U.S. patent application number 13/132979 was filed with the patent office on 2011-12-01 for inhibition and dispersion of biofilms in plants with imidazole-triazole derivatives.
This patent application is currently assigned to NORTH CAROLINA STATE UNIVERSITY. Invention is credited to John Cavanagh, Robert W. Huigens, III, Christian Melander, David F. Ritchie, Steven A. Rogers.
Application Number | 20110294668 13/132979 |
Document ID | / |
Family ID | 42310100 |
Filed Date | 2011-12-01 |
United States Patent
Application |
20110294668 |
Kind Code |
A1 |
Melander; Christian ; et
al. |
December 1, 2011 |
INHIBITION AND DISPERSION OF BIOFILMS IN PLANTS WITH
IMIDAZOLE-TRIAZOLE DERIVATIVES
Abstract
Disclosure is provided for methods of preventing, removing or
inhibiting microbial biofilm formation or microbial infection in a
plant or plant part thereof, including applying thereto a treatment
effective amount of an active compound as described herein, or an
agriculturally acceptable salt thereof. Methods of enhancing a
microbicide (e.g., including a copper, antibiotic, bacteriophage,
etc.) and/or plant defense activator are also provided, including
applying an active compound as described herein. Compositions
comprising an active compound as described herein in an
agriculturally acceptable carrier are also provided, and in some
embodiments the compositions further include a microbicide (e.g.,
including copper, antibiotic, bacteriophage, etc.) and/or plant
defense activator.
Inventors: |
Melander; Christian;
(Raleigh, NC) ; Cavanagh; John; (Cary, NC)
; Ritchie; David F.; (Durham, NC) ; Rogers; Steven
A.; (Lawrence, KS) ; Huigens, III; Robert W.;
(Wilmington, NC) |
Assignee: |
NORTH CAROLINA STATE
UNIVERSITY
RALEIGH
NC
|
Family ID: |
42310100 |
Appl. No.: |
13/132979 |
Filed: |
December 7, 2009 |
PCT Filed: |
December 7, 2009 |
PCT NO: |
PCT/US09/66979 |
371 Date: |
August 16, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61120661 |
Dec 8, 2008 |
|
|
|
Current U.S.
Class: |
504/358 ;
424/630; 424/93.6; 514/394; 514/397 |
Current CPC
Class: |
A01N 63/00 20130101;
A01N 43/653 20130101; A01N 59/20 20130101; A01N 43/647 20130101;
C07D 403/06 20130101 |
Class at
Publication: |
504/358 ;
514/397; 514/394; 424/630; 424/93.6 |
International
Class: |
A01N 43/647 20060101
A01N043/647; A01P 21/00 20060101 A01P021/00; A01P 1/00 20060101
A01P001/00; A01P 3/00 20060101 A01P003/00; A01N 59/20 20060101
A01N059/20; A01N 63/02 20060101 A01N063/02 |
Claims
1. A method of preventing, removing or inhibiting microbial biofilm
formation or microbial infection in a plant or plant part thereof,
comprising applying to said plant or plant part a treatment
effective amount of a compound of Formula (II)(a): ##STR00120##
wherein: R.sup.1a and R.sup.1b are each H; R.sup.2, R.sup.3,
R.sup.5 and are each independently H or alkyl; each occurrence of
R.sup.x, R.sup.y, R.sup.u and R.sup.v is present or absent
(depending upon chain saturation), and are each independently H or
alkyl; R.sup.6 is independently selected from the group consisting
of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol,
sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid
sidechain, amino acid and peptide, wherein R.sup.6 is optionally
substituted with one, two, three or four substituents independently
selected from: halo, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide; n=0 to 10; and m=0 to
20; or an agriculturally acceptable salt thereof; or a compound of
Formula (IV)(a): ##STR00121## wherein: R.sup.1a and R.sup.1b are
each H; R.sup.2, R.sup.3, R.sup.5 and are each independently H or
alkyl; each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is each independently H or alkyl; n=0 to 10; m=0
to 20; and p=0 to 20 or an agriculturally acceptable salt
thereof.
2. The method of claim 1, wherein said plant is a fruit crop plant
or a vegetable crop plant.
3-20. (canceled)
21. The method of claim 1, wherein said microbial biofilm formation
or microbial infection is caused by a fungi.
22. The method of claim 1, wherein said compound is applied to said
plant in an amount effective to treat or control a fungal disease
selected from the group consisting of rots, leaf molds, blights,
wilts, damping-off, spot, root rot, stem rot, mildew, brown spot,
gummosis, melanose, post-bloom fruit drop, scab, alternaria,
canker, flyspeck, fruit blotch, dieback, downy mildews, ear rots,
anthracnose bunts, smut, rust, eyespot and pecky rice.
23-34. (canceled)
35. An agricultural composition comprising: (a) an agriculturally
acceptable carrier; and (b) an antimicrobial or biofilm preventing,
removing or inhibiting a compound of Formula (II)(a): ##STR00122##
wherein: R.sup.1a and R.sup.1b are each H; R.sup.2, R.sup.3,
R.sup.5 and are each independently H or alkyl; each occurrence of
R.sup.x, R.sup.y, R.sup.u and R.sup.v is present or absent
(depending upon chain saturation), and are each independently H or
alkyl; R.sup.6 is independently selected from the group consisting
of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol,
sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid
sidechain, amino acid and peptide, wherein R.sup.6 is optionally
substituted with one, two, three or four substituents independently
selected from: halo, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide; n=0 to 10; and m=0 to
20; or an agriculturally acceptable salt thereof; or a compound of
Formula (IV)(a): ##STR00123## wherein: R.sup.1a and R.sup.1b are
each H; R.sup.2, R.sup.3, R.sup.5 and are each independently H or
alkyl; each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is each independently H or alkyl; n=0 to 10; m=0
to 20; and p=0 to 20 or an agriculturally acceptable salt
thereof.
36. The composition of claim 35, further comprising a
microbicide.
37. The composition of claim 36, wherein said microbicide comprises
copper.
38. (canceled)
39. The composition of claim 35, further comprising an
antibiotic.
40. The composition of claim 35, further comprising a
bacteriophage.
41. The composition of claim 35, further comprising a plant defense
activator.
42. The composition of claim 35, wherein said carrier is an aqueous
carrier or a solid particulate carrier.
43. (canceled)
44. The method of claim 1, wherein said compound is a compound of
Formula (II)(a)(5)(D): ##STR00124## or an agriculturally acceptable
salt thereof.
45. The composition of claim 35, wherein said compound is a
compound of Formula (II)(a)(5)(D): ##STR00125## or an
agriculturally acceptable salt thereof.
46. A method of enhancing the effects of a microbicide comprising
applying a compound of Formula (II)(a): ##STR00126## wherein:
R.sup.1a and R.sup.1b are each H; R.sup.2, R.sup.3, R.sup.5 and are
each independently H or alkyl; each occurrence of R.sup.x, R.sup.y,
R.sup.u and R.sup.v is present or absent (depending upon chain
saturation), and are each independently H or alkyl; R.sup.6 is
independently selected from the group consisting of: H, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide, wherein R.sup.6 is optionally substituted with one, two,
three or four substituents independently selected from: halo,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide,
oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino
acid and peptide; n=0 to 10; and m=0 to 20; or an agriculturally
acceptable salt thereof; or a compound of Formula (IV)(a):
##STR00127## wherein: R.sup.1a and R.sup.1b are each H; R.sup.2,
R.sup.3, R.sup.5 and are each independently H or alkyl; each
occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v, R.sup.z and
R.sup.w is present or absent (depending upon chain saturation), and
is each independently H or alkyl; n=0 to 10; m=0 to 20; and p=0 to
20 or an agriculturally acceptable salt thereof; in combination
with said microbicide.
47. The method of claim 46, wherein said microbicide comprises
copper.
48. (canceled)
49. The method of claim 46, wherein said microbicide is an
antibiotic or a bacteriophage.
50-51. (canceled)
52. The method of claim 46, wherein said active compound is a
compound of Formula (II)(a)(5)(D): ##STR00128## or an
agriculturally acceptable salt thereof.
53. A method of enhancing the effects of a plant defense activator
comprising applying a compound of Formula (II)(a): ##STR00129##
wherein: R.sup.1a and R.sup.1b are each H; R.sup.2, R.sup.3,
R.sup.5 and are each independently H or alkyl; each occurrence of
R.sup.x, R.sup.y, R.sup.u and R.sup.v is present or absent
(depending upon chain saturation), and are each independently H or
alkyl; R.sup.6 is independently selected from the group consisting
of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol,
sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid
sidechain, amino acid and peptide, wherein R.sup.6 is optionally
substituted with one, two, three or four substituents independently
selected from: halo, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide; n=0 to 10; and m=0 to
20; or an agriculturally acceptable salt thereof; or a compound of
Formula (IV)(a): ##STR00130## wherein: R.sup.1a and R.sup.1b are
each H; R.sup.2, R.sup.3, R.sup.5 and are each independently H or
alkyl; each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is each independently H or alkyl; n=0 to 10; m=0
to 20; and p=0 to 20 or an agriculturally acceptable salt thereof;
in combination with said plant defense activator.
54-55. (canceled)
56. The method of claim 53, wherein said active compound is a
compound of Formula (II)(a)(5)(D): ##STR00131## or an
agriculturally acceptable salt thereof.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Application No. 61/120,661, filed Dec. 8, 2008
the disclosure of which is incorporated herein by reference in its
entirety. This application is related to U.S. application Ser. No.
12/426,742, filed Apr. 20, 2009, and published Oct. 22, 2009, as
publication no. 2009/0263438, the disclosure of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to compositions and methods useful
for controlling biofilms and microorganisms in plants, particularly
vascular plants.
BACKGROUND OF THE INVENTION
[0003] New approaches are urgently needed to improve agricultural
production, given the steadily growing global population that is
predicted to reach 6-9 billion persons by mid-century, the
continual strain on existing and finite agricultural lands, and the
recent diversion of valuable agricultural land from production of
crops to production of biomass for fuels. Here we describe new
approaches to increase agricultural production by controlling the
adverse effects of microorganisms on plants.
[0004] The five main crops on which modern societies depend most
heavily include corn, cotton, rice, soybeans, and wheat. All of
these crops are affected in a deleterious manner by biofilm
formation. In addition, other valuable plants such as those
producing fruits and vegetables are similarly affected. Plants
grown for biomass stand to increase as a valuable crop, albeit not
for food, and also can benefit from protection from biofilm
formation. Forestry crops and ornamentals also suffer from
biofilms.
SUMMARY OF THE INVENTION
[0005] The present invention is a method of preventing, removing or
inhibiting microbial biofilm formation or microbial infection in a
plant or plant part thereof, comprising applying to the plant or
plant part a treatment effective amount of a compound selected from
the group consisting of compounds of Formula (I), Formula
(I)(a)(1), Formula (I)(b)(1), Formula (I)(a)(2), Formula (I)(b)(2),
Formula (I)(i), Formula (I)(i)(a), Formula (II), Formula (II)(a),
Formula (II)(i), Formula (II)(i)(a), Formula (III), Formula
(III)(a), Formula (III)(b), Formula (III)(b)(i), Formula
(III)(b)(ii), Formula (IV), Formula (IV)(a), Formula (IV)(i),
Formula (IV)(i)(a), Formula (V), Formula (V)(a), Formula (V)(i),
Formula (V)(i)(a), Formula (VI), Formula (VI)(a), Formula (VI)(i)
and Formula (VI)(i)(a) as described herein, or an agriculturally
acceptable salt thereof.
[0006] In some embodiments, the plant is a fruit or a vegetable
crop plant.
[0007] In some embodiments, the plant is a citrus tree, and the
compound is applied in an amount effective to treat or control a
bacterial disease selected from the group consisting of canker,
bacterial spot, Black Pit (fruit), Blast, citrus variegated
chlorosis, and Citrus Huanglongbing. In some embodiments, the
citrus tree is selected from the group consisting of orange,
grapefruit, Mandarin, lemon, lime and Kumquat.
[0008] In some embodiments, the plant is a pome fruit, and the
compound is applied in an amount effective to treat or control a
bacterial disease selected from the group consisting of Fire
Blight, Crown Gall, Blister spot and Hairy root. In some
embodiments, the pome fruit is selected from the group consisting
of apple, pear, quince, Asian pear, and loquats.
[0009] In some embodiments, the plant is a Musa species such as a
banana, and the compound is applied in an amount effective to treat
or control Ralstonia solanacearum.
[0010] In some embodiments, the plant is a cole (Brassicaceae) such
as cabbage or broccoli, and the compound is applied in an amount
effective to treat or control black rot (Xanthomonas
campestris).
[0011] In some embodiments, the plant is a winegrape, and the
compound is applied in an amount effective to treat or control for
Pierce's disease (Xylella fastidosa) or crown gall (Agrobacterium
vitas, A. tutnefaciens).
[0012] In some embodiments, the plant is a stone fruit or nut
(e.g., peaches, nectarines, plums, almonds, walnuts), and the
compound is applied in an amount effective to treat or control
bacterial spot and/or blight caused by Xanthomonas arboricola;
blight caused by Pseudomonas syringae); crown gall caused by
Agrobacterium tumefaciens; phony peach and plum; or almond leaf
scorch caused by Xylella fastidosa.
[0013] In some embodiments, the plant is a landscape and/or shade
tree (e.g., oak, maple, birch, etc.) for bacterial leaf scorch
disease (e.g., cause by Xylella fastidosa).
[0014] In some embodiments, the plant is a potato, and the compound
is applied in an amount effective to treat or control soft rot or
black leg (Erwinia, Pectobacterium).
[0015] In some embodiments, the plant is a pepper plant, and the
compound is applied in an amount effective to treat or control a
bacterial disease selected from the group consisting of Bacterial
Spot, Bacterial wilt, Bacterial canker, and Syringae seedling
blight and leaf spot.
[0016] In some embodiments, the plant is a tomato plant, and the
compound is applied in an amount effective to treat or control a
bacterial disease selected from the group consisting of: bacterial
canker, bacterial speck, bacterial spot, bacterial stern rot and
fruit rot, Bacterial wilt, Pith necrosis, and Syringae leaf
spot.
[0017] In some embodiments, the plant is a soybean plant, and the
compound is applied in an amount effective to treat or control a
bacterial disease selected from the group consisting of Bacterial
blight, Bacterial pustules, Bacterial wilt, Bacterial crinkle leaf,
Bacterial tan spot, and Wildfire.
[0018] In some embodiments, the plant is corn, and the compound is
applied in an amount effective to treat or control a bacterial
disease selected from the group consisting of: Bacterial leaf
blight, stalk rot, bacterial stripe, chocolate spot, holcus spot
all causes by Pseudomonas species, Bacterial leaf spot caused by
Xanthomonas species, Bacterial stalk rot, top rot and Stewart's
disease caused by Erwinia species, seed rot-seedling blight caused
by Bacillus species, Purple leaf sheath caused by Heimparctsitic
bacteria, Corn stunt caused by Spriroplastita kunkelii, Goss's
bacterial wilt and blight caused by Clivibacter michigcmensis.
[0019] In some embodiments, the plant is cotton, and the compound
is applied in an amount effective to treat or control a bacterial
disease selected from the group consisting of Bacterial blight
caused by Xanthomonas species, and Crown gall caused by
Agrobacterium species and Lint degradation caused by Erwinia
species.
[0020] In some embodiments, the plant is wheat, and the compound is
applied in an amount effective to treat or control a bacterial
disease selected from the group consisting of Bacterial leaf
blight, bacterial sheath rot and Basal glume rot caused by
Pseudomonas species, Bacterial mosaic and Spike blight caused by
Clavibacter species, Black chaff caused by Xanthomonas species, and
Pink seed caused by Erwinia (Pantoea) species.
[0021] In some embodiments, the plant is rice, and the compound is
applied in an amount effective to treat or control a bacterial
disease selected from the group consisting of bacterial blight and
leaf streak caused by Xanthomonas species, Foot rot caused by
Erwinia species, Grain rot caused by Burkholderia species, and
Sheath brown rot caused by Pseudomonas species.
[0022] In some embodiments, the plant is pineapple, and the
compound is applied in an amount effective to treat or control a
bacterial disease selected from the group consisting of bacterial
heart rot, fruit collapse, bacterial fruitlet brown rot, marbled
fruit, pink fruit and soft rot caused by Erwinia species, and
Acetic souring caused by Acetic acid bacteria.
[0023] In some embodiments, the microbial biofilm formation or
microbial infection is caused by a fungi. In some embodiments, the
compound is applied to the plant in an amount effective to treat or
control a fungal disease selected from the group consisting of
rots, leaf molds, blights, wilts, damping-off, spot, root rot, stem
rot, mildew, brown spot, gummosis, melanose, post-bloom fruit drop,
scab, alternaria, canker, flyspeck, fruit blotch, dieback, downy
mildews, ear rots, anthracnose bunts, smut, rust, eyespot and pecky
rice.
[0024] In some embodiments, the plant is citrus, and the compound
is applied in an amount effective to treat or control a fungal
disease selected from the group consisting of: Alternaria brown
spot caused by Alternaria alternaria, Brown rot caused by
Phytophtora citricola, Greasy spot and Greasy spot rind blotch
caused by Mycosphaerella citri, Melanose caused by Diaporthe citri,
Phytophthora foot rot, gummosis and root rot caused by Phytophthora
citrophthora, Phytophthora palmivora, Phytophthora syringae and
other Phytophthora spp, Post bloom fruit drop caused by
Colletotrichum acutatum, and Scab caused by Elsinoe fawcettii.
[0025] In some embodiments, the plant is Pome fruit, and the
compound is applied in an amount effective to treat or control a
fungal disease selected from the group consisting of: Apple scab
caused by Venturia inaequalis, Bitter rot caused by Colletotrichum
gloeosporioides, Diplodia canker caused by Dilpodia mutila,
Phytophthora crown, collar, root and fruit rot caused by
Phytophthora spp., Powdery mildew caused by Podosphaera
leucotricha, Pacific Coast pear rust, Cedar apple rust, Quince rust
caused by Gymnosporangiwn spp., and Flyspeck caused by
Schizothyrium pomi.
[0026] In some embodiments, the plant is Peppers, and the compound
is applied in an amount effective to treat or control a fungal
disease selected from the group consisting of: Anthracnose caused
by Colletotrichum spp., Damping-off and root rot caused by
Rhizoctonia solani, Phytophthora spp., Fusarium spp., and Pythium
spp., Phytophthora blight caused by Phytophthora capsici, and
Verticillium wilt caused by Verticillium albo-atrium.
[0027] In some embodiments, the plant is Tomato, and the compound
is applied in an amount effective to treat or control a fungal
disease selected from the group consisting of: Alternaria stem
canker caused by Alternaria alternaria, Anthracnose caused by
Colletotrichum spp., Fusarium crown, root rot and wilt caused by
Fusarium oxysporum, Gray mold caused by Botrytis cinerea, Late
blight caused by phytophthora infestans, Pythium damping-off and
fruit rot caused by Pythium spp., Rhizoctonia damping-off and fruit
rot caused by Rhizoctonia solani, Septoria leaf spot caused by
Septoria lycopersici, Verticillium wilt caused by Verticillium
albo-atrum, and White mold caused by Sclerotinia sclerotiorwn.
[0028] In some embodiments, the plant is Soybean, and the compound
is applied in an amount effective to treat or control a fungal
disease selected from the group consisting of: Phytophthora root
and stem rot caused by Phytophthora sojae, Pythium root rot,
damping-off and seed decay caused by Pythium spp., Brown stern rot
caused by Phialophora gregata, Rhizoctonia root and stem rot caused
by Rhizoctonia solani, Stern canker, pod and stem blight caused by
Diaporthe phaseolorum, Phomopsis seed decay caused by Phomopsis
longicolla, Charcoal rot caused by Macrophomina phaseolina,
Sclerotinia stem rot caused by Sclerotinia sclerotiorum, Sudden
death syndrome caused by Fusarium solani, and Soybean Rust caused
by Phakopsora pachyrhizi.
[0029] In some embodiments, the plant is Grape, and the compound is
applied in an amount effective to treat or control a fungal disease
selected from the group consisting of: Alternaria rot caused by
Alternaria alternaria, Angular leaf spot caused by Mycosphaerella
angulata, Botrytis bunch rot and blight caused by Botrytis cinerea,
Diplodia cane dieback and bunch rot caused by Diplodia natalensis,
Downy mildew caused by Plasmopara viticola, Phytophthora crown and
root rot caused by Phytophthora spp., Powdery mildew caused by
Uncinula necator, Ripe rot caused by Glomerella cingulata, Septoria
leaf spot caused by Septoria ampelopsidis, and Verticillium wilt
caused by Verticillium dahliae.
[0030] In some embodiments, the plant is Potato, and the compound
is applied in an amount effective to treat or control a fungal
disease selected from the group consisting of: Brown spot, Black
pit and Early blight caused by Alternaria spp., Fusarium dry rot
and wilt caused by Fusarium spp., Gangrene caused by Phoma spp.,
Late blight and Pink rot caused by Phytophthora spp., Rhizoctonia
canker and black scurf caused by Rhizoctonia solani, Rosellinia
black rot caused by Rosellinia spp., Septoria leaf spot caused by
Septoria lycopersici, Stem rot caused by Sclerotium rolfsii,
Verticillium wilt caused by Verticillium albo-atrum, and White mold
caused by Sclerotinia sclerotiorum.
[0031] In some embodiments, the plant is Pineapple, and the
compound is applied in an amount effective to treat or control a
fungal disease selected from the group consisting of: Anthracnose
caused by Colletotrichum ananas, Bull rot and White leaf spot
caused by Chalara paradoxa, Leaf spot caused by Curvularia
eragrostidis, Phytophthora heart rot caused by Phytophthora
cinnamomi and Phytophthora parasitica, Root rot and Seedling blight
caused by Pythium spp., and Leaking brown ring caused by
Tofflieadis dimenationa.
[0032] In some embodiments, the plant is Cotton, and the compound
is applied in an amount effective to treat or control a fungal
disease selected from the group consisting of: Anthracnose caused
by Glomerella gossypii, Boll rot caused by Colletotrichum gossypii,
Fusarium spp., Phytophthora spp., or Rhizoctonia solani, Fusarium
wilt caused by Fusarium oxysporum, Leaf spot caused by Alternaria
spp., Cercospora gossypina, Rhizoctonia solani, and Stemphylium
solani, Lint contamination caused by Aspergillus flavus, Powdery
mildew caused by Leveillula taurica, Cotton rust caused by Puccinia
schedonnardii, Southwestern cotton rust caused by Puccinia
cacabata, Tropical cotton rust caused by Phakopsora gossypii,
Southern blight caused by Sclerotium rolfsii, Seedling disease
complex caused by Colletotrichum gossypii, Fusarium spp., Pythium
spp., Rhizoctonia solani, or Thielaviopsis basicola, Stem canker
caused by Phoma exigua, and Verticillium wilt caused by
Verticillium dahliae.
[0033] In some embodiments, the plant is Corn, and the compound is
applied in an amount effective to treat or control a fungal disease
selected from the group consisting of: Anthracnose caused by
Colletotrichum graminicola, Aspergillus ear and kernel rot caused
by Aspergillus flavus, Banded leaf, sheath spot, root rot and stalk
rot caused by Rhizoctonia solani, Brown spot, Black spot and Stalk
rot caused by Physoderma maydis, Curvularia leaf spot caused by
Curvularia clavata, Diplodia ear rot, stalk rot, seed rot and
seedling blight caused by Dilpodia spp., Downey mildews caused by
Sclerophthora spp. or Peronosclerospora spp., Ear rots caused by
Alternaria alternaria, Ergot caused by Claviceps gigantea, Fusarium
ear, stalk, kernel, root, seed rot, seedling blight caused by
Fusarium spp., Cercospora leaf spot caused by Cercospora
zeae-maydis, Helminthosporium ear rot caused by Helminthosporium
carbonum, Pythium root rot and stalk rot caused by Pythium spp.,
Rhizoctonia ear rot caused by Rhizoctonia zeae, Common corn rust
and Southern corn rust caused by Puccinia spp., Southern blight
caused by Athelia rolfsii, Common smut caused by Ustilago zeae,
Southern corn leaf blight and stalk rot caused by Cochliobolus
heterostrophus, and storage rots caused by Aspergillus spp. and
Penicillium spp.
[0034] In some embodiments, the plant is Rice, and the compound is
applied in an amount effective to treat or control a fungal disease
selected from the group consisting of: Black kernel caused by
Curvularia lunata, Blast caused by Pyricularia oryzae, Brown spot
caused by Cochliobolus miyabeanus, Downy mildew caused by
Sclerophthora macrospora, False smut caused by Ustilaginoidea
Wrens, Narrow brown leaf spot caused by Cercospora janseana, Pecky
rice caused by Fusarium spp., Microdochium oryzae, or Sarocladium
oryzae, Root rot caused by Fusarium spp, or Pythium spp., Seedling
blight caused by fungi (e.g., Cochliobolus miyabeanus, Curvularia
spp., Fusarium spp., Rhizoctonia solani, Sclerotium rolfsii and
Athelia Stackburn caused by Alternaria padwickii, Stem rot caused
by Magnaporthe salvinii, Water-mold (seed-rot and seedling disease)
caused by Achlya spp., Fusarium spp., or Pythium spp.
[0035] In some embodiments, the plant is Wheat, and the compound is
applied in an amount effective to treat or control a fungal disease
selected from the group consisting of: Alternaria leaf blight
caused by Alternaria triticina, Anthracnose caused by
Colletotrichum graminicola, Black head molds caused by Cladosporium
spp., Epicoccum spp., Sporobolomyces spp. or Stemphylium spp.,
Common bunt caused by Tilletia spp., Crown rot, seedling blight and
dryland root rot caused by Fusarium spp. or Gibberella spp., Downey
mildew caused by Sclerophthora macrospora, Dwarf bunt caused by
Tilletia controversa, Ergot caused by Claviceps putpurea, Eyespot
caused by Tapesia yallundae, Leaf rust caused by Puccinia
triticina, Loose smut caused by Ustilago tritici, Microscopia leaf
spot caused by Phaeosphaeria microscopia, Phoma spot caused by
Phoma spp., Powdery mildew caused by Erysiphe graminis, Pythium
root rot, Snow rot caused by Pythium spp., Rhizoctonia root rot
caused by Rhizoctonia solani, Scab (head blight) caused by Fusarium
spp. or Gibberella spp., Southern blight caused by Sclerotium
Speckled snow mold caused by Typhula spp., Stem rust caused by
Puccinia graminis, storage molds caused by Aspergillus spp. or
Penicillium spp., Take-all caused by Gaeumannomyces graminis, and
Zoosporic root rot caused by Lagena radicola.
[0036] A further aspect of the present invention is an agricultural
composition comprising: (a) an agriculturally acceptable carrier
(e.g., an aqueous carrier or a solid particulate carrier); and (b)
an antimicrobial or biofilm preventing, removing or inhibiting
compound selected from the group consisting of compounds of Formula
(I), Formula (I)(a)(1), Formula (I)(b)(1), Formula (I)(a)(2),
Formula (I)(b)(2), Formula (I)(i), Formula (I)(i)(a), Formula (II),
Formula (II)(a), Formula (II)(i), Formula (II)(i)(a), Formula
(III), Formula (III)(a), Formula (III)(b), Formula (III)(b)(i),
Formula (III)(b)(ii), Formula (IV), Formula (IV)(a), Formula
(IV)(i), Formula (IV)(i)(a), Formula (V), Formula (V)(a), Formula
(V)(i), Formula (V)(i)(a), Formula (VI), Formula (VI)(a), Formula
(VI)(i) and Formula (VI)(i)(a) as described herein, or an
agriculturally acceptable salt thereof. In some embodiments, the
composition further includes a microbicide. In some embodiments,
the microbicide comprises copper (e.g., copper hydroxide). In some
embodiments, the microbicide comprises an antibiotic or a
bacteriophage. In some embodiments, the composition further
includes a plant defense activator. In some embodiments, the
composition further includes both a plant defense activator and a
microbicide.
[0037] In some embodiments, the compound is a compound of Formula
(II)(a)(5)(D):
##STR00001##
or an agriculturally acceptable salt thereof.
[0038] Further provided are methods of enhancing the effects of a
microbicide comprising applying an active compound selected from
the group consisting of compounds of Formula (I), Formula
(I)(a)(1), Formula (I)(b)(1), Formula (I)(a)(2), Formula (I)(b)(2),
Formula (I)(i), Formula (I)(i)(a), Formula (II), Formula (II)(a),
Formula (II)(i), Formula (II)(i)(a), Formula (III), Formula
(III)(a), Formula (III)(b), Formula (III)(b)(i), Formula
(III)(b)(ii), Formula (IV), Formula (IV)(a), Formula (IV)(i),
Formula (IV)(i)(a), Formula (V), Formula (V)(a), Formula (V)(i),
Formula (V)(i)(a), Formula (VI), Formula (VI)(a), Formula (VI)(i)
and Formula (VI)(i)(a) as described herein, in combination with
said microbicide. In some embodiments, the microbicide comprises
copper (e.g., copper hydroxide). In some embodiments, the
microbicide is an antibiotic or a bacteriophage. In some
embodiments, the applying step is carried out by applying the
active compound and the microbicide simultaneously. In some
embodiments, the applying step is carried out by applying the
active compound and the microbicide sequentially. In some
embodiments, the compound is a compound of Formula
(II)(a)(5)(D):
##STR00002##
or an agriculturally acceptable salt thereof.
[0039] Also provided are methods of enhancing the effects of a
plant defense activator comprising applying an active compound
selected from the group consisting of compounds of Formula (I),
Formula (I)(a)(1), Formula (I)(b)(1), Formula (I)(a)(2), Formula
(I)(b)(2), Formula (I)(i), Formula (I)(i)(a), Formula (II), Formula
(II)(a), Formula (II)(i), Formula (II)(i)(a), Formula (III),
Formula (III)(a), Formula (III)(b), Formula (III)(b)(i), Formula
(III)(b)(ii), Formula (IV), Formula (IV)(a), Formula (IV)(i),
Formula (IV)(i)(a), Formula (V), Formula (V)(a), Formula (V)(i),
Formula (V)(i)(a), Formula (VI), Formula (VI)(a), Formula (VI)(i)
and Formula (VI)(i)(a) as described herein, in combination with
said plant defense activator. In some embodiments, the applying
step is carried out by applying the active compound and the
microbicide simultaneously. In some embodiments, the applying step
is carried out by applying the active compound and the microbicide
sequentially. In some embodiments, the compound is a compound of
Formula (II)(a)(5)(D):
##STR00003##
[0040] or an agriculturally acceptable salt thereof.
[0041] A further aspect of the present invention is an
antimicrobial or biofilm preventing, removing or inhibiting
compound selected from the group consisting, of compounds of
Formula (I), Formula (I)(a)(1), Formula (I)(b)(1), Formula
(I)(a)(2), Formula (I)(b)(2), Formula (I)(i), Formula (I)(i)(a),
Formula (II), Formula (II)(a), Formula (II)(i), Formula (II)(i)(a),
Formula (III), Formula (III)(a), Formula (III)(b), Formula
(III)(b)(i), Formula (III)(b)(ii), Formula (IV), Formula (IV)(a),
Formula (IV)(i), Formula (IV)(i)(a), Formula (V), Formula (V)(a),
Formula (V)(i), Formula (V)(i)(a), Formula (VI), Formula (VI)(a),
Formula (VI)(i) and Formula (VI)(i)(a) as described herein, for use
in treating or preventing a bacterial or fungal infection in a
plant or plant part as described above and below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1. Construction of the initial 2-AIT library.
[0043] FIG. 2. Variation on tether length.
[0044] FIG. 3. Effects of bacterial spot disease on pepper plants
and crops.
[0045] FIG. 4. Evaluation of foliar disease on inoculated pepper
plants.
[0046] FIG. 5. Pepper fruit yield per inoculated plant.
[0047] FIG. 6. Evaluation of foliar disease on pepper plants
measured by plot average.
[0048] FIG. 7. Average pepper fruit yield per plant/plot, July 1
and 9 harvests.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0049] The present invention is further described below. All patent
references referred to in this patent application are hereby
incorporated by reference in their entirety as if set forth fully
herein.
