NON-INVASIVE VENTILATION WITH HIGH FREQUENCY OSCILLATIONS

Abstract

Compounds of the formula (I) wherein X and Y are independently O, S or NR.sup.5, R.sup.1, R.sup.2 and R.sup.4 are independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6haloalkoxy and R.sup.3 is an aromatic five-membered heterocycle, which can be substituted are useful as a pesticides especially fungicide.

##STR00001##

Claims

1. A system for providing respiratory therapy, the system comprising: a pressure generator configured to generate a pressurized flow of breathable gas for delivery to the airway of a subject; an oscillator configured to cause high frequency pressure level oscillations in the pressurized flow of breathable gas; one or more sensors configured to generate output signals conveying information related to one or more parameters of the gas; and one or more physical computer processors configured by computer-readable instructions to (a) receive an input indicating a base expiratory pressure level and a base inspiratory pressure level; (b) control the pressure generator and the oscillator to generate the pressurized flow of breathable gas such that during exhalation the pressure level of the pressurized flow of breathable gas oscillates based on the received base expiratory pressure level and during inhalation the pressure level of the pressurized flow of breathable gas oscillates based on the received base inspiratory pressure level; and (c) detect expiratory flow limitation and to automatically adjust the base expiratory pressure level responsive to detecting expiratory flow limitation.

2. The system of claim 1, wherein the one or more physical computer processors are configured such that the high frequency pressure level oscillations are superimposed on the pressurized flow of breathable gas generated by the pressure generator.

3. The system of claim 1, wherein the oscillator includes one or more of a valve or an interrupter in a flow path of the pressurized flow of breathable gas.

4. The system of claim 1, wherein the one or more physical computer processors are configured such that detecting expiratory flow limitation is based on the output signals of the one or more sensors.

5. The system of claim 1, wherein the one or more physical computer processors are configured such that detecting expiratory flow limitation is based on one or more output signals of a pulse oximeter, an electromyogram, a pressure sensor, and/or a flow sensor.

6. A method of operation of a respiratory therapy system, the respiratory system comprising a pressure generator, an oscillator, one or more sensors, and one or more physical computer processors, the method comprising: generating a pressurized flow of breathable gas with the pressure generator; oscillating the pressurized flow of breathable gas at a night frequency; generating output signals conveying information related to one or more parameters of the gas with the one or more sensors; receiving an input indicating a base expiratory pressure level and a base inspiratory pressure level; controlling the pressure generator and the oscillator to generate the pressurized flow of breathable gas such that during exhalation the pressure level of the pressurized flow of breathable gas oscillates based on the received base expiratory pressure level and during inhalation the pressure level of the pressurized flow of breathable gas oscillates based on the received base inspiratory pressure level; and detecting expiratory flow limitation and automatically adjusting the base expiratory pressure level responsive to detecting the expiratory flow limitation.

7. The method of claim 6, wherein the high frequency oscillations are superimposed on the pressurized flow of breathable gas generated.

8. The method of claim 6, wherein the high frequency oscillations in the pressurized flow of breathable gas are caused by one or more of a valve or an interrupter in a flow path of the pressurized flow of breathable gas.

9. The method of claim 6, wherein detecting expiratory flow limitation is based on the output signal.

10. The method of claim 6, wherein detecting expiratory flow limitation is based on one or more output signals of a pulse oximeter, an electromyogram, a pressure sensor, and/or a flow sensor.

11. A system for providing respiratory therapy, the system comprising: means for generating a pressurized flow of breathable gas for delivery to the airway of a subject; means for causing high frequency pressure level oscillations in the pressurized flow of breathable gas; means for generating output signals conveying information related to one or more parameters of the gas; means for receiving an input indicating a base expiratory pressure level and a base inspiratory pressure level; means for controlling the generation of the pressurized flow of breathable gas such that during exhalation the pressure level of the pressurized flow of breathable gas oscillates based on the received base expiratory pressure level and during inhalation the pressure level of the pressurized flow of breathable gas oscillates based on the received base inspiratory pressure level; and means for detecting expiratory flow limitation and automatically adjusting the base expiratory pressure level responsive to detecting expiratory flow limitation.

12. The system of claim 11, wherein the high frequency pressure level oscillations are superimposed on the pressurized flow of breathable gas generated by the means for generating a pressurized flow of breathable gas.

13. The system of claim 11, wherein the means for causing high frequency pressure level oscillations include one or more of a valve or an interrupter in a flow path of the pressurized flow of breathable gas.

14. The system of claim 11, wherein the means for detecting expiratory flow limitation includes the output signals.

15. The system of claim 11, wherein the means for detecting expiratory flow limitation includes a pulse oximeter, an electromyogram, a pressure sensor, and/or a flow sensor.

