Europâisches Patentamt European Patent Office ® Publication number: Q 096 870 Office européen des brevets ® EUROPEAN PATENTPATE SPECIFICATION (45) Date of publication of patent spécification: 01.10.86 ® mtci.4: C 07D 233/95 //A61K31/415 (§) Application number: 83105717.9 (g) Dateoffiling: 10.06.83 (H) Ester of metronidazole with N,N-dimethylglycine and acid addition sait thereof. (D Priority: 11.06.82 DK 2643/82 ® Proprietor: A/S Dumex (Dumex Ltd.) 37, Prags Boulevard Post Box No. 1 736 DK-2300 Copenhagen S. (DK) (§) Date of publication of application: 28.12.83 Bulletin 83/52 ® Inventer: Thorbek, Pia Selmers Vaenge 14 (§) Publication of the grant of the patent: DK-2970 Horsholm (DK) 01.10.86 Bulletin 86/40 Inventer: Bundgaard, Hans Tjornevej 36 DK-2970 Horsholm (DK) (fi) Designated Contracting States: Inventer: Larsen, Claus AT BE CH DE FR GB IT Ll NI SE Hulegardsvej 15 DK-4320 Lejre (DK) (S) Références cited: US-A-2944061 (74) Représentative: Patentanwâfte Leinweber & Zîmmermann Rosental7/IIAufg. D-8000 Mùnchen 2 (DE) o N 00 <0 01 O o Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall CL be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been IU paid. (Art. 99(1) European patent convention). Courier Press, Leamington Spa, England. In the systemic treatment of anaerobic infections a parenteral mode of administration is advantageous for patients who are seriously ill and for whom oral administration is not feasible or may be considered to be insufficiently incisive. Heretofore, a practical way of administering a parenteral dose of metronidazole has not been available since the solubility of metronidazole in an aqueous solution is only about 100 mg/ 10 ml and a practical dosage unit is in the 500-650 mg/10 ml range. Those skilled in the art recognize the practical advantages of a single injectable dose of below 5 ml as opposed to the large volume of solution which would be needed to administer a 500-650 mg dose of metronidazole in an aqueous solution. Attempts have been made to improve the solubility of metronidazole in various ways as illustrated by the following examples: British patent application No. 2,000,025 discloses a method of solubilizing metronidazole in water by mixing it with gentisic acid in a ratio of 1:4. U.S. patent No. 4,032,645 describes solutions of metronidazole in water with N,N-dimethylacetamide/ ethanol or propylene glycol/2,2-dimethyl-1,3-dioxolane-4-methanol as co-solvents. However, these methods have two drawbacks: Firstly, the solubility of metronidazole is only augmented to 500-650 mg/10 ml and secondly both require large amounts of substances that are foreign to the human organism. Another conceivable solution to the problem is to administer metronidazole in the form of a derivative which has the desired solubility and which, after parenteral administration, is cleaved by the organism to yield metronidazole. Such--a derivative could be an ester prepared from a pharmacologically acceptable acid. Several esters of metronidazole are known. U.S. patent No. 2,994,061 describes esters of metronidazole with mono- or dicarboxylic aliphatic or aromatic acids. U.S. patent No. 3,696,116 describes esters of metronidazole with carbamic acid. British patent No. 1,270,810 mentions 4-toluene-sulphonic acid ester of metronidazole as an intermediate product. German Offenlegungsschrift No. 2,030,314 describes the ester of methane sulphonic acid with metronidazole. Unfortunately all of these esters are even less soluble in water than metronidazole itself. Half-esters of metronidazole with dicarboxylic acids are known from Belgian patent No. 619672. The sodium salt of the half-ester with succinic acid which is described therein has the required solubility in water. However, the cleavage of the ester in blood serum after parenteral administration is very slow and the compound itself is microbiologically inactive. U.S. patent No. 4,160,827 describes the monoester of phosphoric acid with metronidazole. The salts of this ester with pharmacologically acceptable cations are very soluble in water. Although this ester may turn out to be a clinically useful prodrug, published data indicate a rather slow rate of conversion to metronidazole in vivo. Furthermore, the bioavailability to rats of metronidazole occurring after administration of the phosphate ester is significantly lower than that obtained with metronidazole at the same dosage level, which indicates the excretion of some unchanged phosphate ester. A third type of water-soluble ester derivatives is esters with an ionizable amino function in the acid portion. Various amino acid esters have previously been described as water-soluble bioreversible derivatives of drugs containing a hydroxy group, such as oxazepam and lorazepam (Nudelman et al.: