1. A gastrointestinal-electrical activity mapping andor signal analysis system arranged to receive and process electrical signals from one or more electrodes and spatially map GI smooth muscle electrical activity at said section of the GI tract andor identify as indicative of disease including (but not limited to) gastroparesis andor functional dyspepsia or as useful in the diagnosis of disease mechanisms in gastro-oesophageal reflux disease, or nausea and vomiting disorders, and other gastro-intestinal motility disorders any one of or any of in combination:
propagation of re-entrant or non re-entrant GI electrical activity upwardly within the GI tract, optionally at frequency above about 3.7 cycles per minute (cpm) or 4 cpm, as a result of a re-entrant propagation around the GI tract,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially within the GI tract other than at the normal pacemaker site in the stomach,
propagation of re-entrant GI electrical activity substantially only circumferentially within the GI tract,
propagation of non re-entrant GI electrical activity circumferentially within the GI tract at a velocity andor amplitude higher than the normal (non re-entrant) GI electrical activity in the GI tract andor at a higher circumferential velocity than longitudinal velocity in the GI tract, other than at the normal pacemaker site in the stomach,
propagation of re-entrant GI electrical activity substantially only circumferentially within the GI tract andor at a higher circumferential velocity than longitudinal velocity in the GI tract, other than at the normal pacemaker site in the stomach,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the corpus of the stomach at a velocity above 2 times or between 1.5 and 3.5 times normal velocity in the corpus andor between 1.25 and 2.5 times normal velocity in the antrum, other than at the normal pacemaker site in the stomach, andor with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the corpus,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the antrum of the stomach at a velocity above 1.5 times or between 1.5 and 3.5 times normal velocity in the antrum, and with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the antrum,
propagation of non re-entrant GI electrical activity substantially only circumferentially within the GI tract at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, and other than at the normal pacemaker site in the stomach,
propagation of non re-entran) GI electrical activity circumferentially within the GI tract, at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, and other than at the normal pacemaker site in the stomach,
propagation of any of the above defined GI electrical activity arising from one GI slow wave passing more than once through a same path of tissue conduction, and
propagation of any of the above defined GI electrical activity at an amplitude andor velocity higher than the normal (non-reentrant) GI electrical activity, other than at the normal pacemaker site in the stomach.
2. A system according to claim 1 arranged to identify propagation of re-entrant or non re-entrant GI electrical activity upwardly within the GI tract from the pylorus or antrum or other lower part of the corpus of the stomach in a direction towards an upper part of the corpus at frequency above about 3.7 cycles per minute (cpm) or 4 cpm, as a result of a re-entrant propagation around the GI tract.
3. A system according to claim 1 arranged to identify propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the corpus of the stomach at a velocity above 2 times or between 1.5 and 3.5 times normal velocity in the corpus andor between 1.25 and 2.5 times normal velocity in the antrum.
4. A system according to claim 1 arranged to identify propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the antrum of the stomach at a velocity above 1.5 times or between 1.5 and 3.5 times normal velocity in the antrum, and with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the antrum,
5. A system according to claim 1 arranged to identify propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the corpus of the stomach at a velocity above 2 times or between 1.5 and 3.5 times normal velocity in the corpus andor between 1.25 and 2.5 times normal velocity in the antrum, other than at the normal pacemaker site in the stomach, andor with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the corpus,
6. A system according to claim 1 arranged to identify propagation of non re-entrant GI electrical activity substantially only circumferentially within the GI tract at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, as a result of a conduction problem including a partial or complete conduction block, and other than at the normal pacemaker site in the stomach.
7. A system according to claim 1 arranged to identify propagation of non re-entrant GI electrical activity circumferentially within the GI tract, at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, as a result of a focal event or events or ectopic activity or activities or as a result of an escape activity, and other than at the normal pacemaker site in the stomach.
8. A system according to claim 1 wherein the signal analysis and mapping system is arranged to spatially map and visually display to a user GI electrical activity in real time or near-real time.
