Antifungal Azoles: A Comprehensive Survey of their Structures and Properties

301 Pages·1998·2.46 MB·English

by  Ludwig Zirngibl

Ludwig Zirngibl
Antifiingal Azoles
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WILEY-VCH
Antifungal Azoles: A Comprehensive Survey of their Structures and Properties. Ludwig Zirngibl
Copyright © 1998 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
ISBN: 3-527-29487-2
Further Titles of Interest:
K. Gubernator, H. Bohm
Structure-based Ligand Design
(Series: Methods and Principles in Medicinal Chemistry)
ca. 200 pages, in color, 1998, ISBN: 3-527-29434-4
M.E.Wilf(Ed.)
Burger's Medicinal Chemistry and Drug Discovery
over 4000 pages in 5 volumes, 1997, ISBN: 0-471-57561-5
H. A. Staab, H. Bauer, K. M. Schneider
Azolides in Organic Synthesis and Biochemistry
ca. 500 pages, 1998, ISBN: 3-527-29314-0
Ludwig Zirngibl
Antifungal Azoles
A Comprehensive Survey
of their Structures and Properties
WILEY-VCH
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Dr. Ludwig Zirngibl
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Switzerland
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Deutsche Bibliothek Cataloguing-in-Publication Data:
Zirngibl, Ludwig:
Antifungal azoles : a comprehensive survey of their structures and
properties / Ludwig Zirngibl. - Weinheim ; New York ; Chichester ;
Brisbane ; Singapore ; Toronto : Wiley-VCH, 1998
ISBN 3-527-29487-2
© WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 1998
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Cover Illustration: Photograph of Aspergillus niger, courtesy of Prof. Annemarie Polak
Printed in the Federal Republic of Germany
Contents
1 Introduction 1
Scope, chronology and statistics, beneficial side effects, acknowledgements
2 l-(Hydrogen-, alkyl-, aryl-, heterocyclyl-, arylalkyl-,
heterocyclylalkyl-, diphenylalkyl- and trityl)l-H-azoles 7
2.1 1-Hydrogen- and 1-alkyl-azoles 8
2.1.1 Pyrroles and pyrazoles 8
2.1.2 Imidazoles 8
2.1.3 Azoles 10
2.1.4 Triazoles 12
2.1.5 Tetrazoles 12
2.2 1-Aryl-lH-azoles 13
2.2.1 Pyrazoles 13
2.2.2 Imidazoles 13
2.2.3 1,2,3-Triazoles 13
2.3 1-Heteroaryl-lH-azoles 14
2.3.1 Pyrazoles 14
2.3.2 Imidazoles 14
2.3.3 Azoles and triazoles 15
2.4 1-Benzyl-lH-azoles 16
2.4.1 Pyrazoles 16
2.4.2 Imidazoles 16
2.4.3 Azoles 18
2.4.4 Triazoles 18
2.5 Heteroarylmethyl- and heteroaryl-methylen-azoles 20
2.5.1 Imidazoles 20
2.5.2 Azoles 21
2.5.3 Triazoles 22
2.6 l-(2-Phenyl- and 2- heterocyclyl)ethyl-azoles 22
2.6.1 Pyrazoles 22
2.6.2 Imidazoles 22
2.6.3 Azoles 23
2.6.4 Triazoles 24
2.7 l-(x-Halogeno and x,y-dihalogenoalkyl)lH-azoles 25
2.7.1 1-Halogeno- and 1,2-dihalogen-l-azolylalkanes 25
VI Contents
2.7.2 2-Halogeno-l-azolylalkanes 25
2.7.3 3-Halogeno-l-azolylalkanes 26
2.8 l-(x-Arylalkyl)-lH-azoles 26
