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UNIVERSITÉ FRANÇOIS – RABELAIS DE TOURS

École Doctorale « Santé - Sciences Biologiques - Chimie du Vivant »

and

UNIVERSITY OF LJUBLJANA, FACULTY OF PHARMACY

«Department of Pharmaceutical Chemistry»

A cotutelle thesis submitted in fulfillment of the requirements for

the degree of «Docteur» at the University François Rabelais of

Tours (France) and Doctor of Pharmacy at the University of
Ljubljana (Slovenia)

In

Pharmaceutical Chemistry
Publicly defended on the 1st of March 2013 by

Mitja KOVAČ

in Ljubljana

FLUORATION DE DERIVES DU BENZOVESAMICOL POUR L'OBTENTION DE RADIOLIGANDS POTENTIELS DU TRANSPORTEUR VESICULAIRE DE
L'ACETYLCHOLINE

Under the co-direction of:
Associate Professor Sylvie Mavel (MCU, Tours) and Associate Professor Marko Anderluh
(Ljubljana)

-----------------

JURY for Oral Defense:

Ms MAVEL Sylvie – Associate Professor, University François-Rabelais, Tours, France

Mr ANDERLUH Marko – Associate Professor, University of Ljubljana, Slovenia

Mr DOLLÉ Frédéric – Service Hospitalier Frédéric Joliot, Institut d'Imagerie

BioMédicale - CEA, Orsay, France (Reviewer)

Mr EMOND Patrick – Professor, University François-Rabelais, Tours, France

Ms GMEINER STOPAR Tanja – Assistant Professor, University of Ljubljana, Slovenia (Reviewer) Mr GOBEC Stanislav – Professor, University of Ljubljana, Slovenia (Chairman)

This cotutelle PhD was carried out with the collaboration between the University of Tours

(Laboratoire de Biophysique Médicale et Pharmaceutique, Unité INSERM U930 - FRANCE)

and the University of Ljubljana (Faculty of Pharmacy, Department of Pharmacutical Chemistry - SLOVENIA).

The work was supported by a grant from the Slovene Human Resources Development and
Scholarship Fund, by a grant from the University of Ljubljana (Inovativna shema za

sofinanciranje doktorskega študija za spodbujanje sodelovanja z gospodarstvom in reševanja

aktualnih družbenih izzivov - generacija 2010 Univerza v Ljubljani), and by a SloveniaFrench bilateral collaboration project (project n° BI-FR/12-13-PROTEUS-007).

AKNOWLEDGEMENTS

I would like to extend my most sincere gratitude to my supervisors Dr. Sylvie Mavel and
Dr. Marko Anderluh for their continued direction, training, and encouragement. Their guidance has been inspirational and instructive throughout my journey along this path, and I will continue to draw on the wisdom they have imparted as I move forward.

Special thanks go to Dr. Johnny Vercouille and his team for their training and supervision in the radiopharmaceutical laboratory CERRP (Centre d'Etude et de Recherche sur les Radiopharmaceutiques).

I would like to extend my thanks to Dr. Patrick Emond and Dr. Frédérick Dollé for their

valuable advices and reading the thesis.
Thanks are given to Dr. Tanja Gmeiner Stopar and Dr. Stanislav Gobec for reading the

thesis.

Thanks also to Dr. Sylvie Chalon, and Dr. Mohamed Abarbri. Finally, I would like to thank my mother and all the family who have always been loving, supportive, and a guiding light throughout my life.

RÉSUMÉ

La maladie d’Alzheimer (MA) est une maladie neurodégénérative progressive et l’une des principales démences. Les plaques amyloïdes extracellulaires, les dégénérescences

neurofibrillaires intracellulaires, et la dégénérescence synaptique sont des marqueurs

neurophysiopathologiques de la MA. Il a été montré que la diminution en transporteur vésiculaire de l’acétylcholine (VAChT) est un paramètre neurologique précoce, précédant les signes cliniques de la maladie, et fortement corrélée avec la démence associée à la maladie. L’utilisation de radiotraceur sélectif et spécifique pouvant être utilisé en tomographie par émission de positrons (TEP) ou par tomographie d'émission monophotonique (TEMP) offre la possibilité d’identifier de subtils changements neurologiques aux stades précoces de la maladie, et ainsi aider au diagnostic différentiel de la MA avec d’autres démences corticales

ou sous-corticales.

