1. A process for preparing ()-norcisapride base of formula
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characterized by
a) separating the enantiomers of cis-ethyl 4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-1-piperidine carboxylate by liquid chromatography over a chiral stationary phase, and
b) isolating the fraction having a specific rotation D20 in methanol that is dextrorotatory, and
c) solvolysing said fraction to ()-norcisapride.
2. A process according to claim 1 wherein the chiral stationary phase is a cellulose or amylose polysaccharide.
3. A process according to claim 2 wherein the eluent is a mixture of hexane and an alcohol.
4. A process according to claim 1 wherein solvolysis comprises hydrolysis in a basic aqueous medium.
5. ()-Norcisapride obtainable by a process of any of claims 1 to 4.
6. A compound according to claim 5 containing at least 90% by weight of the ()-stereoisomer and 10% by weight or less of the ()-stereoisomer.
7. A compound according to claim 5 containing more than 99% by weight of the ()-stereoisomer.
8. ()-Norcisapride according to claim 5 substantially free of its ()-stereoisomer.
9. ()-Norcisapride having a specific rotation D20 in methanol that is dextrorotatory
10. ()-Norcisapride having a specific optical rotation D20 of about 5.60 (c1% wv in methanol).
11. ()-Norcisapride having the absolute configuration of (3S,4R)
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(3S,4R)-cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide.
12. A pharmaceutically acceptable acid addition salt of a compound according to any of claims 5 to 11.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as described in any one of claims 5 to 12.
14. A process for preparing a pharmaceutical composition as claimed in claim 13 wherein a therapeutically effective amount of a compound as defined in any one of claims 5 to 12 is intimately mixed with a pharmaceutically acceptable carrier.
15. A method of treating gastro-intestinal disorders in a warm-blooded animal associated with an overstimulation of the 5-HT3-receptor activity which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound as defined in any of claims 5 to 12.
16. A method of treating gastro-intestinal disorders in a warm-blooded animal associated with an understimulation of the 5-HT4-receptor activity which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound as defined in any of claims 5 to 12.
17. A method of treating gastro-intestinal disorders in a warm-blooded animal which are simultaneously associated with an understimulation of the 5-HT4-receptor activity and an overstimulation of the 5-HT3-receptor activity which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound as defined in any of claims 5 to 12.
18. A method according to any of claims 14 to 17 while avoiding central nervous system effects.
19. A method of treating 5-HT3-mediated disorders while substantially avoiding central nervous system effects in a warm-blooded animal which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound as defined in any of claims 5 to 12.
20. A method of claim 19 wherein the disorder is irritable bowel syndrome or diarrhea-predominant irritable-bowel syndrome.
21. A method of claim 19 wherein the disorder is cytotoxic drug emesis or radiation induced emesis.
22. A method of treating eating disorders in a warm-blooded animal which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound as defined in any of claims 5 to 12.
23. A method of claim 22 wherein the eating disorder is anorexia.
24. A method of accelerating intestinal cleansing in a warm-blooded animal which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound as defined in any of claims 5 to 12 and a laxative.
25. A method of claim 24 wherein the laxative is an osmotic agent.
26. A method of claim 24 wherein the laxative is a polyethylene glycol (PEG)-electrolyte solution.
27. A method of treating 5-HT4-mediated disorders while substantially avoiding central nervous system effects in a warm-blooded animal which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound as defined in any of claims 5 to 12.
28. A method of claim 27 wherein the disorder is hampered or impaired gastrointestinal transit.
29. A method of claim 27 wherein the disorder is hampered or impaired gastric emptying.
30. A method of claim 27 wherein the disorder is gastro-oesophageal reflux.
31. A method of claim 27 wherein the disorder is dyspepsia or gastroparesis.
32. Compounds of formula (V) wherein the piperidine ring has the absolute configuration (3S,4R) and PG is methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl or phenylmethyl.
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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 method for forming a synthetic polymeric hydrogel permeation layer on an array of microelectrodes comprising the steps of:
attaching a linker to the array of microelectrodes;
providing a polymerization solution comprising a porogen;
contacting the surface of the array with the polymerization solution;
polymerizing the polymerization solution on the surface of the array to form a permeation layer, wherein the permeation layer is attached to the surface of the array through the linker; and
removing the porogen from the permeation layer, thereby creating void spaces in the permeation layer.
2. The method of claim 1, wherein the porogen is a solid templating porogen.
3. The method of claim 1, wherein the porogen is a liquid templating porogen.
4. The method of claim 1, wherein the porogen is a micelle forming porogen.
5. The method of claim 1, wherein the porogen is a surfactant.
6. The method of claim 5, wherein the surfactant is a Brij surfactant.
7. The method of claim 1, wherein the porogen is removed with a solvent.
8. The method of claim 7, wherein the solvent does not significantly alter a porous structure of the permeation layer.
9. The method of claim 1, wherein the array of microelectrodes comprises electrodes made from a material selected from the group consisting of platinum, silicide, tungsten silicide, titanium silicide, and gold silicide.
10. The method of claim 1, wherein the array of microelectrodes comprises electrodes made from a material selected from the group consisting of aluminum, copper, carbon, iron, silver, gold, palladium, platinum, titanium, tungsten, polysilicon, and indium tin oxide.
11. The method of claim 1, wherein the array of microelectrodes comprise carbon electrodes.
12. The method of claim 1, wherein the array of microelectrodes comprise platinum electrodes.
13. The method of claim 1, wherein the permeation layer forms a mesoporous structure upon removal of the porogen.
14. The method of claim 13, wherein the mesoporous structure defines pores that are between about 100 nm and 1000 nm in diameter.
15. The method of claim 1, wherein the permeation layer forms a nanoporous structure upon removal of the porogen.
16. The method of claim 1, wherein the permeation layer forms a microporous structure upon removal of the porogen.