A. Definitions.
[0050] "Active compound" as used herein refers to the various
embodiments of compounds described in Section B (triazole
derivatives) set forth below.
[0051] "Plant" as used herein includes all members of the plant
kingdom, including higher (or "vascular") plants and lower
("non-vascular") plants, and particularly including all plants in
the divisions Filicinae, Gymnospermae (or "gymnosperm"), and
Angiospermae (or "Angiosperm"). Nonvascular plants of the present
invention include, but are not limited to, bryophytes.
[0052] A plant of the present invention includes, but is not
limited to, a crop plant, a turf grass, an ornamental species, a
species grown for timber or pulp, a species grown for biofuels or
species grown for pharmaceuticals. Additionally, plants of the
present invention include, but are not limited to, tobacco, tomato,
potato, sugar beet, pea, carrot, cauliflower, broccoli, soybean,
canola, sunflower, alfalfa, cotton, rapeseed, Arabidopsis, peach,
pepper, apple, chile, peanut, orange, grape, coffee, cassava,
spinach, lettuce, cucumber, wheat, maize, rye, rice, turfgrass,
oat, barley, sorghum, millet, sugarcane, or banana.
[0053] "Angiosperm" as used herein includes, but is not limited to,
plants of the sub-classes Monocotyledoneae (or monocots) and
Dicotyledoneae (or dicots).
[0054] Monocotyledoneae (or monocots) as used herein includes but
is not limited to Amaryllidaceae--the Amaryllis Family,
Gramineae(Poaceae)--the Grass Family, Liliaceae--the Lily Family,
Orchidaceae--the Orchid Family, Palmae(Aracaceae)--the Palm Family;
and Lemnacea--the duckweed family.
[0055] Dicotyledoneae (or dicots) as used herein includes but is
not limited to Cactacae--the Cactus Family, Compositae
(Asteraceae)--the Sunflower Family, Cruciferae (Brassicaceae)--the
Mustard Family, Cucurbitaceae--the Gourd Family, Ericaceae--the
Heath Family, Euphorbiaceae--the Spurge Family, Lauraceae--the
Laurel Family, Leguminosae (Fabaceae)--the Pea Family,
Rosaceae--the Rose Family, Rutaceae--the Rue Family,
Solanaceae--the Nightshade Family, and Umbelliferae (Apiaceae)--the
Carrot family.
[0056] Gymnospermae (or "Gymnosperms") as used herein includes but
is not limited to conifers.
[0057] "Conifer," as used herein, refers to a member of the order
Coniferae in the sub-phylum Gymnospermae in the phylum Spermaphyta.
Exemplary conifers which may be used in practicing the present
invention are the members of the family Pinaceae, which include,
for example, loblolly pine (Pinus taeda), slash pine (Pinus
elliotii), longleaf pine (Pinus palustris), shortleaf pine (Pinus
echinata), ponderosa pine (Pinus ponderosa), red pine (Pinus
resinosa), jack pine (Pinus banksiana), Eastern white pine (Pinus
strobus), Western white pine (Pinus monticola), sugar pine (Pinus
lambertiana), Iodgepole pine (Pinus contorta), Monterey pine (Pinus
radiata), Afghan pine (Pinus eldarica), Scots pine (Pinus
sylvestris), and Virginia pine (Pinus virdniana); Douglas-fir
(Pseudotsuga menziesii); Western hemlock (Tsuga canadensis); Sitka
spruce (Picea glauca); redwood (Sequoia sempervirens); the true
firs including silver fir (Abies amabilis), grand fir (Abies
grandis) noble fir (Abies procera), white fir (Abies concolor),
balsam fir (Abies balsamea); and the cedars which include Western
red cedar (Thuja plicata), incense cedar (Libocedrus decurrens),
Port Orford cedar (Chamaecyparis lawsoniona), and Alaska
yellow-cedar (Chamaecyparis nootkatensis); and Western larch (Laryx
occidentalis). See, e.g., U.S. Pat. No. 5,122,466 to Stomp et
al.
[0058] "Duckweed" as used herein includes plants of the genus Lemna
(L. aequinoctialis, L. dispenna, L. ecuadoriensis, L. gibba, L.
japonica, L. minor, L. miniscula, L. obscura, L. perpusilla, L.
tenera, L. trisulca, L. turionifera, L. valdivian); genus Spirodela
(S. intermedia, S. polyrrhiza, S. punctata); genus Wolffia (Wa.
angusta, Wa. arrhiza, Wa. australina, Wa. borealis, Wa.
brasiliensis, Wa. columbiana, Wa. elongata, Wa. globosa, Wa.
microscopica, Wa. neglecta) and genus Wolfiella (WI. caudata, WI.
denticulata, WI. gladiata, WI. hyalina, WI. lingulata, WI. repunda,
WI. rotunda, and WI. neotropica). See, e.g., U.S. Pat. No.
7,161,064 to Stomp et al.
[0059] Particular examples of plants include but are not limited to
all cereal and grain crops, herbs and spices, oil seed crops,
sugarcane, vegetable crops, brassica vegetables, bulb vegetables,
cucurbit vegetables and fruit, leafy vegetables, fruiting
vegetables, legume vegetables, root and tuber vegetables, tree,
vine and shrub crops, berry crops, citrus (e.g., orange,
grapefruit, Mandarin (including Tangerine and Satsuma), lemon,
lime, and kumquat), pome fruit (e.g., apple, pear, quince, Asian
pear, loquat, etc.), stone fruit (e.g., peach, apricot, prune,
plum, cherries, almond, etc.), miscellaneous tree food crops,
non-food tree crops, tree nuts, tropical and subtropical trees and
fruit, vine crops, pasture grasses, forage legumes, and rangeland,
grass seed or sod production, pastures, cotton, corn, soybeans,
rice, wheat, greenhouse/shadehouse grown plants, ornamental, plant
nurseries, Christmas trees, golf courses and turf, forestry,
tobacco, orchids, flowers and roses, foliage crops, algae such as
green algae, bryophytes (mosses, liverworts, hornworts), etc. Note
that "foliage crops" refers to the types of plants (ferns, etc.)
that are typically used in home or commercial settings for
decorative purposes; this alone constitutes a very large commercial
industry.
[0060] "Plant part" as used herein refers to seeds, roots, leaves,
shoots, fruits (e.g., apples, pineapples, citrus fruit, etc.),
vegetables, tubers, flowers (e.g., cut flowers such as roses, as
well as the reproductive parts of plants), petals, stem, trunk,
etc., harvested or collected from a plant as described herein. The
plant part of a vascular plant may be a non-vascular part, such as
a seed or meristem (growing tip of a shoot).
[0061] "Applying" as described herein can be carried out directly
or indirectly by any suitable technique, including topically
applying to the plant or plant part, applying to the media in which
the plant or plant part is grown, stored, displayed or maintained
(e.g., adding to water in which the stems of cut flowers are
placed), etc. Note that the plant may be grown in any suitable
media, including but not limited to soil, potting soil, soilless
media such as sand and hydroponic media (including, solution
culture, medium culture, and deep water culture), etc.
[0062] "Agricultural composition" as described herein may be in any
suitable form, including but not limited to: wettable powders, dry
flowables, soluble powders, water dispersibles, liquids, dusts,
emulsifiable concentrates, flowables, fumigants, water dispersible
granules, liquid concentrates, granules, water soluble packages,
wettable powders in water soluble films, emulsions, etc.
[0063] "Triazole" refers to the commonly known structures:
##STR00004##
[0064] "Imidazole" refers to the commonly known structure:
##STR00005##
[0065] "H" refers to a hydrogen atom. "C" refers to a carbon atom.
"N" refers to a nitrogen atom. "O" refers to an oxygen atom. "Halo"
refers to F, Cl, Br or I. The term "hydroxy," as used herein,
refers to an --OH moiety. "Br" refers to a bromine atom. "Cl"
refers to a chlorine atom. "I" refers to an iodine atom. "F" refers
to a fluorine atom.
[0066] An "acyl group" is intended to mean a group --C(O)--R, where
R is a suitable substituent (for example, an acetyl group, a
propionyl group, a butyroyl group, a benzoyl group, or an
alkylbenzoyl group).
[0067] "Alkyl," as used herein, refers to a straight or branched
chain hydrocarbon containing from 1 or 2 to 10 or 20 or more carbon
atoms (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13,
C14, C15, etc.). Representative examples of alkyl include, but are
not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,
n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. In some
embodiments, alkyl groups as described herein are optionally
substituted (e.g., from 1 to 3 or 4 times) with independently
selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide.
[0068] As generally understood by those of ordinary skill in the
art, "saturation" refers to the state in which all available
valence bonds of an atom (e.g., carbon) are attached to other
atoms. Similarly, "unsaturation" refers to the state in which not
all the available valence bonds are attached to other atoms; in
such compounds the extra bonds usually take the form of double or
triple bonds (usually with carbon). For example, a carbon chain is
"saturated" when there are no double or triple bonds present along
the chain or directly connected to the chain (e.g., a carbonyl),
and is "unsaturated" when at least one double or triple bond is
present along the chain or directly connected to the chain (e.g., a
carbonyl). Further, the presence or absence of a substituent
depending upon chain saturation will be understood by those of
ordinary skill in the art to depend upon the valence requirement of
the atom or atoms to which the substituent binds (e.g.,
carbon).
[0069] The term "optionally substituted" indicates that the
specified group is either unsubstituted, or substituted by one or
more suitable substituents. A "substituent" is an atom or atoms
substituted in place of a hydrogen atom on the parent chain or
cycle of an organic molecule, for example, H, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0070] "Alkenyl," as used herein, refers to a straight or branched
chain hydrocarbon containing from 1 or 2 to 10 or 20 or more
carbons, and containing at least one carbon-carbon double bond,
formed structurally, for example, by the replacement of two
hydrogens. Representative examples of "alkenyl" include, but are
not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl,
3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl,
3-decenyl and the like. In some embodiments, alkenyl groups as
described herein are optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0071] "Alkynyl," as used herein, refers to a straight or branched
chain hydrocarbon group containing from 1 or 2 to 10 or 20 or more
carbon atoms, and containing at least one carbon-carbon triple
bond. Representative examples of alkynyl include, but are not
limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,
2-pentynyl, 1-butynyl and the like. In some embodiments, alkynyl
groups as described herein are optionally substituted (e.g., from 1
to 3 or 4 times) with independently selected H, halo, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0072] The term "cycloalkyl," as used herein, refers to a saturated
cyclic hydrocarbon group containing from 3 to 8 carbons or more.
Representative examples of cycloalkyl include, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
In some embodiments, cycloalkyl groups as described herein are
optionally substituted (e.g., from 1 to 3 or 4 times) with
independently selected H, halo, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide.
[0073] "Heterocyclo," as used herein, refers to a monocyclic or a
bicyclic ring system. Monocyclic heterocycle ring systems are
exemplified by any 5 or 6 member ring containing 1, 2, 3, or 4
heteroatoms independently selected from the group consisting, of:
O, N, and S. The 5 member ring has from 0 to 2 double bonds, and
the 6 member ring has from 0-3 double bonds. Representative
examples of monocyclic ring systems include, but are not limited
to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane,
dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine,
isothiazole, isothiazoline, isothiazolidine, isoxazole,
isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline,
oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine,
piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine,
pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine,
tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole,
thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline,
thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone,
sulfoxide, thiopyran, triazine, triazole, trithiane, and the like.
Bicyclic ring systems are exemplified by any of the above
monocyclic ring systems fused to an aryl group as defined herein, a
cycloalkyl group as defined herein, or another monocyclic ring
system as defined herein. Representative examples of bicyclic ring
systems include but are not limited to, for example, benzimidazole,
benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole,
benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine,
1,3-benzodioxole, cinnoline, indazole, indole, indoline,
indolizine, naphthyridine, isobenzofuran, isobenzothiophene,
isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine,
quinoline, quinolizine, quinoxaline, quinazoline,
tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine,
and the like. In some embodiments, heterocyclo groups as described
herein are optionally substituted (e.g., from 1 to 3 or 4 times)
with independently selected H. halo, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide.
[0074] "Aryl" as used herein refers to a fused ring system having
one or more aromatic rings. Representative examples of aryl
include, azulenyl, indanyl, indenyl, naphthyl, phenyl,
tetrahydronaphthyl, and the like. The aryl groups of this invention
can be substituted with 1, 2, 3, 4, or 5 substituents independently
selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,
alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, aryloxy,
azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl,
halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto,
nitro, sulfamyl, sulfo, sulfonate. --NR'R'' (wherein, R' and R''
are independently selected from hydrogen, alkyl, alkylcarbonyl,
aryl, arylalkyl and formyl), and --C(O)NR'R'' (wherein R' and R''
are independently selected from hydrogen, alkyl, alkylcarbonyl,
aryl, arylalkyl, and formyl). In some embodiments, aryl groups as
described herein are optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0075] "Heteroaryl" means a cyclic, aromatic hydrocarbon in which
one or more carbon atoms have been replaced with heteroatoms. If
the heteroaryl group contains more than one heteroatom, the
heteroatoms may be the same or different. Examples of heteroaryl
groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl,
pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl, chromenyl,
xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl,
pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl,
quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl,
and benzo[b]thienyl. Preferred heteroaryl groups are five and six
membered rings and contain from one to three heteroatoms
independently selected from the group consisting of: O, N, and S.
The heteroaryl group, including each heteroatom, can be
unsubstituted or substituted with from 1 to 4 suitable
substituents, as chemically feasible. For example, the heteroatom S
may be substituted with one or two oxo groups, which may be shown
as .dbd.O. In some embodiments, heteroaryl groups as described
herein are optionally substituted (e.g., from 1 to 3 or 4 times)
with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide.
[0076] "Alkoxy," as used herein, refers to an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxy group, as defined herein. Representative examples of alkoxy
include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
In some embodiments, alkoxy groups as described herein are
optionally substituted (e.g., from 1 to 3 or 4 times) with
independently selected H, halo, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide.
[0077] An "amine" or "amino" is intended to mean the group --NH,.
"Optionally substituted" amines refers to --NH.sub.2 groups wherein
none, one or two of the hydrogens is replaced by a suitable
substituent as described herein, such as alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, carbonyl,
carboxy, etc. In some embodiments, one or two of the hydrogens are
optionally substituted with independently selected, halo, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide. Disubstituted amines may have substituents that are
bridging, i.e., form a heterocyclic ring structure that includes
the amine nitrogen.
[0078] An "amide" as used herein refers to an organic functional
group having a carbonyl group (C.dbd.O) linked to a nitrogen atom
(N), or a compound that contains this group, generally depicted
as:
##STR00006##
wherein, R and R' can independently be any covalently-linked atom
or atoms, for example, H, halo, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide.
[0079] A "thiol" or "mercapto" refers to an --SH group or to its
tautomer .dbd.S.
[0080] A "sulfone" as used herein refers to a sulfonyl functional
group, generally depicted as:
##STR00007##
wherein, R can be any covalently-linked atom or atoms, for example,
H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol,
sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid
sidechain, amino acid and peptide.
[0081] A "sulfoxide" as used herein refers to a sulfinyl functional
group, generally depicted as:
##STR00008##
wherein, R can be any covalently-linked atom or atoms, for example,
H. halohydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol,
sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid
sidechain, amino acid and peptide.
[0082] The term "oxo," as used herein, refers to a .dbd.O moiety.
The term "oxy," as used herein, refers to a --O-- moiety.
[0083] "Nitro" refers to the organic compound functional group
--NO.sub.2.
[0084] "Carbonyl" is a functional group having a carbon atom
double-bonded to an oxygen atom (--C.dbd.O). "Carboxy" as used
herein refers to a --COON functional group, also written as
--(C.dbd.O)--OH.
[0085] "Amino acid sidechain" as used herein refers to any of the
20 commonly known groups associated with naturally-occurring amino
acids, or any natural or synthetic homologue thereof. An "amino
acid" includes the sidechain group and the amino group,
alpha-carbon atom, and carboxy groups, as commonly described in the
art. Examples of amino acids include glycine, and glycine that is
substituted with a suitable substituent as described herein, such
as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, carbonyl, carboxy, etc., or an agriculturally
acceptable salt thereof. For example, "Histidine" is one of the 20
most commonly known amino acids found naturally in proteins. It
contains an imidazole side chain substituent. Other examples of
naturally-occurring amino acids include lysine, arginine, aspartic
acid, glutamic acid, asparagine, glutamine, serine, threonine,
tyrosine, alanine, valine, leucine, isoleucine, phenylalanine,
methionine, cryptophan, and cysteine. Also included in the
definitions of "amino acid sidechain" and "amino acid" is proline,
which is commonly included in the definition of an amino acid, but
is technically an imino acid. As used in this application, both the
naturally-occurring L-, and the non-natural D-amino acid
enantiomers are included. The single letter code for amino acids is
A (Ala), C (Cys), D (Asp), E (Glu), F (Phe), G (Gly), H (His), I
(Ile), K (Lys), L (Leu), M (Met), N (Asn), P (Pro), Q (Gln), R
(Arg), S (Ser), T (Thr), V (Val), W (Trp), and Y (Tyr). A "peptide"
is a linear chain of amino acids covalently linked together,
typically through an amide linkage, and contains from 1 or 2 to 10
or 20 or more amino acids, and is also optionally substituted
and/or branched.
[0086] "Agriculturally acceptable salt" is intended to mean a salt
that retains the biological effectiveness of the free acids and
bases of a specified compound and that is not biologically or
otherwise undesirable. Examples of agriculturally acceptable salts
include sulfates, pyrosulfates, bisulfates, sulfites, bisulfates,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycollates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0087] The term "optionally substituted" indicates that the
specified group is either unsubstituted, or substituted by one or
more suitable substituents. A "substituent" is an atom or atoms
substituted in place of a hydrogen atom on the parent chain or
cycle of an organic molecule.
B. Active Compounds.
[0088] Active compounds are provided below. In some of the
embodiments provided in the present invention, active compounds are
derivatives of triazole. In some embodiments, active compounds
include imidazole-triazole conjugates. In some embodiments, active
compounds include 2-aminoimidazole-triazole conjugates ("2-AIT").
Active compounds as described herein can be prepared as detailed
below or in accordance with known procedures or variations thereof
that will be apparent to those skilled in the art.
[0089] As will be appreciated by those of skill in the art, the
active compounds of the various formulas disclosed herein may
contain chiral centers, e.g. asymmetric carbon atoms. Thus, the
present invention is concerned with the synthesis of both: (i)
racemic mixtures of the active compounds, and (ii) enantiomeric
forms of the active compounds. The resolution of racemates into
enantiomeric forms can be done in accordance with known procedures
in the art. For example, the racemate may be converted with an
optically active reagent into a diastereomeric pair, and the
diastereomeric pair subsequently separated into the enantiomeric
forms.
[0090] Geometric isomers of double bonds and the like may also be
present in the compounds disclosed herein, and all such stable
isomers are included within the present invention unless otherwise
specified. Also included in active compounds of the invention are
tautomers (e.g., tautomers of triazole and/or imidazole) and
rotarners.
[0091] All chains defined by the formulas herein which include
three or more carbons may be saturated or unsaturated unless
otherwise indicated.
[0092] Carbons or other atoms along a chain identified by the
Formulas herein may be identified by number, and when identified by
number shall be numbered from left to right. For example:
##STR00009##
[0093] To illustrate where there are two or more discrete chains,
for Formula (II)(i)(a) described below, wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.7 and R.sup.8.dbd.H. and
R.sup.6=phenyl:
##STR00010##
the exemplary structure below shows n=5, saturated, one of either
R.sup.x or R.sup.y=methyl at C4; m=3, unsaturated, R.sup.u=methyl
at C2 (R.sup.v is absent at C2); and R.sup.x, R.sup.y, R.sup.u and
R.sup.v.dbd.H at all other occurrences:
##STR00011##
[0094] Active compounds for carrying out the present invention
include compounds of Formula
##STR00012##
wherein:
[0095] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0096] each occurrence of R.sup.x and R.sup.y is present or absent
(depending upon chain saturation), and is independently selected
from the group consisting of: H, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide; and
[0097] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon; and
[0098] n=0 to 20, saturated or unsaturated;
[0099] or an agriculturally acceptable salt thereof.
[0100] This formula may be optionally substituted (e.g., from 1 to
3 or 4 times) with independently selected H, halo, hydroxy, acyl,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0101] As will be appreciated by those of skill in the art, a given
substituent (R.sup.1-R.sup.8) may be present or absent depending
upon the valence requirement of the atom or atoms to which the
substituent binds (e.g., carbon versus nitrogen).
[0102] In some embodiments of Formula (I), R.sup.1 is a substituted
amino, A, B, F, G and H are each N, and D and E are each carbon,
generally depicted by Formulas (I)(a)(1)-(I)(b)(1):
##STR00013##
wherein:
[0103] R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.5 and R.sup.6
are each independently selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide; and
[0104] each occurrence of R.sup.x and R.sup.y is present or absent
(depending upon chain saturation), and is independently selected
from the group consisting of: H, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide; and
[0105] n=0 to 20;
[0106] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
##STR00014##
wherein:
[0107] R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.5 and R.sup.8
are each independently selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide; and
[0108] each occurrence of R.sup.x and R.sup.y is present or absent
(depending upon chain saturation), and is independently selected
from the group consisting of: H, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide; and
[0109] n=0 to 20;
[0110] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0111] In some embodiments of Formula (I), R.sup.1 is a substituted
amino, A, B, F, G and D are each N, and D and E are each carbon,
generally depicted by Formula (I)(b)(2):
##STR00015##
wherein:
[0112] R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.5 and R.sup.8
are each independently selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0113] each occurrence of R.sup.x and R.sup.y is present or absent
(depending upon chain saturation), and is independently selected
from the group consisting of: H, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide; and
[0114] n=0 to 20;
[0115] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0116] Active compounds further include compounds of Formula
(I)(i):
##STR00016##
wherein:
[0117] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently selected from the group
consisting. of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0118] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon; and
[0119] n=0 to 20, saturated or unsaturated;
[0120] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0121] As will be appreciated by those of skill in the art, a given
substituent (R.sup.1-R.sup.8) may be present or absent depending
upon the valence requirement of the atom or atoms to which the
substituent binds (e.g., carbon versus nitrogen).
[0122] In some embodiments of Formula (I)(i), R.sup.1 is a
substituted amino; R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8.dbd.H; A, B, F, G and H are each N, and D and E are each
carbon, generally depicted by Formula (I)(i)(a):
##STR00017##
wherein:
[0123] R.sup.6 is selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide; and
[0124] n=0 to 20, saturated or unsaturated;
[0125] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidedchain, amino acid and
peptide.
[0126] Active compounds for carrying out the present invention
include compounds of Formula (II):
##STR00018##
wherein:
[0127] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.3, R.sup.6,
R.sup.7 and R.sup.8 are each independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0128] each occurrence of R.sup.x, R.sup.y, R.sup.u and R.sup.v is
present or absent (depending upon chain saturation), and is
independently selected from the group consisting of: H, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0129] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon; and
[0130] n=0 to 20; and
[0131] m=0 to 20;
[0132] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0133] As will be appreciated by those of skill in the art, a given
substituent (R.sup.1-R.sup.8) may be present or absent depending
upon the valence requirement of the atom or atoms to which the
substituent binds (e.g., carbon versus nitrogen).
[0134] In some embodiments of Formula (II), R.sup.1 is a
substituted amino, A, B, F, G and H are each N, and D and E are
each carbon, generally depicted by Formula (II)(a):
##STR00019##
wherein:
[0135] R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.5 and R.sup.6
are each independently selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0136] each occurrence of R.sup.x, R.sup.y, R.sup.u and R.sup.v is
present or absent (depending upon chain saturation), and is
independently selected from the group consisting of: H, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0137] n=0 to 20; and
[0138] m=0 to 20;
[0139] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0140] In some embodiments of Formula (II)(a), R.sup.1a, R.sup.1b,
R.sup.2, R.sup.3 and R.sup.5 are each H and R.sup.6 is phenyl,
examples of which include, but are not limited to, the following
exemplary Formulas. Each occurrence of R.sup.x, R.sup.y, R.sup.u
and R.sup.v present is H unless otherwise indicated.
[0141] Formulas (II)(a)(1)(A)-(II)(a)(1)(D), wherein n=1:
[0142] M=1: m=2:
##STR00020##
[0143] m=3: m=3, R.sup.u=methyl at C2
##STR00021##
[0144] Formulas (II)(a)(2)(A)-(II)(a)(2)(D), wherein n=2:
[0145] m=1: m=2:
##STR00022##
[0146] m=3: m=3, R.sup.u=methyl at C2:
##STR00023##
[0147] Formulas (II)(a)(3)(A-(II)(a)(3)(D), wherein n=3:
[0148] m=1: m=2:
##STR00024##
[0149] m=3: m=3, R.sup.u=methyl at C2:
##STR00025##
[0150] Formula (II)(a)(4)(D), wherein n=4; m=3, R.sup.u=methyl at
C2:
##STR00026##
[0151] Formula (II)(a)(5)(D), wherein n=5; m=3, R.sup.u=methyl at
C2:
##STR00027##
[0152] Formula (II)(a)(6)(D), wherein n=6; m=3, R.sup.u=methyl at
C2:
##STR00028##
[0153] Active compounds further include compounds of Formula
(II)(i):
##STR00029##
wherein:
[0154] R.sup.1 and R.sup.6 are each independently selected from the
group consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0155] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon;
[0156] n=0 to 20, saturated or unsaturated; and
[0157] m=0 to 20, saturated or unsaturated;
[0158] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0159] In some embodiments of Formula (II)(i), R.sup.1 is a
substituted amino, A, B, F, G and H are each N, and D and E are
each carbon, generally depicted by Formula (II)(i)(a):
##STR00030##
wherein:
[0160] R.sup.1a, R.sup.1b and R.sup.6 are each independently
selected from the group consisting of: H, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0161] n=0 to 20, saturated or unsaturated; and
[0162] m=0 to 20, saturated or unsaturated;
[0163] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0164] In some embodiments of Formula (II)(i)(a), R.sup.1a and
R.sup.1b are each H, and R.sup.6 is heteroaryl, examples of which
include, but are not limited to, the following, exemplary
Formulas:
[0165] Formulas (II)(i)(a)(1)(E)-(II)(i)(a)(1)(L), wherein n=1:
[0166] m=1; R.sup.4 is thiophenyl: m=2; R.sup.4 is thiophenyl:
##STR00031##
[0167] m=1; R.sup.4 is furyl:
##STR00032##
[0168] m=1; R.sup.4 is indolyl: m=2; R.sup.4 is indolyl:
##STR00033##
[0169] m=1; R.sup.4 is benzimidazolyl:
##STR00034##
[0170] Further embodiments include Formulas
(II)(i)(a)(2)(E)-(II)(i)(a)(2)(L), wherein n=2; Formulas
(II)(i)(a)(3)(E)-(II)(i)(a)(3)(L), wherein n=3; Formulas
(II)(i)(a)(4)(E)-(II)(i)(a)(4)(L), wherein n=4; Formulas
(II)(i)(a)(5)(E)-(II)(i)(a)(5)(L), wherein n=5; Formulas
(II)(i)(a)(6)(E)-(II)(i)(a)(6)(L), wherein n=6; and so on.
[0171] These formulas may be optionally substituted (e.g., from 1
to 3 or 4 times) with independently selected H, halo, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0172] Also provided are compounds of Formula (III):
##STR00035##
wherein:
[0173] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each
independently selected from the group consisting of: H, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide; and
[0174] A, B, D, E and F are each independently selected from
carbon, N, S and O, wherein at least one of A, B, D, E and F is
carbon;
[0175] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0176] As will be appreciated by those of skill in the art, a given
substituent (R.sup.5-R.sup.9) may be present or absent depending
upon the valence requirement of the atom or atoms to which the
substituent binds (e.g., carbon versus nitrogen).
[0177] In some embodiments of Formula (III), B, D and E are each N,
and A and F are each carbon, generally depicted as Formula
(III)(a):
##STR00036##
wherein:
[0178] R.sup.5, R.sup.6 and R.sup.9 are each independently selected
from the group consisting of: H, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide;
[0179] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0180] In some embodiments of Formula (III), A, D and E are each N,
and B and F are each carbon, generally depicted as Formula
(III)(b):
##STR00037##
wherein:
[0181] R.sup.5, R.sup.6 and R.sup.9 are each independently selected
from the group consisting of: H, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide; and
[0182] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0183] In some embodiments of Formula (III)(b), R6 and R9 are each
H, generally depicted by Formula (III)(b)(i):
##STR00038##
wherein:
[0184] R.sup.3 is selected from the group consisting, of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide,
oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino
acid and peptide; and
[0185] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0186] In some embodiments of Formula (III)(b), R.sup.3 and R.sup.6
are each H, generally depicted by Formula (III)(b)(ii):
##STR00039##
wherein:
[0187] R.sup.9 is selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide,
oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino
acid and peptide; and
[0188] or an agriculturally acceptable salt thereof
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0189] Also provided are compounds of Formula (IV):
##STR00040##
wherein:
[0190] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.s are each independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0191] each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0192] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon; and
[0193] n=0 to 20;
[0194] m=0 to 20; and
[0195] p=0 to 20
[0196] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0197] In some embodiments of Formula (IV), R.sup.1 is a
substituted amino, A, B, F, G and H are each N, and D and E are
each carbon, generally depicted by Formula (IV)(a):
##STR00041##
wherein:
[0198] R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.5 and R.sup.6
are each independently selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0199] each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is independently selected from the group
consisting, of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0200] n=0 to 20;
[0201] m=0 to 20; and
[0202] p=0 to 20
[0203] or an agriculturally acceptable salt thereof.
[0204] This formula may be optionally substituted (e.g., from 1 to
3 or 4 times) with independently selected H, halo, hydroxy, acyl,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0205] In some embodiments, R.sup.6 is a group:
##STR00042##
wherein:
[0206] X, Y and Z are each independently selected from the group
consisting of: H, methyl, Br and Cl.
[0207] In some embodiments, R.sup.6 is a group:
##STR00043##
wherein:
[0208] R.sup.20, R.sup.21, R.sup.22, R.sup.23 and R.sup.24 are each
independently selected from the group consisting of: H, hydroxy,
acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0209] Further provided are compounds of Formula (IV)(i):
##STR00044##
wherein:
[0210] R.sup.1 and R.sup.6 are each independently selected from the
group consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0211] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon;
[0212] n=0 to 20, saturated or unsaturated;
[0213] m=0 to 20, saturated or unsaturated; and
[0214] p=0 to 20, saturated or unsaturated;
[0215] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0216] In some embodiments of Formula (IV)(i), R.sup.1 is a
substituted amino, A, B, F, G and H are each N, and D and E are
each carbon, generally depicted by Formula (IV)(i)(a):
##STR00045##
herein:
[0217] R.sup.1a, R.sup.1b and R.sup.6 are each independently
selected from the group consisting of: H, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0218] n=0 to 20, saturated or unsaturated;
[0219] m=0 to 20, saturated or unsaturated; and
[0220] p=0 to 20, saturated or unsaturated;
[0221] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0222] In some embodiments of Formula (IV)(i)(a), R.sup.1a,
R.sup.1b and R.sup.6 are each H. In some embodiments of Formula
(IV)(i)(a), R.sup.1a and R.sup.1b are each H, and R.sup.6 is aryl
or heteroaryl.