2.9 l-(Alkenyl and alkinyl)-lH-azoles and their halogen derivatives .... 26
2.9.1 l-(l-Alkenyl)azoles 26
2.9.1.1 l-(l-Alkenyl)imidazoles 26
2.9.1.2 l-(l-Alkenyl)-lH-triazoles 27
2.9.2 1-Styrylazoles 28
2.9.3 l-(Allyl- and l-propargyl)-l-azoles and their homologs 30
2.9.3.1 1-Allyl IH-azoles 30
2.9.3.2 1-Propynyl-lH-azoles 31
2.9.3.3 l-(But-3-en-l-yl)azoles 32
2.10 1-Diphenylmethyl-lH-imidazoles 32
2.10.1 l-[l-Phenyl-l-(4-substituted phenyl)methylimidazoles 32
2.10.2 Biphenylylphenylmethyl-lH-imidazoles 32
2.10.3 Vinylogs of 1-diphenylmethyl-lH-azoles 34
2.10.4 l-(2,2-Diphenylethyl)-l-H-azoles 34
2.11 Heterocyclic analogs of l-(diphenyl)methyl-lH-azoles 35
2.11.1 l-(Heterocyclyl-phenyl)methyl-lH-azoles 35
2.11.2 l-Di(heterocyclyl)methyl-lH-azoles 37
2.11.3 Heterocyclic analogs of l-(biphenylyl-phenyl)methyl-lH-azoles 37
2.11.4 Di-heterocyclic analogs of l-(biphenylyl-phenyl)methyl-lH-azoles ... 38
2.12 1-Trityl-lH-imidazoles 38
2.12.1 Clotrimazole: Chemical and pharmaceutical aspects 38
2.12.2 Clotrimazole: microbiological activity 40
2.12.3 Flutrimazole 40
2.12.4 Further close analogs of Clotrimazole 41
2.13 1-Trityl-l-H-azoles with heterocycles replacing phenyl 41
2.14 Tricyclic analogs of 1-diphenylmethyl-lH-azoles 42
3 l-(Mono- di- and trihydroxyalkyl- and alkenyl)-lH-azoles,
their thio analogs and derivatives 45
3.1 Derivatives of l-(hydroxymethyl)-lH-azoles
and their thio derivatives 46
3.1.1 l-(Hydroxymethyl)-lH-pyrazoles and -imidazoles 46
3.1.2 l-(Hydroxymethyl)-lH-triazoles, their ethers,
oximino ethers and esters 47
3.1.3 1-Alkyloxymethyl- and 1-alkylthiomethyl-imidazolium compounds . . 49
3.2 l-(2-Hydroxyalkyl)-lH-azoles 50
3.2.1 a-Substituted l-(2-hydroxyalkyl)-lH-azoles 50
3.2.2 a,cc-Disubstituted l-(2-hydroxyalkyl)-l-H-azoles 50
Contents VII
3.2.2.1 a,cc-Di(halogenalkyl) l-(2-hydroxyalkyl)-lH-azoles 50
3.2.2.2 oc-Alkyl, cycloalkyl, alkenyl and halogenoalkyl-, a-aryl or
heteroaryl-l-(2-hydroxyalkyl)4H-azoles 51
3.2.2.3 a-Alkyl-, a-arylmethyl- and
a-heterocyclylmethyl-l-(2-hydroxyalkyl)-lH-azoles 53
3.2.2.4 a-Alkyl- or -aryl-, a-(2-arylethyl)l-(2-hydroxyalkyl) azoles
and unsaturated analogs 54
3.2.2.5 a,a-Diaryl-l-(2-hydroxyalkyl)-lH-azoles
and related heteroaryl compounds 55
3.2.2.6 a-Aryl-a-arylmethyl-l-(2-hydroxyalkyl)-lH-azoles 57
3.2.2.7 a-Aryl-a-heterocyclylmethyl-l-(2-hydroxyalkyl)-lH-azoles 58
3.2.2.8 Fluconazole: Development strategy, pharmaceutical
and pharmacokinetic aspects 59
3.2.2.9 Fluconazole: Preclinical and clinical aspects, resistance 60
3.2.2.10 Close relatives of fluconazole 61
3.2.2.11 a-Aryl-a-heterocyclylalkyl-l-(2-hydroxyalkyl)-lH-azoles;
further relatives of fluconazole 62
3.2.2.12 a-Bis-arylalkyl-l-(2-hydroxyalkyl)-lH-azoles
and heteroaryl analogs 63
