Arpromidine-related acylguanidines [Elektronische Ressource] : synthesis and structure-activity relationships of a new class of guanidine-type histamine H_1tn2 receptor agonists with reduced basicity / vorgelegt von Prasanta Ghorai
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Arpromidine-related acylguanidines [Elektronische Ressource] : synthesis and structure-activity relationships of a new class of guanidine-type histamine H_1tn2 receptor agonists with reduced basicity / vorgelegt von Prasanta Ghorai

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179 Pages
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Arpromidine-Related Acylguanidines: Synthesis and Structure-Activity Relationships of a New Class of Guanidine-Type Histamine H Receptor Agonists with Reduced Basicity 2 Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie - der Universität Regensburg vorgelegt von Prasanta Ghorai aus Midnapur / Indien 2005 Die vorliegende Arbeit entstand in der Zeit von August 2002 bis Juli 2005 unter der Leitung von Herrn Prof. Dr. A. Buschauer am Institut für Pharmazie der Naturwissen-schaftlichen Fakultät VI – Chemie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im August 2005. Tag der mündlichen Prüfung: 23.08.2005 Prüfungsausschuss: Prof. Dr. S. Elz (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. O. Reiser (Zweitgutachter) Prof. Dr. B. König (Prüfer) To my parents........ Take up one idea. Make that one idea your life - think of it, dream of it, live on idea. Let the brain, muscles, nerves, every part of your body, be full of that idea, and just leave every other idea alone. This is the way to success....................

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Arpromidine-Related Acylguanidines: Synthesis and Structure-
Activity Relationships of a New Class of Guanidine-Type
Histamine H Receptor Agonists with Reduced Basicity 2



Dissertation
zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.)
der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie -
der Universität Regensburg







vorgelegt von
Prasanta Ghorai
aus Midnapur / Indien
2005
































Die vorliegende Arbeit entstand in der Zeit von August 2002 bis Juli 2005 unter der
Leitung von Herrn Prof. Dr. A. Buschauer am Institut für Pharmazie der Naturwissen-
schaftlichen Fakultät VI – Chemie und Pharmazie – der Universität Regensburg.
















Das Promotionsgesuch wurde eingereicht im August 2005.

Tag der mündlichen Prüfung: 23.08.2005

Prüfungsausschuss:
Prof. Dr. S. Elz (Vorsitzender)
Prof. Dr. A. Buschauer (Erstgutachter)
Prof. Dr. O. Reiser (Zweitgutachter)
Prof. Dr. B. König (Prüfer)











































To my parents........













Take up one idea. Make that one idea your life - think of it, dream of it, live on
idea. Let the brain, muscles, nerves, every part of your body, be full of that idea,
and just leave every other idea alone. This is the way to success.
...................Swami Vivekananda

















