[0223] Also provided are compounds of Formula (V):
##STR00046##
wherein:
[0224] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0225] each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0226] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon; and
[0227] n=0 to 20;
[0228] m=0 to 20; and
[0229] p=0 to 20
[0230] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0231] In some embodiments of Formula (V), R.sup.1 is a substituted
amino. A, B, F, G and H are each N, and D and E are each carbon,
generally depicted by Formula (V)(a):
##STR00047##
wherein:
[0232] R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.5 and R.sup.6
are each independently selected from the group consisting of: H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0233] each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is independently selected from the cuoup
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0234] n=0 to 20;
[0235] m=0 to 20; and
[0236] p=0 to 20
[0237] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0238] Further provided are compounds of Formula (V)(i):
##STR00048##
wherein:
[0239] R.sup.1 and R.sup.6 are each independently selected from the
group consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0240] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon;
[0241] n=0 to 20, saturated or unsaturated;
[0242] m=0 to 20, saturated or unsaturated; and
[0243] p=0 to 20, saturated or unsaturated;
[0244] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0245] In some embodiments of Formula (V)(i), R.sup.1 is a
substituted amino, A, B, F, G and H are each N, and D and E are
each carbon, generally depicted by Formula (V)(i)(a):
##STR00049##
wherein:
[0246] R.sup.1a, R.sup.1b and R.sup.6 are each independently
selected from the group consisting of: H, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0247] n=0 to 20, saturated or unsaturated;
[0248] m=0 to 20, saturated or unsaturated; and
[0249] p=0 to 20, saturated or unsaturated;
[0250] or an agriculturally acceptable salt thereof
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0251] In some embodiments of Formula (V)(i)(a), R.sup.1a, R.sup.1b
and R.sup.6 are each H, alkyl, cycloalkyl or heterocyclo. In some
embodiments of Formula (V)(i)(a), R.sup.1a and R.sup.1b are each H,
and R.sup.6 is aryl.
[0252] Also provided are compounds of Formula (VI):
##STR00050##
wherein:
[0253] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0254] each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.v is present or absent (depending, upon chain
saturation), and is independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0255] A, B, D, E, F, U and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon; and
[0256] n=0 to 20;
[0257] m=0 to 20; and
[0258] p=0 to 20;
[0259] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0260] In some embodiments of Formula (VI), R.sup.1 is a
substituted amino, A, B, F, G and H are each N, and D and E are
each carbon, generally depicted by Formula (VI)(a):
##STR00051##
wherein:
[0261] R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.5 and R.sup.6
are each independently selected from the group consisting of H,
hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,
aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo,
oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0262] each occurrence of R.sup.x, R.sup.y, R.sup.u, R.sup.v,
R.sup.z and R.sup.w is present or absent (depending upon chain
saturation), and is independently selected from the group
consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0263] n=0 to 20;
[0264] m=0 to 20; and
[0265] p=0 to 20;
[0266] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0267] Further provided are compounds of Formula (VI)(i):
##STR00052##
wherein:
[0268] R.sup.1 and R.sup.6 are each independently selected from the
group consisting of: H, hydroxy, acyl, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide,
thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy,
amino acid sidechain, amino acid and peptide;
[0269] A, B, D, E, F, G and H are each independently selected from
carbon, N, S and O, wherein at least one of D, E, F, G and H is
carbon;
[0270] n=0 to 20, saturated or unsaturated;
[0271] m=0 to 20, saturated or unsaturated; and
[0272] p=0 to 20, saturated or unsaturated;
[0273] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted (e.g., from 1 to 3 or 4
times) with independently selected H, halo, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide.
[0274] In some embodiments of Formula (VI)(i), R.sup.1 is a
substituted amino, A, B, F, G and H are each N, and D and E are
each carbon, generally depicted by Formula (VI)(i)(a):
##STR00053##
wherein:
[0275] R.sup.1a, R.sup.1b and R.sup.6 are each independently
selected from the group consisting, of: H, hydroxy, acyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro,
carbonyl, carboxy, amino acid sidechain, amino acid and
peptide;
[0276] n=0 to 20, saturated or unsaturated;
[0277] m=0 to 20, saturated or unsaturated; and
[0278] p=0 to 20, saturated or unsaturated;
[0279] or an agriculturally acceptable salt thereof.
This formula may be optionally substituted from 1 to 3 or 4 times)
with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino,
amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl,
carboxy, amino acid sidechain, amino acid and peptide.
[0280] In some embodiments of Formula (VI)(i)(a), R.sup.1a and
R.sup.1b are each H, and R.sup.6 is aryl or heteroaryl.
C. Microbicides and Plant Defense Activators.
[0281] In some embodiments, an active compound described herein is
applied in combination with a microbicide. "Microbicide" as used
herein refers to a substance with the ability to kill or to inhibit
the growth of microorganisms (e.g., bacteria, fungal cells,
protozoa, etc.), which microbicide is not an active compound in the
group herein disclosed of triazole derivatives. Common microbicides
used for microbial control in plants include copper compounds.
Examples of copper compounds include, but are not limited to,
Bordeaux mixture, copper hydroxide, copper oxychloride, copper
sulfate, cuprous oxide, mancopper or oxine-copper. However,
microorganisms (e.g., bacteria such as Xanthomonas and Pseudomonas)
may become resistant to treatment with copper.
[0282] In some embodiments, resistant microorganisms (e.g.,
copper-resistant bacteria) are rendered more susceptible to a
microbicides and/or the effectiveness of treatment with a
microbicides is enhanced upon application in combination with an
active compound described herein (e.g., fruit or vegetable yield is
increased as compared to diseased plant producing the fruit or
vegetable that is untreated or treated only with the
microbicide).
[0283] Other microbicides include, but are not limited to, azoles
such as azaconazole, bitertanol, propiconazole, difenoconazole,
diniconazole, cyproconazole, epoxiconazole, fluquinconazole,
flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole,
ipconazole, tebuconazole, tetraconazole, fenbuconazole,
metconazole, myclobutanil, perfurazoate, penconazole,
bromuconazole, pyrifenox, prochloraz, triadimefon, triadimenol,
triflumizole or triticonazole; pyrimidinyl carbinoles such as
ancymidol, fenarimol or nuarimol; 2-amino-pyrimidine such as
bupirimate, dimethirimol or ethirimol; morpholines such as
dodemorph, fenpropidin, fenpropimorph, spiroxamin or tridemorph;
anilinopyrimidines such as cyprodinil, pyrimethanil or mepanipyrim;
pyrroles such as fenpiclonil or fludioxonil; phenylamides such as
benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace or oxadixyl;
benzimidazoles such as benomyl, carbendazim, debacarb, fuberidazole
or thiabendazole; dicarboximides such as chlozolinate,
dichlozoline, iprodine, myclozoline, procymidone or vinclozolin;
carboxamides such as carboxin, fenfuram, flutolanil, mepronil,
oxycarboxin or thifluzamide; guanidines such as guazatine, dodine
or iminoctadine; strobilurines such as azoxystrobin,
kresoxim-methyl, metominostrobin, SSF-129, methyl
2[(2-trifluoromethyl)-pyrid-6-yloxymethyl]-3-methoxy-acrylate or
2-[{.alpha.[{.alpha.-methyl-3-trifluoromethyl-benzyl)imino]-oxy.quadratur-
e.-o-tolyl]- -glyoxylic acid-methylester-O-methyloxime
(trifloxystrobin); dithiocarbamates such as ferbam, mancozeb,
maneb, metiram, propineb, thiram, zineb or ziram;
N-halomethylthio-dicarboximides such as captafol, captan,
dichlofluanid, fluoromide, folpet or tolyfluanid; nitrophenol
derivatives such as dinocap or nitrothal-isopropyl; organo
phosphorous derivatives such as edifenphos, iprobenphos,
isoprothiolane, phosdiphen, pyrazophos or toclofos-methyl; and
other compounds of diverse structures such as acibenzolar-S-methyl,
hatpin, anilazine, blasticidin-S, chinomethionat, chloroneb,
chlorothalonil, cymoxanil, dichione, diclomezine, dicloran,
diethofencarb, dimethomorph, dithianon, etridiazole, famoxadone,
fenamidone, fentin, ferimzone, fluazinam, flusulfamide, fenhexamid,
fosetyl-aluminium, hymexazol, kasugamycin, methasulfocarb,
pencycuron, phthalide, polyoxins, probenazole, propamocarb,
pyroquilon, quinoxyfen, quintozene, sulfur, triazoxide,
tricyclazole, triforine, validamycin,
(S)-5-methyl-2-methylthio-5-phenyl-3-phenylamino-3,5-di-hydroimidazol-4-o-
-ne (RPA 407213),
3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide
(RH-7281),
N-allyl-4,5-dimethyl-2-trimethylsilylthiophene-3-carboxamide (MON
65500),
4-chloro-4-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfon-amide
(IKF-916),
N-(1-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)-propionamide
(AC 382042) or iprovalicarb (SZX 722).
[0284] An "antibiotic" as used herein is a type of "microbicide."
Common antibiotics include aminoglycosides, carbacephems (e.g.,
loracarbef), carbapenems, cephalosporins, glycopeptides (e.g.,
teicoplanin and vancomycin), macrolides, monobactams (e.g.,
aztreonam) penicillins, polypeptides (e.g., bacitracin, colistin,
polymyxin B), quinolones, sulfonamides, tetracyclines, etc.
Antibiotics treat infections by either killing, or preventing the
growth of microorganisms. Many act to inhibit cell wall synthesis
or other vital protein synthesis of the microorganisms.
[0285] Aminoglycosides are commonly used to treat infections caused
by Gram-negative bacteria. Examples of aminoglycosides include, but
are not limited to amikacin, gentamicin, kanamycin, neomycin,
netilmicin, streptomycin, tobramycin, and paromomycin.
[0286] Carbapenems are broad-spectrum antibiotics, and include, but
are not limited to, ertapenem, doripenem, imipenem/cilstatin, and
meropenem.
[0287] Cephalosporins include, but are not limited to, cefadroxil,
cefazolin, cefalotin (cefalothin), cefalexin, cefaclor,
cefamandole, cefoxitin, cefprozil, loracarbef, cefuroxime,
cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,
cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone,
cefepime, cefpirome, and ceftobiprole.
[0288] Macrolides include, but are not limited to, azithromycin,
clarithromycin, dirithromycin, erythromycin, roxithromycin,
troleandomycin, telithromycin and spectinomycin.
[0289] Penicillins include, but are not limited to, amoxicillin,
ampicillin, azlocillin, bacampicillin, carbenicillin, cloxacillin,
dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin,
oxacillin, penicillin, piperacillin and ticarcillin.
[0290] Quinolones include, but are not limited to, ciprofloxacin,
enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin,
moxifloxacin, norfloxacin, ofloxacin and trovafloxacin.
[0291] Sulfonamides include, but are not limited to, mafenide,
prontosil, sulfacetamide, sulfamethizole, sulfanilamide,
sulfasalazine, sulfisoxazole, trimethoprim, and co-trimoxazole
(trimethoprim-sulfamethoxazole).
[0292] Tetracyclines include, but are not limited to,
demeclocycline, doxycycline, minocycline, oxytetracycline and
tetracycline.
[0293] Other antibiotics include arsphenamine, chloramphenicol,
clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid,
furazolidone, isoniazid, linezolid, metronidazole, mupirocin,
nitrofurantoin, platensimycin, pyrazinamide,
quinupristin/dalfopristin, rifampin (rifampicin), tinidazole,
etc.
[0294] Other microbicides that may be used in combination with the
active compounds of the present invention include bacteriophages
(bacterial viruses) such as Bacillus. Examples of bacteriophage
microbicides include, but are not limited to, AgriPhage.TM.
(OmniLytics, Inc., Salt Lake City, Utah) and Serenade.RTM.
(AgraQuest, Davis, Calif.). See, e.g., U.S. Pat. Nos. 5,919,447 and
6,077,506 to Marrone et al.; U.S. Pat. No. 6,103,228 to Heins et
al.; and U.S. Patent Application Publication 20080152684.
[0295] In some embodiments, an active compound described herein is
applied in combination with a plant defense activator. A "plant
defense activator" as used herein is a compound that improves
disease resistance by activatinv, a plant's natural defense
mechanisms, e.g., induces the plant to produce disease-fighting
compounds. Examples of plant defense activators include, but are
not limited to, prohexadione-calcium (Apogee), Cropset (plant
booster element complex), probenazole, potassium phosphate (e.g.,
ProPhyt.RTM., Helena Chemical Company), hatpin protein (e.g.,
Messenger.RTM., Eden Biosciences Ltd, Bothell, Wash.), acibenzolar
or acibenzolar-S-methyl (e.g., Actigard.TM., Syngenta Crop
Production, Inc, Greensboro, N.C.), streptomycin sulfate,
reynoutria sachalinensis extract (reysa), etc.
D. Agrochemical Compositions.
[0296] Active compounds of the present invention can be used to
prepare agrochemical compositions in like manner as other
antimicrobial compounds. See, e.g., U.S. Pat. Application
2006/0094739; see also U.S. Pat. Nos. 6,617,330; 6,616,952;
6,569,875; 6,541,500, and 6,506,794.
[0297] Active compounds described herein can be used for
protecting, plants against diseases that are caused by
microorganisms, including biofilm-forming microorganisms. The
active compounds can be used in the agricultural sector and related
fields as active ingredients for controlling plant pests. The
active compounds can be used to inhibit or destroy the pests that
occur on plants or parts of plants (fruit, blossoms, leaves, stems,
tubers, roots) of different crops of useful plants, optionally
while at the same time protecting also those parts of the plants
that grow later e.g. from phytopathogenic microorganisms.
[0298] Active compounds may be used as dressing agents for the
treatment of plant propagation material, in particular of seeds
(fruit, tubers, grains) and plant cuttings (e.g. rice), for the
protection against fungal infections as well as against
phytopathogenic fungi occurring in the soil.
[0299] The active compounds can be used in the form of compositions
and can be applied to the crop area or plant to be treated,
simultaneously or in succession with further compounds. These
further compounds can be e.g. fertilizers or micronutrient donors
or other preparations which influence the growth of plants. They
can also be selective herbicides as well as insecticides,
fungicides, bactericides, nematicides, molluscicides, plant growth
regulators, plant activators or mixtures of several of these
preparations, if desired together with further carriers,
surfactants or application promoting adjuvants customarily employed
in the art of formulation.
[0300] Suitable carriers and adjuvants can be solid or liquid and
are substances useful in formulation technology, e.g. natural or
regenerated mineral substances, solvents, dispersants, wetting
agents, tackifiers, thickeners, binders or fertilizers.
[0301] The active compounds are used in unmodified form or,
preferably, together with the adjuvants conventionally employed in
the art of formulation. To this end they are conveniently
formulated in known manner to emulsifiable concentrates, coatable
pastes, directly sprayable or dilutable solutions, dilute
emulsions, wettable powders, soluble powders, dusts, granulates,
and also encapsulations e.g. in polymeric substances. As with the
type of the compositions, the methods of application, such as
spraying, atomizing, dusting, scattering, coating or pouring, are
chosen in accordance with the intended objectives and the
prevailing circumstances.
[0302] The formulation, i.e. the compositions containing the active
compound and, if desired, a solid or liquid adjuvant, are prepared
in known manner, typically by intimately mixing and/or grinding the
compound with extenders, e.g. solvents, solid carriers and,
optionally, surface active compounds (surfactants).
[0303] Suitable carriers and adjuvants may be solid or liquid and
correspond to the substances ordinarily employed in formulation
technology, such as, e.g. natural or regenerated mineral
substances, solvents, dispersants, wetting agents, tackifiers,
thickeners, binding agents or fertilizers. Such carriers are for
example described in WO 97/33890.
[0304] Further surfactants customarily employed in the art of
formulation are known to the expert or can be found in the relevant
literature.
[0305] The agrochemical formulations will usually contain from 0.1
to 99% by weight, preferably from 0.1 to 95% by weight, of a
compound described herein, 99.9 to 1% by weight, preferably 99.8 to
5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by
weight, preferably from 0.1 to 25% by weight, of a surfactant.
[0306] Whereas it is preferred to formulate commercial products as
concentrates, the end user will normally use dilute
formulations.
[0307] The compositions may also contain further adjuvants such as
stabilizers, antifoams, viscosity regulators, binders or tackifiers
as well as fertilizers, micronutrient donors or other formulations
for obtaining special effects.
E. Methods of Use.
[0308] Target crops or plants to be treated with active compounds
and compositions of the invention typically comprise the following
species of plants: cereal (wheat, barley, rye, oat, rice, maize,
sorghum and related species); beet (sugar beet and fodder beet);
pomes, drupes and soft fruit (apples, pears, plums, peaches,
almonds, cherries, strawberries, raspberries and blackberries);
leguminous plants (beans, lentils, peas, soybeans); oil plants
(rape, mustard, poppy, olives, sunflowers, coconut, castor oil
plants, cocoa beans, groundnuts); cucumber plants (pumpkins,
cucumbers, melons); fiber plants (cotton, flax, hemp, jute); citrus
fruit (oranges, lemons, grapefruit, mandarins); vegetables
(spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes,
potatoes, paprika); lauraceae (avocado, cinnamon, camphor) or
plants such as tobacco, nuts, coffee, eggplants, sugar cane, tea,
pepper, vines including grape-bearing vines, hops, bananas,
pineapple, turf and natural rubber plants, as well as ornamentals
(flowers, shrubs, broad-leafed trees and evergreens, such as
conifers). This list does not represent any limitation.
[0309] 1. Bacterial infections. The methods, active compounds and
compositions can be used to treat bacterial infections in a variety
of plants, with specific examples including but not limited to
those set forth below.
[0310] Citrus. In citrus trees (including orange, lemon, lime, and
grapefruit) active compounds and compositions as described herein
can be used to treat or control a variety of microbial diseases,
including but not limited to canker (caused by Xanthomonas
campestris or Xanthomonas axonopodis infection), bacterial spot
(caused by Xanthomonas campestris pv. Citrumelo infection); Black
Pit(fruit) (caused by Pseudomonas syringae infection); Blast
(caused by Pseudomonas syringae infection) citrus variegated
chlorosis (caused by Xylella fastidiosa infection), and Citrus
Huanglongbing (HLB) caused by Candidatus Liberibacter
asiaticus.
[0311] Pome Fruit. In pome fruits (including apple, pear, quince,
Asian pear, and loquat), active compounds and compositions as
described herein can be used to treat or control a variety of
microbial infections, including but not limited to Fire Blight
(caused by Erwinia amylovora infection), Crown Gall (caused by
Agrobacterium tumefaciens infection); Blister spot (caused by
Pseudomonas syringae infection) and Hairy root (caused by
Agrobacterium rhizogenes infection).
[0312] Peppers. In pepper plants, active compounds and compositions
as described herein can be used to treat or control a variety of
microbial infections, including but not limited to: Bacterial Spot
(caused by Xanthomonas campestris pv. vesicatoria infection);
Bacterial wilt (caused by Ralstonia solanacearune infection), and
Syringae seedling blight and leaf spot (caused by Pseudomonas
styingae infection).
[0313] Tomatoes. In tomato plants, active compounds and
compositions as described herein can be used to treat or control a
variety of microbial infections, including but not limited to:
Bacterial canker (caused by Clavibacter michiganesis), Bacterial
speck (caused by Pseudomonas syringae), Bacterial spot (caused by
Xanthomonas campestris vesicatoria), Bacterial stern rot and fruit
rot (caused by Erwinia carotovora), Bacterial wilt (caused by
Ralstonia solanacearum), Pith necrosis (caused by Pseudomonas
corrugate), and Syringae leaf spot (caused by Pseudomonas
syringae).
[0314] Soybeans. In soybeans, active compounds and compositions as
described herein can be used to treat or control a variety of
microbial infections, including but not limited to: Bacterial
blight (caused by Pseudomonas amygdale), Bacterial pustules (caused
by Xanthomonas axonopodis pv. Glycines), and Bacterial wilt (caused
by Ralstonia solanacearum or Curtobacterium flaccumfaciens).
[0315] Corn, Cotton, Wheat and Rice. In corn, cotton, wheat and
rice, active compounds and compositions as described herein can be
used to treat or control a variety of microbial infections,
including but not limited to: bacterial blights, leaf spots and
leaf streak caused by Xanthomonas species; bacterial sheath rot,
stripe and spot caused by Pseudomonas species; and to bacterial
stalk and top rot, wilt, foot rot, pink seed and lint degradation
caused by Erwinia species.
[0316] Pineapple. In pineapple, active compounds and compositions
as described herein can be used to treat or control a variety of
microbial infections, including but not limited to: Bacterial heart
rot and Fruit collapse (caused by Erwinia chrysanthemi), Bacterial
fruitlet brown rot (caused by Erwinia ananas), Marbled fruit and
Pink fruit (caused by Erwinia herbicola), Soft rot (caused by
Erwinia carotovora), and Acetic souring (caused by Acetic acid
bacteria).
[0317] The above listing is but a sampling, and active compounds
and compositions as described herein may also be used to treat or
control bacteria (some of which are named above) in a variety of
plants. For example, the bacteria Xylella fastidiosa infects citrus
trees as noted above (citrus variegated chlorosis), and also
infects grapevines (Pierce's disease). Other plant hosts of Xylella
fastidiosa include, but are not limited to, ornamentals, oleander
(leaf scorch), almond, coffee, maple, mulberry, elm, sycamore,
alfalfa, etc. Similarly, Ralstonia solanacearum infects soybeans
(bacterial wilt) as well as banana (Moko disease), tobacco
(Granville wilt), geranium (southern bacterial wilt), potato (brown
rot) and a wide variety of other plants, including ginger and
mulberry.
[0318] 2. Fungal infections. In addition to treating or controlling
bacterial infections, active compounds and compositions as
described herein can be used to treat or control fungal infections
such as rots, leaf molds, blights, wilts, damping-off, spot, root
rot, stem rot, mildew, brown spot, gummosis, melanose, post-bloom
fruit drop, scab, alternaria, canker, flyspeck, fruit blotch,
dieback, downy mildews, ear rots, anthracnose bunts, smut, rust,
eyespot and pecky rice. Genera of plant-pathogenic fungi that can
be treated or controlled by the active compounds, compositions, and
methods described herein include but are not limited to: Pythium
spp., Fusarium spp., Rhizoctonia spp., Cercospora spp., Alternaria
spp., Colletotrichum spp., Ustilago spp., Phoma spp., Gibberella
spp. Penicillium spp., Gloinerella spp. Diplodia spp., Curvularia
spp., Sclerospora spp., Peronosclerospora spp., Cercospora spp.,
Puccinia spp., Ustilago spp., Aspergillus spp., Phomopsis spp.,
Diaporthe spp., Botrytis spp., Verticillium spp., Phytophthors
spp.
[0319] Particular fungal infections that can be treated or
controlled by the methods, compounds and compositions described
herein, in vegetables and greenhouse crops, include Phytophthora
blight (caused by Phytophthora capsici) and Pythium damping-off
(caused by Pythium spp).
[0320] Note that Phytophthora also has adverse effects on crops
ranging from pineapples to cotton. It can kill woody citrus
seedlings and young citrus trees (oranges, grapefruits, lemons,
limes). In the greenhouse, germinating seed and seedlings are very
susceptible to damping-off caused by Phytophthora, Pythium,
Sclerotina and Rhizoctonia species. The cost to the grower to lose
his crop to any of these fungi is substantial. The loss can happen
at transplant time or when the crop is ready to be harvested.
[0321] The problems of fungi are not restricted to traditional
crops but also extend to forestry products and have worldwide
scope. Phytophthorct cinnamonzi is a soil-borne water mould that
leads to a condition in plants called "root rot" or "dieback." P.
cinnamomi causes root rot affecting woody ornamentals including
azalea, dogwood, forsythia, Fraser fir, hemlock, Japanese holly,
juniper, rhododendron, white pine, and American chestnut. P.
cinnamomi is responsible for the destruction of the elegant
American chestnut tree. In Australia, P. cinnamomi has spread
through the forests of western Australia, and into coastal forests
of Victoria, where entire plant ecosystems are being obliterated.
Given that P. cinnamomi is a soil-borne water mould that infects
the roots, almost the entire action takes place below ground. This
problem highlights the importance of developing new compounds to
counter fungal infections, even those that directly affect only the
roots of the plant rather than the more visible effects on fruits
or vegetables.
[0322] Active compounds of the invention can be applied to plants
or plant loci in accordance with known techniques. The compound(s)
can be tank mixed with other agricultural, turf, ornamental
nursery, forestry and all other plant-labeled compatible
pesticides. The compound(s) can be applied to seed. The compound(s)
can be applied to edible and non-edible crops. The compound(s) can
be applied to roots and all other parts of all plants. The
compound(s) can be applied in greenhouses. The compound(s) can be
applied and used in food-processing facilities. The compound(s) can
be applied to plastic food bags and containers. The compound(s) can
be applied as a solid, as its free base, or as a salt. The salts
can include, but are not limited to, HI, HCl, HBr, H.sub.2SO.sub.4,
acetic acid, and trifluoroacetic acid. The compound(s) can applied
as a solution from 0.0001% to 99.9%. The compound(s) can be applied
as a solid or solution with copper-based cidal compounds. The
compound(s) can be applied with specific additional active agents,
including but not limited to bactericides, fungicides, pesticides,
biological insecticides and microbial insecticides.
[0323] Application can be carried out with any suitable equipment
or technique, such as: Aerial--Fixed wing. and Helicopter; Ground
Broadcast Spray--Boom or boomless system, pull-type sprayer,
floaters, pick-up sprayers, spray coupes, speed sprayers, and other
broadcast equipment, water wagons and water bags; Low pressure boom
sprayers, High pressure sprayers; Air blast sprayers; Low volume
air sprayers (mist blowers); Ultra-low volume sprayers (ULV);
Aerosol Generators (foggers); Dusters; Soil Injector; Hand-Held or
High-Volume Spray Equipment--knapsack and backpack sprayers,
pump-up pressure sprayers, hand guns, motorized spray equipment;
Selective Equipment--Recirculating sprayers, shielded and hooded
sprayers; Controlled droplet applicator (CDA) hand-held or
boom-mounted applicators that produce a spray consisting of a
narrow range of droplet size; Any and all greenhouse sprayers;
Micro-sprinkler or drip irrigation systems; Chemigation.
[0324] One method of applying an active compound of the invention,
or an agrochemical composition which contains at least one of said
compounds, is foliar application. The frequency of application and
the rate of application will depend on the risk of infestation by
the corresponding pathogen. However, the active compounds can also
penetrate the plant through the roots via the soil (systemic
action) by drenching the locus of the plant with a liquid
formulation, or by applying the compounds in solid form to the
soil, e.g. in granular form (soil application). In crops of water
such as rice, such granulates can be applied to the flooded rice
field. The active compounds may also be applied to seeds (coating)
by impregnating the seeds or tubers either with a liquid
formulation of the fungicide or coating them with a solid
formulation.
[0325] The term locus as used herein is intended to embrace the
fields on which the treated crop plants are growing, or where the
seeds of cultivated plants are sown, or the place where the seed
will be placed into the soil. The term seed is intended to embrace
plant propagating material such as cuttings, seedlings, seeds, and
germinated or soaked seeds.
[0326] Advantageous rates of application are normally from 5 g to 2
kg of active ingredient (a.i.) per hectare (ha), preferably from 10
g to 1 kg a.i./ha, most preferably from 20 g to 600 g a.i./ha. When
used as seed drenching agent, convenient dosages are from 10 mg to
1 g of active substance per kg, of seeds.
F. Combination Treatments.
[0327] In some embodiments, methods of enhancing the effects of a
microbicide (such as a microbicide comprising copper, e.g.,
Kocide.RTM. 2000 or Kocide.RTM. 3000 (DuPont.TM., with active
ingredient copper hydroxide) are disclosed, comprising the step of
applying an active compound in combination with a microbicide, the
active compound being applied in an amount effective to enhance the
effects of the microbicide.
[0328] In some embodiments, methods of enhancing the effects of a
plant defense activator are disclosed, comprising the step of
applying an active compound in combination with a plant defense
activator, the active compound being applied in an amount effective
to enhance the effects of the plant defense activator.
[0329] "Enhancing" the effects of a microbicide by applying an
active compound in combination with the microbicide refers to
increasing the effectiveness of the microbicide, such that the
microorganism killing and/or growth inhibition is higher at a
certain concentration of the microbicide applied in combination
with the active compound than without. In some embodiments, a
bacteria or other microorganism is "sensitized" to the effects of a
microbicide, such that the bacteria or other microorganism that was
resistant to the microbicide prior to applying the active compound
(e.g., little to none, or less than 20, 10, 5 or 1% are killed upon
application) is rendered vulnerable to that microbicide upon or
after applying the active compound (e.g., greater than 20, 30, 40,
50, 60, 70, 80, 90, or 95% or more are killed).
[0330] Similarly, "enhancing" the effects of a plant defense
activator by applying an active compound in combination with the
plant defense activator refers to increasing the effectiveness of
the plant defense activator, such that the microorganism killing
and/or growth inhibition is higher at a certain concentration of
the plant defense activator applied in combination with the active
compound than without. In some embodiments, a bacteria or other
microorganism is "sensitized" to the effects of a plant defense
activator, such that the bacteria or other microorganism that was
resistant to the effects of the plant defense activator prior to
applying the active compound (e.g., little to none, or less than
20, 10, 5 or 1% are killed upon application) is rendered vulnerable
to the effects of that plant defense activator upon or after
applying the active compound (e.g., greater than 20, 30, 40, 50,
60, 70, 80, 90, or 95% or more are killed).
[0331] As used herein, the application of two or more compounds
(inclusive of active compounds and microbicides) "in combination"
means that the two compounds are applied closely enough in time
that the application of or presence of one alters the biological
effects of the other. The two compounds may be applied
simultaneously (concurrently) or sequentially.
[0332] Simultaneous application of the compounds may be carried out
by mixing the compounds prior to application, or by applying the
compounds at the same point in time but at different sites of the
plant or using different types of applications, or applied at times
sufficiently close that the results observed are indistinguishable
from those achieved when the compounds are applied at the same
point in time.
[0333] Sequential application of the compounds may be carried out
by applying, e.g., an active compound at some point in time prior
to application of a microbicide, such that the prior application of
active compound enhances the effects of the microbicide (e.g.,
percentage of microorganisms killed and/or slowing the growth of
microorganisms). In some embodiments, an active compound is applied
at some point in time prior to the initial application of a
microbicide. Alternatively, the microbicide may be applied at some
point in time prior to the application of an active compound, and
optionally, applied again at some point in time after the
application of an active compound.
EXAMPLES
Example 1
Synthesis of 2-aminoimidazole-triazole (2-AIT) Chemical Library
[0334] There is a paucity of reactions that have been reported to
be compatible with 2-aminoimidazoles. To test the applicability of
the Cu(I)-catalyzed [3+2] alkyne/azide cycloaddition (Click
reaction, see Kolb et al., Angewandte Chemie-International Edition
2001, 11, 2004-2021; Rodionov et al., Angewandte
Chemie-International Edition 2005, 15, 2210-2215), we synthesized
the alkyne derived 2-aminoimidzole 1 and tested its ability to
participate in a Cu(I)-catalyzed [3+2] cycloaddition with benzyl
azide.
##STR00054##
[0335] The alkyne derived 2-aminoimidazole (2-AI) was synthesized
as outlined in Scheme 1. Amino acid 2 (Kotha et al., Tetrahedron
2002, 45, 9203-9208) was subjected to small scale Akabori reduction
(Akabori, Berichte Der Deutschen Chemischen Gesellschaft 1933, 66,
151-158), which, followed by condensation with cyanamide (Xu Yz et
al., J Org Chem 1997, 3, 456-464) delivered the target alkyne 2-AI
1 in 88% yield. With 1 in hand, we explored various conditions to
elicit the Cu-catalyzed [3+2] cycloaddition between 1 and benzyl
azide (Table 1).
TABLE-US-00001 TABLE 1 ##STR00055## ##STR00056## ##STR00057## Scale
(mg) Cu(I) Source.sup.a Solvent Base Temp Yield 20 CuI THF DIEA RT
NR 20 CuI THF DIEA 40.degree. C. NR 20 CuSO.sub.4/NaAsc
EtOH/H.sub.2O (1:1) -- RT NR 20 CuSO.sub.4/NaAsc EtOH/H.sub.2O
(1:1) -- 40.degree. C. 86% 100 CuSO.sub.4/NaAsc EtOH/H.sub.2O (1:1)
-- 40.degree. C. Decomp 100 CuSO.sub.4/NaAsc t-BuOH/H.sub.2O/ -- RT
93% CH.sub.2Cl.sub.2 (1:1:1) .sup.aNaAsc = Sodium Ascorbate
[0336] Reactions in THF using, Cu(I) yielded no reaction and only
returned starting material. We then switched to using CuSO.sub.4
and sodium ascorbate in a 1:1 solvent mixture of H.sub.2O/EtOH.