Le (2R,3R)-5-IBVM, dérivé du benzovésamicol, est un ligand de haute affinité et sélectivité du VAChT, et est le seul radiotraceur utilisé en imagerie humaine par TEMP pour le diagnostic de la MA. Or, la TEP présente des avantages par rapport à la TEMP telle qu'une meilleure détection, meilleure résolution de l'image et possibilité de quantification. Sachant que l’analogue fluoré du 5-IBVM devrait présenter une affinité et sélectivité pour le VAChT du même ordre, nous avons donc synthétisé les énantiomères du 5-FBVM et nous avons développé des méthodes d'introduction régiosélective d'ion fluorure en position 5 du benzovésamicol, qui est une position non activée. Pour cela, nous avons choisi comme précurseur, la fonction triazène (Ar-N=N-NR2) en tant que «groupe partant » pour l'obtention d'aryles fluorés.

En partant d'études théoriques de fluoro-dediazénation, nous avons synthétisé les

énantiomères du 5-FBVM, dans un rendement de 25%, en utilisant le t-butyle de nitrite

comme agent de diazotation et l'éthérate de trifluorure de bore en tant qu'agent de fluoration. Des études de modélisation moléculaire (QSAR), faites sur 32 composés de type vésamicol, ont été réalisées en tenant compte de la stéréospécificité du site de fixation du VAChT. L'évaluation in vitro a montré la très bonne affinité pour le VAChT des 2 énantiomères, du même ordre que le 5-IBVM, comme le prédisaient les études QSAR. Le (2S,3S)-5-FBVM présente une meilleure sélectivité vis-à-vis des récepteurs 1 et pourrait être un traceur

potentiel pour l'imagerie in vivo des neurones cholinergiques.

Actuellement un des facteurs limitants du développement de la technologie TEP est l'introduction d'un ion fluorure sur un système aromatique non activé. Nous nous sommes donc focalisés dans un deuxième temps sur la fluoration d'aryles non activés possédant un triazène. Nous avons recherché un acide n'interférant pas lors d'un potentiel radiomarquage. Nous avons étudié différentes conditions expérimentales (acide, solvant, et agent de fluoration) pour la fluoration du 3,3-diéthyl-1-naphtyltriazène choisi comme modèle d'étude. À partir des résultats obtenus en chimie froide, l'acide polyphosphorique (PPA) dans un solvant chloré est le plus prometteur et de plus innovant dans ce type de réaction. De plus, en se basant sur la chimie de coordination des triazènes avec le trifluorure de bore, nous proposons que la fluoro-detriazénation pourrait être obtenue, avec uniquement de l'éthérate de trifluorure de bore, sans addition d'acide protique, à partir d'une température suffisante. Nous avons confirmé cette hypothèse sur le naphtyltriazène ainsi que sur des phényltriazènes para- substitués en comparant chauffage traditionnel et chauffage par micro-ondes. Nous avons validé notre méthode en fluorant un système plus complexe, à savoir le 5-TBV qui a conduit

au 5-FBVM dans un rendement de 72%, sous micro-onde, dans le tétrachlorure de carbone.

Des tests préliminaires de radiomarquage du 5-TBV, en utilisant le PPA dans le chloroforme sous micro-onde ont donné des résultats prometteurs.

Mots Clés: fluorination, triazène, benzovésamicol, VAChT, TEP

ABSTRACT

Alzheimer's disease (AD), a progressive neurodegenerative and terminal disorder, is the most common cause of dementia in the elderly. Extracellular amyloid plaques, intracellular neurofibrillary tangles, and degeneration of the synaptic terminals are the most characteristic neuropathophysiological hallmarks of AD. It has been shown that deficiencies in vesicular acetylcholine transporter (VAChT) are among the earliest neuronal changes, preceding clinical symptoms of the disease, and showing a strong correlation with the severity of dementia. Thus, the use of selective and specific radiotracer functional imaging modalities, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), offers non-invasive in vivo identification of subtle neurological changes in the early stages of AD and, therefore, offers value in the differential diagnosis of AD from other cortical and subcortical dementias.