Acknowledgements


This thesis grew out of a series of dialogues with my supervisor Prof. Dr. Armin
Buschauer. His comments on chapter drafts are themselves a course in critical thought
upon which I will always draw. So, I take this opportunity to express my sincere gratitude
to him, for his assistance, encouragement, guidance and great support during my doctoral
research endeavor for the past three years.
I would like to acknowledge GRK 760 (supported by DFG) for providing me
financial support for three years to carry out my research work here.
Many thanks to Prof. Dr. Oliver Reiser for his recommendations and thoughtful
ideas during the development of new synthetic methods.
I am very grateful to Prof. Dr. Sigurd Elz for his kind efforts to investigate the
synthesized compounds on different isolated systems, Prof. Roland Seifert (University of
Kansas, Kansas, USA, and University of Regensburg, Germany) for the pharmacological
evaluation on the GTPase assays, Prof. Dr. Günther Bernhardt for important discussions
about analytical methods.
I am also indebted to Mr. M. Keller for helping me to perform analytical HPLC and
providing me information about the pharmacokinetic studies. Thanks are also due to Dr.
T. Burgemeister and his team for the detailed and quick NMR-analysis as well as Dr. K.
Mayer, Mr. J. Kiermaier and Mr. W. Söllner for the mass spectrometry and Mr. G.
Wandinger and Mr. Schüller for elemental analysis. I would like to thank Ms. N. Kastner-
Pustet for chiral HPLC analysis, Ms. S. Bollwein for handling the capillary electro-
2+phoresis technique and Ms. Evi Schreiber for performing the experiments on Ca assay.
I would like to gratefully acknowledge my lab-colleagues Ms. Anja Kraus for
providing me some of her research work for the discussion in my thesis and Ms.
Georgiana Petrache for her responsible behaviour in the laboratory and cooperation. This
thesis gradually emerged amid the friendships that animated my years in Regensburg
University. Many thanks to my group members, especially, Dr. S. Salmen, Mr. A.
Brennauer, Mr. S. Braun, Mr. M. Spickenreither, Mr. H. Preuß, Mr. R. Ziemeck, Dr. E.
Schneider.
My Indian friends kindled a spirit of optimism and a broader attitude as they
initiated a new era of development back in our country. Many thanks to Soma,
Aaishwarya, Rabi, Mani, Pijus, Shantanu, Patil, Yogesh, Prantik, Vinod and also the
present and previous Indian fellows at University of Regensburg, Germany.
I especially remember today three who marked the way, my teacher Mr. Subhamay
Mishra who initiated the story of my career in Science; Mr. Manas Santra who motivated
and opened the revolutionary door; Dr. Sudhir Pal who indicated a way forward.
I am forever grateful to my parents and brother who gently offer a counsel and
unconditional support at each turn of the road.


Table of Contents

Page
Chapter 1 Introduction
1.1 Histamine and its receptors 1
1.2 Histamine H receptors and their ligands 4 2
1.2.1 Histamine H receptor antagonists 4 2
1.2.2 HistamH recepagonists 5 2
1.2.3 Species selectivity of histamine H receptor agonosts 14 2
1.3 References 18
Chapter 2 Objectives 25
GChapter 3 Synthesis and Pharmacological Activity of N -Acylated
Imidazolylpropylguanidines
3.1 Introduction 29
3.2 Chemistry 31
G 3.2.1 Retrosynthetic analysis of N -acylated imidazolyl
alkylguanidines 31
3.2.2 Synthesis of S-methyl thiourea
3.2.3 homohistamine 32
G 3.2.4 Synthesis of N -acylated imidazolylpropylguanidines via
the S-methyl thiourea and cyanamide route 32
3.2.5 Protection of guanidine 33
3.2.6 Synthesis of the imidazolylpropylguanidine building block 34
3.2.7 the imidazolylethylguanidine building block 35
3.2.8 Synthesis of the arylalkylguanidine building block
3.2.9 the alkanoic acids 36
3.2.10 Synthesis of the acylguanidines 38
3.3 Pharmacological results and discussion 41
Histamine H R agonism on the isolated guinea-pig right atrium 43 2
Species selectivity - agonism on guinea-pig and human H R-G fusion 2 s α
proteins 45
3.4 Conclusion 52
3.5 Experimental section 53
3.5.1 Chemistry
General procedures 53
3.5.2 Pharmacological methods 95
3.6 References 99
Chapter 4 Synthesis and Pharmacological Activity of N-Acyl-N’-[3-(2-
amino-4-methylthiazol-5-yl)propyl]guanidines: Towards
Improved H Receptor Selectivity 2
4.1 Introduction 103
4.2 Chemistry 106
4.3 Pharmacological results and discussion 108
4.4 Conclusion 113
4.5 Experimental section 114
4.5.1 Chemistry 114
4.5.2 Pharmacological methods 124
4.6 References 126
GChapter 5 Synthesis and Pharmacological Activity of Chiral N -
Acylated Heteroarylpropylguanidines
5.1 Introduction 129
5.2 Chemistry 130
5.3 Pharmacological results and discussion 141
5.4 Conclusion 144
5.5 Experimental section 145
5.5.1 Chemistry 145
5.5.2 Pharmacological methods 153
5.6 References
Chapter 6 Summary 155

Apendix 159
Abstracts and Publications 163
Curriculum Vitae 165