9. A system according to claim 1 wherein the signal analysis and mapping system is arranged to map GI electrical activity as an activation time map of the GI electrical activity.
10. A system according to claim 1 wherein the signal analysis and mapping system is arranged to map GI electrical activity as a velocity map indicative of the direction and speed of the GI electrical activity.
11. A system according to claim 1 wherein the signal analysis and mapping system is arranged to map GI electrical activity as an amplitude map of the amplitude of the GI electrical activity.
12. A system according to claim 1 wherein the signal analysis and mapping system is arranged to map the GI electrical activity as a contour plot of the GI electrical activity.
13. A system according to claim 1 wherein the signal analysis and mapping system is arranged to map the GI electrical activity on an anatomical model of at least the section of the GI tract.
14. A system according to claim 1 wherein the signal analysis and mapping system comprises a database of one or more anatomical model geometries of one or more sections of the GI tract.
15. A system according to claim 1 wherein the signal analysis and processing system is arranged to analyse the GI electrical activity for events indicative of GI slow waves and then to cluster the detected events into groups each relating to a common GI slow wave based on temporal closeness.
16. A system according to claim 15 wherein the signal analysis and processing system is arranged to analyse the GI electrical activity for events indicative of slow waves by falling edge detection and a time varying threshold.
17. A system according to claim 15 wherein the signal processing and mapping system is arranged to cluster the detected events by a region growing using polynomial surface estimate stabilization method.
18. A system according to claim 1 arranged to identify and report abnormal GI electrical activity.
19. A system according to claim 1 arranged to display the position of electrodes of the array on a map or anatomical model of at least a section of the GI tract.
20. A system according to claim 1 arranged to map the GI electrical activity as an animation.
21. A system according to claim 1 comprising a catheter insertable into the gastro-intestinal (GI) tract, or other electrode-carrier for contacting an exterior serosal surface of the GI tract, and comprising an array of electrodes for contacting a surface of a section of the GI tract to detect electrical potentials at multiple electrodes.
22. A system according to claim 21 wherein the catheter comprises an electrode carrier carrying on an exterior surface the array of electrodes and expandable when in place to cause the electrodes to contact the interior surface of the GI tract.
23. A method for analysing andor mapping GI electrical activity which comprises acquiring electrical potentials from at least one electrode contacting a surface of a section of the GI tract and spatially mapping from the electrical signals GI electrical activity at said section of the GI tract, and identifying as indicative of disease including (but not limited to) gastroparesis andor functional dyspepsia or as useful in the diagnosis of disease mechanisms in gastro-oesophageal reflux disease, or nausea and vomiting disorders and other gastro-intestinal motility disorders any one of or any of in combination:
propagation of re-entrant or non re-entrant GI electrical activity upwardly within the GI tract, optionally at frequency above about 3.7 cycles per minute (cpm) or 4 cpm, as a result of a re-entrant propagation around the GI tract,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially within the GI tract other than at the normal pacemaker site in the stomach,
propagation of re-entrant GI electrical activity substantially only circumferentially within the GI tract,
propagation of non re-entrant GI electrical activity circumferentially within the GI tract at a velocity andor amplitude higher than the normal (non re-entrant) GI electrical activity in the GI tract andor at a higher circumferential velocity than longitudinal velocity in the GI tract, other than at the normal pacemaker site in the stomach,
propagation of re-entrant GI electrical activity substantially only circumferentially within the GI tract andor at a higher circumferential velocity than longitudinal velocity in the GI tract, other than at the normal pacemaker site in the stomach,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the corpus of the stomach at a velocity above 2 times or between 1.5 and 3.5 times normal velocity in the corpus andor between 1.25 and 2.5 times normal velocity in the antrum, other than at the normal pacemaker site in the stomach, andor with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the corpus,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the antrum of the stomach at a velocity above 1.5 times or between 1.5 and 3.5 times normal velocity in the antrum, and with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the antrum,
propagation of non re-entrant GI electrical activity substantially only circumferentially within the GI tract at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, and other than at the normal pacemaker site in the stomach,
propagation of non re-entran) GI electrical activity circumferentially within the GI tract, at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, and other than at the normal pacemaker site in the stomach,
propagation of any of the above defined GI electrical activity arising from one GI slow wave passing more than once through a same path of tissue conduction, and
propagation of any of the above defined GI electrical activity at an amplitude andor velocity higher than the normal (non-reentrant) GI electrical activity, other than at the normal pacemaker site in the stomach.