Description

EXAMPLE 1

[0130] This Example Illustrates the Preparation of (2E)-2-[4-(2,5-dichloro-3-thienyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-yl-acetonitrile (Compound I.h.25)

a) Preparation of 2-chloro-1-(2,5-dichloro-3-thienyl)ethanol

[0131] Sodium borohydride (93 mg, 2.35 mmol) is added as a solid in portions at 0° C. to a solution of 2-chloro-1-(2,5-dichloro-3-thienyl)ethanone (2 g, 8.71 mmol) in methanol (12 mL). The reaction mixture is further stirred at room temperature for two hours and is quenched carefully with a saturated aqueous solution of ammonium chloride (15 mL). The aqueous mixture is extracted with methyl-ter-butylether. The combined organic phases are washed with brine, dried with sodium sulphate, filtered and are evaporated. Purification by chromatography on silica gel (heptanes/ethylacetate 20:1) give 2-chloro-1-(2,5-dichloro-3-thienyl)ethanol as pale yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.92 (s, 1H), 5.02 (td, J=3.7, 8.4 Hz, 1H), 3.74 (dd, J=3.7, 11.4 Hz, 1H), 3.62 (dd, J=8.4, 11.4 Hz, 1H), 2.64 (d, J=3.7 Hz, 1H). GC-MS (CI): m/z=232 (M+1).

b) Preparation of [2-chloro-1-(2,5-dichloro-3-thienyl)ethyl] methanesulfonate

[0132] Methanesulfonyl chloride (102 μL, 1.3 mmol) is added at 0° C. to a solution of 2-chloro-1-(2,5-dichloro-3-thienyl)ethanol (300 mg, 1.3 mmol) and triethylamine (0.2 mL, 1.43 mmol) in ethyl acetate (2 mL). The resulting white suspension is stirred at 0° C. for 30 minutes and is filtered. The filtrate is diluted with H.sub.2O (10 mL) and the biphasic mixture is decanted. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine, dried with sodium sulphate, filtered and evaporated to give [2-chloro-1-(2,5-dichloro-3-thienyl)ethyl] methanesulfonate as pale yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.90 (s, 1H), 5.78 (dd, J=5.1, 7.7 Hz, 1H), 3.88-3.73 (m, 2H), 3.67 (s, 1H), 3.03 (s, 3H).

c) Preparation of (2E)-2-[4-(2,5-dichloro-3-thienyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-yl-acetonitrile (Compound I.h.25)

[0133] A 25 mL flask is charged with powdered KOH (211 mg, 3.23 mmol), DMSO (3 mL), purged with Argon and is cooled at 10° C. with a water bath. A solution of 2-imidazol-1-ylacetonitrile (166 mg, 1.55 mmol) and CS.sub.2 (0.195 mL, 3.23 mmol) in DMSO (3 mL) is then added slowly to give an orange mixture. The cooling bath is removed and the reaction is stirred at room temperature for 30 minutes. A solution of [2-chloro-1-(2,5-dichloro-3-thienyl)ethyl] methanesulfonate (400 mg, 1.29 mmol) in DMSO (2 mL) is then added dropwise. After 30 minutes, the reaction mixture is poured into H.sub.2O (15 mL). The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with brine, dried with Na.sub.2SO.sub.4, filtered and evaporated to give a crude pale yellow residue. Purification by chromatography on silica gel (heptanes/ethyl acetate, 5:1-1:1-1:3) afford (2E)-2-[4-(2,5-dichloro-3-thienyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-yl-acetonitrile (Compound I.h.25) as a white solid. Mp=117-119° C. .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.63 (s, 1H), 7.18 (s, 1H), 7.05 (t, J=1.3 Hz, 1H), 6.96 (s, 1H), 5.39 (dd, J=5.2, 8.7 Hz, 1H), 3.74 (dd, J=5.2, 11.9 Hz, 1H), 3.63 (dd, J=8.7, 11.9 Hz, 1H). MS (ESI): m/z=360, 362 (M+1).

[0134] Table 1 below illustrates examples of individual compounds of formula (I) according to the invention.

TABLE-US-00008 TABLE 1 individual compounds of formula (I) according to the invention Comp. No. X Y R.sup.1 R.sup.2 R.sup.4 1 NH NH H H H 2 NH NH CH.sub.3 H H 3 NH NH CH.sub.3 CH.sub.3 H 4 NH NH H H CH.sub.3 5 NH O H H H 6 NH O CH.sub.3 H H 7 NH O CH.sub.3 CH.sub.3 H 8 NH O H H CH.sub.3 9 NH S H H H 10 NH S CH.sub.3 H H 11 NH S CH.sub.3 CH.sub.3 H 12 NH S H H CH.sub.3 13 O NH H H H 14 O NH CH.sub.3 H H 15 O NH CH.sub.3 CH.sub.3 H 16 O NH H H CH.sub.3 17 O O H H H 18 O O CH.sub.3 H H 19 O O CH.sub.3 CH.sub.3 H 20 O O H H CH.sub.3 21 S NH H H H 22 S NH CH.sub.3 H H 23 S NH CH.sub.3 CH.sub.3 H 24 S NH H H CH.sub.3 25 S S H H H 26 S S CH.sub.3 H H 27 S S CH.sub.3 CH.sub.3 H 28 S S H H CH.sub.3
where
a) 28 compounds of formula (I.a):