Again, no reaction was noted. However, when the reaction was heated
to 40.degree. C. we noted clean conversion to the desired 2-AIT
conjugate 3 in 86% yield. Unfortunately, when the reaction was
scaled up, we observed a significant amount of decomposition. Room
temperature click reactions have been noted when a 1:1:1 solvent
mixture of H.sub.2O/EtOH/CH.sub.2Cl.sub.2 (Lee et al., Tetrahedron
Letters 2006, 29, 5105-5109) is employed instead of the 1:1
H.sub.2O/EtOH mixture. When these reaction conditions were tested,
we observed conversion to 3 in 93% yield.
[0337] With the methodology established to access 2-AIT conjugates,
we employed the synthetic approach outlined in Scheme 1 to
synthesize 2-AI alkynes 4 and 5 in which we systematically extended
the methylene space between the alkyne and the 2-AI. The click
reaction was then performed between each of the 2-AI alkynes and 12
azides to yield an initial 2-AIT library (shown below). Each
compound was characterized (.sup.1H NMR, .sup.13C NMR, HRMS).
[0338] In conclusion, we have developed a synthetic approach to
access 2-aminoimidazole/triazole (2-AIT) conjugates that is
underpinned by the Cu(I)-catalyzed [3+2] alkyne/azide
cycloaddition. Using, this chemistry we have assembled a focused
library of 2-AIT conjugates.
1. Experimental Protocols for 2-AIT Conjugate Synthesis
[0339] All reagents used for chemical synthesis were purchased from
commercially available sources and used without further
purification. Chromatography was performed using 60 A mesh standard
grade silica gel from Sorbtech (Sorbent Technologies, Inc.,
Atlanta, Ga.). NMR solvents were obtained from Cambridge Isotope
Laboratories, Inc. (Andover, Mass.) and used as received. .sup.1H
NMR (300 MHz or 400 MHz) and .sup.13C NMR (75 MHz or 100 MHz)
spectra were recorded at 25.degree. C. on Varian Mercury
spectrometers. Chemical shifts (6) are given in ppm relative to
tetramethylsilane or the respective NMR solvent; coupling constants
(J) are in hertz (Hz). Abbreviations used are s=singlet, bs=broad
singlet, d=doublet, dd=doublet of doublets, t=triplet, dt=doublet
of triplets, bt=broad triplet, qt=quartet, m=multiplet, bm=broad
multiplet and br=broad. High and low resolution mass spectra were
obtained at the North Carolina State Mass Spectrometry Laboratory
for Biotechnology. FAB experiments were carried out with a JOEL
HX110HF mass spectrometer while ESI experiments were carried out on
an Agilent LC-TOF mass spectrometers.
Chemical Library:
##STR00058## ##STR00059## ##STR00060## ##STR00061##
[0340] Synthesis:
##STR00062##
[0342] To a 50 mL round-bottomed flask equipped with a magnetic
stirbar was added 3-furan methanol (1.00 g, 10.2 mmol) and a
solution of diphenyl phosphoryl azide (3.37 g, 12.2 mmol) in
toluene (30 mL). The stirring solution is allowed to cool to
0.degree. C. in which 1,8 Diazabycyclo [5.4.0.] undec-7-ene (1.86
g, 12.2 mmol) was added dropwise. The reaction is allowed to slowly
warm to ambient temperature for an additional 16 hours of stirring.
After this period, the reaction mixture is washed with water
(2.times.20 mL) and then with 5% HCl (20 mL). Volatiles are
evaporated under reduced pressure. The resulting residue is then
purified by column chromatography (1:9 ethyl acetate/hexane)
providing 3-azidomethyl furan (1.19 g, 95%) as a colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.46 (d, 1H), .delta.
7.44 (s, 1H), .delta. 6.42 (d, 1H), .delta. 4.20 (s, 2H). ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 144.1, 141.1, 110.4,
92.1, 45.8 ppm; LRMS (EI) calcd for C.sub.5H.sub.5N.sub.3O (M+)
123, found 123.
##STR00063##
[0343] Following the same procedure used to synthesize
3-azidomethyl furan, indole-3-methanol (2.00 g, 13.6 mmol) was
converted to 3-azodomethyl indole (1.31 g, 56%) as a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.19 (bs, 1H), .delta.
7.71 (d, 1H), .delta. 7.39 (m, 2H), .delta. 7.19 (m, 2H), .delta.
4.54 (s, 2H) ppm; .sub.13C NMR (75 MHz, CDCl.sub.3) .delta. 130.3,
125.9, 125.3, 122.2, 120.3, 120.3, 119.7, 118.7, 111.9 ppm; LRMS
(EI) calcd for C.sub.9H.sub.8N.sub.4 (M+) 172, found 172.
##STR00064##
[0344] Following the same procedure used to synthesize
3-azidomethyl furan, furfuryl alcohol (2.50 g, 25.5 mmol) was
converted to 2-azidomethyl furan (2.96 g, 95%) as a colorless oil.
.sup.1H. NMR (300 MHz, CDCl.sub.3) .delta. 7.43 (d, 1H), .delta.
6.36 (m, 2H), .delta. 4.29 (s, 2H) ppm; .sub.13C NMR (75 MHz,
CDCl.sub.3) .delta. 148.2, 110.7, 109.6, 47.2 ppm; LRMS (EI) calcd
for C.sub.5H.sub.5N.sub.3O (M+) 123, found 123.
##STR00065##
[0345] Following the same procedure used to synthesize
3-azidomethyl furan, thiophene-3-methanol (3.14 g, 27.6 mmol) was
converted to 3-azidomethyl thiophene (3.72 g, 97%) as a colorless
oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.38 (d, 1H),
.delta. 7.23 (s, 1H), .delta. 7.10 (d, 1H) .delta. 4.36 (s, 2H)
ppm; .sup.13C (75 MHz, CDCl.sub.3) .delta. 136.4, 127.6, 127.1,
124.0 49.9 ppm; LRMS (EI) calcd for C.sub.5H.sub.5N.sub.3S (M+)
139, found 139.
##STR00066##
[0346] 2-chloroethyl-5, 6-dimethyl-1H-benzimidazole was synthesized
through the treatment of 4,5-dimethyl-1,2-phenylenediamine to
conditions outlined by Hortelano (Raban et al., Org. Chem. 1985, 50
(13), 2205-2210). The resulting product was transformed to
2-azidomethyl-5,6-dimethyl-1H-benzimidazole following conditions
outlined by Hankovszky resulting in a yellow solid (Hiales et al.,
Synthesis 1978, 4, 313-315). H NMR (300 MHz, CDCl.sub.3) .delta.
7.26 (s, 2H), .delta. 4.72 (s, 2H), .delta. 2.37 (s, 6H) ppm;
.sub.13C NMR (75 MHz, DMSO) .delta. 153.7, 134.3, 130.1, 125.1,
124.6, 117.2, 113.6, 48.0, 20.6, 19.6 ppm; HRMS (FAB) calcd for
C.sub.10H.sub.11N.sub.5 (M+) 201.1014, found 201.1010.
##STR00067##
[0347] To a 100 mL round-bottomed flask equipped with a magnetic
stir was added trans-2-methyl-3-phenyl-2-propen-1-ol (2.00 g, 13.5
mmol) and 75 mL of methylene chloride. The solution was then cooled
to 0.degree. C. while stirring. Then, triethylamine (2.75 g, 27.0
mmol) is added followed by a dropwise addition of methanesulfonyl
chloride (2.34 g, 20.4 mmol) and a two hour stir period. The
reaction mixture is washed with water (2.times.75 mL), dried with
sodium sulfate and then concentrated de vacuo. The crude mixture is
then dissolved in 75 mL of DMF and then stirred via magnetic stir
bar. To this mixture, sodium azide (1.76 g, 27.0 mmol) is added.
The reaction mixture is then heated to 80.degree. C. and allowed to
stir for two hours. At this time, volatiles are concentrated de
vacuo and the resulting residue is purified via column
chromatography (1:9 ethyl acetate/hexane) providing,
(3-Azido-2-methyl propenyl)-benzene (2.08 g, 89%) as a colorless
oil. .sub.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.36-7.25 (m, 5H),
.delta. 6.53 (s, 1H), .delta. 3.87 (s, 2H) ppm; .sub.13C NMR (75
MHz, CDCl.sub.3) .delta. 129.4, 129.2, 128.9, 128.6, 128.4, 127.1,
59.9, 52.0, 22.3, 16.5 ppm; LRMS (EI) calcd for
C.sub.10H.sub.11N.sub.3 (M+) 173, found 173.
##STR00068##
[0348] Following, the same procedure used to synthesize
(3-Azido-2-methyl-propenyl)benzene, thiophene-3-ethanol (2.00 g,
15.5 mmol) was converted to 3-azidoethyl-thiophene (2.06 g, 86%) as
a colorless oil. .sub.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.36 (s,
1H), .delta. 7.14 (d, 1H), .delta. 7.04 (d, 1H), .delta. 3.54 (t,
2H), .delta. 2.98 (t, 2H) ppm; .sub.13C NMR (75 MHz, CDCl.sub.3)
.delta. 138.7, 128.4, 126.3, 122.2, 52.0, 30.1 ppm; LRMS (EI) calcd
for C.sub.6H.sub.7N.sub.3S (M+) 153, found 153.
##STR00069##
[0349] 2-Amino-hex-5-ynoic acid methyl ester hydrochloride was
synthesized using the same methods previously reported for the
synthesis of 2-Amino-pent-4-ynoic acid methyl ester hydrochloride
(Kotha et al., Tetrahedron 2002, 58, 9203-9208). .sub.1H NMR (300
MHz, D20) .delta. 4.16 (t, 1H). .delta. 3.71 (s, 3H), .delta. 2.32
(t, 1H), .delta. 2.29 (m, 2H), .delta. 2.06 (m, 2H) ppm; .sub.13C
NMR (75 MHz, D.sub.2O) .delta. 170.4, 82.4, 71.4, 53.9, 52.1, 28.7,
14.4 ppm; HRMS (ESI) calcd for C.sub.7H.sub.11NO.sub.2 (M+)
142.0859, found 142.862.
##STR00070##
[0350] 2-Amino-hept-6-ynoic acid methyl ester hydrochloride was
synthesized using the same methods previously reported for the
synthesis of 2-Amino-pent-4-ynoic acid methyl ester hydrochloride
(Kotha et al., Tetrahedron 2002, 58, 9203-9208). .sub.1H NMR (300
MHz, DMSO) .delta. 8.75 (s, 2H), .delta. 3.99 (m, 1H), .delta. 3.72
(s, 3H), .delta. 2.82 (t, 1H), .delta. 2.17 (m, 2H), .delta. 1.89
(m, 2H), .delta. 1.51 (m, 2H) ppm; .sub.13C NMR (75 MHz, DMSO)
.delta. 163.7, 83.1, 69.2, 60.9, 30.6, 29.5, 23.9, 17.6 ppm; HRMS
(ESI) calcd for C.sub.8H.sub.13NO.sub.2 (M+) 156.1019, found
156.1017.
##STR00071##
[0351] 2-Amino-oct-7-ynoic acid methyl ester hydrochloride was
synthesized using the same methods previously reported for the
synthesis of 2-Amino-pent-4-ynoic acid methyl ester hydrochloride
(Kotha et al., Tetrahedron 2002, 58, 9203-9208). .sub.1H NMR (300
MHz, D.sub.2O) .delta. 4.16 (t, 1H), .delta. 3.84 (s, 3H), .delta.
2.35 (t, 1H), .delta. 2.24 (m, 2H), .delta. 1.95 (m, 2H), .delta. 6
1.52 (m, 4H) ppm; .sub.13C NMR (75 MHz, D.sub.2O) .delta. 170.9,
85.6, 69.6, 53.6, 52.9, 29.3, 27.0, 23.4, 17.3 ppm; HRMS (ESI)
calcd for C.sub.9H.sub.15NO.sub.2 (M+) 170.1176, found
170.1171.
##STR00072##
[0352] 2-Amino-non-8-ynoic acid methyl ester hydrochloride was
synthesized using the same methods previously reported for the
synthesis of 2-Amino-pent-4-ynoic acid methyl ester hydrochloride
(Kotha et al., Tetrahedron 2002, 58, 9203-9208). .sub.1H NMR (300
MHz, D.sub.2O) .delta. 4.21 (t, 1H), .delta. 3.90 (s, 3H), .delta.
2.41 (t, 1H), .delta. 2.28 (m, 2H), .delta. 2.01 (m, 2H), .delta.
1.51 (m, 6H) ppm; .sub.13C NMR (75 MHz, D.sub.2O) .delta. 171.1,
86.4, 69.4, 53.7, 53.1, 29.8, 27.5, 27.4, 23.8, 17.6 ppm; HRMS
(ESI) calcd for C.sub.10H.sub.18NO.sub.2 (M+) 184.1332, found
184.1329.
##STR00073##
[0353] 2-Amino-dec-9-ynoic acid methyl ester hydrochloride was
synthesized using, the same methods previously reported for the
synthesis of 2-Amino-pent-4-ynoic acid methyl ester hydrochloride
(Kotha et al., Tetrahedron 2002, 58, 9203-9208). .sub.1H NMR (300
MHz, D.sub.2O) .delta. 4.16 (t, 1H), .delta. 3.86 (s, 3H), .delta.
2.36 (t, 1H), .delta. 2.21 (m, 2H), .delta. 1.98 (m, 2H), .delta.
1.55-1.39 (m, 8H) ppm; .sub.13C NMR (75 MHz, D.sub.2O) .delta.
171.2, 86.7, 69.3, 53.7, 53.1, 29.8, 27.7, 27.7, 27.6, 24.1, 17.6
ppm; HRMS (ESI) calcd for C.sub.11H.sub.20NO.sub.2 (M+) 198.1488,
found 198.1488.
##STR00074##
[0354] 2-Amino-pent-4-ynoic acid methyl ester hydrochloride (2.91
g, 17.8 mmol) was treated to an Akabori reduction followed by a
cyanamide condensation employing conditions previously reported to
produce 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (1.65 g,
59%) as a yellow oil (Olofson et al., Journal of Organic Chemistry
1997, 62, (23), 7918-7919). .sub.1H NMR (300 MHz, CD.sub.3OD)
.delta. 6.30 (s, 1H), .delta. 5.02 (d, 2H), .delta. 2.26 (t, 1H)
ppm; .sub.13C NMR (75 MHz, CD.sub.3OD) .delta. 150.1, 127.2, 109.6,
83.6, 69.8, 15.9 ppm; HRMS (ESI) calcd for C.sub.6H.sub.7N.sub.3
(M+) 122.0712, found 122.0713.
##STR00075##
[0355] 2-Amino-hex-5-ynoic acid methyl ester hydrochloride (2.53 g,
14.2 mmol) was treated to an Akabori reduction followed by a
cyanamide condensation employing conditions previously reported to
produce 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (1.17 g,
48%) as a pale yellow oil (Olofson et al., Journal of Organic
Chemistry 1997, 62, (23), 7918-7919). .sub.1H NMR (300 MHz,
CD.sub.3OD) .delta. 6.52 (s, 1H), .delta. 2.61 (t, 2H), .delta.
2.42 (m, 2H), .delta. 2.27 (t, 1H) ppm; .sub.13C NMR (75 MHz,
CD.sub.3OD) .delta. 147.4, 126.2, 109.4, 81.9, 69.9, 23.8, 17.4
ppm; HRMS (ESI) calcd for C.sub.7H.sub.10N.sub.3 (M+) 136.0869,
found 136.0865.
##STR00076##
[0356] 2-Amino-hept-6-ynoic acid methyl ester hydrochloride (2.00
g, 10.4 mmol) was treated to an Akabori reduction followed by a
cyanamide condensation employing conditions previously reported to
produce 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (1.75 g,
90%) as a pale oil (Olofson et al., Journal of Organic Chemistry
1997, 62, (23), 7918-7919). .sub.1H NMR (300 MHz, CDCl.sub.3)
.delta. 6.68 (bs, 2H), .delta. 6.24 (s, 1H), .delta. 2.51 (t, 2H),
.delta. 2.17 (t, 1H), .delta. 1.95 (s, 1H), .delta. 1.74 (m, 2H)
ppm; .sub.13C NMR (75 MHz, CDCl.sub.3) .delta. 148.3, 132.7, 111.6,
84.4, 69.1, 28.0, 26.0, 18.2 ppm; HRMS (ESI) calcd for
C.sub.10H.sub.16N.sub.3 (M+) 150.1026, found 150.1029:
##STR00077##
[0357] 2-Amino-oct-7-ynoic acid methyl ester hydrochloride (2.90 g,
14.1 mmol) was treated to an Akabori reduction followed by a
cyanamide condensation employing conditions previously reported to
produce 4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (2.45 g,
87%) as a pale yellow solid (Olofson et al., Journal of Organic
Chemistry 1997, 62, (23), 7918-7919). .sub.1H NMR (300 MHz,
CD.sub.3OD) .delta. 6.43 (s, 1H), .delta. 2.44 (t, 2H), 2.14 (t,
1H), .delta. 2.12 (m, 2H), .delta. 1.64 (m, 2H), .delta. 1.47 (m,
2H) ppm; .sub.13C NMR (75 MHz, CD.sub.3OD) .delta. 147.3, 127.6,
108.5, 83.4, 68.7, 27.7, 27.1, 23.8, 17.5 ppm; HRMS (ESI) calcd for
C.sub.9H.sub.14N.sub.3 (M+) 164.1182, found 164.1182.
##STR00078##
[0358] 2-Amino-non-8-ynoic acid methyl ester hydrochloride (2.02 g,
9.20 mmol) was treated to an Akabori reduction followed by a
cyanamide condensation employing conditions previously reported to
produce 4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (1.04 g,
53%) as a pale yellow solid (Olofson et al., Journal of Organic
Chemistry 1997, 62, (23), 7918-7919). .sub.1H NMR (300 MHz,
CD.sub.3OD) .delta. 6.17 (s, 1H), .delta. 2.19 (t, 2H), .delta.
1.90 (t, 1H), .delta. 1.86 (m, 2H), .delta. 1.24-1.13 (m, 6H) ppm;
.sub.13C NMR (75 MHz, CD.sub.3OD) .delta. 147.5, 128.3, 108.8,
83.8, 65.5, 28.4, 28.3, 28.2, 24.5, 17.8 ppm; HRMS (ESI) calcd for
C.sub.10H.sub.16N.sub.3 (M+) 178.1338, found 178.1337.
##STR00079##
[0359] 2-Amino-dec-9-ynoic acid methyl ester hydrochloride (1.50 g,
6.42 mmol) was treated to an Akabori reduction followed by a
cyanamide condensation employing conditions previously reported to
produce 4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.774 g,
53%) as a pale yellow solid (Olofson et al., Journal of Organic
Chemistry 1997, 62, (23), 7918-7919). .sub.1H NMR (400 MHz,
CD.sub.3OD) .delta. 6.09 (s, 1H), .delta. 2.19 (t, 2H), .delta.
1.95 (t, 1H), 1.93 (m, 2H), .delta. 1.39-1.11 (m, 8H) ppm; .sub.13C
NMR (75 MHz, CD.sub.3OD) .delta. 148.5, 131.0, 110.1, 83.9, 68.3,
28.6, 28.5, 28.4, 28.3, 25.7, 17.8 ppm; HRMS (ESI) calcd for
C.sub.11H.sub.18N.sub.3 (M+) 192.1495, found 192.1495.
##STR00080##
[0360] To a 50 mL round-bottomed flask equipped with a magnetic
stirbar was added 1-H-1,2,3-triazole (0.192 g, 2.78 mmol) and DMF
(10 mL) and then cooled to 0.degree. C. while stirring. Then,
sodium hydride (60% dispersion in mineral oil) (0.133 g, 3.33 mmol)
is added to the reaction mixture and was slowly allowed to warm to
ambient temperature. Then, 1-iodo-4 pentyne (0.647 g, 3.33 mmol)
was added dropwise. The reaction mixture was then heated to
80.degree. C. and allowed to stir for 2.5 hours. Water (20 mL) was
then added to the reaction mixture and then extracted with ethyl
acetate (2.times.20 mL). The organic phase was dried with sodium
sulfate and concentrated de vacuo followed by a purification by
column chromatography (ethyl acetate/hexane) to produce
1-Pent-4-ynyl-1H-[1,2,3]triazole (0.349 g, 93%) as a colorless oil.
.sub.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.67 (s, 1H), .delta.
7.59 (s, 1H), .delta. 4.53 (t, 2H), .delta. 2.20 (t, 2H), .delta.
2.17 (m, 2H), .delta. 2.04 (s, 1H) ppm; .sub.13C NMR (75 MHz,
CDCl.sub.3) .delta. 133.9, 123.9, 82.2, 70.4, 48.7, 28.9. 15.7 ppm;
HRMS (ESI) calcd for C.sub.7H.sub.10N.sub.3 (M+) 136.0869, found
136.0866.
[0361] General procedure for click reactions: The terminal alkyne
(1.0 equiv.) was dissolved in a 1:1:1 mixture of tert-butyl
alcohol, water and methylene chloride (ca. 10 mL per 0.300 g of
terminal alkyne). To this solution, the appropriate azide (1.2
equiv.) was added while stirring vigorously at room temperature.
Copper (II) sulfate pentahydrate (15 mol %) and sodium ascorbate
(45 mol %) were then added sequentially to the solution. Reaction
mixtures were allowed to stir until completion via TLC analysis
(12-24 hrs). The solvents were then removed de vacuo in which the
resulting residue was dissolved in methanol and purified by flash
chromatography (10-20% ammonia saturated methanol: methylene
chloride). The resulting fractions were evaporated under reduced
pressure followed by a 24 hr high vacuum treatment to remove all
ammonia traces. Methanol saturated with HCl is then added to the
purified product in which all volatiles are then removed under
reduced pressure.
##STR00081##
[0362] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.127 g,
0.809 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene
(0.168 g, 0.971 mmol) following the general procedure for click
reactions outlined above to produce
4-[1-(2-Methyl-3-phenyl-allyl)-1H[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-
-ylamine hydrochloride (0.244 g, 91%) of a pale yellow solid.
.sub.1H NMR (300 MHz, D.sub.2O) .delta. 7.94 (s, 1H), .delta.
7.40-7.35 (m, 5H), .delta. 6.56 (s, 1H), .delta. 5.10 (s, 2H),
.delta. 3.99 (s, 2H), .delta. 1.76 (s, 3H) ppm; .sub.13C .delta.
145.8, 138.1, 136.9, 136.5, 136.4, 132.8, 128.3, 128.0, 127.6,
125.3, 123.4, 49.3, 23.8, 23.4; HRMS (ESI) calcd for
C.sub.16H.sub.18N.sub.6 (M+) 295.1665, found 295.1665.
##STR00082##
[0363] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.095 g,
0.603 mmol) was reacted with benzyl azide (0.096 g, 0.723 mmol)
following the general procedure for click reactions outlined above
to produce 4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol
2-ylamine hydrochloride (0.151 g. 86%) of a pale yellow solid.
.sub.1H NMR (300 MHz, D.sub.2O) .delta. 7.79 (s, 1H), .delta.
7.42-7.35 (m, 5H), .delta. 6.43 (s, 1H), .delta. 5.58 (s, 2H),
.delta. 3.86 (s, 2H) ppm; .sub.13C .delta. 145.4, 136.6, 135.4,
128.8, 128.7, 126.9, 126.8, 126.3, 124.1, 121.8, 109.6, 53.3, 24.1
ppm; HRMS (ESI) calcd for C.sub.13H.sub.16N.sub.6O (M+) 254.1352,
found 254.1352.
##STR00083##
[0364] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g,
0.639 mmol) was reacted with 3-azidomethyl-furan (0.094 g, 0.767
mmol) following the general procedure for click reactions outlined
above to produce
4-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol-2-
-ylamine hydrochloride (0.077 g, 43%) of a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.12 (s, 1H), .delta.
7.60 (s, 1H), .delta. 7.38 (s, 1H), .delta. 6.53 (s, 1H), .delta.
6.37 (s, 1H), .delta. 5.46 (s, 2H), .delta. 3.95 (s, 2H) ppm;
.sub.13C NMR (75 MHz, CD.sub.3OD) .delta. 146.1, 145.3, 144.1,
141.0, 123.3, 123.1, 110.3, 110.2, 109.9, 51.3, 19.9 ppm; HRMS
(ESI) calcd for C.sub.11H.sub.12N.sub.6O (M+) 244.1145, found
244.1145.
##STR00084##
[0365] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g,
0.061 mmol) was reacted with 2-azidomethyl-furan (0.089 g, 0.729
mmol) following the general procedure for click reactions outlined
above to produce
4-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol-2-
-ylamine hydrochloride (0.078 g, 46%) as a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.93 (s, 1H), .delta.
7.41 (s, 1H), 6.49 (s, 2H), .delta. 6.32 (s, 1H), .delta. 5.56 (s,
2H), .delta. 3.89 (s, 2H) ppm; .sub.13C NMR (75 MHz, CD.sub.3OD)
.delta. 146.2, 146.1, 142.4, 141.5, 122.3, 122.2, 108.9, 109.2,
108.8, 51.6, 18,9 ppm; HRMS (ESI) calcd for
C.sub.11H.sub.12N.sub.6O (M+) 245.1145, found 245.1147.
##STR00085##
[0366] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096
(0.061 mmol) was reacted with 3-azidomethyl thiophene (0.102 g,
0.732 mmol) following the general procedure for click reactions
outlined above to produce
4-(1-Thiophen-3-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1Himidazol-
-2-ylamine hydrochloride (0.079 g, 44%) of a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.18 (s, 1H), .delta.
7.44 (s, 1H), .delta. 7.30 (d, 1H), .delta. 6.98 (d, 1H), .delta.
6.53 (s, 1H), .delta. 5.57 (s, 2H), .delta. 3.95 (s, 2H) ppm;
.sub.13C (75 MHz, CD.sub.3OD) .delta. 145.7, 145.1, 143.7, 139.7,
129.8, 121.8, 111.5, 109.8, 109.2, 52.7, 21.5 ppm; HRMS (ESI) calcd
for C.sub.11H.sub.12N.sub.6S (M+) 260.0919, found 260.0919.
##STR00086##
[0367] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g,
0.641 mmol was reacted with 3-(2-Azido-ethyl)-thiophene (0.118 g,
0.769 mmol) following the general procedure for click reactions
outlined above to produce 4-[1-(2-Thiophen-3-yl-ethyl)-1H
[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine hydrochloride
(0.119 g, 60%) of a pale yellow solid. .sub.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.42 (s, 1H), .delta. 7.19 (t, 1H), .delta.
6.90 (s, 1H), .quadrature. 6.78 (d, 1H), .delta. 6.09 (s, 1H),
.delta. 4.47 (t, 2H), .delta. 3.67 (s, 2H), .delta. 3.09 (t, 2H)
ppm; .sub.13C; (75 MHz, CD.sub.3OD) .delta. 151.2, 145.7, 137.7,
130.5, 127.8, 125.8, 122.9, 121.9, 110.3, 50.798, 30.7, 23.3 ppm;
HRMS (ESI) calcd for C.sub.12H.sub.14N.sub.6S (M+) 274.1001, found
274.1007.
##STR00087##
[0368] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.047 g,
0.295 mmol) was reacted with
2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.071 g, 0.354 mmol)
following the general procedure for click reactions outlined above
to produce 4-[1-(5,6
Dimethyl-1H-benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]-1H-im-
idazol-2-ylamine dihydrochloride (0.029 g, 25%) of a yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.09 (s, 1H), .delta.
7.45 (s, 2H), .delta. 6.52 (s, 1H), .delta. 6.08 (s, 2H), .delta.
3.93 (s, 2H), .delta. 2.35 (s, 6H) ppm; .sub.13C (75 MHz,
CD.sub.3OD) .delta. 142.2, 136.9, 136.6, 124.5, 124.3, 113.8,
113.4, 110.0, 100.4, 85.8, 80.6, 75.3, 74.1, 45.0, 20.9, 19.28 ppm;
HRMS (ESI) calcd for C.sub.16H.sub.18N.sub.8 (M+) 323.1727, found
323.1734.
##STR00088##
[0369] 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.091 g,
0.576 mmol) was reacted with 2-azidomethyl-1H-benzimidazole, which
was synthesized using previously reported methods (Hiales et al.,
Synthesis 1978, 4, 313-315), (0.120 g,0.691 mmol) following the
general procedure for click reactions outlined above to produce
4-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]
1Himidazol-2-ylamine dihydrochloride (0.125 g, 59%) of a yellow
solid. .sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.01 (s, 1H),
.delta. 7.58 (d, 2H), .delta. 7.31 (t, 2H), .delta. 6.44 (s, 1H),
.delta. 5.98 (s, 2H) .delta. 3.84 (s, 2H) ppm; .sub.13C (75 MHz.
CD.sub.3OD) .delta. 135.6, 124.7, 123.7, 123.5, 122.8, 112.8,
112.3, 108.4, 83.6, 78.9, 74.0, 73.2, 44.2, 19.3 ppm; HRMS (ESI)
calcd for C.sub.14H.sub.14N.sub.8 (M+) 295.1414, found
295.1420.
##STR00089##
[0370] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0735 g,
0.428 mmol) was reacted with (3-azido-propyl) benzene, which was
synthesized using previously reported methods (Suenaga et al.,
Tetrahedron Letters 2003, 44, 5799-5801), (0.083 g, 0.514 mmol)
following the general procedure for click reactions outlined above
to produce
4-{2-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-yl-
amine hydrochloride (0.051 g, 36%) of a pale yellow oil. .sub.1H
NMR (300 MHz, CD.sub.3OD) .delta. 7.87 (s, 1H), .delta. 7.32-7.22
(m, 5H), .delta. 6.54 (s, 1H), .delta. 4.31 (t, 2H), .delta. 3.05
(t, 2H), .delta. 2.93 (t, 2H), .delta. 2.67 (t, 2H), .delta. 2.23
(m, 2H) ppm; .sub.13C (75 MHz CD.sub.3OD) .delta. 153.3, 146.6,
140.4, 134.3, 128.8, 128.7, 128.6, 126.6, 121.5, 67.5, 53.9. 32.8,
32.9, 29.5 ppm; HRMS (ESI) calcd for C.sub.16H.sub.20N.sub.6 (M+)
296.1822, found 296.1828.
##STR00090##
[0371] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.062 g,
0.362) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.075
g, 0.434 mmol) following, the general procedure for click reactions
outlined above to produce
4-{2-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imida-
zol-2-ylamine hydrochloride (0.054 g, 43%) of a pale yellow oil.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.39 (s, 1H), .delta.
7.12-7.07 (m, 5H), .delta. 6.54 (s, 1H), .delta. 6.36 (s, 1H),
.delta. 5.09 (s, 2H), .delta. 3.01 (t, 2H), .delta. 2.76 (t, 2H),
.delta. 1.60 (s, 3H) ppm; .sub.13C; 147.7, 143.1, 136.3, 132.7,
129.9, 128.9, 128.6, 128.5, 128.2, 127.4, 127.1, 124.9, 109.9,
61.2, 23.0, 22.3, 14.7 ppm; HRMS (ESI) calcd for
C.sub.16H.sub.20N.sub.6 (M+) 308.1749, found 308.1742.
##STR00091##
[0372] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.068 g,
0.399 mmol) was reacted with 2-azidomethyl furan (0.059 g, 0.478
mmol) following the general procedure for click reactions outlined
above to produce
4-[2-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidaz-
ol-2-ylamine hydrochloride (0.085 g, 72%) of a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.06 (s, 1H), .delta.
7.53 (s, 1H), .delta. 6.59 (t, 1H), .delta. 6.49 (s, 1H), .delta.
6.44 (dd, 1H), .delta. 3.05 (t, 2H), .delta. 2.89 (t, 2H) ppm;
.sub.13C (75 MHz, CD.sub.3OD) .delta. 156.4, 154.9, 147.5, 144.1,
126.0, 125.1, 123.8, 110.7, 109.3, 69.8, 23.8, 17.4 ppm; HRMS (ESI)
calcd for C.sub.12H.sub.14N.sub.6O (M+) 259.1301, found
259.1305.