24-39. (canceled)
40. A gastrointestinal-electrical activity mapping andor signal analysis system arranged to receive and process electrical signals from one or more electrodes and spatially map GI smooth muscle electrical activity at said section of the GI tract andor identify as indicative of disease including (but not limited to) gastroparesis andor functional dyspepsia or as useful in the diagnosis of disease mechanisms in gastro-oesophageal reflux disease, or nausea and vomiting disorders, and other gastro-intestinal motility disorders any one of or any of in combination:
propagation of re-entrant or non re-entrant GI electrical activity upwardly within the GI tract, optionally at frequency above about 3.7 cycles per minute (cpm) or 4 cpm, as a result of a re-entrant propagation around the GI tract,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially within the GI tract other than at the normal pacemaker site in the stomach,
propagation of re-entrant GI electrical activity substantially only circumferentially within the GI tract,
propagation of non re-entrant GI electrical activity circumferentially within the GI tract at a velocity andor amplitude higher than the normal (non re-entrant) GI electrical activity in the GI tract andor at a higher circumferential velocity than longitudinal velocity in the GI tract, other than at the normal pacemaker site in the stomach,
propagation of re-entrant GI electrical activity substantially only circumferentially within the GI tract andor at a higher circumferential velocity than longitudinal velocity in the GI tract, other than at the normal pacemaker site in the stomach,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the corpus of the stomach at a velocity above 2 times or between 1.5 and 3.5 times normal velocity in the corpus andor between 1.25 and 2.5 times normal velocity in the antrum, other than at the normal pacemaker site in the stomach, andor with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the corpus,
propagation of re-entrant or non re-entrant GI electrical activity circumferentially in the antrum of the stomach at a velocity above 1.5 times or between 1.5 and 3.5 times normal velocity in the antrum, and with an amplitude of above 2 times or between 1.5 and 3.5 times the normal amplitude in the antrum,
propagation of non re-entrant GI electrical activity substantially only circumferentially within the GI tract at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, and other than at the normal pacemaker site in the stomach,
propagation of non re-entran) GI electrical activity circumferentially within the GI tract, at a velocity above 2 times or between 1.5 and 3.5 times normal velocity andor with an amplitude of above 2 times or between 1.5 and 3.5 times normal amplitude, and other than at the normal pacemaker site in the stomach,
propagation of any of the above defined GI electrical activity arising from one GI slow wave passing more than once through a same path of tissue conduction, and
propagation of any of the above defined GI electrical activity at an amplitude andor velocity higher than the normal (non-reentrant) GI electrical activity, other than at the normal pacemaker site in the stomach,
the signal analysis and mapping system being arranged to spatially map and visually display to a user GI electrical activity in real time or near-real time at least one of:
an activation time map of the GI electrical activity,
a velocity map indicative of the direction and speed of the GI electrical activity,
an amplitude map of the amplitude of the GI electrical activity, and
a contour plot of the GI electrical activity,
as an animation on an anatomical model of at least the section of the GI tract.