##STR00019##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
b) 28 compounds of formula (I.b):

##STR00020##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
c) 28 compounds of formula (I.c):

##STR00021##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
d) 28 compounds of formula (I.d):

##STR00022##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
e) 28 compounds of formula (I.e):

##STR00023##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
f) 28 compounds of formula (I.f):

##STR00024##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
g) 28 compounds of formula (I.g):

##STR00025##

Wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
h) 28 compounds of formula (I.h):

##STR00026##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
i) 28 compounds of formula (I.i):

##STR00027##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
j) 28 compounds of formula (I.j):

##STR00028##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
k) 28 compounds of formula (I.k):

##STR00029##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
m) 28 compounds of formula (I.m):

##STR00030##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
n) 28 compounds of formula (I.n):

##STR00031##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
o) 28 compounds of formula (I.o):

##STR00032##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
p) 28 compounds of formula (I.p):

##STR00033##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
q) 28 compounds of formula (I.q):

##STR00034##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
r) 28 compounds of formula (I.r):

##STR00035##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
s) 28 compounds of formula (I.s):

##STR00036##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
t) 28 compounds of formula (I.t):

##STR00037##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
u) 28 compounds of formula (I.u):

##STR00038##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
v) 28 compounds of formula (I.v):

##STR00039##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
w) 28 compounds of formula (I.w):

##STR00040##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
x) 28 compounds of formula (I.x):

##STR00041##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
y) 28 compounds of formula (I.y):

##STR00042##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
z) 28 compounds of formula (I.z):

##STR00043##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
aa) 28 compounds of formula (I.aa):

##STR00044##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ab) 28 compounds of formula (I.ab):

##STR00045##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ac) 28 compounds of formula (I.ac):

##STR00046##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ad) 28 compounds of formula (I.ad):

##STR00047##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ae) 28 compounds of formula (I.ae):

##STR00048##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
af) 28 compounds of formula (I.af):

##STR00049##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ag) 28 compounds of formula (I.ag):

##STR00050##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ah) 28 compounds of formula (I.ah):

##STR00051##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ai) 28 compounds of formula (I.ai):

##STR00052##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
aj) 28 compounds of formula (I.aj):

##STR00053##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ak) 28 compounds of formula (I.ak):

##STR00054##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
am) 28 compounds of formula (I.am):

##STR00055##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
an) 28 compounds of formula (I.an):

##STR00056##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ao) 28 compounds of formula (I.ao):

##STR00057##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ap) 28 compounds of formula (I.ap):

##STR00058##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
aq) 28 compounds of formula (I.aq):

##STR00059##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ar) 28 compounds of formula (I.ar):

##STR00060##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
as) 28 compounds of formula (I.as):

##STR00061##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
at) 28 compounds of formula (I.at):

##STR00062##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
au) 28 compounds of formula (I.au):

##STR00063##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
av) 28 compounds of formula (I.av):

##STR00064##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
aw) 28 compounds of formula (I.aw):

##STR00065##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ax) 28 compounds of formula (I.ax):

##STR00066##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ay) 28 compounds of formula (I.ay):

##STR00067##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
az) 28 compounds of formula (I.az):

##STR00068##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
ba) 28 compounds of formula (I.ba):

##STR00069##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.
bb) 28 compounds of formula (I.bb):

##STR00070##

wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in Table 1.

[0135] Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus and the method is: (ACQUITY UPLC from Waters, Phenomenex Gemini C18, 3 μm particle size (3 micrometer particle size), 110 Angstrom, 30×3 mm column, 1.7 mL/min., 60° C., H.sub.2O+0.05% HCOOH (95%)/CH.sub.3CN/MeOH 4:1+0.04% HCOOH (5%)—2 min.—CH.sub.3CN/MeOH 4:1+0.04% HCOOH (5%)—0.8 min., ACQUITY SQD Mass Spectrometer from Waters, ionization method: electrospray (ESI), Polarity: positive ions, Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature (° C.) 150, Desolvation Temperature (° C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700)).