3.2.3 cc,p-Disubstituted l-(2-hydroxyalkyl)- IH-azoles 64
3.2.3.1 a-Alkyl-, (3-(alkyl, aryl- or aralkyl)-l-(2-hydroxyalkyl)-lH-azoles .... 64
3.2.3.2 a-(Aryl or aralkyl),
(3-(alkyl, aryl or aralkyl)-l-(2-hydroxyalkyl)-lH-azoles 65
3.2.4 a,a,p- and a,(3,(i-trisubstituted, and
a,a-p,(5-tetrasubstituted l-(2-hydroxyalkyl)-lH-azoles 65
3.2.5 l-(2-Hydroxyalkyl)-lH-azoles with a- and/or (3-carbon
as part of a cycloalkane 66
3.3 Ethers of 2-hydroxyalkyl-lH-azoles 68
3.3.1 a-Substituted l-(2-alkoxyalkyl and
2-alkenoxyalkyl)-lH-azoles 68
3.3.1.1 a-Substituted [2-functionally substituted alkoxy)]-lH-azoles 70
3.3.2 l-(2-Aryl- or heterocyclyl-oxy)alkyl-lH-azoles 70
3.3.3 l-[2-(Halogenophenyl)]methyloxy)alkyl-lH-imidazoles;
the econazole/miconazole family 70
3.3.3.1 General aspects 70
3.3.3.2 Econazole and miconazole: Chemical and pharmaceutical aspects ... 71
3.3.3.3 Econazole and miconazole: Preclinical and clinical aspects 72
3.3.3.4 Isoconazole and other close relatives 73
3.3.3.5 Further l-(2-subst. phenylmethyloxy)-alkyl-lH-azoles
related to miconazole 73
3.3.3.6 l-(2-Heterocyclylalkoxy)alkyl-lH-azoles 74
3.3.4 p-Aryl-l(2-hydroxyethyl)-lH-azole ethers 75
3.3.5 Cyclic analogs of l(2-hydroxyalkyl)-alkyl-lH-azole ethers 76
3.4 Thioanalogs of the econazole/miconazole family 76
3.4.1 l-(l-(2-Alkylthio)alkyl-lH-azoles 76
VIII Contents
3.4.2 l-(2-Aryl- or heterocyclyl-thio)alkyl-lH-azoles 77
3.4.3 l-(2-Benzylthio)alkyl-lH-azoles 77
3.5 Esters and carbamates of l-(2-hydroxyalkyl)-lH-azoles 78
3.6 l-(3-Hydroxyalkyl)-lH-azoles,
their thio analogs, homologs and derivatives 79
3.6.1 l-(3-Hydroxyalkyl)4H-azoles and their ethers 79
3.6.2 Homologs and cyclic analogs of l-(3-hydroxyalkyl)-lH-azoles 80
3.7 l-(x-Hydroxy-l-alkenyl)-lH-azoles 81
3.7.1 l-(l-Hydroxy-alken-l-yl)-lH-azoles, their ethers and homologs 81
3.7.2 l-[2-(Alkoxy- or alkylthio)-ethenyl]-lH-azoles 82
3.7.3 l-(2-Aryloxy-alkyloxy)-(l-alkenyl)-lH-azoles 84
3.7.4 1- and 2-Azol-l-yl-l-propen-3-ols 85
3.7.5 a-(Azol-l-ylmethyl)-allylalcohols and their derivatives 87
3.7.6 a-(Azol-l-ylmethyl)propargyl alcohols 88
3.7.7 Cyclic analogs of azolyl-vinyl-carbinols 89
3.8 l-(l,2-Dihydroxy-alkyl)-lH-azoles, their derivatives and analogs .... 90
3.8.1 Monoderived l-(l,2-dihydroxy-alkyl)-lH-azoles 90
3.8.2 l-(l-Thio-2-hydroxyalkyl)-lH-azole derivatives 94
3.9 l-(l-subst. Phenoxy-2-hydroxy-alkyl)-lH-azole
esters and carbamates 94
3.10 l-(2,2- and 3,3-Dihydroxy- and dithioalkyl)-
IH-azoles semiketals and ketals ; 95
3.10.1 l-(2,2-Dihydroxyalkyl)-lH-azole semiketals and ketals 95
3.10.2 l-(2,2-Dithioalkyl)-lH-imidazole semiketals and ketals 96
3.10.3 l-(3,3-Dihydroxyalkyl)-lH-azole ketals 96
3.11 l-(x,y-Di- and x,y,z-Trihydroxyalkyl)-lH-
azoles, their ethers, thioethers and analogs 96