J. Pharm. Sci. 63,1880-1885 (1974)), hydrocortisone (Kawamura et al.: Yakugaku Zasshi 91, 863-870 (1971)) and a pyridazin-3-one derivative (Fogt et al.: J. Med. Chem. 23, 1445-1448 (1980)), but only sparse information is available on their hydrolysis under physiological conditions. Amino acid esters with metronidazole have been unknown hitherto. However, it has now been found that aminocarboxylic acid esters with metronidazole are soluble in water and that acid addition salts thereof are very soluble in water. In most cases solutions containing more than 20% w/v of such acid addition salts can be obtained. Table 1 shows the half-lives for the hydrolysis to metronidazole of a series of such metronidazole esters in 80% human plasma (pH 7.4) and in 0.05 M phosphate buffer (pH 7.4) at 37°C. Table 1 shows the widely differing ability of the various amino acid esters to undergo hydrolysis in human plasma and in buffer. As will appear from Table 1 the half-life of the 3-dimethylaminopropionate is only slightly shorter in human plasma compared to buffer and whereas the half-life of the 4-dimethylaminobutyrate is relatively much shorter in plasma than in buffer 4 in plasma is still so long that the 4-dimethylaminobutyrate is unsuited as a prodrug of metronidazole. The same applies to the 4-methyl-1-piperazinoacetate and 3- aminopropionate. The esters derived from N,N-dimethylglycine and N-propylglycine have short half-lives in plasma, and consequently these compounds appear to be suitable candidates as prodrugs of metronidazole. Selection of the optimum prodrug derivative should take into account several other criteria such as the in vitro stability in 'bulk form and in aqueous solution, toxicity of both the prodrug and the aminoacid moiety released from the derivative, and the ease of synthesis and purification. Based on these criteria the N,N-dimethylglycine ester of metronidazole and acid addition salts thereof have been found to be very suitable prodrugs of metronidazole. The novel compounds of the invention are metronidazole esters having the formula I: and acid addition salts thereof. A preferred acid addition salt of the N,N-dimethylglycine ester of the invention is the hydrochloride salt. The novel compounds of the invention may be prepared (a) by reacting metronidazole having the formula II: with a halogenacetyl halide having the general formula III: wherein Hal and Hal' each is selected from the group consisting of chloro and bromo atoms to form a compound having the general formula IV: wherein Hal has the meaning defined above, optionally reacting the compound having the general formula IV with an alkali metal iodide dissolved in an organic solvent to form a compound having the formula V: reacting a compound having the formula IV or V with dimethylamine to form a compound having the formula I and optionally converting said compound into an acid addition salt thereof, or (b) esterifying metronidazole having the formula II with N,N-dimethylglycine in the presence of N,N'- dicyclohexylcarbodiimide to form a compound having the formula I and optionally converting said compound into an acid addition salt thereof. Metronidazole is preferably reacted with the halogenoacetyl halide having the formula III in a suitable solvent, e.g. methylene chloride, and in the presence of about one equivalent of a base, such as pyridine. The alkali metal iodide used in the preparation of the compound having the formula V is preferably sodium or potassium iodide and the reaction is preferably carried out in acetone. The reaction between the compound having the formula IV or V and dimethylamine is preferably carried out in a non-hydroxylic solvent in which the compound having the formula IV or V is soluble, e.g. acetone. The preferred reaction temperature is room temperature or a temperature below room temperature. The esterification of metronidazole is preferably carried out at room temperature. The conversion of the ester obtained by methods (a) and (b) into the corresponding acid addition salt is effected with a suitable pharmacologically acceptable acid, e.g. hydrochloric acid. The solubility in water of the hydrochloride of metronidazole N,N-dimethylglycinate exceeds 50% w/v or 1.7 M at 20°C, the pH of the 1-20% w/v solutions being 4.4-4.6. The solubility of metronidazole in aqueous solutions of pH >3 and at 25°C is 1% w/v or 0.058 M. The effect of temperature on the rate of hydrolysis of metronidazole N,N-dimethylglycinate was studied in 0.05 M acetate buffer of pH 4.4 over the temperature range 23-50°C. The results obtained are illustrated in Fig. 1 of the drawings. Fig. 1 shows an Arrhenius plot in which the logarithm of the observed pseudo-first-order rate constants has been plotted against the reciprocal of the absolute temperature.