##STR00092##
[0373] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.078 g,
0.45 mmol) was reacted with 3-(2-Azido-ethyl)-thiophene (0.083 g,
0.543 mmol) following the general procedure for click reactions
outlined above to produce
4-{2-[1-(2-Thiophen-3-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-
-imidazol-2-ylamine hydrochloride (0.069 g, 47%) of a pale yellow
oil. .sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.33 (s, 1H),
.delta. 7.19 (dd, 1H), .delta. 6.85 (d, 1H), .delta. 6.72 (d, 1H),
.delta. 6.06 (s, 1H), .delta. 4.45 (t, 2H), .delta. 3.08 (t, 2H),
.delta. 2.79 (t, 2H), .delta. 2.59 (t, 2H), ppm .sub.13C (75 MHz,
CD.sub.3OD) .delta. 149.3, 147.0, 137.7, 132.1, 127.7, 125.8,
122.4, 121.9, 110.6, 50.8, 30.7, 26.6, 24.8 ppm; HRMS (ESI) calcd
for C.sub.13H.sub.17N.sub.6S (M+) 289.1229, found 289.1231.
##STR00093##
[0374] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g,
0.383 mmol) was reacted with (3-azido-propenyl)-benzene, which was
synthesized using previously reported methods (Rad et al.,
Tetrahedron Letters 2007, 48, 3445-3449), (0.079 g, 0.460 mmol)
following the general procedure for click reactions outlined above
to produce
4-{2-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-yla-
mine hydrochloride (0.049 g, 39%) of a pale yellow oil. .sub.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.19 (s, 1H), .delta. 7.44 (d, 2H),
.delta. 7.29 (m, 3H), .delta. 6.73 (d, 1H), .delta. 6.53 (s, 1H),
.delta. 6.42 (m, 2H), .delta. 5.24 (d, 2H), .delta. 3.07 (t, 2H),
.delta. 2.88 (t, 2H) ppm; .sub.13C 148.6, 145.3, 139.4, 139.2,
129.8, 129.7, 129.6, 128.5, 128.4, 127.6, 54.6, 47.3. 45.9, 26.3,
22.6 ppm; HRMS (ESI) calcd for C.sub.16H.sub.19N.sub.6 (M+)
295.1665, found 295.1670.
##STR00094##
[0375] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g,
0.384 mmol) was reacted with 3-azidomethyl-furan (0.057 g, 0.461
mmol) following the general procedure for click reactions outlined
above to produce
4-[2-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidaz-
ol-2-ylamine hydrochloride (0.061 g, 54%) as a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.70 (s, 1H), .delta.
7.61 (s, 1H), .delta. 7.46 (s, 1H), .delta. 6.42 (s, 1H), .delta.
6.38 (s, 1H), .delta. 5.41 (s, 2H), .delta. 2.95 (t, 2H), .delta.
2.83 (t, 2H) ppm; .sub.13C (75 MHz, CD.sub.3OD) .delta. 146.3,
144.2, 141.6, 141.5, 126.5, 122.3, 120.2, 109.9, 109.1, 44.8, 24.2,
23.9 ppm; HRMS (ESI) calcd for C.sub.12H.sub.14N.sub.6O (M+)
259.1301, found 259.1306.
##STR00095##
[0376] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.073 g,
0.423 mmol) was reacted with benzyl azide (0.068 g, 0.509 mmol)
following the general procedure for click reactions outlined above
to produce
4-[2-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine
hydrochloride (0.059 g, 46%) as a pale yellow oil. .sub.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.83 (d, 1H), .delta. 7.37-7.24 (m, 5H),
.delta. 6.44 (d, 1H), .delta. 5.54 (d, 2H), .delta. 2.96 (m, 2H),
.delta. 2.83 (m, 2H) ppm; .sub.13C (75 MHz, CD.sub.3OD) .delta.
163.7, 147.3, 146.4, 135.7, 128.8, 128.4, 127.9, 127.8, 126.5,
122.6, 109.1, 53.7, 24.1, 23.9 ppm; HRMS (ESI) calcd for
C.sub.14H.sub.16N.sub.6 (M+) 269.1515, found 269.1513.
##STR00096##
[0377] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.073 g,
0.429 mmol) was reacted with 3-azidomethyl-indole (0.089 g, 0.515
mmol) following the general procedure for click reactions outlined
above to produce
4-{2-[1-(1H-Indol-3-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1Him-
idazol-2-ylamine hydrochloride (0.086 g, 58%) as a yellow oil.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.11 (s, 1H), .delta.
7.84 (m, 2H), .delta. 7.41 (m, 2H), .delta. 7.06 (d, 1H), .delta.
5.66 (s, 2H), .delta. 3.04 (t, 2H), .delta. 2.85 (t, 2H) ppm;
.sub.13C (75 MHz, CD.sub.3OD) .delta. 147.5, 144.9, 144.8, 134.7,
131.9, 127.2, 127.1, 127.1, 125.8, 125.3, 124.4, 109.5, 49.9, 23.6,
23.2 ppm; HRMS (ESI) calcd for C.sub.17H.sub.19N.sub.7 (M+)
321.1701, found 321.1704.
##STR00097##
[0378] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.061 g,
0.361 mmol) was reacted with 2-azidomethyl-1-H-benzimidazole (0.075
g, 0.433 mmol) following the general procedure for click reactions
outlined above to produce
4-{2-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-i-
midazol-2-ylamine dihydrochloride (0.066 g, 48%) of a yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.05 (s, 1H), .delta.
7.68 (m. 2H), .delta. 7.48 (m, 2H), .delta. 6.38 (s, 1H), .delta.
6.15 (s, 2H'), .delta. 2.90 (t, 2H), .delta. 2.76 (t, 2H) ppm;
.sub.13C (75 MHz, CD.sub.3OD) .delta. 146.9, 146.8, 131.3, 127.0,
126.4, 124.1, 114.1, 109.2, 44.7, 24.0, 23.9 ppm; HRMS (ESI) calcd
for C.sub.15H.sub.17N.sub.8 (M+) 309.1570, found 309.1572.
##STR00098##
[0379] 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0734 g,
0.432 mmol) was reacted with
2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.104 g, 0.518 mmol)
following the general procedure for click reactions outlined above
to produce
4-{2-[1-(5,6-Dimethyl-1Hbenzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-
-ethyl}-1H-imidazol-2-ylamine dihydrochloride (0.104 g, 59%) of a
pale yellow solid. .sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.70
(s, 1H), .delta. 7.19 (s, 2H), .delta. 6.23 (s, 1H), .delta. 5.66
(s, 2H), .delta. 2.85 (t, 2H), .delta. 2.68 (t, 2H), .quadrature.
2.21 (s, 6H) ppm; .sub.13C (75 MHz, CD.sub.3OD) .delta. 148.2,
147.0, 146.9, 132.3, 128.9, 122.8, 120.0, 115.1, 109.7, 100.4,
25.1, 24.4, 19.2 ppm; HRMS (ESI) calcd for C.sub.17H.sub.20N.sub.8
(M+) 337.1883, found 337.1886.
##STR00099##
[0380] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.050 g,
0.269 mmol) was reacted with (3-azido-propyl) benzene (0.044 g,
0.273 mmol) following the general procedure for click reactions
outlined above to produce
4-{3-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imid-
azol-2-ylamine hydrochloride (0.0318 g, 34%) as a pale yellow
solid. .sub.1H NMR (300 MHz, DMSO) .delta. 7.91 (s, 1H), .delta.
7.29-7.17 (m, 5H), .delta. 6.62 (s, 2H), .delta. 6.57 (s, 1H),
.delta. 4.29 (t, 2H), .delta. 2.59 (t, 2H), .delta. 2.53 (t, 2H),
.delta. 2.43 (t, 2H) .delta. 2.09 (m, 2H), .delta. 1.83 (m, 2H)
ppm; .sub.13C NMR (75 MHz, DMSO) .delta. 163.6, 156.2, 155.1,
147.4, 146.9, 141.4, 129.1, 127.1, 126.7, 122.6, 109.4, 49.4, 32.6,
32.0, 28.1, 24.9, 24.2 ppm; HRMS (ESI) calcd for
C.sub.17H.sub.22N.sub.6 (M+) 310.1978, found 310.1977.
##STR00100##
[0381] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.063 g,
0.340 mmol) was reacted with 3-azidomethyl-furan (0.050 g, 0.406
mmol) following, the general procedure for click reactions outlined
above to produce
4-[3-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1Himidaz-
ol-2-ylamine hydrochloride (0.061 g, 58%) as a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.70 (s, 1H), .delta.
7.56 (s, 1H), .delta. 7.41 (s, 1H), .delta. 6.44 (s, 1H), .delta.
6.35 (s, 1H), .delta. 5.35 (s, 2H), .delta. 2.65 (t, 2H), .delta.
2.45 (t, 2H), .delta. 1.86 (m, 2H) ppm; .sub.13C NMR (75 MHz,
CD.sub.3OD) .delta. 147.3, 147.3, 144.2, 141.6, 127.2, 122.1,
120.2, 109.9, 108.8, 44.7, 27.8, 24.2, 23.6 ppms; HRMS (ESI) calcd
for C.sub.13H.sub.16N.sub.6O (M+) 272.1458, found 272.1462.
##STR00101##
[0382] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.093 g,
0.500 mmol) was reacted with 2-azidomethyl-furan (0.074 g, 0.601
mmol) following the general procedure for click reactions outlined
above to produce
4-[3-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1Himidaz-
ol-2-ylamine hydrochloride (0.075, 50%) as a pale yellow solid.
.sub.1H NMR (300 MHz, DMSO) .delta. 7.85 (s, 1H), .delta. 7.65 (s,
1H), .delta. 6.70 (s, 2H), .delta. 6.64 (s, 1H), .delta. 6.52 (t,
1H), .delta. 6.46 (s, 1H), .delta. 5.58 (s, 2H), .delta. 2.61 (t,
2H), .delta. 2.41 (t, 2H), .delta. 1.82 (m, 2H) ppm; .sub.13C NMR
(75 MHz, DMSO) .delta. 163.6, 149.4, 147.9, 147.4, 144.3, 128.5,
122.6, 111,5, 110.3, 109.9, 46.3, 28.4, 24.9 ppm; HRMS (ESI) calcd
for C.sub.13H.sub.16N.sub.6O (M+) 272.1458, found 272.1460.
##STR00102##
[0383] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g,
0.486 mmol) was reacted with 3-Azidomethyl-thiophene (0.081 g,
0.582 mmol) following the general procedure for click reactions
outlined above to produce
4-[3-(1-Thiophen-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1H-im-
idazol-2-ylamine hydrochloride (0.0727 g, 46%) as a pale yellow
solid. .sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.61 (s, 1H),
.delta. 7.24 (s, 1H), .delta. 7.23 (d, 1H), .delta. 6.87 (d, 1H),
.delta. 6.29 (s, 1H), .delta. 2.54 (t, 2H), 2.33 (t, 2H), .delta.
1.75 (m, 2H) ppm; .sub.13C NMR (75 MHz, CD.sub.3OD) .delta. 147.6,
147.4, 147.3, 136.1, 127.9, 127.0, 126.9, 124.2, 122.2, 109.1,
53.1, 27.9, 24.3; HRMS (ESI) calcd for C.sub.1H.sub.16N.sub.6S (M+)
289.1229, found 289.1234.
##STR00103##
[0384] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g,
0.517 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene
(0.110 g, 0.635 mmol) following the general procedure for click
reactions outlined above to produce
5-{3-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imid-
azol-2-ylamine hydrochloride (0.076, 41%) as a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.65 (s, 1H), .delta.
7.14-7.04 (m, 5H), .delta. 6.35 (s, 1H), .delta. 6.28 (s, 1H),
.delta. 4.94 (s, 2H), .delta. 2.57 (t, 2H), .delta. 2.34 (t, 2H),
.delta. 1.75 (m, 2H), .delta. 1.57 (s, 3H) ppm; .sub.13C NMR (75
MHz, CD.sub.3OD) .delta. 147.5, 136.9, 132.5, 129.7, 128.8, 128.6,
128.4, 128.3, 128.2, 126.9, 122.5, 109.2, 58.1, 61.9, 28.0, 24.3,
24.3, 24.1, 14.6 ppm; HRMS (ESI) calcd for C.sub.18H.sub.22N.sub.6
(M+) 323.1978, found 323.1984.
##STR00104##
[0385] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.081 g,
0.437 mmol) was reacted with benzyl azide (0.071 g, 0.533 mmol)
following the general procedure for click reactions outlined above
to produce
4-[3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-propyl]-1H-imidazol-2-ylamine
hydrochloride (0.073 g, 53%) as a pale yellow solid. .sub.1H NMR
(300 MHz, DMSO) .delta. 7.93 (s, 1H), .delta. 7.37-7.27 (m, 5H),
.delta. 6.63 (s, 2H), .delta. 6.44 (s, 1H), .delta. 2.61 (t, 2H),
.delta. 2.40 (t, 2H), .delta. 1.82 (m, 2H) ppm; .sub.13C NMR (75
MHz, DMSO) .delta. 163.5, 148.1, 147.4, 135.9, 129.4, 128.7, 128.5,
128.4, 122.8, 122.8, 115.9, 109.9, 53.3, 28.5, 25.0; HRMS (ESI)
calcd for C.sub.15H.sub.18N.sub.6 (M+) 282.1665, found
282.1674.
##STR00105##
[0386] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g,
0.485 mmol) was reacted with 3-(2-Azido-ethyl)-thiophene (0.089 g,
0.581 mmol) following the general procedure for click reactions
outlined above to produce
4-{3-[1-(2-Thiophen-3-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1-
H-imidazol-2-ylamine hydrochloride (0.067 g, 41%) as a pale yellow
solid. .sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.42 (s, 1H),
.delta. 7.12 (d, 1H), .delta. 6.83 (s, 1H), .delta. 6.70 (d, 1H),
.delta. 6.29 (s, 1H), .delta. 4.41 (t, 2H), .delta. 3.04 (t, 2H),
.delta. 2.50 (t, 2H), .delta. 2.29 (t, 2H), .delta. 1.72 (m, 2H)
ppm; .sub.13C NMR (75 MHz, CD.sub.3OD) .delta. 146.8, 146.8, 137.7,
127.8, 127.6, 125.7, 122.6, 121.9, 109.0, 50.7, 30.7, 27.9, 23.7
ppm; HRMS (ESI) calcd for C.sub.14H.sub.18N.sub.6S (M+) 302.1313,
found 302.1317.
##STR00106##
[0387] 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.115 g,
0.620 mmol) was reacted with (3-azido-propenyl)-benzene (0.119 g,
0.748 mmol) following, the general procedure for click reactions
outlined above to produce
4-{3-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1Himidaz-
ol- 2-ylamine hydrochloride (0.082 g, 43%) as a pale yellow solid.
.sub.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.34-7.24 (m, 6H),
.delta. 6.67 (d, 1H), .delta. 6.34 (q, 1H), .delta. 6.25 (s, 1H),
.delta. 5.08 (d, 2H), .delta. 2.72 (t, 2H), .delta. 2.47 (t, 2H),
.delta. 1.91 (m, 2H) ppm; .sub.13C (75 MHz, CD.sub.3OD) 149.1,
137.9, 133.5, 129.5, 128.9, 128.7, 128.3, 128.2, 127.7, 126.8,
54.8, 48.9, 31.3, 29.6, 27.5 ppm ; HRMS (ESI) calcd for
C.sub.17H.sub.21N.sub.6 (M+) 308.1822, found 308.1821.
##STR00107##
[0388] 4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (0.089 g,
0.4.47 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene
(0.085 g, 0.491 mmol) following the general procedure for click
reactions outlined above to produce
4-{4-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-butyl}-1H-imida-
zol-2-ylamine (0.132 g, 79%) as a pale yellow solid. .sub.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.36 (s, 1H), 7.03 (m, 5H), 6.49 (s,
1H), 6.25 (s, 1H), 5.05 (s, 2H), .delta. 2.67 (t, 2H), .delta. 2.73
(t, 2H), .delta. 1.56 (s, 3H), .delta. 1.42 (m, 4H) ppm; .sub.13C
(75 MHz, CD.sub.3OD) .delta. 147.3, 144.7, 136.4, 132.7, 129.9,
128.9, 128.6, 128.5, 128.3, 127.5, 127.2, 126.9, 108.7, 61.2, 27.4,
27.3, 23.8, 22.8, 14.8 ppm; HRMS (ESI) calcd for
C.sub.19H.sub.24N.sub.6 (M+) 336.2135, found 336.2134.
##STR00108##
[0389] 4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (0.060 g,
0.281 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene
(0.058 g, 0.336 mmol) following the general procedure for click
reactions outlined above to produce
4-{5-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-pentyl}-1H-imid-
azol-2-ylamine hydrochloride (0.064 g, 65%) as a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.23 (s, 1H), .delta.
6.93-6.83 (m, 5H), .delta. 6.38 (s, 1H), .delta. 6.08 (s, 1H),
.delta. 4.93 (s, 2H), .delta. 2.51 (t, 2H), .delta. 2.09 (t, 2H),
.delta. 1.43 (s, 3H), .delta. 1.41 (m, 2H), .delta. 1.25 (m, 2H),
.delta. 1.05 (m, 2H) ppm; .sub.13C (75 MHz, CD.sub.3OD) .delta.
147.7, 144.8, 136.3, 132.8, 129.8, 128.9, 128.6, 128.5, 128.2,
127.6, 127.5, 127.0, 108.5, 61.3, 28.0, 27.6, 27.5, 24.0, 22.9,
14.7 ppm; HRMS (ESI) calcd for C.sub.20H.sub.27N.sub.6 (M+)
351.2291, found 351.2291.
##STR00109##
[0390] 4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.098 g,
0.568 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene
(0.118 g, 0.681 mmol) following the general procedure for click
reactions outlined above to produce
4-{6-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-hexyl}-1H-imida-
zol-2-ylamine hydrochloride (0.147 g, 85%) as a pale yellow solid.
.sub.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.42 (s, 1H), .delta.
7.25-7.15 (m, 5H), .delta. 6.65 (s, 1H), .delta. 6.36 (s, 1H),
.delta. 5.23 (s, 2H), .delta. 2.78 (t, 2H), .delta. 2.38 (t, 2H),
.delta. 1.74 (s, 3H), .delta. 1.64 (m, 2H), .delta. 1.51 (m, 2H),
.delta. 1.33 (m, 4H) ppm; .sub.13C (75 MHz, CD.sub.3OD) .delta.
147.5, 136.3, 132.9, 132.8, 129.9, 128.9, 128.6, 128.5, 128.3,
127.7; HRMS (ESI) calcd for C.sub.21H.sub.29N.sub.6 (M+) 365.2448,
found 365.2448.
##STR00110##
[0391] 1-Pent-4-ynyl-1H-[1,2,3]triazole (0.100 g, 0.739 mmol) was
reacted with (3-Azido-2-methylpropenyl)-benzene (0.154 g, 0.889
mmol) following the general procedure for click reactions outlined
above to produce
1-(2-Methyl-3-phenyl-allyl)-4-(3-[1,2,3]triazol-1-yl-propyl)-1H-[1,2,3]tr-
iazole (0.227 g, Quantitative) as a white solid. .sub.1H NMR (300
MHz, DMSO) .delta. 7.91 (s, 1H), .delta. 7.77 (s, 2H), .delta.
7.40-7.25 (m, 5H), .delta. 6.47 (s, 1H), .delta. 5.05 (s, 2H),
.delta. 4.48 (t, 2H), .delta. 2.62 (t, 2H), .delta. 2.50 (t, 2H),
.delta. 2.21 (m, 2H), .delta. 1.74 (s, 3H) ppm; .sub.13C (75 MHz,
DMSO) .delta. 146.4, 137.1, 134.8, 133.6, 132.8, 129.4, 129.3,
129.2, 128.9, 127.6, 123.0, 57.9, 54.0, 32.9, 29.6, 22.7, 16.2 ppm;
HRMS (ESI) calcd for C.sub.17H.sub.21N.sub.6 (M+) 309.1822, found
309.1821.
Example 2
Activity Testing of 2-AIT Library Members
[0392] A standard crystal violet reporter assay is employed to
assess the effect of compounds from the 2-amino on the formation of
biofilms. Among others, the following strains are tested:
[0393] Xanthomonas Xccl
[0394] Xanthomonas Xcv.135
[0395] Xanthomonas Xcv5
[0396] Xanthomonas Xccp
[0397] Xanthomonas Xcp60
[0398] Xanthomonas Xcp25
[0399] Ralstonia solanacearum K66
Xanthomonas is a Gram-negative rod-shaped bacterium that is a
common plant pathogen. Xanthomonas bacteria grow almost exclusively
in plants. Xanthomonas species testing includes X. vesicatoria
(crop=tomato), X. euvesicatoria (crop=pepper), X. campestris
(crop=crucifers, particularly cabbage), X. zinniae (crop=zinnia),
and X. fragariae (crop=strawberry). Ralstonia solanacearum is a
Gram-negative bacterium that is found in soil.
[0400] Bacteria are allowed to form biofilms in a multi-well plate
in the absence or presence of one or more compounds. Planktonic (or
free growing) bacteria are then removed, wells washed vigorously,
and crystal violet added. Crystal violet stains the remaining
bacteria which, following ethanol solubilization, is quantitated by
spectrophotometry (A.sub.540). Time-dependent and
concentration-dependent analysis of each compound are
performed.
Example 3
Activity Testing of 2-AIT Library Members on Xanthomonas
[0401] Biofilm formation on PVC microtiter wells was accomplished
using Xanthomonas strains Xcv 135 (known to infect peppers and
tomatoes) and Xcv 5 (known to infect tomatoes but not peppers) as
models. The Starting Optical Density (OD at 600 nm) for biofilm
attachment assay was 0.55, the temperature for this assay was
28.degree. C., the duration of incubation was 6 hours under, and
the assay was static.
[0402] Biofilm inhibition results are as follows for screens with
Xcv 135. The Xcv 5 strain is tested in the same manner.
TABLE-US-00002 Compound Screened % Inhibition at 20 .mu.M (vs. Xcv
135) Formula (II)(a)(5)(D) 86% Formula (II)(a)(6)(D) 85% Formula
(II)(i)(a)(2)(J) 0% ##STR00111## ##STR00112## ##STR00113##
Example 4
Activity Testing in Pepper Plants Inoculated with Xanthomonas
euvesicatoria (Bacterial Spot)
[0403] To test the effects of the triazole derivatives for plant
biofilm inhibition activity, the compound of Formula (II)(a)(5)(D)
was used as an exemplary compound (the "biofilm
inhibitor/disperser" or "BFI" in the text hereinafter of Example
4).
##STR00114##
The compound was evaluated under field conditions to determine
whether it controls or enhances control of bacterial spot (caused
by the bacterium Xanthomonas euvesicatoria) of pepper when applied
alone or in tank-mixtures with a copper (Kocide 3000), an
antibiotic (GWN-9350, gentamicin), or a putative plant defense
activator (Prophyt). Tests were performed April-July 2008 at the
North Carolina Agricultural Research Service Sandhills Research
Station, Montgomery County.
[0404] EXPERIMENTAL DESIGN and TREATMENT APPLICATIONS: Each
treatment consisted of two 7-plant rows running east-west
replicated in a four-block completely randomized design. Each
7-plant row was 10.5 ft.times.2 ft. This area was used to calculate
the quantity of spray material extrapolated for a per acre basis.
Plants of bell pepper cultivar `X3R-Camelot` were transplanted to
the field on Apr. 24, 2008. On May 6, two plants in the south row
of each plot of each treatment were inoculated with a suspension of
copper-resistant strains of the bacterial pathogen. These plants
were destined to serve as the inoculum source for each plot. Each
of the spray test materials was mixed in 1.5 liters of water and
applied using a backpack sprayer by making a single pass on each
side of the plant row. Treatments were applied weekly starting
immediately after the plants had been inoculated May 6 followed by
7 additional weekly sprays for a total of 8 applications through
June 24.
[0405] DATA: Ratings of foliar disease were started May 22, when
symptoms were observed on the inoculated plants and continued
weekly through June 25. Disease was most severe on the inoculated
plants and then spread to the non-inoculated plants. Data from
these two groups (inoculated plants and the non-inoculated) were
evaluated separately. The results are expressed as disease progress
over time using the calculated Area Under the Disease Progress
Curve (AUDPC). Two fruit harvests were done; July 1 and 8. Because
there had been plant loss in some plots, the number of plants per
plot was counted and yields (number of fruit and weight) were
calculated and are reported on a per plant basis per treatment.
Results are presented in Table 2 below.
TABLE-US-00003 TABLE 2 Mean AUDPC Mean Mean number Mean fruit
Treatment & rate/acre (based on for inoculated AUDPC for pepper
yield 100 gal water/acre) plants* entire plot* fruit/plant
(lb)/plant 1-NT Check 162 a** 45 a** 6.0 ab** 1.85 ab** 2-Kocide
3000 (30% MCE) 123 b 37 ab 6.5 ab 1.86 ab 1.25 lb 3-BFI 0.467 oz
(35 mg/L) 113 b 42 a 4.8 b 1.46 b 4-GWN-9350 (10%) 3.5 lb + 74 c 15
c 8.6 a 2.52 a GWN-65 1.0 pt 5-ProPhyt 5.0 pt 114 b 37 ab 6.5 ab
2.06 ab 6-ProPhyt 5.0 pt + 64 c 25 bc 6.3 ab 1.74 b BFI 0.467 oz
(35 mg/L) 7-GWN-9350 + GWN-65 1.0 41 c 12 c 8.3 a 2.51 a pt + BFI
0.467 oz (35 mg/L) 8-Kocide 3000 1.25 lb + 62 c 16 c 8.6 a 2.54 a
BFI 0.467 oz (35 mg/L) L.S.D. .alpha. = 0.05 34 16 2.6 0.76 and
probability of > treatment F 0.0001 0.0006 0.0466 0.0483 value
*0-9 rating scale with 0 = no disease, 1 = at least 1 diseased
leaf, 2 = 1-5% foliage diseased or defoliated, 3 = 6-10%, 4 =
11-15%, 5 = 16-25%, 6 = 26-50%, 7 = 51-75%, 8 = 76-99%, and 9 =
100% leaves diseased or plant completely defoliated. **Means within
a column followed by the same letter do not differ significantly,
L.S.D. .alpha. = 0.05.
Example 5
Activity Testing in Fungus
[0406] The compound of Formula (II)(a)(5)(D) was used as an
exemplary compound to evaluate the ability of 2-AIT compounds to
inhibit the formation of Candida albicans biofilms.
##STR00115##
It was screened at 100 .mu.M for its ability to inhibit to the
formation of C. albicans biofilms using a crystal violet reporter
assay. Briefly, biofilms were allowed to form for 24 hours in a
96-well microtiter plate in the absence or presence of 100 .mu.M of
the compound. The wells were subsequently washed thoroughly with
water to remove free-floating and loosely adherent fungus, and then
treated with crystal violet. Crystal violet stains the remaining
surface attached fungus (i.e. the biofilm), which following
solublization, can be quantified by spectrophotometry
(A.sub.540).
[0407] From this initial screen, we determined that the exemplary
compound was able to inhibit C. albicans formation by 12% at 100
.mu.M. Follow up growth curves at 100 .mu.M demonstrated that this
anti-biofilm activity was non-fungicidal (data not shown).
[0408] With this initial success of inhibiting fungal biofilms with
a 2-AI derivative, we asked the question whether analogue synthesis
could deliver alternative 2-AIT derivatives with enhanced
anti-biofilm activity in the context of fungal biofilms. Previous
work in our lab has demonstrated that 2-AI-based inhibitors of
biofilms can be sub-divided into three separate sections: 1) the
2-AI head, 2) the linker region, and 3) the tail region. Structure
activity relationship (SAR) data indicates that selectivity and
activity can be tuned/enhanced by modification of the tail
region.
##STR00116##
[0409] Based upon this data, we synthesized a new pilot library of
2-AI derivatives for anti-biofilm testing in which diversity could
be rapidly assembled via substituents off the triazole ring through
commercially available carboxylic acids.
[0410] The synthetic approach to this library is outlined in Scheme
2. In our previous synthesis of 2-AIT conjugates, we employed the
alkyne-derived 2-AI as a precursor to the Cu.sup.1-mediated [3+2]
alkyne/azide cycloaddition (click reaction). Although this reaction
worked well, purification of the resulting product was cumbersome
due to the use of copious amounts of ammonia saturated methanol for
column chromatography. Therefore, we decided to revise the route by
employing a boc-protected 2-AI alkyne that would allow more
traditional means of purification (i.e. methanol/dichloromethane
columns). The boc-protected scaffold was synthesized from
7-octynoic acid by treatment with oxayl chloride followed by
diazomethane and quenching the resulting .alpha.-diazo ketone with
HBr to generate the intermediate .alpha.-bromo ketone. Cyclization
with boc-guanidine then delivered the target 2-AI alkyne 5.
##STR00117## ##STR00118## ##STR00119##
[0411] Once 5 had been synthesized, we assembled a diverse array of
azido amides to employ in the click reaction to create our pilot
library of 2-AIT conjugates. Briefly, 2-bromo-ethylamine was
treated with sodium azide to deliver 2-azido-ethylamine, which
following acylation (via the respective acid chloride) generated
the azido amides for elaboration into the 2-AIT pilot library. Each
azido amide was then subjected to the click reaction with the 2-AI
5. Boc-deprotection (TFA/CH.sub.2Cl.sub.2) followed by counterion
exchange (trifluoroacetate for chloride) delivered the target 2-AIT
library for anti-biofilm screening.
[0412] Each member of the pilot library was assayed at 100 .mu.M
for its ability to inhibit the formation of C. albicans biofilms
using the crystal violet reporter assay. From this assay, 2-AIT
derivatives 7f and 7m were determined to be the most potent.
Subsequent dose response studies revealed that 7f had an IC.sub.50
of 2.9 .mu.M while 7m had an IC.sub.50 of 3.3 .mu.M (Table 3).
Growth curve and colony count analysis of 7f and 7m at respective
IC.sub.50 values demonstrated their antibiofilm activity to be
non-fungicidal (data not shown).
[0413] Next, we addressed whether 7f and 7m could disperse
pre-formed C. albicans biofilms. C. albicans was allowed to
establish biofilms in 96-well microtiter plate for 24 hours. Plates
were then washed to remove any free floating or loosely adherent
fungus. The appropriate 2-AIT (7f and 7m) was then added to each
well at 75 .mu.M and the plate was allowed to incubate at
37.degree. C. for 24 hours. Wells were then washed with water and
stained with CV to quantify any remaining biofilms. In comparison
to biofilms treated with media only, compound 7f dispersed 56%
while 7m dispersed 62% of the pre-formed biofilm. Once we had
established that both compounds could disperse pre-formed biofilms,
we quantified this effect by determining 7f and 7m's EC.sub.50
value against pre-formed C. albicans biofilms. Here, EC.sub.50 is
defined as the concentration at which the compound will disperse
50% of a pre-formed biofilm. Dose response studies revealed
EC.sub.50's of 37.2 .mu.M and 24.7 .mu.M for 7f and 7m respectively
(Table 1). From a medical perspective, molecules that simply
inhibit the formation of a biofilm could be used in a prophylactic
sense; however, given that a majority of patients already have an
established biofilm infection when they seek medical intervention,
molecules that are effective against a pre-formed biofilm are more
clinically significant.
[0414] Once we had established that these next generation 2-AIT
conjugates had the ability to inhibit and disperse C. albicans
biofilms, we addressed whether members of this library would also
inhibit and disperse biofilms from Cryptococcus neoformans, an
opportunistic fungal strain known to infect immunosuppressed
patients, especially those with HIV infections. Initial screening
of our library showed that 7e and 7m had potent anti-biofilm
activity against C. neoformans. Follow up dose response studies
revealed IC.sub.50's of 1.3 .mu.M and 8.0 .mu.M (Table 3).
Comparison of fungal growth in the presence or absence of either
compound indicated that each compound was not fungicidal.
Unfortunately, neither of these compounds was able to disperse
pre-formed C. neoformans biofilms at the concentrations tested.
TABLE-US-00004 TABLE 3 Fungal biofilm inhibition and dispersion.