3.11.1 l-(2,3-Dihydroxyalkyl)-lH-azoles and their ethers 96
3.11.2 Cyclic and thio analogs of l-(2,3-dihydroxyalkyl)-lH-azoles 99
3.11.3 l-(2-Hydroxy-3-thio-alkyl)lH-azole derivatives 100
3.11.4 l-(2,x-Dihydroxy-alkyl)-lH-azoles and their thio
and cyclic analogs 103
3.11.5 2-[(lH-Azol-l-yl)-l,x-dihydroxyalkanes and their thio analogs 104
3.11.6 l-(x,y,z-Trihydroxyalkyl)-lH-azoles and their thio analogs 105
3.11.7 2-(x,y,z-Trihydroxyalkyl)-lH-azoles and their thio analogs 106
3.12 l-(Dihydroxyalkenyl- and alkinyl)-lH-azoles 106
3.12.1 l-(x,y-Dihydroxyalkenyl)-lH-azoles,
their thio derivatives and cyclic analogs 106
3.12.2 x-(y,z-Dihydroxy-alkinyl-lH-azoles and derivatives 107
3.13 l-(l,2-Oxidoethyl)-lH-azoles 107
3.14 l-(x,y-Oxido-alk-z-enyl)-lH-azoles 108
Contents IX
3.15 w-(x-Hydroxy-y,z-oxidoalkyl)-lH-azoles 109
3.16 Azolylmethyl-oxetanes 109
4 l-(Oxo-alkyl-, oxo-alkenyl, hydroxyalkylcarbonyl
and dioxoalkyl)-lH-azoles and their derivatives Ill
4.1 IH-Azol-l-ylmethyl-ketones 112
4.2 2-(lH-Azol-l-yl)-ethyl-ketones 113
4.3 x-(lH-Azol-l-yl)alkyl-y,z-diketones 115
4.4 x-(lH-Azol-l-yl)-l-alkene-y-ones 116
4.4.1 l-(lH-Azol-l-yl)-l-alkene-3-ones and cyclic analogs 116
4.4.2 2-(lH-Azol-l-yl)-l-alken-3-ones 117
4.4.3 2-(lH-Azol-l-ylmethyl)-l-alken-3-ones 118
4.4.4 3-(lH-Azol-l-yl)-l-alken-4-ones 118
4.4.5 4-(l-H-Azol-l-yl)-l-alken-3-ones 118
4.4.6 4-(lH-Azolyl-l-yl)-l-alken-5-ones 119
4.4.7 6-(lH-Azol-l-yl)-l-alken-7-ones 119
4.5 l-(lH-Azol-l-yl)-x-hydroxyalkan-y-als or-ones and derivatives 119
4.5.1 l-(lH-Azolyl-l-hydroxy)alkan-2-one ethers 119
4.5.1.1 l-(lH-Imidazolyl-phenoxy)alkan-2-ones 119
4.5.1.2 l-(lH-Triazolyl-l-phenoxy)alkan-2-ones and analogs 120
4.5.1.3 l-(lH-Azol-l-yl-l-hydroxy)alkan-2-ones,
their thio analogs and derivatives 121
4.5.2 l-(Azol-l-yl)-2-hydroxyalkan-x-ones 121
4.5.3 l-(Azol-l-yl)-3-hydroxy-2-ketone ethers 123
4.6 2-(lH-Azol-l-yl)-x-hydroxy or x,x'- dihydroxyalkane-y-ones,
their thio analogs and derivatives 123
4.6.1 2-(lH-Azol-l-yl)-l-hydroxy-alkan-3-ones and their thio analogs .... 123
4.6.2 2-(lH-Azol-l-yl)-l-hydroxyalkan-4-ones 123
4.6.3 2-(lH-Azol-l-yl)-4-hydroxyalkan-l-one ethers 124
4.6.4 l-(Azol-l-ylmethyl)-l,2-dihydroxy-alkyl 3-aldehyde derivatives 124
4.7 l-(l,2-Diacyrvinyl)azoles, IH-azolyl-vinyldiacetals, and -thioketals . . . 125
4.8 l-(lH-Azol-l-yl)-l-hydroxyalkyl-3-ketones
with other functions in oc'-position 125
4.9 l-(lH-Azol-l-yl)-2-hydroxyethylz-aldehydes
or -ketones, their ethers and thio analogs 126
4.9.1 l-(lH-Azol-l-yl)-2-hydroxyalkyl 3-aldehyde acetals 126
4.9.2 l-(lH-Azol-l-yl)-2-hydroxyethyl-3-ketones 126
4.10 x-(lH-Azol-l-yl)-l-hydroxyalkyl/ or 1-hydroxyalkenyl-z-ketones .... 127
4.10.1 2-(lH-Azol-l-yl)-l-hydroxyalkyl-3-ketones 127
4.10.2 x-(lH-Azol-l-yl)-l-hydroxyalkyl-z-ketones 127