Load more

Recommended publications
  • The Reactions of N-Methylformamide and N,N-Dimethylformamide with OH and Their Cite This: Phys
    PCCP View Article Online PAPER View Journal | View Issue The reactions of N-methylformamide and N,N-dimethylformamide with OH and their Cite this: Phys. Chem. Chem. Phys., 2015, 17,7046 photo-oxidation under atmospheric conditions: experimental and theoretical studies† ab b c c Arne Joakim C. Bunkan, Jens Hetzler, Toma´ˇs Mikoviny, Armin Wisthaler, Claus J. Nielsena and Matthias Olzmann*b The reactions of OH radicals with CH3NHCHO (N-methylformamide, MF) and (CH3)2NCHO (N,N-dimethyl- formamide, DMF) have been studied by experimental and computational methods. Rate coefficients were determined as a function of temperature (T = 260–295 K) and pressure (P = 30–600 mbar) by the flash photolysis/laser-induced fluorescence technique. OH radicals were produced by laser flash photolysis of 2,4-pentanedione or tert-butyl hydroperoxide under pseudo-first order conditions in an excess of the Creative Commons Attribution 3.0 Unported Licence. corresponding amide. The rate coefficients obtained show negative temperature dependences that can À12 À1 3 À1 be parameterized as follows: kOH+MF = (1.3 Æ 0.4) Â 10 exp(3.7 kJ mol /(RT)) cm s and kOH+DMF = À13 À1 3 À1 (5.5 Æ 1.7) Â 10 exp(6.6 kJ mol /(RT)) cm s . The rate coefficient kOH+MF shows very weak positive pressure dependence whereas kOH+DMF was found to be independent of pressure. The Arrhenius equations given, within their uncertainty, are valid for the entire pressure range of our experiments. Furthermore, MF and DMF smog-chamber photo-oxidation experiments were monitored by proton- transfer-reaction time-of-flight mass spectrometry.
    [Show full text]
  • Evaluating Analytical Methods for Detecting Unknown Chemicals in Recycled Water
    PROJECT NO. 4992 Evaluating Analytical Methods for Detecting Unknown Chemicals in Recycled Water Evaluating Analytical Methods for Detecting Unknown Chemicals in Recycled Water Prepared by: Keith A. Maruya Charles S. Wong Southern California Coastal Water Research Project Authority 2020 The Water Research Foundation (WRF) is a nonprofit (501c3) organization which provides a unified source for One Water research and a strong presence in relationships with partner organizations, government and regulatory agencies, and Congress. The foundation conducts research in all areas of drinking water, wastewater, stormwater, and water reuse. The Water Research Foundation’s research portfolio is valued at over $700 million. The Foundation plays an important role in the translation and dissemination of applied research, technology demonstration, and education, through creation of research‐based educational tools and technology exchange opportunities. WRF serves as a leader and model for collaboration across the water industry and its materials are used to inform policymakers and the public on the science, economic value, and environmental benefits of using and recovering resources found in water, as well as the feasibility of implementing new technologies. For more information, contact: The Water Research Foundation Alexandria, VA Office Denver, CO Office 1199 North Fairfax Street, Suite 900 6666 West Quincy Avenue Alexandria, VA 22314‐1445 Denver, Colorado 80235‐3098 Tel: 571.384.2100 Tel: 303.347.6100 www.waterrf.org [email protected] ©Copyright 2020 by The Water Research Foundation. All rights reserved. Permission to copy must be obtained from The Water Research Foundation. WRF ISBN: 978‐1‐60573‐503‐0 WRF Project Number: 4992 This report was prepared by the organization(s) named below as an account of work sponsored by The Water Research Foundation.