Benzovesamicol-related ligand (2R,3R)-5-IBVM has a high affinity and enough selectivity for the VAChT, and is the only SPECT VAChT radiotracer used in human to obtain an early diagnosis of AD. Regarding physico-chemical properties of fluorine-19 and fluorine-18, and PET advantages over SPECT in terms of higher detection efficiency, better spatial resolution and possibility for quantification, it is expected that the fluoro analog of 5-IBVM should be of the same order of affinity and selectivity for the VAChT. Thus, we have prepared pure enantiomers of 5-FBVM and developed method for regioselective introduction of fluorine into the 5-position of non-activated benzovesamicol scaffold. We have chosen as a precursor system triazene function (Ar-N=N-NR2) as a leaving group for arylfluorination.

Firstly, we built theoretical model by studying characteristics of fluoro-de-diazoniation process. Accordingly, we have synthesized pure enantiomers of 5-FBVM from amino analog 5-ABV in around 25% yield by using t-butyl nitrite as diazonating agent and boron trifluoride etherate as fluorinating agent. Furthermore, to demonstrate the suitability of a triazene as a leaving group, the fluoro-de-triazenation of the corresponding triazene precursor (5-TBV), using triflic acid to trigger triazene moiety decomposition and boron trifluoride etherate, afforded 5-FBVM in reasonable yield (25%). QSAR studies based on 32 vesamicol derivatives taking into account the stereoselectivity of the VAChT binding site were performed. Both enantiomers exhibited high in vitro VAChT binding affinities determined by radioligand displacement studies and were in the same range as 5-IBVM as predicted by 3D QSAR studies. (2S,3S)-5-FBVM was more selective over σ1 receptors and could be a potential PET radioligand for in vivo mapping of cholinergic terminals.

Actually, one of the main limitations in aromatic nucleophilic fluorination is that arylfluorides are only satisfactory obtained on “activated system”. As new techniques to incorporate fluoride are needed for PET technology, we focused our research in the second step on fluorination of non-activated aryl skeleton from triazene precursor. We sought for the appropriate acid to trigger triazene decomposition but with no interference in the radiofluorination step. We studied different conditions (acid, solvent, and fluorinating agent) for the fluorination of 3,3-diethyl-1-naphthyltriazene (1-NT), chosen as precursor model. According to the results in the non-radioactive attempts, polyphosphoric acid (PPA) proved to be the most suitable one in chlorinated solvents, although had never been used in this type of reaction. Furthermore, from coordination chemistry of triazene derivatives with boron trifluoride, we proposed that fluoro-de-triazenation can be successfully accomplished by the only presence of boron trifluoride without any protic acid at elevated temperature. Our hypothesis was first confirmed on 1-NT. This methodology was also extended on several para-substituted 3,3-diethyl-1-aryltriazenes by conventional and microwave heating. To prove that the method is applicable to obtain more complex arylfluorides too, 5-FBVM was accomplished in high yield (72%) with microwave heating in tetrachloromethane.

Preliminary tests were transposed to F-18 radiolabelling. Encouraging results were obtained by radiofluorination of 5-TBV using PPA in chloroform with microwave heating.

Keywords: fluorination, triazene, benzovesamicol, VAChT, PET

ABBREVIATIONS

A-

conjugate base acetylcholine

ACh AChE AChEI AD

acetylcholine esterase acetylcholinesterase inhibitor Alzheimer's disease amyloid beta peptide amyloid precursor protein

adenosine triphosphate

choline acetyltransferase choline transporter

Aβ

APP

ATP

ChAT ChT CSF CT

cerebrospinal fluid computerized tomography deuteron

d

decay corrected

D.c.

diisopropylethylamine dementia with Lewy body electron-withdrawing group frontotemporal dementia gas chromatography high-pressure liquid chromatography leaving group

