Substituted pyridines for the development of novel therapeutics - antifungals and antidiabetics [Elektronische Ressource] = Substituierte Pyridine für die Entwicklung neuer antifungischer und antidiabetischer Wirkstoffe / vorgelegt von Katarzyna Kaczanowska

Kk

Sujets

• Naturwissenschaften

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2010
• Nombre de lectures: 16
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Substituted Pyridines for the Development
of Novel Therapeutics - Antifungals and
Antidiabetics

Substituierte Pyridine für die Entwicklung
neuer antifungischer und antidiabetischer
Wirkstoffe

DISSERTATION

der Fakultät für Chemie und Pharmazie
der Eberhard Karls Universität Tübingen

zur Erlangung des Grades eines Doktors
der Naturwissenschaften


2010

vorgelegt von
Katarzyna Kaczanowska



















Tag der mündlichen Prüfung: 24. August 2010

Dekan: Prof. Dr. Lars Wesemann
1. Berichterstatter: Prof. Dr. Karl-Heinz Wiesmüller
2. Berichterstatter: Prof. Dr. Klaus Albert This Dissertation was carried out from August 2007 to August 2010 at EMC microcollections
GmbH, Tübingen and at the Institute of Organic Chemistry, Eberhard Karls Universität
Tübingen under the supervision of:

Prof. Dr. Karl-Heinz Wiesmüller
and
Prof. Dr. Klaus Albert

























Acknowledgment

I wish to thank my supervisors Prof. Dr. Karl-Heinz Wiesmüller and Prof. Dr. Klaus Albert.
I appreciate the constructive discussions with and advises from Dr. Arnaud-Pierre Schaffner,
Dr. Holger Eickhoff, Prof. Dr. Günther Jung and Prof. Dr. Eberhard Breitmaier.
I thank Dr. Dorothee Wistuba for the FT-ICR-MS measurements and Dr. Klaus Eichele for
the support in the NMR analysis.
I wish to thank Dr. Hartmut Röhm for ‘guiding’ me through the University and for all his
help.
I acknowledge Dr. Steffen Rupp (Fraunhofer Institute, Germany), Prof. Dr. Karl Kuchler
(University and Biocenter of Vienna, Austria) and Prof. Dr. Gerald Kleymann (Eberhard
Karls Universität Tübingen) for performing antifungal screening.
I am grateful for financial support of the EC Marie Curie RTN “CanTrain” (CT-2004-
512481).


















Contents

Abbreviations
..........................................................................................................................1 1. Introduction
2. Objectives ..............................................................................................................................3
3. Pyridines as scaffolds for antifungals and antidiabetics......................................................4
3. 1 Pyridines as antifungal agents ..............................................................................................4
3. 2 Pyridines as DPP-4 inhibitors for treatment of diabetes mellitus.........................................12
3. 2. 1 Approaches for diabetes treatment...........................................................................12
3. 2. 2 Inhibition of DPP-4 - a novel target for antidiabetics development ..........................14
4. Results and discussion.........................................................................................................19
4. 1 Random collection of pyridines and pyrazolopyridines.......................................................19
4. 1. 1 Solid phase synthesis of pyridines and pyrazolopyridines........................................19
4. 1. 2 Synthesis of pyridine derivatives in solution............................................................25
4. 1. 2. 1 Synthesis of pyridine carboxylic acids.......................................................26
4. 1. 2. 2 Synthesis of pyridine carboxylic acid N-oxides .........................................28
4. 1. 2. 3 Synthesis of pyridine carboxylic acid amides ............................................29
4. 1. 2. 4 Synthesis of pyridine hydrazides ...............................................................31
4. 1. 2. 5 Synthesis of dicyanopyridines ...................................................................32
4. 1. 2. 6 Synthesis of nicotinic amides ....................................................................32
4. 1. 2. 7 Synthesis of pyridine N-hydroxyamidines .................................................33
4. 1. 2. 8 Synthesis of pyridine tetrazoles .................................................................35
4. 1. 2. 9 Synthesis of pyrrolopyridines....................................................................37
4. 1. 3 Antifungal screening ...............................................................................................39
4. 2 Novel DPP-4 inhibitors - focused compound collection......................................................42
4. 2. 1 Design of potential DPP-4 inhibitors.......................................................................42
4. 2. 2 Synthesis of potential DPP-4 inhibitors ...................................................................45
4. 2. 2. 1 Synthesis of 5-aminomethyl-6-methyl-4-aryl-pyridine-2-carboxylic acid
amides .....................................................................................................................45
4. 2. 2. 2 Synthesis of 6-aminomethyl-2-methyl-4-aryl-nicotinamides......................48
4. 2. 2. 3 Synthesis of 3-aminomethyl-2-methyl-6-aryl-isonicotinamides .................49
4. 2. 3 Biological screening and structure activity relationship ...........................................51
5. Summary .............................................................................................................................57
6. Experimental part...............................................................................................................59
6. 1 Syntheses ...........................................................................................................................59
6. 1. 1 General ...................................................................................................................59 6. 1. 2 Synthesis protocols..................................................................................................59
6. 1. 2. 1 Synthesis of (E)-2-oxo-4-aryl-but-3-enoic acids 59 - general procedure.....59
6. 1. 2. 2 Synthesis of (E)-4-oxo-4-aryl-but-2-enoic acids 60 - general procedure.....59
6. 1. 2. 3 Synthesis of pyridines 74, 72, 81 and pyrazolopyridines 78, 83, 85 -
general procedures...................................................................................................59
6. 1. 2. 4 Synthesis of pyrimidines ...........................................................................78
6. 1. 2. 5 Synthesis of pyridine N-oxides ..................................................................83
6. 1. 2. 5. 1 General procedure for the synthesis of pyridine N-oxides 93 ...83
6. 1. 2. 5. 2 General procedure for the synthesis of pyridine N-oxides 98 ...85
6. 1. 2. 6 General procedure for the amidation - synthesis of 94 and 99....................86
6. 1. 2. 7 General procedure for the synthesis of pyridine hydrazides 100...............105
6. 1. 2. 8 General procedure for the synthesis of dicyanopyridines 95 and 101 .......105
6. 1. 2. 9 General procedure for the synthesis of nicotinic amides 96.....................108
6. 1. 2. 10 Synthesis of pyridine N-hydroxyamidine 102 ........................................109
6. 1. 2. 11 Synthesis of pyridine tetrazoles .............................................................110
6. 1. 2. 12 Synthesis of pyrrolopyridines ................................................................112
6. 1. 2. 13 Synthesis of 5-aminomethyl-pyridines 120............................................115
6. 1. 2. 13. 1 Route A.............................................................................115
6. 1. 2. 13. 2 Route B .............................................................................126
6. 1. 2. 13. 3 Synthesis of 120h ..............................................................129
6. 1. 2. 14 Synthesis of 6-aminomethyl-pyridines 121............................................130
6. 1. 2. 15 Synthesis of 3-aminomethyl-pyridines 122............................................135
6. 1. 2. 15. 1 Route A.............................................................................................135
6. 1. 2. 15. 2 Route B .............................................................................................138
6. 2 Biological screening.........................................................................................................139
7. Literature ..........................................................................................................................147








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