TABLE-US-00009 TABLE 2 Melting point and LC/MS data for compounds of Table 1 Melting Compound No. point (° C.) LC/MS I.e.25 Rt = 0.86 min; MS: m/z = 326 (M + 1) I.h.25 117-119 I.y.25 Rt = 0.89 min; MS: m/z = 392 (M + 1) I.ad.25 147-148 I.am.25 Rt = 0.73 min; MS: m/z = 371 (M + 1) I.ar.25 188-189 I.x.25 47-55 I.z.25 Rt = 0.83 min; MS: m/z = 360 (M + 1) I.aa.25 Rt = 0.83 min; MS: m/z = 360 (M + 1) I.ac.25 Rt = 0.81 min; MS: m/z = 358 (M + 1) I.an.25 Rt = 0.73 min; MS: m/z = 373 (M + 1) I.as.25 188-190 I.bb.25 Rt = 0.88 min; MS: m/z = 386 (M + 1)

BIOLOGICAL EXAMPLES

[0136] Alternaria solani/Tomato/Leaf Disc (Early Blight)

[0137] Tomato leaf disks cv. Baby are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf disks are incubated at 23° C./21° C. (day/night) and 80% rh under a light regime of 12/12 h (light/dark) in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check disk leaf disks (5-7 days after application).

[0138] Compounds I.e.25, I.h.25, I.y.25, I.am.25, I.x.25, I.aa.25 and I.ac.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0139] Blumeria raminis f. sp. tritici (Erysiphe raminis f. sp. tritici)/Wheat/Leaf Disc Preventative (Powdery Mildew on Wheat)

[0140] Wheat leaf segments cv. Kanzler are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated by shaking powdery mildew infected plants above the test plates 1 day after application. The inoculated leaf disks are incubated at 20° C. and 60% rh under a light regime of 24 h darkness followed by 12 h light/12 h darkness in a climate chamber and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check leaf segments (6-8 days after application).

[0141] Compounds I.e.25, I.h.25, I.y.25, I.ad.25, I.am.25, I.x.25, I.z.25, I.aa.25, I.ac.25 and I.bb.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Botrvotinia fuckeliana (Botrvtis cinerea)/Liquid Culture (Gray Mould)

[0142] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.

[0143] Compounds I.e.25, I.h.25, I.y.25, I.ad.25, I.am.25, I.x.25, I.z.25, I.aa.25 and I.ac.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Fusarium culmorum/Liquid Culture (Head Blight)

[0144] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.

[0145] Compounds I.e.25, I.h.25, I.y.25, I.ad.25, I.am.25, I.x.25, I.z.25 and I.aa.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Gaeumannomyces graminis/Liquid Culture (Take-all of Cereals)

[0146] Mycelial fragments of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.

[0147] Compounds I.e.25, I.y.25, I.ad.25, I.am.25, I.z.25, I.aa.25 and I.ac.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Glomerella lacenarium (Colletotrichum lacenarium)/Liquid Culture (Anthracnose)

[0148] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is measured photometrically 3-4 days after application.

[0149] Compounds I.e.25, I.h.25, I.ad.25, I.am.25, I.x.25, I.z.25, I.aa.25 and I.ac.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Magnaporthe grisea (Pyricularia oryzae)/Rice/Leaf Disc Preventative (Rice Blast)

[0150] Rice leaf segments cv. Ballila are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segments are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments are incubated at 22° C. and 80% rh under a light regime of 24 h darkness followed by 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5-7 days after application).

[0151] Compound I.y.25 and I.z.25 at 200 ppm gives at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Monocraphella nivalis (Microdochium nivale)/Liquid Culture (Foot Rot Cereals)

[0152] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.

[0153] Compounds I.e.25, I.h.25, I.y.25, I.ad.25, I.am.25, I.x.25, I.z.25, I.aa.25 and I.ac.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Mycosphaerella arachidis (Cercospora arachidicola)/Liquid Culture (Early Leaf Spot)

[0154] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.

[0155] Compounds I.e.25, I.h.25, I.y.25, I.ad.25, I.am.25, I.x.25, I.z.25, I.aa.25, I.ac.25 and I.as.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Mycosphaerella raminicola (Septoria tritici)/Liquid Culture (Septoria Blotch)

[0156] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.

[0157] Compounds I.h.25, I.y.25, I.ad.25, I.am.25, I.x.25, I.z.25, I.aa.25 and I.ac.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Pyrenophora teres/Barley/Leaf Disc Preventative (Net Blotch)

[0158] Barley leaf segments cv. Hasso are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segments are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments are incubated at 20° C. and 65% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5-7 days after application).

[0159] Compounds I.e.25, I.h.25, I.y.25, I.ad.25, I.am.25, I.x.25, I.z.25, I.aa.25, I.ac.25 and I.an.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

Thanatephorus cucumeris (Rhizoctonia solani)/Liquid Culture (Foot Rot, Damping-Off)

[0160] Mycelia fragments of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format), the nutrient broth containing the fungal material is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.

[0161] Compounds I.e.25, I.y.25, I.am.25, I.x.25, I.z.25 and I.ac.25 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.