Compound IC.sub.50 (.mu.M) EC.sub.50 (.mu.M) C. albicans 7f 2.9
.+-. 0.7 37.2 .+-. 5.7 7m 3.3 .+-. 1.6 24.7 .+-. 4.5 S. cerevisiae
7g 2.7 .+-. 0.1 207.4 .+-. 7.3 7h 50.4 .+-. 2.2 353.7 .+-. 7.3 7j
130.6 .+-. 16.9 >400 C. neoformans 7e 1.3 .+-. 0.3 -- 7m 8.0
.+-. 3.4 --
[0415] Synthesis: All reagents used for chemical synthesis were
purchased from commercially available sources and used without
further purification. Chromatography was performed using 60 .ANG.
mesh standard grade silica gel from Sorbtech. NMR solvents were
obtained from Cambridge Isotope Labs and used as is. .sup.1H NMR
(300 MHz or 400 MHz) and .sup.13C NMR (75 MHz or 100 MHz) spectra
were recorded at 25.degree. C. on Varian Mercury spectrometers.
Chemical shifts (.delta.) are given in ppm relative to
tetramethylsilane or the respective NMR solvent; coupling constants
(J) are in hertz (Hz). Abbreviations used are s=singlet, bs=broad
singlet, d=doublet, dd=doublet of doublets, t=triplet, dt=doublet
of triplets, bt=broad triplet, qt=quartet, m=multiplet, bm=broad
multiplet and br=broad.
[0416] N-(2-azidoethyl)tetradecanamide: To a 25 mL round-bottomed
flask equipped with a magnetic stir bar was added 2-azidoethanamine
(0.102 g, 1.18 mmol), DCM (5 mL) and then triethylamine (0.239 g,
2.37 mmol). To this reaction mixture, tetradecanoyl chloride (0.292
g, 1.18 mmol) was added dropwise and allowed to stir at room
temperature for 24 hr. Then, the reaction mixture was concentrated
de vacuo and then purified via silica gel column chromatography
(100% dichloromethane to 1:40 methanol:dichloromethane) to give
N-(2-azidoethyl)tetradecanamide (0.245 g, 79% yield). NMR (300 MHz,
CDCl.sub.3) .delta. 5.86 (s, 1H), .delta. 3.42 (s, 4H), .delta.
2.18 (t, J=7.8 Hz, 2H), .delta. 1.62 (m, 2H), .delta. 1.24 (m,
20H), .delta. 0.87 (t, J=3.9 Hz, 3H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 173.7, 51.2, 39.1, 36.9, 32.1, 29.9, 29.8,
29.7, 29.6, 29.5, 25.9, 22.9, 14.4 ppm; HRMS (ESI) calcd for
C.sub.16H.sub.32N.sub.4O (M+) 296.2576, found 296.2566.
[0417] N-(2-azidoethyl)octadec-9-enamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, octadec-9-enoyl chloride (0.374 g,
1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol)
and triethylamine (0.252 g, 2.49 mmol) in dichloromethane (5 mL) to
give
[0418] N-(2-azidoethyl)octadec-9-enamide (0.309 g, 71% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.30 (s, 1H), .delta.
5.29 (m, 2H), .delta. 3.39 (d, J =2.1 Hz, 2H), .delta. 3.38 (d,
J=2.4 Hz, 2H), .delta. 2.19 (t, J=7.2 Hz, 2H), .delta. 1.97 (m,
4H), .delta. 1.59 (t, J=7.5 Hz, 2H), .delta. 1.26 (m, 20H), .delta.
9.84 (t, J=6.6 Hz, 3H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 173.9, 130.2, 129.9, 51.1, 39.1, 36.8, 32.1, 30.0, 29.9,
29.7, 29.5, 29.4, 29.3, 27.4, 27.3, 25.9, 22.9, 14.3 ppm; HRMS
(ESI) calcd for C.sub.20H.sub.38N.sub.4O (M+) 350.3046, found
350.3039.
[0419] N-(2-azidoethyl)thiophene-2-sulfonamide: As in the synthesis
of N-(2-azidoethyl)tetradecanamide, thiophene-2-sulfonyl chloride
(0.218 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g,
1.19 mmol) and triethylamine (0.241 g, 2.39 mmol) in
dichloromethane (5 mL) to give
N-(2-azidoethyl)thiophene-2-sulfonamide (0.221 g, 80% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.62 (d, J=1.2 Hz, 1H),
.delta. 7.59 (d, J=1.2 Hz, 1H), 7.08 (t, J=3.9 Hz, 1H), 5.52 (s.
1H), 3.41 (t, J=5.4 Hz, 2H), 3.17 (q, J=5.4, 3.8 Hz, 2H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 140.6, 132.7, 132.6,
127.9, 50.9, 42.9 ppm; HRMS (ESI) calcd for
C.sub.6H.sub.8N.sub.4O.sub.2S.sub.2 (M+) 232.0089, found
232.0084.
[0420] N-(2-azidoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide:
As in the synthesis of N-(2-azidoethyl)tetradecanamide,
5-(dimethylamino)naphthalene-1-sulfonyl chloride (0.321 g, 1.19
mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and
triethylamine (0.241 g, 2.38 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide
(0.328 g, 86% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.52 (d, J=8.4 Hz, 1H), .delta. 8.28 (d, J=8.4 Hz, 1H), .delta.
8.22 (d, J=0.9 Hz, 1H), .delta. 7.53 (t, J=8.1 Hz, 1H), .delta.
7.50 (t, J=7.5 Hz, 1H), .delta. 7.17 (d, J=7.8 Hz, 1H), .delta.
5.58 (t, J=1.8 Hz, 1H), .delta. 3.28 (t, J=5.7 Hz, 2H), .delta.
3.03 (q, J=6.3, 5.7 Hz, 2H), .delta. 2.85 (s, 6H) ppm; .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 152.3, 134.8, 130.9, 130.1, 129.7,
128.9, 123.4, 118.9, 115.6, 51.0, 45.6, 42.6 ppm; HRMS (ESI) calcd
for C.sub.14H.sub.17N.sub.5O.sub.2S (M+) 319.1103, found
319.1104.
[0421] N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide: As
in the synthesis of N-(2-azidoethyl)tetradecanamide,
2,3,4,5,6-pentamethylbenzene-1-sulfonyl chloride (0.304 g, 1.23
mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and
triethylamine (0.249 g, 2.46 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide
(0.296 g, 81% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
5.12 (t, J=3.9 Hz, 1H) .delta. 3.35 (t, J=5.4 Hz, 2H), .delta. 3.05
(q, J=6.0, 5.1 Hz, 2H), 2.59 (s, 6H), .delta. 2.28 (s, 3H), 2.24
(s, 6H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 139.9,
136.1, 135.2, 134.2, 51.1, 42.3, 19.2, 17.9, 17.3 ppm; HRMS (ESI)
calcd for C.sub.13H.sub.20N.sub.4O.sub.2S (M+) 296.1307, found
296.1304.
[0422] N-(2-azidoethyl)benzenesulfonamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, benzenesulfonyl chloride (0.201 g,
1.16 mmol) was reacted with 2-azidoethanamine (0.100 g, 1.16 mmol)
and triethylamine (0.235 g, 2.32 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)benzenesulfonamide (0.289 g, 84% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.90 (d, J=1.8 Hz, 2H),
.delta. 7.55 (m, 3H), .delta. 5.47 (s, 1H), .delta. 3.39 (t, J=5.1
Hz, 2H), .delta. 3.12 (t, J=5.4 Hz, 2H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 139.8, 133.2, 129.5, 127.2, 50.9, 42.6 ppm;
HRMS (ESI) calcd for C.sub.6H.sub.8N.sub.4O.sub.2S (M+) 226.0524,
found 226.0523.
[0423] (E)-N-(2-azidoethyl)-4-phenylbut-3-enamide: As in the
synthesis of N-(2-azidoethyl)tetradecanamide,
(E)-4-phenylbut-3-enoyl chloride (0.198 g, 1.19 mmol) was reacted
with 2-azidoethanamine (0.114 g, 1.19 mmol) and triethylamine
(0.239 g, 2.37 mmol) in dichloromethane (5 mL) to give
(E)-N-(2-azidoethyl)-4-phenylbut-3-enamide (0.168 g, 55% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.68 (d, J=15.6 Hz, 1H),
.delta. 7.45 (d, J=3.3 Hz, 2H), .delta. 7.29 (m, 3H), .delta. 7.04
(t, J=4.1 Hz, 1H), .delta. 6.59 (d, J=15.9 Hz, 1H), .delta. 3.55
(q, J=6.0, 5.1 Hz, 2H), .delta. 3.47 (t, J=1.5 Hz, 2H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 166.9, 141.6, 134.9,
130.1, 129.1, 128.1, 120.8, 51.1, 39.4 ppm; HRMS (ESI) calcd for
C.sub.11H.sub.12N.sub.4O (M+) 216.1011, found 216.1005.
[0424] N-(2-azidoethyl)-2-(phenylthio)acetamide: As in the
synthesis of N-(2-azidoethyl)tetradecanamide, 2-(phenylthio)acetyl
chloride (0.222 g, 1.19 mmol) was reacted with 2-azidoethanamine
(0.102 g, 1.19 mmol) and triethylamine (0.240 g, 2.37 mmol) in
dichloromethane (5 mL) to give
N-(2-azidoethyl)-2-(phenylthio)acetamide (0.179 g, 64% yield).
[0425] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.29 (m, 4H),
.delta. 7.18 (m, 2H), .delta. 3.60 (s, 2H), 3.34 (m, 4H) ppm;
[0426] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 168.6, 134.8,
129.5, 128.6, 127.1, 50.8, 39.3, 37.7 ppm; HRMS (ESI) calcd for
C.sub.10H.sub.12N.sub.4OS (M+) 236.0732, found 236.0729.
[0427] N-(2-azidoethyl)palmitamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, (0.338 g. 1.23 mmol) was reacted
with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine
(0.249 g, 2.46 mmol) in dichloromethane (5 mL) to give
N-(2-azidoethyl)palmitamide (0.336 g, 84% yield). .sup.1H NMR (300
MHz, CDCl.sub.3) 6 6.11 (s, 1H), .delta. 3.41 (s, 4H), .delta. 2.17
(t, J=7.5 Hz, 2H), .delta. 1.60 (m, 2H), .delta. 1.23 (m, 24H),
.delta. 0.85 (t, 6.3 Hz, 3H) ppm;
[0428] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 173.9, 51.1, 39.1,
36.9, 32.1, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 25.9, 22.9, 14.3
ppm; HRMS (ESI) calcd for C.sub.18H.sub.36N.sub.4O (M+) 324.2889,
found 324.2879.
[0429] N-(2-azidoethyl)decanamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, decanoyl chloride (0.251 g, 1.32
mmol) was reacted with 2-azidoethanamine (0.114 g, 1.32 mmol) and
triethylamine (0.267 g, 2.64 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)decanamide (0.262 g, 83% yield). .sup.1H NMR
(300 MHz, CDCI.sub.3) .delta. 6.49 (s, 1H), .delta. 3.36 (s, 2H),
.delta. 3.35 (s, 2H), .delta. 2.14 (t, J=7.2 Hz, 2H), .delta. 1.46
(m, 2H), .delta. 1.21 (m, 12H), .delta. 0.81 (t, J=6.0 Hz, 3H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 174.1, 50.9, 39.1, 36.8,
32.0, 29.7, 29.6, 29.5, 29.4, 25.9, 22.8, 14.3 ppm; HRMS (ESI)
calcd for C.sub.12H.sub.24N.sub.4O (M+) 240.1950, found
240.1947.
[0430] N-(2-azidoethyl)-2-iodobenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, 2-iodobenzoyl chloride (0.312 g,
1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol)
and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-2-iodobenzamide (0.272 g, 74% yield). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.84 (d, J=7.2 Hz, 1H), .delta.
7.33 (m, 2H), .delta. 7.08 (t, J=3.3 Hz, 1H), .delta. 6.51 (s, 1H),
.delta. 3.54 (s, 2H), .delta. 3.53 (s, 2H) ppm; .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 169.9, 141.9, 140.0, 131.5, 128.4, 128.4,
92.7, 50.8, 39.6 ppm; HRMS (ESI) calcd for C.sub.9H.sub.9IN.sub.4O
(M+) 315.9821, found 315.9820.
[0431] N-(2-azidoethyl)-4-tert-butylbenzamide: As in the synthesis
of N-(2-azidoethyl)tetradecanamide, 4-tert-butylbenzoyl chloride
(0.244 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g,
1.23 mmol) and triethylamine (0.249 g, 2.47 mmol) in
dichloromethane (5 mL) to give
N-(2-azidoethyl)-4-tert-butylbenzamide (0.221 g, 73% yield).
[0432] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.73 (d, J=6.6 Hz,
2H), .delta. 7.43 (d, J=9.0 Hz, 2H), .delta. 6.95 (t, J=3.9 Hz,
1H), .delta. 3.59 (q, J=5.4, 5.7 Hz, 2H), .delta. 3.50 (t, J=5.1
Hz, 2H), .delta. 1.31 (s, 9H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 168.2, 155.4, 131.4, 127.2, 125.8, 51.1, 39.7,
35.2, 31.4 ppm; HRMS (ESI) calcd for C.sub.13H.sub.18N.sub.4O (M+)
246.1480, found 246.1479.
[0433] N-(2-azidoethyl)-3,5-difluorobenzamide: As in the synthesis
of N-(2-azidoethyl)tetradecanamide, 3,5-difluorobenzoyl chloride
(0.219 g, 1.24 mmol) was reacted with 2-azidoethanamine (0.107 g,
1.24 mmol) and triethylamine (0.251 g, 2.48 mmol) in
dichloromethane (5 mL) to give
N-(2-azidoethyl)-3,5-difluorobenzamide (0.280 g, 59% yield).
[0434] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.32 (s, 2H), 7.29
(s, 1H), 6.91 (t, J=2.4 Hz, 1H), 3.58 (q, J=5.7, 5.1 Hz, 2H), 3.51
(t, J=4.8 Hz, 2H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
165.9, 164.7, 161.5, 161.4, 137.6, 110.7, 106.9, 50.7, 39.9 ppm;
HRMS (ESI) calcd for C.sub.9H.sub.8F2N.sub.4O.sub.2S (M+) 226.0666,
found 226.0662.
[0435] N-(2-azidoethyl)-2,4,6-trichlorobenzamide: As in the
synthesis of N-(2-azidoethyl)tetradecanamide, (0.301 g, 1.23 mmol)
was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and
triethylamine (0.249 g, 2.47 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-2,4,6-trichlorobenzamide (0.317 g, 88%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.27 (2H, s),
.delta. 6.88 (s, 1H), .delta. 3.54 (s, 2H), .delta. 3.53 (s, 2H)
ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 164.4, 135.9, 134.3,
132.9, 128.2, 50.7, 39.4 ppm; HRMS (ESI) calcd for
C.sub.9H.sub.7N.sub.4O (M+) 291.9685, found 291.9681.
[0436] N-(2-azidoethyl)-2-naphthamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, 2-naphthoyl chloride (0.237 g,
1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol)
and triethylamine (0.252 g, 2.49 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-2-naphthamide (0.234 g, 77% yield). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.69 (s, 1H), .delta. 7.84 (m,
4H), .delta. 7.50 (m, 2H), 6.97 (t, J=4.2 Hz, 1H), .delta. 3.68 (q,
J=4.8, 1.2 Hz, 2H), 3.56 (t, J=3.0 Hz, 2H) ppm; .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 168.3, 135.1, 132.8, 131.5, 129.2, 128.8,
128.0, 127.9, 127.1, 123.8, 51.2, 39.8 ppm; HRMS (ESI) calcd for
C.sub.13H.sub.12N.sub.4O (M+) 240.1011, found 240.1007.
[0437] N-(2-azidoethyl)-4-heptylbenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, 4-heptylbenzoyl chloride (0.289 g,
1.21 mmol) was reacted with 2-azidoethanamine (0.104 g, 1.21 mmol)
and triethylamine (0.245 g, 2.42 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4-heptylbenzamide (0.260 g, 75% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.73 (d, J=7.8 Hz, 2H),
.delta. 7.19 (d, J=7.8 Hz, 3H), .delta. 3.57 (q, J=5.7, 5.4 Hz,
2H), .delta. 3.47 (t, J=5.7 Hz, 2H), .delta. 2.61 (t, J=7.5 Hz,
2H), .delta. 1.61 (m, 2H), .delta. 1.26 (m, 8H), .delta. 0.87 (t,
J=6.0 Hz, 3H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 168.3,
147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.0, 31.4, 29.4,
29.3, 22.9, 14.3 ppm; HRMS (ESI) calcd for C.sub.16H.sub.24N.sub.4O
(M+) 288.1950, found 288.1943.
[0438] N-(2-azidoethyl)-4-butylbenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, (0.242 g, 1.22 mmol) was reacted
with 2-azidoethanamine (0.105 g, 1.22 mmol) and triethylamine
(0.246 g, 2.43 mmol) in dichloromethane (5 mL) to give
N-(2-azidoethyl)-4-butylbenzamide (0.224 g, 75% yield). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.73 (d, J=8.4 Hz, 2H), .delta. 7.39
(t, J=1.8 Hz, 1H), .delta. 7.17 (d, J=8,1 Hz, 2H), .delta. 3.55 (q,
J=8.7, 5.7 Hz, 2H), .delta. 3.45 (t, J=5.7 Hz, 2H), .delta. 2.60
(t, J=7.8 Hz, 2H), .delta. 1.56 (m, 2H), .delta. 1.30 (m, 2H),
.delta. 0.90 (t, J=4.2 Hz, 3H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 168.5, 147.2, 131.7, 128.8, 127.4, 50.9, 39.7,
35.7, 33.5, 22.5, 14.1 ppm; HRMS (ESI) calcd for
C.sub.13H.sub.18N.sub.4O (M+) 246.1481, found 246.1476.
[0439] N-(2-azidoethyl)-4-hexylbenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, 4-hexylbenzoyl chloride (0.293 g,
1.30 mmol) was reacted with 2-azidoethanamine (0.112 g, 1.30 mmol)
and triethylamine (0.264 g, 2.61 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4-hexylbenzamide (0.299 g, 84% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.75 (d, J=8.1 Hz, 2H),
.delta. 7.43 (t, J-3.9 Hz, 1H), .delta. 7.17 (d, J=7.8 Hz, 2H), 6
3.55 (q, J=6.3, 5.7 Hz, 2H), 6 3.46 (t, J=5.7 Hz, 2H), .delta. 2.59
(t, J=7.5 Hz, 2H), .delta. 1.58 (m, 2H), .delta. 1.29 (m, 4H),
.delta. 0.87 (t, J=6.9 Hz, 3H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 168.6, 147.3, 131.7, 130.3, 128.8, 127.5, 50.9,
39.7, 35.9, 31.6, 31.1, 22.7, 14.2 ppm; HRMS (ESI) calcd for
C.sub.15H.sub.22N.sub.4O (M+) 274.1794, found 274.1789.
[0440] N-(2-azidoethyl)-4-pentylbenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, 4-pentylbenzoyl chloride (0.283 g,
1.35 mmol) was reacted with 2-azidoethanamine (0.116 g, 1.35 mmol)
and triethylamine (0.273 g, 2.69 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4-pentylbenzamide (0.267 g, 76% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.74 (d, J=8.1 Hz, 2H),
.delta. 7.61 (t, J=5.1 Hz, 1H), .delta. 7.15 (d, J=8.4 Hz, 2H),
.delta. 3.54 (q, J=5.7, 5.1 Hz, 2H), .delta. 3.44 (t, J=5.7 Hz,
2H), .delta. 2.58 (t, J=7.5 Hz, 2H), .delta. 1.57 (m, 2H), .delta.
1.26 (m, 4H), .delta. 0.86 (t, J=6.6 Hz, 3H) ppm; .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 168.6, 147.2, 131.7, 128.7, 127.5, 50.8,
39.7, 35.9, 31.6, 31.1, 22.7, 14.2 ppm; HRMS (ESI) calcd for
C.sub.14H.sub.20N.sub.4O (M+) 260.1637, found 260.1632.
[0441] N-(2-azidoethyl)biphenyl-4-carboxamide: As in the synthesis
of N-(2-azidoethyl)tetradecanamide, (0.283 g, 1.31 mmol) was
reacted with 2-azidoethanamine (0.113 g, 1.31 mmol) and
triethylamine (0.264 g, 2.61 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)biphenyl-4-carboxamide (0.297 g, 85% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.88 (d, 2H), .delta.
7.67 (m, 4H), .delta. 7.44 (m, 3H), .delta. 6.63 (s, 1H), .delta.
3.67 (q, J=6.0, 1.8 Hz, 2H), .delta. 3.58 (t, J=6.0 Hz, 2H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 167.8, 144.8, 140.1,
132.9, 129.2, 128.3, 127.8, 127.5, 127.4, 51.2, 39.7 ppm; HRMS
(ESI) calcd for C.sub.15H.sub.14N.sub.4O (M+) 266.1168, found
266.1162.
[0442]
N-(2-azidoethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide: As
in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.529 g, 1.38
mmol) was reacted with 2-azidoethanamine (0.119 g, 1.38 mmol) and
triethylamine (0.279 g, 2.75 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide
(0.331 g, 69% yield). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
6.84 (s, 1H), .delta. 3.91 (s, 3H), .delta. 3.50 (t, J=3.6 Hz, 2H),
.delta. 3.25 (t, J=1.5 Hz, 2H) ppm; .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 161.7, 127.7, 114.7, 111.4, 97.8, 50.4, 38.9,
35.1 ppm; HRMS (ESI) calcd for C.sub.8H.sub.9N.sub.5O (M+)
348.9174, found 348.9183.
[0443] N-(2-azidoethyl)-1H-pyrrole-2-carboxamide: As in the
synthesis of N-(2-azidoethyl)tetradecanamide, (0.249 g, 1.17 mmol)
was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and
triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-1H-pyrrole-2-carboxamide (0.137 g, 66%
yield). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 6.88 (d, J=1.5
Hz, 1H), .delta. 6.77 (d, J=2.4 Hz, 1H), .delta. 6.14 (t, J=2.4 Hz,
1H), .delta. 3.46 (t, J=5.7 Hz, 2H), .delta. 3.37 (q, J=5.7, 14.7
Hz, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 162.9,
125.6, 122.2, 121.9, 110.9, 109.2, 50.6, 38.9 ppm; HRMS (ESI) calcd
for C.sub.7H.sub.9N.sub.5O (M+) 179.0807, found 179.0803.
[0444] N-(2-azidoethyl)-4-bromo-1H-pyrrole-2-carboxamide: As in the
synthesis of N-(2-azidoethyl)tetradecanamide, (0.408 g, 1.34 mmol)
was reacted with 2-azidoethanamine (0.115 g, 1.34 mmol) and
triethylamine (0.270 g, 2.67 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4-bromo-1H-pyrrole-2-carboxamide (0.299 g,
82% yield). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 6.93 (s, 1H),
.delta. 6.80 (s, 1H), .delta. 3.49 (t, J=0.6 Hz, 2H), .delta. 3.41
(t, J=0.9 Hz, 2H) ppm;
[0445] .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 161.7, 126.1,
122.0, 112.4, 96.4, 50.5, 38.9 ppm; HRMS (ESI) calcd for
C.sub.7H.sub.8BrN.sub.5O (M+) 256.9912, found 256.9908.
[0446] N-(2-azidoethyl)-4-nonylbenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, the acid chloride (0.354 g, 1.40
mmol) was reacted with 2-azidoethanamine (0.121 g, 1.40 mmol) and
triethylamine (0.284 g, 2.80 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4-nonylbenzamide (0.339 g, 80% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.21 (s, 1H), .delta.
3.40 (s, 4H), .delta. 2.19 (t, J=7.2 Hz, 2H), .delta. 1.62 (t,
J=6.0 Hz, 2H), .delta. 1.22 (bs, 14 H), .delta. 0.842 (t, J=6.3 Hz,
3H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 173.8, 51.1,
30.1, 36.8, 32.1, 29.8, 29.7, 29.6, 29.5, 29.2, 25.9, 22.9, 14.3
ppm; HRMS (ESI) calcd for C.sub.14H.sub.28N.sub.4O (M+) 268.2263,
found 268.2259.
[0447] N-(2-azidoethyl)-4-nonylbenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, (0.383 g, 1.43 mmol) the acid
chloride was reacted with 2-azidoethanamine (0.124 g, 1.43 mmol)
and triethylamine (0.290 g, 2.87 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4-nonylbenzamide (0.441 g, 97% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.72 (d, 2H), .delta.
7.26 (t, 1H), .delta. 7.18 (d, 2H), .delta. 3.57 (q, 2H), .delta.
3.45 (t, 2H), .delta. 2.60 (t, 2H), .delta. 1.58 (m, 2H), .delta.
1.27 (m, 12H), .delta. 0.86 (t, 3H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 168.5, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7,
36.1, 32.1, 31.5, 29.8, 29.7, 29.6, 29.5, 22.9, 14.4 ppm; HRMS
(ESI) calcd for C.sub.18H.sub.28N.sub.4O (M+) 316.2263, found
316.2268.
[0448] N-(2-azidoethyl)-4-octylbenzamide: As in the synthesis of
N-(2-azidoethyl)tetradecanamide, (0.262 g, 1.19 mmol) the acid
chloride was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol)
and triethylamine (0.242 g, 2.39 mmol) in dichloromethane (5 mL) to
give N-(2-azidoethyl)-4-octylbenzamide (0.220 g, 69% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.73 (d, 2H), .delta.
7.37 (t, 1H), .delta. 7.17 (d, 2H), .delta.3.56 (q, 2H), .delta.
3.44 (t, 2H), .delta. 2.59 (t, 2H), .delta. 1.58 (m, 2H), .delta.
1.27 (m, 10H), .delta.0.86 (t, 3H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 168.4, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7,
36.1, 32.1, 31.5, 29.7, 29.5, 29.5, 22.9, 14.3 ppm; HRMS (ESI)
calcd for C.sub.17H.sub.28N.sub.4O (M+) 302.2107, found
302.2104.
[0449] (E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide: To a 25 mL
round-bottomed flask equipped with a magnetic stir bar was added
(E)-2-methyl-3-phenylacrylic acid (0.0.512 g, 3.15 mmol) and
dichloromethane (10 mL). Oxalyl chloride (0.400 g, 3.15 mmol) was
added dropwise to the reaction mixture and allowed to stir for one
hour. Then, the reaction mixture was concentrated de vacuo. To the
crude mixture was then added dichloromethane (10 mL),
2-azidoethanamine (0.299 g, 3.47 mmol) and then triethylamine
(0.351 g, 3.47 mmol) and allowed to stir for two hours. The
reaction mixture was then concentrated de vacuo and then purified
via silica gel column chromatography (100% dichloromethane to 1:40
methanol:dichloromethane) to give
(E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide (0.698 g, 96%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.39 (m, 6H),
.delta. 7.01 (s, 1H), .delta. 3.51 (t, J=4.5 Hz, 2H), .delta. 3.45
(t, J=4.8 Hz, 2H), .delta. 2.13 (s, 3H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 170.5, 136.2, 134.5, 132.0, 130.3, 129.6,
128.9, 128.6, 128.3, 50.9, 39.8, 14.5 ppm; HRMS (ESI) calcd for
C.sub.12H.sub.14N.sub.4O (M+) 230.1168, found 230.1165.
[0450]
N-(2-azidoethyl)-2',4'-difluoro-3-hydroxybiphenyl-4-carboxamide: To
a 25 mL round-bottomed flask equipped with a magnetic stir bar was
added 2',4'-difluoro-3-hydroxybiphenyl-4-carboxylic acid (0.301,
1.20 mmol), N,N-Dimethylformamide (5 mL),
N,N'-Dicyclohexylcarbodiimide (0.248 g, 1.20 mmol) and
n-methylmorpholine (0.25 mL). The reaction mixture was cooled to
0.degree. C. and allowed to stir. Then, 2-azidoethanamine (0.1037
g, 1.20 mmol) was added dropwise and allowed to slowly warm to room
temperature while stirring for 24 hr. The reaction mixture was
diluted with water, extracted with dichloromethane, washed with 1N
HCl, washed with saturated sodium bicarbonate, washed with brine
and then concentrated de vacuo. The resulting residue was then
purified via silica gel column chromatography (1:40 methanol:
dichloromethane to 1:10 methanol:dichloromethane) to give
N-(2-azidoethyl)-2',4'-difluoro-3-hydroxybiphenyl-4-carboxamide
(0.232 g, 61% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.60 (s, 1H), .delta. 7.47 (d, J=6.0 Hz, 1H), .delta. 7.29 (m, 2H),
.delta. 7.02 (d, J=6.6 Hz, 1H), .delta. 6.88 (m, 2H) ppm; .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 170.3, 160.8, 135.1, 131.3, 131.2,
131.3, 131.2, 126.8, 118.8, 114.6, 112.0, 111.8, 104.8, 104.6,
104.3, 50.7, 39.3 ppm; HRMS (ESI) calcd for
C.sub.15H.sub.12F.sub.2N.sub.4O.sub.3 (M+) 318.0928, found
318.0933.
[0451] General procedure for click reactions and subsequent Boc
deprotection: The terminal alkyne (1.0 equiv.) was dissolved in a
1:1:1 mixture of ethanol, water and methylene chloride (ca. 9 mL
per 0.300 g of terminal alkyne). To this solution, the appropriate
azide (1.0 equiv.) was added while stirring vigorously at room
temperature. Copper (II) sulfate (15 mol %) and sodium ascorbate
(45 mol %) were then added sequentially to the solution. Reaction
mixtures were allowed to stir until completion via TLC analysis
(12-24 hrs). The solvents were then removed de vacuo in which the
resulting residue was dissolved in dichloromethane and purified via
silica gel column chromatography (1:40 methanol:dichloromethane to
1:10 methanol: dichloromethane). To remove the Boc protecting
group, the resulting product was then dissolved in a 1:4
trifluoroacetic acid: dichloromethane mixture and allowed to stir
for 5 hr. Upon completion, the reaction mixture was concentrated de
vacuo and then left on a high vacuum overnight. Then, methanol
supplemented with HCl was added to the product forming the HCl salt
of the deprotected product and then was concentrated de vacuo. The
resulting residue was washed with diethyl ether and then placed on
a high vacuum overnight.
[0452]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-2-(phenylthio)acetamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.112 g, 0.405
mmol) was reacted with N-(2-azidoethyl)-2-(phenylthio)acetamide
(0.096 g, 0.405 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(2-(phenylthio)acetamido)ethyl)-1H-1,2,3-triazol-4-yl)-
pentyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.45 (s, 1H), .delta. 7.19 (m, 5H), .delta.
7.13 (s, 1H), .delta. 6.43 (s, 1H), .delta. 6.13 (bs, 2H), .delta.
4.29 (s, 2H), .delta. 3.68 (s, 2H), .delta. 3.57 (s, 2H), .delta.
2.56 (s, 2H), .delta. 2.35 (s, 2H), .delta. 1.52 (m, 15H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 187.8, 172.0, 169.1,
162.4, 156.9, 135.0, 129.5, 128.3, 126.8, 121.8, 85.00, 49.4, 39.9,
37.4, 29.4, 28.9, 28.4, 28.2, 27.6, 25.6 ppm; HRMS (ESI) calcd for
C.sub.25H.sub.35N.sub.7O.sub.3S (M+) 513.2522, found 513.2522,
which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-2-(phenylthio)acetamide hydrochloride (0.133 g, 73% yield).
.sup.1H NMR (300 MHz, CD.sub.:30D) .delta. 8.47 (s, 1H), .delta.
7.30 (s, 4H), .delta. 7.19 (s, 1H), .delta. 6.58 (s, 1H), .delta.
4.66 (s, 2H), .delta. 3.76 (s, 2H), .delta. 3.64 (s, 2H), .delta.
2.84 (s, 2H), .delta. 2.34 (s, 2H), .delta. 1.73 (s, 2H), .delta.
1.64 (s, 2H), .delta. 1.26 (s, 2H) ppm; .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 170.9, 159.3, 158.9, 147.2, 135.6, 128.1,
128.9, 127.6, 126.6, 108.7, 108.6, 39.1, 37.5, 37.2, 36.6, 36.1,
30.8, 28.1, 27.9, 27.7, 24.2, 23.7, 23.6 ppm; HRMS (ESI) calcd for
C.sub.20H.sub.27N.sub.7OS (M+) 413.1998, found 413.1991.
