1. A modulator of at least one of glucocorticoid biosynthesis, degradation or receptor activation for use in preventing or treating symptoms andor diseases associated with jet lag.
2. The modulator of claim 1 wherein administration of said modulator to a subject results in a directional change of the time point of maximum amounts of glucocorticoids in the subject as compared to the time point of maximum amounts of glucocorticoids in said subject not treated with the modulator.
3. The modulator of claim 2 which is selected from the group consisting of a small organic molecule, an antibody or a fragment or derivative thereof, an aptamer, an siRNA, an shRNA, an miRNA, a ribozyme, and an antisense nucleic acid molecule.
4. The modulator of claim 2 wherein the symptoms andor diseases associated with jet lag are selected from the group consisting of sleep disruption, impaired cognitive skills, loss of appetite, depression, reduced psychomotor coordination, gastrointestinal disturbances, decreased alertness, malignant cell growth, temporal lobe atrophy and cardiomyopathies.
5. The modulator of claim 4, wherein the amplitude of maximum glucocorticoid amounts is not significantly altered.
6. The modulator of claim 4, wherein the time point of maximum amounts of glucocorticoids in a subject treated with said modulator is earlier than the time point of maximum amounts of glucocorticoids from a subject not treated with the modulator and wherein this earlier time point results from the administration of the modulator in the first half of the rest phase of the subject to be treated.
7. The modulator of claim 4, wherein the time point of maximum amounts of glucocorticoids in a subject treated with the modulator is later than the time point of maximum amounts of glucocorticoids from a subject not treated with the modulator and wherein this later time point results from the administration of the modulator in the first half of the active phase of the subject to be treated.
8. The modulator of claim 2 which is administered at least one time prior to andor at the time of initiating activities that cause jet-lag.
9. The modulator of claim 8 which is administered once a day.
10. The modulator of claim 1 wherein the modulator is metyrapone.
11. A method of preventing or treating symptoms andor diseases associated with jet lag comprising administering a pharmaceutically effective amount of a modulator of claim 2.
12. The method of claim 11 wherein the modulator is selected from the group consisting of a small organic molecule, an antibody or a fragment or derivative thereof, an aptamer, an siRNA, an shRNA, an miRNA, a ribozyme, and an antisense nucleic acid molecule.
13. The method of claim 11 wherein the symptoms andor diseases associated with jet lag are selected from the group consisting of sleep disruption, impaired cognitive skills, loss of appetite, depression, reduced psychomotor coordination, gastrointestinal disturbances, decreased alertness, malignant cell growth, temporal lobe atrophy and cardiomyopathies.
14. The method of claim 13, wherein the amplitude of maximum glucocorticoid amounts is not significantly altered.
15. The method of claim 13, wherein the time point of maximum amounts of glucocorticoids in a subject treated with said modulator is earlier than the time point of maximum amounts of glucocorticoids from a subject not treated with the modulator and wherein this earlier time point results from the administration of the modulator in the first half of the rest phase of the subject to be treated.
16. The method of claim 13, wherein the time point of maximum amounts of glucocorticoids in a subject treated with the modulator is later than the time point of maximum amounts of glucocorticoids from a subject not treated with the modulator and wherein this later time point results from the administration of the modulator in the first half of the active phase of the subject to be treated.
17. The method of claim 11 wherein the modulator is administered at least one time prior to andor at the time of initiating activities that cause jet-lag.
18. The method of claim 17 wherein the modulator is administered once a day.
19. The method of claim 11 wherein the modulator is metyrapone.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A process for the preparation of compounds of formula (III)
wherein
R1 is hydrogen, alkyl, haloalkyl, or halogen;
R2 is hydrogen, alkyl, haloalkyl, or halogen;
R3 is hydrogen, cyano or alkynyl;
Ar is an optionally substituted aryl or heteroaryl group
comprising reacting a carboxylic acid of formula (IV)
with an alcohol of the formula (V)
in the presence of a catalyst selected from zirconium containing catalysts, hafnium containing catalysts, iron containing catalysts, cobalt containing catalysts, tin containing catalysts, titanium containing catalysts, ammonium salt catalysts, and boronic acid containing catalysts.
2. The process according to claim 1 wherein the catalyst is a zirconium compound, a hafnium compound, an ammonium salt or a boronic acid compound.
3. The process according to claim 2 wherein the catalyst is a zirconium (IV) compound.
4. The process according to claim 3 wherein the catalyst is ZrCl4 or a solvent complex thereof.
5. The process according to claim 1, wherein the catalyst is ZrCl4 or a solvent complex thereof, HfCl4 or a solvent complex thereof, Ph2NH2+OTf\u2212 or boric acid.
6. The process according to claim 1, wherein R1 and R2 are independently selected from hydrogen, halogen, C1-C4 alkyl and C1-C4 haloalkyl.
7. The process according to claim 1, wherein R3 is selected from hydrogen, cyano or C3-C4 alkynyl.
8. The process according to claim 1, wherein Ar is phenyl substituted with one or more groups selected from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and phenoxy.
9. The process according to claim 1 wherein the carboxylic acid of formula (IV) has the formula (VIII)
10. The process according to claim 1 wherein the alcohol of formula (V) has the formula (IX)
11. The process according to claim 1 wherein the alcohol of formula (V) has the formula (XI)
12. The process according to claim 10 for the preparation of tefluthrin (VII)
13. The process according to claim 11 for the preparation of lambda cyhalothrin (X)
14. The process according to claim 11 for the preparation of gamma cyhalothrin (XIV)