DIPEA DLB EWG FTD GC HPLC LG

mild cognitive impairment magnetic resonance imaging neutron

MCI MRI

n

non-decay corrected neurofibrilary tangles nuclear magnetic resonance proton

N.d.c. NFT NMR

p

phosphoric anhydride Parkinson's disease dementia

PA PDD

phosphatase

PP

positron emission tomography polyphosphoric acid

PET PPA PPAR PS

peroxisome proliferator-activated receptor presenilin radiochemical yield

RCY SA

specific activity structural magnetic resonance imaging

synaptosome-associated proteins

senile plaque

sMRI

SNAP

SP

single photon emission computed tomography retention time

SPECT

tR

triethylamine

TEA TLC VAChT VaD

VAMP

ν

thin-layer chromatography vesicular acetylcholine transporter vascular dementia

vesicle-associated membrane proteins

neutrino

TABLE OF CHEMICAL NAMES AND STRUCTURES

  • Chemical name
  • Structure

HO

5-amino-3-(4-phenyl-piperidin-1-yl)-1,2,3,4- tetrahydro-naphthalen-2-ol: 5- aminobenzovesamicol

N
H2N

5-ABV

HO

5-(3,3-diethyltriaz-1-enyl)-3-(4- phenylpiperidin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-ol: 5-ABV- diethyltriazene

N

  • Et2N
  • N
  • N

5-TBV

HO

5-fluoro-3-(4-phenyl-piperidin-1-yl)-1,2,3,4- tetrahydro-naphthalen-2-ol: 5- fluorobenzovesamicol

N
F

5-FBVM

  • N
  • N
  • NEt2

2,2-diethyl-1-(naphthalen-5- ylimino)hydrazine: 3,3-diethyl-1- naphthyltriazene

1-NT
1-fluoronaphthalene
1-NF

F

  • N
  • N
  • NEt2

1-(4-tolylimino)-2,2-diethylhydrazine

CH3

F

1-fluoro-4-methylbenzene

CH3

  • N
  • N
  • NEt2

1-(4-nitrophenylimino)-2,2-diethylhydrazine

NO2

F

1-fluoro-4-nitrobenzene

NO2

  • N
  • N
  • NEt2

1-(4-butoxyphenylimino)-2,2- diethylhydrazine

O

F

1-butoxy-4-fluorobenzene

O

  • N
  • N
  • NEt2

1-(4-iodophenylimino)-2,2-diethylhydrazine

I

F

1-fluoro-4-iodobenzene

I

  • N
  • N
  • NEt2

1-(4-cyanophenylimino)-2,2-diethylhydrazine

CN

F

4-fluorobenzonitrile

CN

TABLE OF CONTENTS

1. INTRODUCTION................................................................................................................ 1

1.1. Positron Emision Tomography........................................................................................ 2 1.2. Strategies for 18F-labelling............................................................................................... 7
1.2.1. Direct electrophilic 18F-fluorination.......................................................................... 8 1.2.2. Direct nucleophilic 18F-fluorination.......................................................................... 9 1.2.2.1. Direct aliphatic 18F-nucleophilic substitution reactions....................................... 11 1.2.2.2. Direct aromatic 18F-nucleophilic substitution reactions....................................... 12 1.2.3. Indirect 18F-labelling reactions................................................................................ 16
1.3. 18F-labelled Aryl-Tracers through Direct Introduction of [18F]fluoride into
Electron-Rich Arenes .................................................................................................... 18
1.4. Alzheimer's disease........................................................................................................ 57
1.4.1. Epidemiology and risk factors of Alzheimer’s disease........................................... 57 1.4.2. Neurophysiology and pathology of Alzheimer’s disease ....................................... 58 1.4.3. Pharmaceutical management and research directions............................................. 62 1.4.4. The diagnosis of Alzheimer’s disease by PET ....................................................... 65
1.5. Vesicular acetylcholine transporter (VAChT) and the most promising
PET imaging tracers ...................................................................................................... 68
1.6. Synthesis of 5-aminobenzovesamicol (5-ABV) and its enantiomers............................ 71