[0453]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)-
ethyl)thiophene-2-sulfonamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.105 g, 0.379
mmol) was reacted with N-(2-azidoethyl)thiophene-2-sulfonamide
(0.099 g, 0.379 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(thiophene-2-sulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)-
pentyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.49 (s, 3H), .delta. 7.39 (s, 1H), .delta.
6.99 (s, 1H), .delta. 6.41 (bm, 3H), .delta. 443 (s, 2H), .delta.
3.42 (s, 2H), .delta. 2.54 (s, 2H), .delta. 2.09 (s, 2H), .delta.
1.51 (m, 13H), .delta. 1.19 (s, 2H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 150.8, 149.4, 148.1, 141.1, 138.3, 132.2,
132.1, 127.7, 122.6, 85.2, 53.8, 50.2, 43.2, 31.2, 29.9, 29.2,
28.8, 28.1, 25.5 ppm; HRMS (ESI) calcd for
C.sub.21H.sub.31N.sub.7O.sub.4S.sub.2 (M+) 509.1879, found
509.1879, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
thiophene-2-sulfonamide hydrochloride (0.098 g, 58% yield). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.37 (s, 1H), .delta. 7.76 (s,
1H), .delta. 7.57 (s, 1H), .delta. 7.11 (s, 1H), .delta. 6.46 (s,
1H), .delta. 4.79 (s, 2H), .delta. 3.55 (s, 2H), .delta. 2.50 (s,
2H), .delta. 1.66-1.18 (bm, 8H) ppm; .sup.13C NMR (100 MHz,
CD.sub.3OD) .delta. 175.6, 155.6, 147.2, 140.9, 132.7, 132.3,
127.8, 127.7, 108.8, 53.1, 42.2, 36.8, 28.1, 27.8, 27.5, 24.9,
24.3, 23.8 ppm; HRMS (ESI) calcd for
C.sub.16H.sub.23N.sub.7O.sub.2S.sub.2 (M+) 409.1355, found
409.1354.
[0454]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-5-(dimethylamino)naphthalene-1-sulfonamide hydrochloride:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate
(0.112 g, 0.403 mmol) was reacted with
N-(2-azidoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide (0.140
g, 0.403 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-1H--
1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.48 (d, J=8.4 Hz, 1H), .delta. 8.24
(d, J=8.4 Hz, 1H), .delta. 8.17 (d, J=7.2 Hz, 1H), .delta. 7.44 (m,
3H), .delta. 7.09 (s, 1H), .delta. 7.07 (d, J=7.5 Hz, 1H), .delta.
6.44 (s, 1H), .delta. 6.09 (bs, 2H), .delta. 4.32 (s, 2H), .delta.
3.36 (s, 2H), .delta. 2.52 (s, 2H), .delta. 2.22 (s, 2H), .delta.
1.43 (m, 13H), .delta. 1.22 (s, 2H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 176.9, 152.1, 149.6, 148.0, 138.6, 135.1,
130.7, 130.1, 129.7, 129.4, 128.5, 123.3, 122.4, 119.1, 115.5,
84.9, 67.5, 50.3, 50.2, 45.6, 42.9, 37.9, 29.1, 28.9, 28.2, 28.0,
25.5 ppm; HRMS (ESI) calcd for C.sub.29H.sub.40N.sub.8O.sub.4S (M+)
596.2893, found 596.2881, which was subsequently deprotected to
give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-5-(dimethylamino)naphthalene-1-sulfonamide hydrochloride (0.139 g,
65% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.70 (t,
J=4.8 Hz, 2H), .delta. 8.31 (s, 1H), .delta. 8.08 (s, 2H), .delta.
7.82 (s, 2H), .delta. 6.43 (s, 1H), .delta. 4.55 (s, 2H), .delta.
3.32 (s, 8H), 2.63 (s, 2H), .delta. 2.48 (s, 2H), .delta. 1.66 (s,
4H), .delta. 1.40 (s, 2H) ppm; .sup.13C NMR (100 MHz, CD.sub.3OD)
.delta. 159.9, 147.3, 140.7, 136.8, 129.9, 129.3, 127.8, 127.7,
126.5, 119.3, 108.6, 108.4, 76.7, 67.3, 51.5, 42.3, 37.4, 36.5,
28.3, 27.9, 27.6, 24.1, 24.0, 23.7 ppm; HRMS (ESI) calcd for
C.sub.24H.sub.32N.sub.8O.sub.2S (M+) 496.2369, found 496.2359.
[0455] tert-butyl
2-amino-4-(5-(1-(2-(phenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl-
)-1H-imidazole-1-carboxylate hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.114 g, 0.410
mmol) was reacted with N-(2-azidoethyl)benzenesulfonamide (0.104 g,
0.410 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(phenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl-
)-1H-imidazole-1-carboxylate NMR (300 MHz, CDCl.sub.3) .delta. 7.81
(d, J=6.9 Hz, 2H), .delta. 7.44 (m, 5H), .delta. 6.44 (s, 1H),
.delta. 6.07 (s, 2H), .delta. 4.42 (t, J=5.7 Hz, 2H), .delta. 3.36
(t, J=5.4 Hz, 2H), .delta. 2.57 (t, J=7.2 Hz, 2H), .delta. 2.20 (s,
2H), .delta. 1.47 (m, 13H), .delta. 1.29 (s, 2H) ppm; .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 202.9, 149.5, 148.2, 140.2, 132.8,
129.4, 127.1, 122.5, 106.5, 85.0, 53.7, 50.3, 42.9, 32.7, 31.2,
29.9, 29.2, 28.9, 28.2, 26.3, 25.5 ppm; HRMS (ESI) calcd for
C.sub.23H.sub.33N.sub.7O.sub.4S (M+) 503.2315, found 503.2310,
which was subsequently deprotected to give tert-butyl
2-amino-4-(5-(1-(2-(phenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl-
)-1H-imidazole-1-carboxylate hydrochloride (0.142 g, 64% yield).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.81 (d, J=6.6 Hz, 2H),
.delta. 7.56 (m, 4H), .delta. 6.47 (s, 1H), .delta. 4.62 (s, 2H),
.delta. 3.41 (s, 2H), .delta. 2.78 (s, 2H), .delta. 2.48 (s, 2H),
.delta. 1.72 (s, 2H), .delta. 1.63 (s, 2H), .delta. 1.42 (s, 2H)
ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 176.2, 165.6, 259.9,
147.3, 140.2, 132.8, 129.3, 127.7, 126.8, 108.5, 108.4, 515.8,
42.3, 28.1, 27.9, 27.6, 24.1 ppm; HRMS (ESI) calcd for
C.sub.18H.sub.25N.sub.7O.sub.2S (M+) 403.1790, found 403.1781.
[0456]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide hydrochloride:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate
(0.120 g, 0.434 mmol) was reacted with
N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide (0.141 g,
0.434 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(2,3,4,5,6-pentamethylphenylsulfonamido)ethyl)-1H-1,2,-
3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.30 (s, 1H), .delta. 7.01 (s, 1H),
.delta. 6.44 (s, 1H), .delta. 6.17 (s, 2H), .delta. 4.35 (s, 2H),
.delta. 3.34 (s, 2H), .delta.2.47 (s, 2H), .delta. 2.48 (s, 6H),
.delta. 2.20 (m, 11H), .delta. 1.43 (m, 15H) ppm; .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 149.6, 148.1, 139.7, 136.2, 134.9, 134.3,
122.4, 84.9, 53.7, 50.2, 42.5, 31.1, 29.3, 28.9, 28.4, 28.2, 25.6,
19.1, 17.9, 17.2 ppm; HRMS (ESI) calcd for
C.sub.28H.sub.43N.sub.7O.sub.4S (M+) 573.3097, found 573.3086,
which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-2,3,4,5,6-pentamethylbenzenesulfonamide hydrochloride (0.143 g,
76% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.11 (s, 1H),
.delta. 6.42 (s, 1H), .delta. 4.48 (s, 2H), .delta. 3.34 (s, 2H),
.delta. 2.65 (s, 2H), .delta. 2.40 (s, 8H), .delta. 2.12 (s, 9H),
.delta. 1.58 (s, 4H), .delta. 1.19 (s, 2H) ppm; .sup.13C NMR (100
MHz, CD.sub.3OD) .delta. 159.9, 147.3, 139.6, 136.1, 134.8, 134.0,
127.8, 127.6, 108.6, 108.4, 54.1, 51.5, 41.8, 36.5, 28.2, 28.1,
27.7, 24.1, 23.7, 18.2, 16.8, 16.1 ppm; HRMS (ESI) calcd for
C.sub.23H.sub.35N.sub.7O.sub.2S (M+) 473.2573, found 473.2565.
[0457]
(E)-N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-
-yl)ethyl)-2-methyl-3-phenylacrylamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.1103 g, 0.397
mmol) was reacted with
(E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide (0.092 g, 0.397
mmol) following the general click procedure to give (E)-tert-butyl
2-amino-4-(5-(1-(2-(2-methyl-3-phenylacrylamido)ethyl)-1H-1,2,3-triazol-4-
-yl)pentyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.28 (m, 7H), .delta. 6.94 (s, 2H), 6.06 (s,
2H), .delta. 4.46 (s, 2H), .delta. 3.79 (s, 2H), .delta. 2.61 (s,
2H), .delta. 2.27 (s, 2H), .delta. 1.99 (s, 3H), .delta. 1.49 (bs,
11H), .delta. 1.18 (s, 4H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 192.4, 191.3, 170.4, 150.9, 140.2, 136.2, 134.8, 131.6,
129.6, 128.6, 128.1, 122.1, 95.8, 85.2, 74.3, 53.7, 52.6, 50.7,
49.4, 40.1, 29.9, 29.3, 28.9, 28.2, 25.6, 14.4 ppm; HRMS (ESI)
calcd for C.sub.27H.sub.37N.sub.7O.sub.3 (M+) 507.2958, found
507.2942, which was subsequently deprotected to give
(E)-N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)et-
hyl)-2-methyl-3-phenylacrylamide hydrochloride (0.148 g, 84%
yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.78 (s, 1H),
.delta. 7.33 (s, 4H), .delta. 7.26 (s, 1H), .delta. 7.19 (s, 1H),
.delta. 6.42 (s, 1H), .delta. 4.78 (s, 2H), .delta. 3.84 (s, 2H),
.delta. 2.87 (s, 2H), .delta. 2.44 (s, 2H), .delta. 1.99 (s, 3H),
.delta. 1.76 (s, 2H), .delta. 1.59 (s, 2H), .delta. 1.42 (s, 2H)
ppm; .sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 174.7, 136.0,
134.4, 131.5, 129.3, 128.7, 128.3, 128.0, 127.6, 108.6, 94.6, 53.1,
39.2, 27.6, 27.9, 27.7, 27.6, 24.1, 23.8, 23.1, 14.3, 13.4 ppm;
HRMS (ESI) calcd for C.sub.22H.sub.29N.sub.7O (M+) 407.2434, found
407.2429.
[0458]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)cinnamamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.106 g, 0.384
mmol) was reacted with N-(2-azidoethyl)cinnamamide (0.083 g, 0.384
mmol) following the general click procedure to give (E)-tert-butyl
2-amino-4-(5-(1-(2-cinnamamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imi-
dazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.67
(s, 1H), .delta. 7.51 (d, J=11.1 Hz, 1H), .delta. 7.28 (m, 6H),
.delta. 6.45 (t, J=14.1 Hz, 2H), .delta. 6.08 (s, 2H), .delta. 4.47
(s, 2H), .delta. 3.79 (s, 2H), .delta. 2.57 (s, 2H), .delta. 2.23
(s, 2H), .delta. 1.50 (bs, 13H), .delta. 1.28 (s, 2H) ppm; .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 166.9, 150.4, 149.5, 148.3, 141.2,
138.9, 134.9, 129.9, 128.9, 128.0, 122.1, 120.8, 106.5, 84.8, 53.7,
49.5, 39.9, 31.1, 29.3, 28.9, 28.3, 28.2, 25.6 ppm; HRMS (ESI)
calcd for C.sub.26H.sub.35N.sub.7O.sub.3 (M+) 493.2801, found
493.2800, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
cinnamamide hydrochloride (0.097 g, 59% yield). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.10 (s, 1H), .delta. 7.49 (s, 3H),
.delta. 7.32 (s, 3H), .delta. 6.30 d, J=10.8 Hz, 1H), .delta. 6.39
(s, 1H), .delta. 4.66 (s, 2H), .delta. 3.83 (s, 2H), .delta. 2.73
(s, 2H), .delta. 2.40 (s, 2H), .delta. 1.57 (s, 2H), .delta. 1.55
(s, 2H), .delta. 1.36 (s, 2H) ppm; .sup.13C NMR (100 MHz,
CD.sub.3OD) .delta. 167.8, 160.5, 150.2, 147.3, 141.1, 134.8,
130.7, 129.9, 128.8, 127.8, 127.6, 124.9, 23 9, 120.2, 108.5,
108.3, 53.1, 39.3, 36.5, 30.6, 28.4, 28.1, 27.6, 26.5, 24.2, 24.1,
23.7 ppm; HRMS (ESI) calcd for C.sub.21H.sub.27N.sub.7O (M+)
393.2277, found 393.2273.
[0459]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)heptadec-8-enamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (g, mmol) was
reacted with N-(2-azidoethyl)octadec-9-enamide (g, mmol) following
the general click procedure to give tert-butyl
2-amino-4-(5-(1-(2-heptadec-8-enamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-
-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.26 (s, 1H), .delta. 6.81 (s, 1H), .delta. 6.42 (s, 2H),
.delta. 5.88 (s, 1H), .delta. 5.27 (s, 2H), .delta. 4.38 (s, 2H),
.delta. 3.65 (s, 2H), .delta. 2.60 (s, 2H), .delta. 2.09 (s, 2H),
.delta. 1.53-1.01 (m, 35H), 0.79 (t, J=6.3 Hz, 3H) ppm; .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 174.2, 173.8, 148.3, 130.3, 130.1,
129.9, 129.8, 121.9, 85.1, 67.1, 49.5, 39.5, 39.1, 38.0, 37.7,
36.7, 36.6, 32.8, 32.3, 32.1, 31.7, 29.9, 29.8, 29.7, 29.5, 29.3,
29.2, 28.9, 28.7, 28.1, 28.0, 27.9, 27.4, 27.3, 27.3, 26.9, 25.9,
25.6, 25.3, 22.9, 22.8, 22.6, 14.3, 14.2 ppm; HRMS (ESI) calcd for
C.sub.35H.sub.61N.sub.7O.sub.3 (M+) 627.4836, found 627.4823, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)pentyl)-
heptadec-8-enamide hydrochloride (0.128 g, 66% yield). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.36 (s, 1H), .delta. 6.96 (s, 1H),
.delta. 6.45 (s, 1H), .delta. 6.09 (s, 1H), .delta. 4.58 (s, 2H),
.delta. 3.58 (s, 2H), .delta. 2.75 (s, 2H), .delta. 2.10 (s, 2H),
.delta. 1.96 (s, 4H), .delta. 1.69 (s, 2H), .delta. 1.41 (m, 4H),
1.23 (s, 24H), .delta. 0.84 (s, 3H) ppm; .sup.13C NMR (100 MHz,
CD.sub.3OD) .delta. 175.5, 158.8, 155.7, 147.3, 129.7, 129.6,
127.6, 108.5, 94.6, 76.7, 51.3, 50.4, 48.6, 48.4, 48.2, 47.9, 47.8,
47.5, 47.3, 38.9, 37.5, 36.6, 45.9, 45.8, 33.9, 32.6, 31.9, 31.5,
29.8, 29.5, 29.4, 29.3, 29.2, 29.1, 28.2, 27.8, 27.0, 25.8, 24.9,
24.2, 23.8, 22.5, 13.5, 13.3 ppm; HRMS (ESI) calcd for
C.sub.30H.sub.53N.sub.7O (M+) 527.4312, found 527.4298.
[0460]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)decanamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.114 g, 0.412
mmol) was reacted with N-(2-azidoethyl)decanamide (0.099 g, 0.412
mmol) following the general click procedure to give tert-butyl
2-amino-4-(5-(1-(2-decanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imid-
azole-1-carboxylate .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.23
(s, 1H), .delta. 6.57 (s, 1H), .delta. 6.43 (s, 1H), .delta. 6.09
(s, 2H), .delta. 4.38 (s, 2H), .delta. 3.67 (s, 2H), .delta. 2.61
(t, J=5.4 Hz, 2H), .delta. 2.08 (s, 2H), .delta. 2.08 (t, J=5.7 Hz,
2H), .delta. 1.42 (m, 15H), .delta. 1.17 (m, 14H), .delta. 0.79 (t,
J=4.5 Hz, 3H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
174.2, 149.7, 148.4, 138.8, 121.9, 106.6, 84.9, 49.5, 39.5, 36.7,
32.1, 31.3, 30.6, 29.9, 29.7, 29.6, 29.5, 29.5, 29.3, 29.0, 28.3,
28.2, 25.9, 25.6, 25.5, 22.9, 14.3 ppm; HRMS (ESI) calcd for
C.sub.27H.sub.47N.sub.7O.sub.3 (M+) 517.3740, found 517.3736, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
decanamide hydrochloride (0.137 g, 73% yield). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 8.55 (s, 1H), .delta. 6.53 (s, 1H), 4.72
(s, 2H), .delta. 3.75 (s, 2H), 2.89 (s, 2H), .delta. 2.54 (t, J=6.8
Hz, 2H), .delta. 2.16 (t, J=7.2 Hz, 2H), .delta. 1.81 (s, 2H),
.delta. 1.69 (s, 2H), .delta. 1.49 (m, 4H), .delta. 1.28 (s, 12H),
.delta. 0.89 (t, 3H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta.
175.7, 147.3, 128.5, 127.6, 125.1, 120.8, 108.6, 108.4, 105.6,
63.1, 59.3, 52.5, 48.6, 48.3, 48.1, 47.9, 47.7, 47.5, 57.3, 38.7,
336.6, 35.8, 36.6, 35.8, 31.8, 30.6, 29.4, 29.3, 29.3, 29.2, 28.0,
27.8, 27.7, 25.8, 24.1, 23.9, 23.3, 22.6 ppm; HRMS (ESI) calcd for
C.sub.22H.sub.39N.sub.7O (M+) 417.3216, found 417.3209.
[0461]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)dodecanamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.107 g, 0.387
mmol) was reacted with N-(2-azidoethyl)dodecanamide (0.104 g, 0.387
mmol) following the general click procedure to give tert-butyl
2-amino-4-(5-(1-(2-dodecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-im-
idazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.36 (s, 1H), .delta. 6.94 (s, 1H), .delta. 6.49 (s, 1H), .delta.
6.23 (s, 2H), .delta. 4.46 (t, J=5.1 Hz, 2H), .delta. 3.74 (q,
J=5.1, 5.7 Hz, 2H), .delta. 2.68 (t, J=7.5 Hz, 2H), .delta. 2.34
(t, J=6.9 Hz, 2H), .delta. 2.16 (t, J=7.5 Hz, 2H), .delta. 1.54 (m,
13H), .delta. 1.47 (m, 2H), .delta. 1.24 (m, 18H), .delta. 0.87 (t,
J=6.6 Hz, 3H), ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
174.3, 150.4, 149.5, 148.3, 138.5, 121.9, 106.5, 84.9, 49.5, 39.5,
36.6, 34.1, 32.1, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3, 28.9, 28.2,
28.1, 29.0, 26.9. 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for
C.sub.29H.sub.51N.sub.7O.sub.3 (M+) 545.4053, found 545.4053, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
dodecanamide hydrochloride (0.155 g, 83% yield). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.31 (s, 1H), .delta. 6.49 (s, 1H),
.delta. 4.63 (s, 2H), .delta. 3.97 (s, 2H), .delta. 2.81 (s, 2H),
.delta. 2.51 (t, J=7.2 Hz, 2H), .delta. 2.14 (t, J=7.2 Hz, 2H),
.delta. 1.76 (s, 2H), .delta. 1.67 (s, 2H), .delta. 1.51 (s, 2H),
.delta. 1.44 (s, 2H), .delta. 1.26 (bs, 16H), .delta. 0.71 (s, 3H)
ppm; .sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 175.6, 159.4,
147.3, 127.6, 108.5, 51.3, 48.6, 38.8, 35.8, 31.9, 29.6, 29.5,
29.4, 29.3, 29.2, 28.2, 28.1, 27.7, 24.8, 24.2, 23.9, 22.6, 22.5,
13.4, 13.3 ppm; HRMS (ESI) calcd for C.sub.24H.sub.43N.sub.7O (M+)
445.3429, found 445.3524.
[0462]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)tetradecanamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.111 g, 0.401
mmol) was reacted with N-(2-azidoethyl)tetradecanamide (0.130 g,
0.401 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-tetradecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-
-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.26 (s, 1H), .delta. 6.85 (s, 1H), .delta. 6.42 (s, 1H), .delta.
6.05 (s, 1H), .delta. 4.38 (s, 2H), .delta. 3.66 (s, 2H), .delta.
2.60 (s, 2H), .delta. 2.11 (s, 2H), .delta. 2.08 (t, J=3.6 Hz, 2H),
.delta. 1.41 (m, 13H), .delta. 1.32 (s, 2H), .delta. 1.17 (s, 18H),
.delta. 0.77 (t, J=6.6 Hz, 3H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 202.9, 174.3, 149.6, 148.3, 121.9, 100.1, 84.8,
49.5, 42.3, 39.5, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.5,
29.3, 28.9, 28.1, 25.9, 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for
C.sub.31H.sub.55N.sub.7O.sub.3(M+) 573.4366, found 573.4365, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
tetradecanamide hydrochloride (0.118 g, 87% yield). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.51 (s, 1H), .delta. 6.53 (s, 1H),
.delta. 4.71 (s, 2H), .delta. 3.75 (s, 2H), .delta. 2.89 (s, 2H),
.delta. 2.54 (t, J=6.8 Hz, 2H), .delta. 2.17 (t, J=6.8 Hz, 2H),
.delta. 1.80 (s, 2H), .delta. 1.69 (s, 2H), .delta. 1.54 (s, 2H),
.delta. 1.48 (s, 2H), .delta. 1.28 (s, 20H), 0.88 (t, J=6.8 Hz, 3H)
ppm; .sup.13 C NMR (100 MHz, CD.sub.3OD) .delta. 175.6, 161.8,
147.2, 127.6, 127.4, 108.5, 52.3, 38.8, 36.6, 35.8, 31.9, 30.6,
29.7, 29.6, 29.5, 29.4, 29.2, 28.0, 27.9, 27.7, 25.8, 24.1, 23.6,
23.4, 22.6, 13.4 ppm; HRMS (ESI) calcd for C.sub.26H.sub.47N.sub.7O
(M+) 473.3842, found 473.3834.
[0463]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)palmitamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.087 g, 0.313
mmol) was reacted with N-(2-azidoethyl)palmitamide (0.102 g, 0.313
mmol) following the general click procedure to give tert-butyl
2-amino-4-(5-(1-(2-palmitamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imi-
dazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.29
(s, 1H), .delta. 6.78 (t, J=4.5 Hz, 1H), .delta. 6.41 (s, 1H),
.delta. 6.19 (s, 2H), .delta. 4.39 (t, J=5.4 Hz, 2H), .delta. 3.67
(q, J=5.5, 4.8 Hz, 2H), .delta. 2.61 (t, J=6.9 Hz, 2H), .delta.
2.12 (t, J=6.5 Hz, 2H), .delta. 2.07 (t, J=7.5 Hz, 2H), .delta.
1.42 (m, 13H), .delta. 1.42 (m, 2H), .delta. 1.32 (m, 22H), 0.81
(t, J=5.4 Hz, 3H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
176.8, 174.3, 173.9, 149.5, 148.3, 121.9, 106.4, 85.0, 67.2, 51.1,
49.5, 39.5, 39.1, 38.1, 36.8, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6,
29.5, 29.3, 28.9, 28.3, 28.2, 27.9, 25.9, 25.6, 22.9, 14.3 ppm;
HRMS (ESI) calcd for C.sub.33H.sub.59N.sub.7O.sub.3 (M+) 601.4679,
found 601.4671, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
palmitamide hydrochloride (0.155 g, 92% yield). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 8.59 (s, 1H), .delta. 6.53 (s, 1H),
.delta. 4.72 (s, 2H), .delta. 3.75 (s, 2H), .delta. 2.90 (s, 2H),
.delta. 2.54 (s, 2H), .delta. 2.16 (t, J=7.2 Hz, 2H), .delta. 1.80
(s, 2H), .delta. 1.69 (s, 2H), .delta. 1.51 (s, 4H), .delta. 1.28
(bs, 24H), .delta. 0.71 (t, J=6.3 Hz, 3H) ppm; .sup.13C NMR (75
MHz, CD.sub.3OD) .delta. 175.7, 147.2, 145.6, 128.4, 127.6, 108.6,
67.2, 52.7, 37.4, 36.5, 35.8, 31.9, 29.7, 29.5, 29.4, 29.2, 28.0,
27.9, 27.8, 27.7, 25.8, 24.1, 23.6, 23.2, 22.6 ppm; HRMS (ESI)
calcd for C.sub.28H.sub.51N.sub.7O (M+) 501.4155, found
501.4143.
[0464]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide hydrochloride:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate
(0.116 g, 0.417 mmol) was reacted with
N-(2-azidoethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide
(0.145 g, 0.417 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamido)ethyl)--
1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.76 (s, 1H), .delta. 7.32 (s,
1H), .delta. 6.81 (s, 1H), .delta. 6.49 (s, 1H), .delta. 6.17 (s,
2H), .delta. 4.52 (s, 2H), .delta. 3.94 (s, 3H), .delta. 3.84 (s,
2H), .delta. 2.65 (t, J=7.2 Hz, 2H), .delta. 2.30 (m, 2H),
.delta.1.58 (m, 13H), .delta. 1.35 (m, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 161.2, 149.6, 148.2, 138.8, 127.4, 122.2,
114.9, 111.9, 106.5, 98.2, 84.5, 49.5, 39.7, 35.9, 29.3, 28.9,
28.2, 28.0, 27.7, 25.6 ppm; HRMS (ESI) calcd for
C.sub.23H.sub.32N.sub.8O.sub.3(M+) 626.0964, found 626.0960, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (0.151
g, 64% yield). .sup.1N NMR (400 MHz, CD.sub.3OD) .delta. 8.24 (s,
1H), .delta. 6.86 (s, 1H), .delta. 6.56 (s, 1H), .delta. 4.71 (s,
2H), .delta. 3.81 (s, 5H), 2.78 (s, 2H), .delta. 2.44 (t, J=7.2 Hz,
2H), .delta. 1.69 (s, 2H), .delta. 1.59 (s, 2H), .delta. 1.37 (s,
2H) ppm; .sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 161.4, 150.2,
159.8, 159.4, 147.3, 127.6, 127.3, 114.9, 111.6, 108.4, 97.9, 51.3,
39.0, 35.2, 28.3, 28.0, 27.6, 24.2, 23.8 ppm; HRMS (ESI) calcd for
C.sub.18H.sub.24Br.sub.2N.sub.8O (M+) 526.0439, found 526.0425.
[0465]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4-bromo-1H-pyrrole-2-carboxamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.104 g, 0.375
mmol) was reacted with
N-(2-azidoethyl)-4-bromo-1H-pyrrole-2-carboxamide (0.131 g, 0.375
mmol) following the general click procedure to give tert-butyl
2-amino-4-(5-(1-(2-(4-bromo-1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-tria-
zol-4-yl)pentyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 11.44 (s, 1H), .delta. 7.84 (s, 1H), .delta.
7.28 (s, 1H), .delta. 6.84 (s, 1H), .delta. 6.74 (s, 1H), .delta.
6.46 (s, 1H), .delta. 4.89 (s, 2H), .delta. 3.82 (s, 2H), .delta.
2.57 (s, 2H), .delta. 2.28 (s, 2H), .delta. 1.55 (m, 13H), .delta.
1.29 (m, 2H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 186.8,
161.4, 150.7, 149.3, 148.2, 137.6, 126.3, 122.5, 122.1, 113.1,
100.4, 96.9, 85.4, 49.6, 29.1, 28.7, 28.2, 27.7, 25.5 ppm; HRMS
(ESI) calcd for C.sub.22H.sub.31BrN.sub.8O.sub.3(M+) 534.1703,
found 534.1705, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-bromo-1H-pyrrole-2-carboxamide hydrochloride (0.129 g, 73%
yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.42 (s, 1H),
.delta. 6.93 (s, 1H), .delta. 6.82 (s, 1H), .delta. 6.47 (s, 1H),
.delta. 4.76 (s, 2H), .delta. 3.87 (s, 2H), .delta. 2.79 (s, 2H),
.delta. 2.45 (s, 2H), .delta. 1.69 (s, 2H), .delta. 1.60 (s, 2H),
.delta. 1.37 (s, 2H) ppm; .sup.13C NMR (100 MHz, CD.sub.3OD)
.delta. 161.4, 159.5, 159.1, 147.3, 147.2, 127.6, 125.8, 122.3,
122.1, 112.8, 108.6, 108.5, 96.4, 51.9, 38.9, 28.0, 27.9, 27.6,
24.1, 23.6 ppm; HRMS (ESI) calcd for C.sub.17H.sub.23BrN.sub.8O
(M+) 434.1178, found 434.1171.
[0466]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-1H-pyrrole-2-carboxamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.097 g, 0.349
mmol) was reacted with N-(2-azidoethyl)-1H-pyrrole-2-carboxamide
(0.063 g, 0.349 mmol) following the general click procedure to give
tert-butyl 4-(5-(1-(2-(1H-carboxylate .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.18 (s, 1H), .delta. 7.36 (d, J=5.7 Hz, 2H),
.delta. 7.24 (s, 1H), .delta. 6.84 (t, J=8.1 Hz, 1H), .delta. 6.43
(s, 1H), .delta. 6.04 (s, 2H), 4.49 (s, 2H), .delta. 3.89 (s, 2H),
.delta. 2.53 (s, 2H), .delta. 2.09 (s, 2H), .delta. 1.44 (m, 13H),
.delta. 1.24 (s, 2H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
165.9, 164.8, 164.6, 161.5, 137.5, 122.3, 111.0, 110.7, 107.5,
107.1, 106.8, 85.1, 49.4, 40.5, 29.3, 28.9, 28.2, 25.5 ppm; HRMS
(ESI) calcd for C.sub.22H.sub.32N.sub.8O.sub.3(M+) 456.2597, found
456.2590, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-1H-pyrrole-2-carboxamide hydrochloride (0.129 g, 94% yield).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.65 (s, 1H), .delta.
7.41 (s, 2H), .delta. 7.17 (s, 1H), .delta. 6.50 (s, 1H), .delta.
4.74 (s, 2H), .delta. 3.98 (s, 2H), .delta. 2.88 (s, 2H), .delta.
2.49 (s, 2H), .delta. 1.78 (m, 4H), .delta. 1.44 (s, 2H) ppm;
.sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 166.3, 164.5, 162.0,
161.9, 137.4, 110.6, 110.3, 110.2, 108.5, 17.1, 106.8, 59.3, 52.4,
39.5, 36.5, 27.9, 27.8, 27.6, 24.1, 23.5, 23.3 ppm; HRMS (ESI)
calcd for C.sub.17H.sub.24H.sub.8O (M+) 356.2073, found
356.2080.
[0467]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4-tert-butylbenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.070 g, 0.253
mmol) was reacted with N-(2-azidoethyl)-4-tert-butylbenzamide
(0.062 g, 0.253 mmol) following, the general click procedure to
give tert-butyl
2-amino-4-(5-(1-(2-(4-tert-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pe-
ntyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.71 (d, J=7.5 Hz, 2H), .delta. 7.64 (t, J=5.7 Hz, 1H),
.delta. 7.36 (d, J=7.5 Hz, 2H), .delta. 7.27 (s, 1H), .delta. 6.42
(s, 1H), .delta. 5.99 (s, 2H), .delta. 4.51 (t, J=5.7 Hz, 2H),
.delta. 3.88 (q, J=5.1, 5.3 Hz, 2H), .delta. 2.58 (t, J=7.5 Hz,
2H), .delta. 2.22 (t, J=7.5 Hz, 2H), .delta. 1.52 (m, 13H), .delta.