    [Show full text]
  • N,N-Dimethylformamide
    This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization, or the World Health Organization. Concise International Chemical Assessment Document 31 N,N-DIMETHYLFORMAMIDE Please note that the layout and pagination of this pdf file are not identical to those of the printed CICAD First draft prepared by G. Long and M.E. Meek, Environmental Health Directorate, Health Canada, and M. Lewis, Commercial Chemicals Evaluation Branch, Environment Canada Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization Geneva, 2001 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety.
    [Show full text]
  • Nitrosamines EMEA-H-A5(3)-1490
    25 June 2020 EMA/369136/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Procedure under Article 5(3) of Regulation EC (No) 726/2004 Nitrosamine impurities in human medicinal products Procedure number: EMEA/H/A-5(3)/1490 Note: Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ...................................................................................... 2 1. Information on the procedure ............................................................... 7 2. Scientific discussion .............................................................................. 7 2.1. Introduction......................................................................................................... 7 2.2. Quality and safety aspects ..................................................................................... 7 2.2.1. Root causes for presence of N-nitrosamines in medicinal products and measures to mitigate them............................................................................................................. 8 2.2.2. Presence and formation of N-nitrosamines
    [Show full text]
  • Cellulose Fiber Dissolution in Sodium Hydroxide Solution at Low Temperature: Dissolution Kinetics and Solubility Improvement
    CELLULOSE FIBER DISSOLUTION IN SODIUM HYDROXIDE SOLUTION AT LOW TEMPERATURE: DISSOLUTION KINETICS AND SOLUBILITY IMPROVEMENT A Thesis Presented to The Academic Faculty by Ying Wang In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Department of Chemical and Biomolecular Engineering Georgia Institute of Technology December, 2008 CELLULOSE FIBER DISSOLUTION IN SODIUM HYDROXIDE SOLUTION AT LOW TEMPERATURE: DISSOLUTION KINETICS AND SOLUBILITY IMPROVEMENT Approved by: Professor Yulin Deng, Professor James Frederick Committee Chair Department of Chemical and Department of Chemical and Biomolecular Engineering Biomolecular Engineering Georgia Institute of Technology Georgia Institute of Technology Professor Yulin Deng, Advisor Professor Jeffery Hsieh Department of Chemical and Department of Chemical and Biomolecular Engineering Biomolecular Engineering Georgia Institute of Technology Georgia Institute of Technology Professor Yulin Deng Professor Arthur J. Ragauskas Department of Chemical and Department of Chemistry Biomolecular Engineering Georgia Institute of Technology Georgia Institute of Technology Professor Sujit Banerjee Date Approved: July 22nd, 2008 Department of Chemical and Biomolecular Engineering Georgia Institute of Technology ACKNOWLEDGEMENTS I would like to take this precious opportunity to thank my adviser, Dr. Yulin Deng, for his patience and life-benefiting guidance for my research. Thanks to my husband, Jing, who gave me unconditioning support and enlightening discussion; to my daugh- ter, Zhanqi, who forces me to search the most efficient way to use limited time and resources; also, to my parents and my elder brother for their love. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................ iii LIST OF TABLES................................. vii LIST OF FIGURES ................................ viii LIST OF SYMBOLS OR ABBREVIATIONS.................. xi SUMMARY..................................... xiii I INTRODUCTION.............................. 1 1.1 Objectives .