2. AIMS AND SCOPE ........................................................................................................... 73 3. RESULTS AND DISCUSSION......................................................................................... 76

3.1. Theoretical model for efficient one-pot fluoro-de-diazoniation.................................... 77 3.2. Synthesis of 5-FBVM and its enantiomers via fluoro-de-diazoniation......................... 82 3.3. Theoretical model for efficient fluoro-de-triazenation and synthesis of
5-FBVM from the corresponding triazene precursor .................................................... 86
3.4. 3D QSAR study, synthesis, and in vitro evaluation of (+)-5-FBVM as potential
PET radioligand for the vesicular acetylcholine transporter (VAChT)......................... 88
3.5. Aromatic fluoro-de-triazenation with boron trifluoride diethyl etherate under non protic acid conditions..................................................................................................... 99
3.6. Examination of reaction parameters for radio-fluoro-de-triazenation of 5-TBV ........ 106 3.7. Radiochemistry............................................................................................................ 110
3.7.1. Preparation of [18F]TBAF using TRACERlab™ FX F-N synthesizer................... 110 3.7.2. N.c.a. 18F-radiofluoro-de-triazenation of 5-TBV.................................................. 112

4. EXPERIMENTAL ........................................................................................................... 116

4.1. General information..................................................................................................... 117 4.2. Chemistry..................................................................................................................... 117
4.2.1. One-pot fluoro-de-diazoniation of 5-aminobenzovesamicol (5-ABV) in
1,2-dichlorobenzene.............................................................................................. 117
4.2.2. One-pot fluoro-de-diazoniation of 5-aminobenzovesamicol (5-ABV) in ionic liquid ........................................................................................................ 118
4.2.3. Fluoro-de-triazenation of 3,3-diethyl-1-naphthyltriazene (1-NT) using
KF/Kryptofix® complex and triflic acid (TfOH) in dichloromethane................... 118
4.2.4. Fluoro-de-triazenation of 3,3-diethyl-1-naphthyltriazene (1-NT) using tetra-n- butylammonium fluoride (TBAF) and triflic acid (TfOH) in chloroform ........... 119
4.2.5. Fluoro-de-triazenation of 3,3-diethyl-1-naphthyltriazene (1-NT) using tetra-n- butylammonium fluoride (TBAF) and polyphosphoric acid (PPA) in chloroform ........................................................................................................ 119
4.2.6. General procedure for the fluoro-de-triazenation of
3,3-diethyl-1-naphthyltriazene (1-NT) with different amounts of polyphosphoric acid (PPA)................................................................................... 120
4.2.7. General procedure for the fluoro-de-triazenation of
3,3-diethyl-1-naphthyltriazene (1-NT) with different fluoride sources................ 120
4.2.8. General procedure for the de-triazenation of 5-TBV with polyphosphoric acid (PPA).......................................................................... 121
4.3. Radiochemistry............................................................................................................ 121
4.3.1. Preparation of [18F]TBAF using TRACERlab™ FX F-N synthesizer.................. 121 4.3.2. General procedure for the thermal n.c.a. 18F-radiofluoro-de-triazenation of 5-TBV............................................................................................................... 121
4.3.3. General procedure for the microwave-assisted n.c.a.
18F-radiofluoro-de-triazenation of 5-TBV ............................................................ 122

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  • UNITED STATES PATENT OFFICE 2,677,686 PYRAZINEDERVATIVES and METHO) of PREPARING the SAME Victor K