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 compound having the general formula (I):
in which
R1 represents either a C1-6 alkyl optionally substituted by one to three substituents selected from halogen, trifluoromethyl, hydroxyl, C1-6 alkoxy, C1-6 thioalkyl, thiophene and phenyl; or a C3-7 cycloalkyl, or a thiophene, or a benzothiophene, or a pyridinyl, or a furanyl or a phenyl; the said phenyl groups being optionally substituted by one to three substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, hydroxyl, methylenedioxy, phenoxy, benzyloxy and trifluoromethyl;
R2 and R\u20322 represent, independently of one another, a substituent selected from hydrogen, halogen, hydroxyl, C1-3 alkoxy, C1-3 alkyl, C3-7 cycloalkyl and O\u2014C(O)\u2014C1-6 alkyl group, or R2 and R\u20322 together form an oxo group;
R3 represents either hydrogen or C1-6 alkyl optionally substituted by hydroxyl, C1-6 cycloalkyl or C1-3 alkoxy;
R4 is Z and R5 is selected from hydrogen, C1-7 alkyl, and trifluoromethyl, R4 and R5 are Z; wherein
Z represents a heteroaromatic group, the said heteroaromatic group being optionally substituted by a group R8; R8 representing either a C1-4 alkyl which is itself optionally substituted by a CN, a phenyl or a phenoxy; or a phenyl; the said phenyl and phenoxy groups being optionally substituted by 1 to 3 groups selected from halogen, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl; or
said compound in the form of a salt, or a hydrate or a solvate of said compound or said salt.
2. A compound according to claim 1, wherein:
R1 represents a C1-6 alkyl or a phenyl which is optionally substituted by 1 to 3 halogen atoms;
R2 and R\u20322 represent, independently of one another, hydrogen or hydroxyl;
R3 represents C1-6 alkyl;
G represents a C1-7 alkyl or a single bond;
M represents a phenyl which is optionally substituted by one or more halogens;
J represents hydrogen or a group \u2014Y\u2014K;
Y represents a single bond, oxygen or \u2014O\u2014C1-4 alkylene-;
K represents a phenyl group which is optionally substituted by one or more groups selected from halogen, C1-3 alkyl and trifluoromethyl;
with the proviso that at least one group R4 or R5 represents a group Z;
Z represents CN, SO2NR6R7 or a heteroaromatic group, said heteroaromatic group being optionally substituted by a group R8; R8 representing either C1-4 alkyl which is itself optionally substituted by phenyl; or phenyl; and
R6 and R7 represent, independently of one another, either hydrogen, or C1-6 alkyl optionally substituted by phenyl or by naphthalenyl; or a phenyl or an indanyl; said phenyl groups being optionally substituted by one or two groups selected from C1-3 alkoxy, phenyl or halogen; or R6 and R7, together with the nitrogen atom to which they are attached, form a benzopiperidine ring; or
said compound in the form of a salt, or a hydrate or a solvate of said compound or said salt.
3. A compound of formula (I) according to claim 1, wherein:
R1 represents C1-4 alkyl, or a phenyl substituted by two fluorine atoms;
R2 and R\u20322 represent, independently of one another, hydrogen or hydroxyl; and
R3 represents C1-4 alkyl; or
said compound in the form of a salt, or a hydrate or a solvate of said compound or said salt.
4. The compound of claim 3 wherein R1 is selected from isopropyl and tert-butyl.
5. The compound of claim 3 wherein R3 is selected from methyl, ethyl and propyl.
6. A process for preparing a compound of formula (I) according to claim 1, which comprises the step of carrying out a peptide coupling of a 2-aminothiazole of formula (III)
with an acylamino acid of formula (II)
in which R1, R2, R\u20322, R3, R4 and R5 are as defined in claim 1.
7. A process for preparing a compound of formula (I) according to claim 1, which comprises the step of carrying out a peptide coupling of a compound of formula (IV)
with an amine of formula (VI)
in which R1, R2, R\u20322, R3, R4 and R5 are as defined in claim 1.
8. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1, in the form of a pharmaceutically acceptable base, salt, hydrate or solvate, said composition further comprising one or more pharmaceutically acceptable excipients.