    [Show full text]
  • Chemical Innovation Technologies to Make Processes and Products More Sustainable
    United States Government Accountability Office Center for Science, Technology, and Engineering Natural Resources and Environment Report to Congressional Requesters February 2018 TECHNOLOGY ASSESSMENT Chemical Innovation Technologies to Make Processes and Products More Sustainable GAO-18-307 The cover image displays a word cloud generated from the transcript of the meeting we convened with 24 experts in the field of sustainable chemistry. The size of the words in the cloud corresponds to the frequency with which each word appeared in the transcript. In most cases, similar words—such as singular and plural versions of the same word— were combined into a single term. Words that were unrelated to the topic of sustainable chemistry were removed. The images around the periphery are stylized representations of chemical molecules that seek to illustrate a new conceptual framework, whereby molecules can be transformed to provide better performance; however, they are not intended to represent specific chemical compounds. TECHNOLOGY ASSESSMENT Highlights of GAO-18-307, a report to congressional requesters Chemical Innovation February 2018 Technologies to Make Processes and Products More Sustainable Why GAO did this study What GAO found Chemistry contributes to virtually every Stakeholders lack agreement on how to define sustainable chemistry and how to aspect of modern life and the chemical measure or assess the sustainability of chemical processes and products; these industry supports more than 25 percent differences hinder the development and adoption of more sustainable chemistry of the gross domestic product of the technologies. However, based on a review of the literature and stakeholder United States. While these are positive interviews, GAO identified several common themes underlying what sustainable contributions, chemical production can chemistry strives to achieve, including: have negative health and environmental · improve the efficiency with which natural resources—including energy, consequences.
    [Show full text]
  • Background Document for N,N-Dimethylacetamide (DMAC)
    1(14) 29 November 2012 Background document for N,N-Dimethylacetamide (DMAC) Document developed in the context of ECHA’s fourth Recommendation for the inclusion of substances in Annex XIV Information comprising confidential comments submitted during public consultation, or relating to content of Registration dossiers which is of such nature that it may potentially harm the commercial interest of companies if it was disclosed, is provided in a confidential annex to this document. 1. Identity of the substance Chemical name: N,N-Dimethylacetamide (DMAC) EC Number: 204-826-4 CAS Number: 127-19-5 IUPAC Name: N,N-Dimethylacetamide 2. Background information 2.1. Intrinsic properties N,N-Dimethylacetamide (DMAC) was identified as a Substance of Very High Concern (SVHC) according to Article 57 (c) as it is classified in Annex VI, part 3, Table 3.1 (the list of harmonised classification and labelling of hazardous substances) of Regulation (EC) No 1272/2008 as toxic for reproduction 1B, H360D (“May damage the unborn child”)1, and was therefore included in the Candidate List for authorisation on 19 December 2011 following ECHA’s decision ED/77/2011. 1 This corresponds to a classification as toxic for reproduction category 2 (R61: May cause harm to the unborn child) in Annex VI, part 3, Table 3.2 (the list of harmonised classification and labelling of hazardous substances from Annex I to Directive 67/548/EEC) of Regulation (EC) N° 1272/2008 2(14) 2.2. Imports, exports, manufacture and uses 2.2.1. Volume(s), imports/exports In 2010 the total manufactured volume was in the range of 15,000-20,000 tonnes.
    [Show full text]
  • Casting Solvent Interactions with Sulfonated Poly(Ether Ether Ketone) During Proton Exchange Membrane Fabrication Robertson, G
    NRC Publications Archive Archives des publications du CNRC Casting solvent interactions with sulfonated poly(ether ether ketone) during proton exchange membrane fabrication Robertson, G. P.; Mikhailenko, S.; Wang, K.; Xing, P.; Guiver, Michael; Kaliaguine, S. This publication could be one of several versions: author’s original, accepted manuscript or the publisher’s version. / La version de cette publication peut être l’une des suivantes : la version prépublication de l’auteur, la version acceptée du manuscrit ou la version de l’éditeur. For the publisher’s version, please access the DOI link below./ Pour consulter la version de l’éditeur, utilisez le lien DOI ci-dessous. Publisher’s version / Version de l'éditeur: https://doi.org/10.1016/S0376-7388(03)00193-5 Journal of Membrane Science, 219, 2003 NRC Publications Record / Notice d'Archives des publications de CNRC: https://nrc-publications.canada.ca/eng/view/object/?id=f679ee01-07be-4893-ae77-d95e9e933d5d https://publications-cnrc.canada.ca/fra/voir/objet/?id=f679ee01-07be-4893-ae77-d95e9e933d5d Access and use of this website and the material on it are subject to the Terms and Conditions set forth at https://nrc-publications.canada.ca/eng/copyright READ THESE TERMS AND CONDITIONS CAREFULLY BEFORE USING THIS WEBSITE. L’accès à ce site Web et l’utilisation de son contenu sont assujettis aux conditions présentées dans le site https://publications-cnrc.canada.ca/fra/droits LISEZ CES CONDITIONS ATTENTIVEMENT AVANT D’UTILISER CE SITE WEB. Questions? Contact the NRC Publications Archive team at [email protected]. If you wish to email the authors directly, please see the first page of the publication for their contact information.