    UNITED STATES PATENT OFFICE 2,677,686 PYRAZINEDERVATIVES and METHO) of PREPARING the SAME Victor K

    Patented May 4, 1954 2,677,686 UNITED STATES PATENT OFFICE 2,677,686 PYRAZINEDERVATIVES AND METHO) OF PREPARING THE SAME Victor K. Smith, Jr., Feari River, and Samuel Kushner, Nanuet, N. Y., assignors to American Cyanamid Company, New York, N. Y., a corpo ration of Maine No Drawing. Application 5uly 22, 1952, Serial No. 300,336 8 Claims. (C. 260-250) 2 This invention relates to mono-substituted ous layer is extracted with a solvent, such as di pyrazine. More particularly, it relates to substi ethyl ether. The ether can be concentrated and tuted-2-carbonyl pyrazine. the desired compound crystallized out Or the The role of vitamins in nutrition is well known ether can be removed and the product distilled. i and assumes greater importance as new informa 5, The reaction of the present invention may be tion is made available concerning the particular carried out at a temperature of -10° to 15° C. function of each. Recently it has been found The reaction is complete in from about a few that folic acid was effective in curing macrocytic ininutes up to about tWO hours. anemias and other blood conditions. Also, Com The process of the present invention is de pounds which are folic acid antagonistS, Such as scribed in greater particularity by the following aninopterin, have been found useful in treating specific examples which are given by way of ill abnormal blood conditions such as leukemia. lustration and not limitation. it is well established that nicotinamide is an im Eacample 1 portant, vitamin of the B complex group and its deficiency is the specific cause of pelagira.
  • United Sttes Atent 0 ICC Patented Feb

    United Sttes Atent 0 ICC Patented Feb

    p , ‘ 2,924,620 United Sttes atent 0 ICC Patented Feb. 9, 1960 1 2 gish or fails entirely. It is highly desirable that the acti 2,924,620 vating group be easily and economically removed after it has served its purpose. Even with the activating PROCESS FOR THE PREPARATION OF N-acetyl group, the reaction is rather slow, about 20 to DIPHENYLAMINES 24 hours at elevated temperatures being required to Robert K. Miller, New Castle, Del., assignor to E. I. du achieve practical yields of the product of the condensation. Pont de Nemonrs and Company, Wilmington, Del., a It is an object of the present invention to utilize corporation of Delaware formanilides in the Ullmann condensation with aryl halides wherein the diarylamine is directly recoverable N0 Drawing. Application March 30, 1959 10 from the reaction mass. Serial No. 802,664 it is a further object of this invention to eliminate the 5 Claims. (Cl. 260-576) need for prolonged hydrolysis of the reaction product obtained from N-acetyl primary aromatic amine and aryl The present invention is directed to a novel method halide. ' for producing diphenylamines; this invention is particu 15 It is a further object of this invention to produce un larly useful in the preparation of unsymmetrical diphenyl expectedly high yields of diarylamine. amines. It is a speci?c object of the present invention to pro This application is a continuation-in-part of copending vide a simpli?ed and economically practical Ullmann applications Serial No. 592,732, ?led June 21, 1956 and condensation method for preparing 3-chlorodiphenyl application Serial No.
  • Visualizza/Apri

    Visualizza/Apri

    UNIVERSITY OF CATANIA FACULTY OF PHARMACY DEPARTMENT OF PHARMACEUTICAL SCIENCES INTERNATIONAL DOCTORATE IN PHARMACEUTICAL SCIENCES XXIII Cycle SEMMELWEIS UNIVERSITY - BUDAPEST FACULTY OF PHARMACY DEPARTMENT OF ORGANIC CHEMISTRY ______________________________________________________ Dr. Antonino Grillo Design and synthesis of new vinca alkaloid derivatives as potential sigma-2 receptor ligands __________________ DOCTORATE THESIS __________________ Coordinator and Supervisor: Prof. Giuseppe Ronsisvalle Co-supervisor: Prof. Péter Mátyus ACADEMIC YEAR 2009-2010 Table of Contents INTRODUCTION 3 SIGMA RECEPTOR SUBCLASSES 5 ANATOMICAL DISTRIBUTION AND RELATED FUNCTIONS 8 NERVOUS SYSTEM 8 PERIPHERAL ORGANS 9 PROPOSED ENDOGENOUS LIGANDS FOR SIGMA RECEPTORS 11 SIGMA-1 RECEPTOR 13 CHARACTERIZATION 13 SUBCELLULAR LOCALIZATION 14 SIGNAL TRANSDUCTION MECHANISM AND MODULATORY ACTION 15 SELECTIVE SIGMA-1 LIGANDS AND PHARMACOPHORIC MODEL 16 SIGMA-2 RECEPTOR 18 CHARACTERIZATION 18 SUBCELLULAR LOCALIZATION 19 SIGMA-2 RECEPTORS AND THE REGULATION OF MOTOR FUNCTION 20 SIGMA-2 RECEPTORS AND CELL DEATH 21 SIGMA-2 LIGANDS AS PROBES FOR IMAGING IN VITRO AND IN VIVO 24 SIGMA-2 LIGANDS 27 PROPOSED PHARMACOPHORIC MODEL FOR SIGMA-2 RECEPTOR 33 IBOGAINE: PHARMACOLOGICAL PROFILE 35 IBOGAINE AND ITS RELATED ALKALOIDS: SAR 37 AIMS OF THE WORK AND DRUG DESIGN 39 INDIVIDUATION OF A NATURAL SCAFFOLD 39 SUPERIMPOSITION STUDY: VINCA-DERIVATIVES UPON IBOGAINE 41 DESIGNED LIGANDS 44 CHEMISTRY 48 RESULTS 53 FINAL REMARKS 54 EXPERIMENTAL SECTION 55 MATERIALS AND METHODS 55 MONOGRAPHIES 56 REFERENCES 79 2 Introduction Sigma receptors were first proposed in the mid-1970s thanks to the studies of Martin and co-workers (1976). They demonstrated that the mania syndrome observed on animal models, after treatment with the bezomorphanic derivative (±)-N-allyl-normetazocine (code number: (±)-SKF 10,047) (Fig.
  • Back of Jenny Mccarthy S Angle Bob Hair Back of Jenny