1.21 (m, 11H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 168.2,
155.3, 150.4, 149.6, 148.3, 138.9, 131.2, 127.3, 125.6, 122.2,
106.5, 84.8, 49.4, 40.2, 35.1, 31.3, 31.1, 29.3, 28.9, 28.3, 28.2,
28.1, 25.6 ppm; HRMS (ESI) calcd for C.sub.28H.sub.41N.sub.7O.sub.3
(M+) 523.3271, found 523.3270, which was subsequently deprotected
to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-tert-butylbenzamide hydrochloride (0.105 g, 90% yield). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.48 (s, 1H), .delta. 7.76 (d,
J=6.3 Hz, 2H), .delta. 7.48 (d, J=6.3 Hz, 2H), .delta. 6.50 (s,
1H), .delta. 4.84 (s, 2H), .delta. 3.95 (s, 2H), .delta. 2.85 (s,
2H), .delta. 2.46 (t, J=5.4 Hz, 2H), .delta. 1.73 (s, 2H), .delta.
1.57 (m, 2H), .delta. 1.39 (s, 2H), .delta. 1.31 (s, 9H) ppm;
.sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 169.2, 155.6, 147.3,
130.8, 129.9, 127.6, 127.2, 127.1, 126.7, 125.4, 125.3, 119.5,
108.6, 108.5, 52.3, 39.4, 34.6, 30.4, 27.9, 27.8, 27.6, 24.1, 23.2,
22.2 ppm; HRMS (ESI) calcd for C.sub.23H.sub.33N.sub.7O (M+)
423.2747, found 423.2741.
[0468]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-2-naphthamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.095 g, 0.344
mmol) was reacted with N-(2-azidoethyl)-2-naphthamide (0.083 g,
0.344 mmol) following the general click procedure to give
tert-butyl
4-(5-(1-(2-(2-naphthamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-2-amino-1H-
-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.24 (s, 1H), .delta. 8.01 (s, 1H), .delta. 7.72 (m, 4H), .delta.
7.39 (m, 2H), .delta. 7.26 (s, 1H), .delta. 6.33 (s, 1H), .delta.
6.04 (s, 2H), .delta. 4.51 (s, 2H), .delta. 3.88 (s, 2H), .delta.
2.48 (t, 2H), .delta. 2.12 (s, 2H), .delta. 1.47 (m, 13H), .delta.
1.17 (s, 2H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 168.5,
150.4, 149.5, 148.3, 138.6, 134.9, 132.7, 131.4, 129.2, 128.5,
128.1, 127.9, 126.8, 124.0, 122.3, 106.5, 84.9, 49.4, 40.4, 29.9,
29.2, 28.9, 28.6, 28.2, 27.9, 28.6, 27.9, 27.8, 25.6 ppm; HRMS
(ESI) calcd for C.sub.28H.sub.35N.sub.7O.sub.3 (M+) 517.2801, found
517.2792, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-2-naphthamide hydrochloride (0.140 g, 90% yield). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. ppm; HRMS (ESI) calcd for C.sub.23H.sub.27N.sub.7O (M+)
417.2277, found 417.2274.
[0469]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-2-iodobenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.083 g, 0.299
mmol) was reacted with N-(2-azidoethyl)-2-iodobenzamide (0.095 g,
0.299 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(2-iodobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)--
1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.74 (d, J=7.5 Hz, 2H), .delta. 7.57 (t, J=4.5 Hz, 1H),
.delta. 7.36 (s, 1H), .delta. 7.22 (s, 2H), .delta. 6.97 (m, 1H),
.delta. 6.39 (s, 1H), .delta. 5.97 (s, 2H), .delta. 4.48 (t, J=5.1
Hz, 2H), .delta. 3.85 (m, 2H), .delta. 2.44 (t, J=7.5 Hz, 2H),
.delta. 2.18 (t. J=6.6 Hz, 2H), .delta. 1.45 (m, 13H, .delta. 1.18
(m, 2H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 170.3,
150.4, 149.5, 148.2, 141.8, 139.9, 138.7, 131.3, 128.4, 128.3,
122.3, 106.5, 92.8, 84.9, 49.2, 40.5, 29.2, 28.9, 28.3, 28.2, 28.0,
25.5 ppm; HRMS (ESI) calcd for C.sub.24H.sub.32IN.sub.7O.sub.3 (M+)
593.1611, found 593.1603, which was subsequently deprotected to
give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-2-iodobenzamide hydrochloride (0.125 g, 79% yield). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.35 (s, 1H), .delta. 7.88 (d, J=7.8
Hz, 1H), .delta. 7.45 (t, J=6.9 Hz, 1H), .delta. 7.34 (d, J=6.9 Hz,
1H), .delta. 7.15 (t, J=7.5 Hz, 1H), .delta. 6.47 (s, 1H), .delta.
4.78 (s, 2H), .delta. 3.99 (s, 2H), .delta. 2.83 (s, 2H), .delta.
2.44 (t, J=6.9 Hz, 2H), .delta. 1.76 (s, 2H), .delta. 1.64 (s, 2H),
.delta. 1.29 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta.
171.6, 159.2, 147.3, 142.1, 139.8, 131.2, 128.2, 127.7, 124.4,
92.1, 52.2, 40.8, 39.4, 31.2, 28.3, 28.1, 27.7, 24.1, 20.9, 15.9,
10.7 ppm; HRMS (ESI) calcd for C.sub.19H.sub.24IN.sub.7O (M+)
493.1087, found 493.1085.
[0470]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4-heptylbenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.125 g, 0.449
mmol) was reacted with N-(2-azidoethyl)-4-heptylbenzamide (0.129 g,
0.449 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(4-heptylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl-
)-1H-imidazole-1-carboxylate .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.78 (s, 1H), .delta. 7.65 (d, 2H), .delta. 7.27 (s, 1H),
.delta. 7.09 (d, 2H), .delta. 6.39 (s, 1H), .delta. 6.22 (s, 2H),
.delta. 4.47 (s, 2H), .delta. 3.81 (s, 2H), .delta. 3.96 (s, 4H),
.delta. 2.20 (s, 2H), .delta. 2.05 (s, 2H), 1.48 (m, 12H), .delta.
1.17 (m, 8H), .delta. 0.77 (t, J=6.4 Hz, 3H); .sup.13C NMR (100
MHz, CDCl.sub.3) .delta. 168.3, 149.6, 148.2, 147.1, 138.6, 131.5,
128.6, 127.4, 122.1, 106.4, 84.8, 67.1, 49.4, 40.2, 37.9, 36.9,
31.9, 31.3, 31.1, 29.8, 28.4, 29.3, 28.9, 28.3, 28.1, 28.0, 25.5,
22.8, 14.3 ppm; HRMS (ESI) calcd for
C.sub.31H.sub.47N.sub.7O.sub.3(M+) 565.3704, found 656.3737, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-heptylbenzamide hydrochloride (0.194 g, 86% yield). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.25 (s, 1H), .delta. 7.71 (d, J=5.4
Hz, 2H), .delta. 7.24 (d, J=5.7 Hz, 2H), .delta. 6.45 (s, 1H),
.delta. 4.74 (s, 2H), 3.90 (s, 2H), .delta. 2.63 (s, 2H), .delta.
2.61 (t, 2H), .delta. 2.41 (s, 2H), .delta. 1.58 (m, 6H), .delta.
1.26 (m, 10H), .delta. 0.85 (t, J=4.8 Hz, 3H) ppm; .sup.13C NMR
(100 MHz, CD.sub.3OD) .delta. 169.2, 150.2, 147.4, 131.2, 128.5,
127.6, 127.3, 108.4, 51.4, 39.6, 36.5, 35.6, 31.8, 331.3, 29.1,
29.1, 28.3, 28.0, 27.7, 24.1, 22.6, 13.4, 13.3 ppm; HRMS (ESI)
calcd for C.sub.26H.sub.39N.sub.7O (M+) 465.3216, found
465.3207.
[0471]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4-hexylbenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.097 g, 0.349
mmol) was reacted with N-(2-azidoethyl)-4-hexylbenzamide (0.096 g,
0.349 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(4-hexylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-
-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.65 (d, J=8.1 Hz, 2H), .delta. 7.55 (t, J=6.7 Hz, 1H),
.delta. 7.26 (s, 1H), .delta. 7.09 (d, J=7.8 Hz, 2H), .delta. 6.39
(s, 1H), .delta. 6.04 (s, 2H), .delta. 4.48 (t, J=4.8 Hz, 2H),
.delta. 3.83 (q, J=5.6, 4.8 Hz, 2H), .delta. 2.56 (q, J=7.5, 8.1
Hz, 4H), .delta. 2.24 (t, J=6.9 Hz, 2H), .delta. 1.50 (m, 13H),
.delta. 1.21 (m, 1H), .delta. 0.77 (t, J=5.7 Hz, 3H) ppm; .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 168.3, 148.3, 147.3, 138.7, 131.4,
128.7, 127.4, 122.2, 106.4, 84.9, 73.9, 49.5, 40.2, 36.0, 31.8,
31.3, 29.9, 29.3, 29.1, 28.9, 28.2, 28.1, 28.0, 25.6, 22.8, 14.3
ppm; HRMS (ESI) calcd for C.sub.30H.sub.45N.sub.7O.sub.3 (M+)
551.3584, found 551.3581, which was subsequently deprotected to
give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-hexylbenzamide hydrochloride (0.164 g, 96% yield). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.28 (s, 1H), .delta. 7.67 (d, J=7.6
Hz, 2H), .delta. 7.21 (d, J=7.6 Hz, 2H), .delta. 6.43 (s, 1H),
.delta. 4.72 (s, 2H), .delta. 3.87 (s, 2H), .delta. 2.74 (s, 2H),
.delta. 2.58 (t, J=7.6 Hz, 2H), .delta. 2.31 (t, J=6.8 Hz, 2H),
.delta. 1.66 (s, 2H), .delta. 1.55 (s, 4H), .delta. 1.35 (s, 2H),
.delta. 1.25 (s, 6H), .delta. 0.66 (t, J=8.8 Hz, 3H) ppm; .sup.13C
NMR (100 MHz, CD.sub.3OD) .delta. 169.2, 159.5, 147.4, 147.3,
131.2, 108.4, 51.2, 48.5, 48.3, 48.1, 47.9, 47.7, 47.5, 47.3, 39.5,
36.5, 35.6, 31.6, 31.7, 31.2, 28.8, 28.2, 27.9, 27.7, 24.1, 23.9,
22.6, 13.3, 9.9 ppm; HRMS (ESI) calcd for C.sub.25H.sub.37N.sub.7O
(M+) 451.3059, found 451.3058.
[0472]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4-butylbenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.443
mmol) was reacted with N-(2-azidoethyl)-4-butylbenzamide (0.109 g,
0.443 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(4-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-
-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.67 (s, 1H), .delta. 7.67 (d, J=7.5 Hz, 2H), .delta. 7.29
(s, 1H), .delta. 7.11 (d, J=7.5 Hz, 2H), .delta. 6.42 (s, 1H),
.delta. 6.25 (s, 2H), .delta. 4.48 (s, 2H), .delta. 3.83 (s, 2H),
.delta. 2.56 (t, J=7.2 Hz, 4H), .delta. 2.21 (s, 2H), 1.47 (m,
13H), .delta. 1.21 (m, 4H), .delta. 0.83 (t, J=7.2 Hz, 3H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta.168.3, 140.6, 149.5,
148.2, 147.1, 138.4, 131.5, 128.7, 127.4, 122.2, 106.4, 84.9, 49.4,
40.2, 35.7, 33.5, 29.2, 28.9, 28.3, 28.1, 27.9, 25.5, 22.4, 14.1
ppm; HRMS (ESI) calcd for C.sub.28H.sub.41N.sub.7O.sub.3 (M+)
523.3271, found 523.3261, which was subsequently deprotected to
give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-butylbenzamide hydrochloride (0.191 g, 94% yield). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.43 (s, 1H), .delta. 7.69 (s, 2H),
.delta. 7.22 (s, 2H), .delta. 6.44 (s, 1H), .delta. 4.73 (s, 2H),
.delta. 3.89 (s, 2H), .delta. 3.34 (s, 2H), .delta. 2.59 (s, 4H),
.delta. 2.41 (s, 2H), .delta. 1.54 (s, 4H), .delta. 1.29 (s, 4H),
.delta. 0.88 (t, J=6.9 Hz, 3H) ppm; .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 169.2, 165.1, 160.3, 158.1, 147.4, 141.4,
131.2, 128.5, 127.7, 127.3, 126.9, 92.9, 39.6, 36.3, 33.4, 30.9,
28.0, 27.7, 24.1, 22.2, 13.2, 12.1, 10.9, 8.9, 6.2, 2.5 ppm; HRMS
(ESI) calcd for C.sub.23H.sub.33N.sub.7O (M+) 423.2747, found
423.2738.
[0473]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4-pentylbenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.113 g, 0.408
mmol) was reacted with
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
biphenyl-4-carboxamide hydrochloride (0.106 g, 0.408 mmol)
following the general click procedure to give tert-butyl
2-amino-4-(5-(1-(2-(4-pentylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl-
)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.75 (s, 1H), .delta. 7.67 (d, J=7.5 Hz, 2H), .delta. 7.27
(s, 1H), .delta. 7.12 (d, J=7.8 Hz, 2H), .delta. 4.48 (s, 2H),
.delta. 3.84 (s, 2H), .delta. 2.55 (m, 4H), .delta. 2.22 (s, 2H),
.delta. 1.50 (s, 13H), .delta. 1.23 (s, 8H), .delta. 0.80 (t, J=5.7
Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm 168.3,
150.5, 149.5, 147.2, 138.6, 131.5, 128.7, 127.4, 106.4, 84.8, 49.4,
40.2, 35.9, 31.6, 31.0, 29.3, 28.9, 28.1, 27.9, 25.6, 22.6, 14.2;
HRMS (ESI) calcd for C.sub.29H.sub.43N.sub.7O.sub.3 (M+) 537.3427,
found 537.3420, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-pentylbenzamide hydrochloride (0.178 g, 92% yield). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.41 (s, 1H), .delta. 7.69 (d, J=7.5
Hz, 2H), .delta. 7.21 (d, J=7.2 Hz, 2H), .delta. 6.46 (s, 1H),
.delta. 4.84 (s, 2H), .delta. 3.90 (s, 2H), .delta. 2.79 (s, 2H),
.delta. 2.58 (t, J=7.8 Hz, 2H), .delta. 2.39 (t, J=7.2 Hz, 2H),
.delta. 1.68 (s, 2H), .delta. 1.55 (s, 4H), .delta. 1.26 (s, 6H),
.delta. 0.84 (t, J=6.6 Hz, 3H) ppm; .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 169.2, 159.5, 158.9, 147.5, 147.3, 131.1,
128.5, 127.6, 127.4, 108.5, 54.2, 51.9, 39.5, 35.6, 31.4, 30.9,
30.6, 28.4, 27.9, 27.6, 26.9, 24.1, 23.5, 22.9, 22.4, 13.3 ppm;
HRMS (ESI) calcd for C.sub.24H.sub.35N.sub.7O (M+) 437.2903, found
437.2892.
[0474]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-2,4,6-trichlorobenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.088 g, 0.318
mmol) was reacted with N-(2-azidoethyl)-2,4,6-trichlorobenzamide
(0.093 g, 0.318 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(2,4,6-trichlorobenzamido)ethyl)-1H-1,2,3-triazol-4-yl-
)pentyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.22 (s, 1H), .delta. 7.34 (s, 1H), .delta.
7.26 (s, 2H), .delta. 6.42 (s, 1H), .delta. 5.97 (s, 2H), .delta.
4.51 (s, 2H), .delta. 3.94 (s, 2H), .delta. 2.45 (t, 2H), .delta.
2.20 (s, 2H), .delta. 1.47 (m 13H), .delta. 1.21 (m, 2H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 164.7, 148.0, 135.7,
134.6, 132.9, 128.7, 128.1, 127.3, 122.3, 84.9, 53.7, 49.3, 39.9,
31.8, 29.2, 28.9, 28.2, 25.5, 22.8, 14.3 ppm; HRMS (ESI) calcd for
C.sub.24H.sub.30Cl.sub.3N.sub.7O.sub.3 (M+) 569.1476, found
569.1477, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-2,4,6-trichlorobenzamide hydrochloride (0.116 g, 72% yield).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.36 (s, 1H), .delta.
7.45 (s, 2H), .delta. 6.46 (s, 1H), .delta. 4.77 (s, 2H), .delta.
3.97 (s, 2H), .delta. 2.80 (s, 2H), .delta. 2.48 (t, J=6.9 Hz, 2H),
.delta. 1.73 (s, 2H), .delta. 1.62 (s, 2H), .delta. 1.41 (s, 2H)
ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 165.5, 147.3, 136.9,
134.5, 132.7, 128.2, 128.0, 127.6, 108.6, 51.2, 39.0, 28.1, 27.7,
24.1, 23.8 ppm; HRMS (ESI) calcd for
C.sub.19H.sub.22Cl.sub.3N.sub.7O (M+) 469.0951, found 469.0941.
[0475]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-3,5-difluorobenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.442
mmol) was reacted with N-(2-azidoethyl)-3,5-difluorobenzamide
(0.100 g, 0.442 mmol) following, the general click procedure to
give tert-butyl
2-amino-4-(5-(1-(2-(3,5-difluorobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pe-
ntyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.25 (s, 1H), .delta. 7.39 (m, 3H), .delta. 6.88 (t, J=4.8
Hz, 1H), .delta. 6.43 (s, 1H), .delta. 6.38 (bs, 2H), .delta. 4.55
(s, 2H), .delta. 3.93 (s, 2H), .delta. 2.56 (t, J=5.1 Hz, 2H),
.delta. 2.24 (s, 2H), .delta. 1.55 (m, 14H), .delta. 1.23 (s, 2H)
ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 165.9, 164.3, 164.2,
161.9, 150.3, 149.3, 148.2, 137.6, 1214, 111.0, 110.8, 107.3,
107.1, 106.8, 106.6, 85.5, 49.3, 40.4, 29.9, 29.5, 29.1, 28.7,
28.2, 27.9, 27.5, 25.4 ppm; HRMS (ESI) calcd for
C.sub.24H.sub.31F.sub.2N.sub.7O.sub.3(M+) 503.2456, found 503.2458,
which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-3,5-difluorobenzamide hydrochloride (0.115 g, 59% yield). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.55 (s, 1H), .delta. 7.42 (d,
J=2.0 Hz, 2H), .delta. 7.29 (t, J=2.40 Hz, 1H), .delta. 6.51 (s,
1H), .delta. 4.84 (t, J=4.8 Hz, 2H), .delta. 3.96 (q, J=13.2, 4.8
Hz, 2H), .delta. 2.89 (t, J=7.2 Hz, 2H), .delta. 2.49 (t, J=7.2 Hz,
2H), .delta. 1.79 (m, 2H), .delta. 1.75 (m, 2H), .delta. 1.44 (m,
2H) ppm; .sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 164.5, 164.4,
127.6, 126.9, 110.6, 110.6, 110.3, 108.5, 107.1, 106.8, 106.6,
52.5, 39.5, 30.4, 27.9, 27.8, 27.6, 24.0, 23.8, 23.1 ppm; HRMS
(ESI) calcd for C.sub.19H.sub.23F.sub.2N.sub.7O (M+) 403.1932,
found 403.1926.
[0476]
N-(2-(4-(5-(2-amino4H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)e-
thyl)biphenyl-4-carboxamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.093 g, 0.334
mmol) was reacted with N-(2-azidoethyl)biphenyl-4-carboxamide
(0.089 g, 0.334 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-biphenyl-4-ylcarboxamidoethyl)-1H-1,2,3-triazol-4-yl)p-
entyl)-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.91 (d, J=5.1 Hz, 3H), .delta. 7.57 (t, J=8.4 Hz, 4H),
.delta. 7.44 (t, J=6.9 Hz, 3H), .delta. 7.34 (1H), .delta. 4.60 (t,
J=5.1 Hz, 2H), .delta. 3.96 (q, J=5.1, 5.4 Hz, 2H), .delta. 2.63
(t, J=7.2 Hz, 2H), .delta. 2.27 (t, J=7.5 Hz, 2H), .delta. 1.62 (m,
13H), .delta. 1.33 (m, 2H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 168.0, 149.6, 148.3, 144.6, 140.1, 138.8, 132.8, 129.1,
128.2, 128.0, 127.4, 127.3, 122.2, 84.9, 49.4, 40.3, 29.3, 28.9,
28.3, 28.2, 28.1, 25.6 ppm; HRMS (ESI) calcd for
C.sub.30H.sub.37N.sub.7O.sub.3 (M+) 543.2958, found 543.2949, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3
-triazol-1-yl)ethyl)biphenyl-4-carboxamide hydrochloride (0.093 g,
58% yield). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.35 (s, 1H),
.delta. 7.88 (d, J=8.1 Hz, 2H), .delta. 7.65 (d, J=8.4 Hz, 2H),
.delta. 7.57 (d, J=7.5 Hz, 2H), .delta. 7.39 (t, J=7.5 Hz, 2H),
.delta. 7.34 (t, J=7.2 Hz, 1H), .delta. 6.39 (s, 1H), .delta. 4.81
(s, 2H), .delta. 3.96 (s, 2H), .delta. 2.78 (s, 2H), .delta. 2.37
(t, J=7.5 Hz, 2H), .delta. 1.67 (s, 2H), .delta. 1.56 (t, 2H),
.delta. 1.33 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta.
203.6, 158.9, 160.1, 159.5, 159.1, 159.0, 158.5, 149.8, 147.2,
144.6, 132.4, 128.9, 127.9, 127.6, 126.9, 126.4, 108.4, 51.7, 39.5,
27.9, 27.6, 24.0, 23.5, 7.2 ppm; HRMS (ESI) calcd for
C.sub.25H.sub.29N.sub.7O (M+) 443.2434, found 443.2423.
[0477]
N-(2-4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)e-
thyl)-4-octylbenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.078 g, 0.282
mmol) was reacted with N-(2-azidoethyl)-4-octylbenzamide (0.085 g,
0.282 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(4-octylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-
-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.64 (s, 2H), .delta. 7.47 (s, 1H), .delta. 7.21 (s, 1H),
.delta. 7.09 (s, 2H), .delta. 6.47 (bs, 3H), .delta. 4.48 (s, 2H),
.delta. 3.84 (s, 2H), .delta. 2.53 (s, 4H), .delta. 2.28 (t, J=15.9
Hz, 2H), .delta. 1.51 (bs, 6H), .delta. 1.18 (bs, 10H), 0.77 (t,
J=6.6 Hz, 3H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 180.7,
180.2, 168.3, 147.4, 142.4, 139.2, 131.4, 128.8, 127.4, 107.4,
49.6, 40.2, 36.1, 32.1, 31.4, 29.9, 29.6, 29.5, 28.8, 28.2, 28.1,
25.4, 22.9, 14.3 ppm; HRMS (ESI) calcd for
C.sub.32H.sub.49N.sub.7O.sub.3 (M+) 579.3896, found 579.3890, which
was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-octylbenzamide hydrochloride (0.097 g, 67% yield). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.65 (s, 2H), .delta. 7.23 (s, 3H),
.delta. 6.45 (s, 1H), .delta. 3.97 (s, 4H), .delta. 2.60 (s, 4H),
.delta. 2.47 (s, 2H), .delta. 1.57 (m, 6H), .delta. 1.27 (bm, 12H),
.delta. 0.83 (t, J=6.4 Hz, 3H) ppm; .sup.13C NMR (100 MHz,
CD.sub.3OD) .delta. 183.5, 172.0, 169.3, 161.8, 153.9, 147.4,
131.2, 128.5, 127.7, 127.3, 119.1, 108.8, 104.7, 94.6, 63.4, 38.7,
35.6, 31.8, 31.3, 29.3, 29.2, 29.1, 28.1, 27.7, 27.1, 24.2, 22.5,
13.3, 12.6 ppm; HRMS (ESI) calcd for C.sub.27H.sub.41N.sub.7O (M+)
479.3372, found 479.3378.
[0478]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-4-nonylbenzamide hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (g, mmol) was
reacted with (g, mmol) following the general click procedure to
give tert-butyl
2-amino-4-(5-(1-(2-(4-nonylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-
-1H-imidazole-1-carboxylate .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.70 (d, J=7.2 Hz, 2H), .delta. 7.29 (s, 1H), .delta. 7.27
(t, J=8.7 Hz, 1H), .delta. 7.16 (d, J=7.2 Hz, 2H), .delta. 4.53 (s,
2H), .delta. 3.91 (s, 2H), .delta. 2.61 (m, 4H), .delta. 2.41 (m,
1H), .delta. 2.14 (s, 1H), .delta. 1.56 (bs, 15H), .delta. 1.23
(bs, 14H), .delta. 0.83 (t, J=6.6 Hz, 3H) ppm; .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 188.1, 169.7, 168.3, 164.4, 148.0, 147.4,
131.4, 128.8, 127.4, 122.2, 51.6, 49.5, 40.2, 36.0, 32.1, 31.4,
29.7, 29.6, 29.5, 29.4, 29.3, 28.2, 25.6, 22.9, 14.3 ppm; HRMS
(ESI) calcd for C.sub.33H.sub.51N.sub.7O.sub.3 (M+) 593.4053, found
593.4049, which was subsequently deprotected to give
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-
-4-nonylbenzamide hydrochloride (0.183 g, 74% yield). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.66 (s, 1H), .delta. 7.69 (s, 2H),
.delta. 7.25 (s, 2H), .delta. 6.54 (s, 1H), .delta. 4.81 (s, 2H),
.delta. 3.62 (s, 2H), .delta. 2.85 (s, 2H), .delta. 2.63 (s, 2H),
.delta. 2.46 (s, 2H), .delta. 1.75 (s, 2H), .delta. 1.39 (s, 4H),
.delta. 1.29 (m, 14H), .delta. 0.88 (s, 3H) ppm; .sup.13C NMR (100
MHz, CD.sub.3OD) .delta. 205.0, 169.2, 147.5, 147.3, 131.2, 128.5,
127.3, 108.9, 108.6, 96.0, 52.4, 51.6, 39.3, 38.9, 35.6, 31.9,
31.3, 30.6, 29.5, 29.4, 29.3, 29.2, 28.1, 27.9, 27.7, 24.1, 23.6,
22.6, 13.4 ppm; HRMS (ESI) calcd for C.sub.28H.sub.43N.sub.7O (M+)
493.3529, found 493.3522.
[0479]
N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)-
ethyl)-2',4'-difluoro-3-hydroxybiphenyl-4-carboxamide
hydrochloride: tert-butyl
2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.085 g, 0.306
mmol) was reacted with
N-(2-azidoethyl)-2',4'-difluoro-3-hydroxybiphenyl-4-carboxamide
(0.097 g, 0.306 mmol) following the general click procedure to give
tert-butyl
2-amino-4-(5-(1-(2-(2',4'-difluoro-3-hydroxybiphenyl-4-ylcarboxamido)ethy-
l)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.54 (S, 1H), .delta. 7.83 (s,
1H), .delta. 7.37 (d, J=7.2 Hz, 1H), .delta. 7.28 (s, 1H), .delta.
7.18 (s, 1H), .delta. 6.89 (d, J=7.8 Hz, 1H), .delta. 6.72 (s, 2H),
.delta. 6.39 (s, 1H), .delta. 4.57 (s, 2H), .delta. 3.81 (s, 2H),
.delta. 3.34 (s, 1H), .delta. 2.47 (s, 2H), .delta. 2.07 (s, 2H),
.delta. 1.49 (m, 13H), .delta. 1.17 (s, 2H) ppm; .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 169.5, 163.7, 161.3, 160.5, 159.9, 150.5,
149.2, 148.2, 137.1, 136.3, 134.5, 131.4, 12.8, 126.8, 124.4,
122.3, 117.9, 116.1, 111.9, 111.6, 106.7, 104.8, 104.4, 104.1,
85.8, 50.5, 49.4, 46.6, 50.0, 37.9, 29.9, 28.9, 28.5, 28.3, 28.1,
27.4, 25.3, 25.0 ppm; HRMS (ESI) calcd for
C.sub.30H.sub.35F.sub.2N.sub.4O.sub.4(M+) 595.2729, found 595.2717,
which was subsequently deprotected to give (0.137 g, 84%
yield).
[0480] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.60 (s, 1H),
.delta. 7.89 (s, 1H), .delta. 7.52 (s, 2H), .delta. 6.97 (t, J=6.3
Hz, 3H), .delta. 6.45 (s, 1H), .delta. 4.81 (s, 2H), .delta. 2.78
(s, 2H), .delta. 2.42 (s, 2H), .delta. 1.72 (s, 2H), .delta. 1.61
(d, J=7.8 Hz, 2H), .delta. 1.38 (s, 2H) ppm; .sup.13C NMR (100 MHz,
CD.sub.3OD) .delta. 172.9, 169.8, 161.6, 159.5, 147.2, 134.4,
131.7, 128.4, 127.6, 126.0, 117.5, 115.6, 111.7, 111.5, 108.5,
104.2, 104.0, 103.7, 94.6, 51.9, 39.0, 27.9, 27.6, 26.8, 24.1, 23.8
ppm; HRMS (ESI) calcd for C.sub.25H.sub.27F.sub.2N.sub.7O.sub.2(M+)
459.2194, found 459.2190.
[0481] Procedure to Determine the Inhibitory Effect of Test
Compounds on C. albicans, C. neoformans and a mixed S.
epidermidis/C. albicans Biofilm Formation: Inhibition assays were
performed by taking an overnight culture of yeast or yeast/bacteria
strain and subculturing it at an OD.sub.600 of 0.05 into YPD (Yeast
extract, peptone and dextrose (BD 242820)) media for the yeast
alone or tryptic soy broth for the S. epidermidis/C. albicans.
Stock solutions of predetermined concentrations of the test
compound were then made in the necessary media. These stock
solutions were aliquoted (100 .mu.L) into the wells of the 96-well
PVC microtiter plate. Sample plates were then wrapped in GLAD Press
n' Seal.RTM. followed by an incubation under stationary conditions
for 24 h at 37.degree. C. After incubation, the media was discarded
from the wells and the plates were washed thoroughly with water.
Plates were then stained with 100 .mu.L of 0.1% solution of crystal
violet (CV) and then incubated at ambient temperature for 30 min.
Plates were washed with water again and the remaining stain was
solubilized with 200 .mu.L of 95% ethanol. A sample of 125 .mu.L of
solubilized CV stain from each well was transferred to the
corresponding wells of a polystyrene microtiter dish. Biofilm
inhibition was quantitated by measuring the OD.sub.540 of each well
in which a negative control lane wherein no biofilm was formed
served as a background and was subtracted out.
[0482] Procedure to Determine the Dispersal Effect of Test
Compounds on C. albicans and C. neoformans Preformed Biofilms:
Dispersion assays were performed by taking an overnight culture of
bacterial strain and subculturing, it at an OD.sub.600 of 0.01 into
Yeast extract, peptone and dextrose (BD 242820) media. The
resulting bacterial suspension was aliquoted (100 .mu.L) into the
wells of a 96-well PVC microtiter plate. Plates were then wrapped
in GLAD Press n' Seal.RTM. followed by an incubation under
stationary conditions at ambient temperature to establish the
biofilms. After 24 h, the media was discarded from the wells and
the plates were washed thoroughly with water. Stock solutions of
predetermined concentrations of the test compound were then made in
the necessary media. These stock solutions were aliquoted (100
.mu.L) into the wells of the 96-well PVC microtiter plate with the
established biofilms. Media alone was added to a subset of the
wells to serve as a control. Sample Plates were then incubated for
24 h at 37.degree. C. After incubation, the media was discarded
from the wells and the plates were washed thoroughly with water.
Plates were then stained with 100 .mu.L of 0.1% solution of crystal
violet (CV) and then incubated at ambient temperature for 30 min.
Plates were washed with water again and the remaining stain was
solubilized with 200 .mu.L of 95% ethanol. A sample of 125 .mu.L of
solubilized CV stain from each well was transferred to the
corresponding wells of a polystyrene microtiter dish. Biofilm
dispersion was quantitated by measuring the OD.sub.540 of each well
in which a negative control lane wherein no biofilm was formed
served as a background and was subtracted out.
[0483] The foregoing is illustrative of the present invention, and
is not to be construed as limiting thereof. The invention is
defined by the following claims, with equivalents of the claims to
be included therein.
* * * * *