    [Show full text]
  • N,N-Dimethylacetamide
    safety data sheet according to Regulation (EC) No. 1907/2006 (REACH), amended by 2015/830/EU N,N-Dimethylacetamide ≥99 %, for synthesis article number: 3617 date of compilation: 2016-06-07 Version: 1.0 en SECTION 1: Identification of the substance/mixture and of the company/undertaking 1.1 Product identifier Identification of the substance N,N-Dimethylacetamide Article number 3617 Registration number (REACH) 01-2119459339-27-xxxx Index No 616-011-00-4 EC number 204-826-4 CAS number 127-19-5 1.2 Relevant identified uses of the substance or mixture and uses advised against Identified uses: laboratory chemical 1.3 Details of the supplier of the safety data sheet Carl Roth GmbH + Co KG Schoemperlenstr. 3-5 D-76185 Karlsruhe Germany Telephone: +49 (0) 721 - 56 06 0 Telefax: +49 (0) 721 - 56 06 149 e-mail: [email protected] Website: www.carlroth.de Competent person responsible for the safety data : Department Health, Safety and Environment sheet e-mail (competent person) : [email protected] 1.4 Emergency telephone number Emergency information service Poison Centre Munich: +49/(0)89 19240 SECTION 2: Hazards identification 2.1 Classification of the substance or mixture Classification according to Regulation (EC) No 1272/2008 (CLP) Classification acc. to GHS Section Hazard class Hazard class and cat- Hazard egory state- ment 3.1D acute toxicity (dermal) (Acute Tox. 4) H312 3.1I acute toxicity (inhal.) (Acute Tox. 4) H332 3.3 serious eye damage/eye irritation (Eye Irrit. 2) H319 3.7 reproductive toxicity (Repr. 1B) H360D United Kingdom (en) Page 1 / 14 safety data sheet according to Regulation (EC) No.
    [Show full text]
  • Studies of TRIMETHYLGLYCINE OR BETAINE
    Studies of TRIMETHYLGLYCINE OR BETAINE GENERAL DESCRIPTION Trimethylglycine or Betaine ( Betaine is also called Betaine but we do not use this name because we can confuse it with Betaine Chloride; this is a strong acidifier that is taken only at mealtimes, and may cause gastric irritation ), extracted from sugar beets, is obtained from pure molasses, and separated by chromatography; it is a powerful methylating agent and plays a particularly important role in the process of detoxification of homocysteine ( a powerful oxidant and free radical generator ), which, as known, is one of the major cause of heart and vascular diseases. Recent American studies have shown the value and effectiveness of T. as a dietary supplement that can give the following benefits: - Adjuvant in cardiovascular disease - Adjuvant in sporting competitions - Adjuvant in liver diseases - Adjuvant in baldness - Adjuvant in depression - Adjuvant in hepatitis - Adjuvant in alcohol-induced hepatitis fatty liver - Adjuvant in chronic general fatigue - Increasing S-adenosyl-methionine levels - Conflicting arteriosclerosis - Decreasing apopletic stroke risk - Decreasing fat tissue amount - Improving glucose metabolism - Improving dry mouth - Improving homocisteinuria which does not respond to pyridoxine improving use of oxygen - Improving oxygen utilization - Reducing triglycerides levels in liver - Reducing Cholesterol - Reducing liver lipidosis - Useful for immune deficiency deficit (immunomodulating) - Useful for hyperhomocysteinemia STRUCTURE AND PROPERTIES From a structural standpoint, T. differs from dimethylglycine in presence of a third methyl group (CH3). T. operates very successfully in methylation or trans-methylation process, which is the process by which methyl groups (CH3) are transferred from one molecule to another; it is a biochemical process essential to life, health and regeneration of body cells.