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  • Chemical Names and CAS Numbers Final

    Chemical Names and CAS Numbers Final

    Chemical Abstract Chemical Formula Chemical Name Service (CAS) Number C3H8O 1‐propanol C4H7BrO2 2‐bromobutyric acid 80‐58‐0 GeH3COOH 2‐germaacetic acid C4H10 2‐methylpropane 75‐28‐5 C3H8O 2‐propanol 67‐63‐0 C6H10O3 4‐acetylbutyric acid 448671 C4H7BrO2 4‐bromobutyric acid 2623‐87‐2 CH3CHO acetaldehyde CH3CONH2 acetamide C8H9NO2 acetaminophen 103‐90‐2 − C2H3O2 acetate ion − CH3COO acetate ion C2H4O2 acetic acid 64‐19‐7 CH3COOH acetic acid (CH3)2CO acetone CH3COCl acetyl chloride C2H2 acetylene 74‐86‐2 HCCH acetylene C9H8O4 acetylsalicylic acid 50‐78‐2 H2C(CH)CN acrylonitrile C3H7NO2 Ala C3H7NO2 alanine 56‐41‐7 NaAlSi3O3 albite AlSb aluminium antimonide 25152‐52‐7 AlAs aluminium arsenide 22831‐42‐1 AlBO2 aluminium borate 61279‐70‐7 AlBO aluminium boron oxide 12041‐48‐4 AlBr3 aluminium bromide 7727‐15‐3 AlBr3•6H2O aluminium bromide hexahydrate 2149397 AlCl4Cs aluminium caesium tetrachloride 17992‐03‐9 AlCl3 aluminium chloride (anhydrous) 7446‐70‐0 AlCl3•6H2O aluminium chloride hexahydrate 7784‐13‐6 AlClO aluminium chloride oxide 13596‐11‐7 AlB2 aluminium diboride 12041‐50‐8 AlF2 aluminium difluoride 13569‐23‐8 AlF2O aluminium difluoride oxide 38344‐66‐0 AlB12 aluminium dodecaboride 12041‐54‐2 Al2F6 aluminium fluoride 17949‐86‐9 AlF3 aluminium fluoride 7784‐18‐1 Al(CHO2)3 aluminium formate 7360‐53‐4 1 of 75 Chemical Abstract Chemical Formula Chemical Name Service (CAS) Number Al(OH)3 aluminium hydroxide 21645‐51‐2 Al2I6 aluminium iodide 18898‐35‐6 AlI3 aluminium iodide 7784‐23‐8 AlBr aluminium monobromide 22359‐97‐3 AlCl aluminium monochloride
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