    [Show full text]
  • Identification of Folate Binding Protein of Mitochondria As Dimethylglycine Dehydrogenase (Flavoprotein/Sarcosine Dehydrogenase/Tetrahydrofolate) ARTHUR J
    Proc. Natl. Acad. Sci. USA Vol. 77, No. 8, pp. 4484-4488, August 1980 Biochemistry Identification of folate binding protein of mitochondria as dimethylglycine dehydrogenase (flavoprotein/sarcosine dehydrogenase/tetrahydrofolate) ARTHUR J. WITTWER* AND CONRAD WAGNERt Department of Biochemistry, Vanderbilt University and Veterans Administration Medical Center, Nashville, Tennessee 37203 Communicated by Sidney P. Colowick, April 24,1980 ABSTRACT The folate-binding protein of rat liver mito- Preparation of Tetrahydro[3H]folic Acid (H4[3HJPteGIu). chondria [Zamierowski, M. & Wagner, C. (1977) J. BioL Chem. [3',5',7,9-3H]PteGlu, potassium salt (20 Ci/mmol; 1 Ci = 3.7 252,933-9381 has been purified to homogeneity by a combina- tion of gel filtration, DEAE-cellulose, and affinity chromatog- X 101' becquerels) was obtained from Amersham. Unlabeled raphy. This protein was assayed by its ability to bind tetrahv- PteGlu (Sigma) was added to adjust the specific activity to 20 dro[3H folic acid in vitro. The purified protein contains tightly ,uCi/Amol. H4[3',5',7,9-3H]PteGlu was synthesized by chemical bound flavin and has a molecular weight of about 90,000 as reduction with NaBH4 (2). To 0.70 ml of 0.066 M Tris-HCI at determined by sodium dodecyl sulfate electrophoresis. This pH 7.8 was added 0.30 ml of a solution containing 0.40 protein also displays dimethylglycine deh drogenase [NN- ,gmol dimethylglycine: (acceptor) oxidoreductase (deme ylating), EC (8 ,Ci) of [3H]PteGlu. This solution was stirred in the dark 1.5.99.21 activity which copurifies with the folatebinding ac- under nitrogen at room temperature, and 0.25 ml of NaBH4 tivity.
    [Show full text]
  • N,N-Dimethylacetamide (Dmac) Cas N°:127-19-5
    OECD SIDS N,N-DIMETHYLACETAMIDE (DMAC) FOREWORD INTRODUCTION N,N-DIMETHYLACETAMIDE (DMAC) CAS N°:127-19-5 UNEP PUBLICATIONS 1 OECD SIDS N,N-DIMETHYLACETAMIDE (DMAC) SIDS Initial Assessment Report for 13th SIAM (Bern, Switzerland, 6-9 November 2001) Chemical Name: N,N -Dimethylacetamide CAS No: 127-19-5 Sponsor Country: Italy National SIDS Contact Point in Sponsor Country: Dr. R.Binetti Istituto Superiore di Sanità Viale Regina Elena 299 00161 Roma, Italy Tel : 39-06-49387170 Fax : 39-06-49387170 E-mail : [email protected] History: This HPV chemical has been assigned to Italy in phase I of the OECD HPVC Programme. It was discussed at SIAM 3 (1995), but according to the majority of delegates information was lacking. At the SIAM 11 (January 2001) a revised report was submitted too late for consideration, so that it was added to the agenda for the SIAM 12 (June 2001), but again comments couldn’t be resolved at the meeting. Testing: No testing ( x ) Testing ( ) Comments : Deadline for circulation: Date of Circulation: Revised : September 2001 2 UNEP PUBLICATIONS OECD SIDS N,N-DIMETHYLACETAMIDE (DMAC) SIDS INITIAL ASSESSMENT PROFILE CAS No. 127-19-5 Chemical Name N,N-Dimethylacetamide (DMAC) Structural Formula CH3CON(CH3)2 RECOMMENDATIONS The chemical is currently of low priority for further work. SUMMARY CONCLUSIONS OF THE SIAR Human Health DMAC is well-absorbed orally, by inhalat ion and dermally. There are adequate data with which to evaluate the potential hazard to human health of this compound. DMAC has low toxicity by ingestion: the oral LD 50 ranges from 3000 mg/kg bw to 6000 mg/ Kg in rats and > 5000 mg/Kg bw in rabbits.
    [Show full text]