Author: claimsbot

1. An indazolamide of formula I:
wherein
X is an NHC(O) or C(O)NH group,
R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C1-3 alkyl or C1-3 alkoxy group,
R2 is a hydrogen atom or a linear or branched C1-6 alkyl group or an aryl(C1-3)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C1-3 alkyl and C1-3 alkoxy,
R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C1-3 alkyl, C1-3 alkoxy, di(C1-3)alkylamino, acetylamino or O\u2014(C1-3)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O,
R5, R6, R7 and R8, which may be identical or different, are H or methyl;
and acid-addition salts thereof with pharmaceutically acceptable organic and mineral acids.
2. An indazolamide according to claim 1, wherein R1 is H, methyl or methoxy.
3. An indazolamide according to claim 1, wherein R2 is H, methyl or isopropyl.
4. An indazolamide according to claim 1, wherein R3 is H, methyl, hydroxyl, amino or dimethylamino.
5. An indazolamide according to claim 1, wherein R4 is H, methyl or hydroxyl.
6. An indazolamide according to claim 1, wherein R5, R6, R7 and R8 are H.
7. An indazolamide according to claim 1, wherein it is a salt of addition of a pharmaceutically acceptable acid selected from the group consisting of oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid, lactic acid, methanesulphonic acid, para-toluenesulphonic acid, hydrochloric acid, phosphoric acid and sulphuric acid.
8. N3-((1-(2-Oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)- 1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
9. A hydrochloride salt of the compound of claim 8.
10. N3-((1-(2-Oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
11. A tosylate salt of the compound of claim 10.
12. N3-((1-(2-Oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-benzyl-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
13. A hydrochloride salt of the compound of claim 12.
14. N3-((1-(2-Oxo-2-((4-((phenylmethyl)oxy)phenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
15. N3-((1-(2-((4-Hydroxyphenyl)amino)-2-oxoethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
16. A hydrochloride salt of the compound of claim 15.
17. N3-((1-(2-Oxo-2-((4-nitrophenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
18. N3-((1-(2-Oxo-2-((4-aminophenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
19. A dihydrochloride salt of the compound of claim 18.
20. 5-Methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
21. A hydrochloride salt of the compound of claim 20.
22. 5-Methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
23. A hydrochloride salt of the compound of claim 22.
24. N3-((1-(2-Oxo-2-((4-(dimethylamino)phenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
25. A dihydrochloride salt of the compound of claim 24.
26. N3-((1-(2-Oxo-2-((2,6-dimethylphenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof
27. An oxalate salt of the compound of claim 26.
28. A process for preparing an indazolamide of formula I:
wherein
X is an NHC(O) or C(O)NH group,
R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C1-3 alkyl or C1-3 alkoxy group,
R2 is a hydrogen atom or a linear or branched C1-6 alkyl group or an aryl(C1-3)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C1-3 alkyl and C1-3 alkoxy,
R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C1-3 alkyl, C1-3 alkoxy, di(C1-3)alkylamino, acetylamino or O\u2014(C1-3)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O,
R5, R6, R7 and R8, which may be identical or different, are H or methyl;
and acid-addition salts thereof with pharmaceutically acceptable organic and mineral acids,
wherein it comprises the following stages:
a) condensing an amine of formula (II)
in which
X, R3, R4, R5, R6, R7 and R8 have the meanings given above,
with an indazolecarboxylic acid derivative of formula (IIIa)
in which
R1 and R2 have the meanings given above, and
Y is a chlorine or bromine atom, or a group OR or OC(O)R, in which R is an alkyl with a linear or branched chain comprising from 1 to 6 carbon atoms,
or of formula (IIIb)
in which
R1 has the meanings given above,
to give the indazolamide of formula (I), and
b) optionally, forming an acid-addition salt of the indazolamide of formula (I) with a pharmaceutically acceptable organic or mineral acid.
29. The process according to claim 28, wherein stage (a) is performed by reacting a compound of formula (II) with a compound of formula (IIIa) in which Y is chlorine or with a compound of formula (IIIb) in the presence of a suitable diluent at a temperature in the range between 0 and 140\xb0 C. for a time of between 0.5 and 20 hours.
30. The process according to claim 29, wherein the reaction temperature is in the range between 15 and 40\xb0 C.
31. The process according to claim 29, wherein the reaction time ranges from 1 to 14 hours.
32. The process according to claim 29, wherein the diluent is aprotic.
33. The process according to claim 32, wherein the diluent is an aprotic apolar diluent.
34. The process according to claim 9, wherein when Y is chlorine or bromine, the abovementioned stage a) is performed in the presence of an organic or mineral acid acceptor.
35. A pharmaceutical composition containing an effective amount of a compound of formula (I):
wherein
X is an NHC(O) or C(O)NH group,
R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C1-3 alkyl or C1-3 alkoxy group,
R2 is a hydrogen atom or a linear or branched C1-6 alkyl group or an aryl(C1-3)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C1-3 alkyl and C1-3 alkoxy,
R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C1-3 alkyl, C1-3 alkoxy, di(C1-3)alkylamino, acetylamino or O-(C1-3)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O,
R5, R6, R7 and R8, which may be identical or different, are H or methyl;
or of an acid-addition salt thereof with a pharmaceutically acceptable acid, and
at least one pharmaceutically acceptable inert ingredient.
36. A method of treating chronic pain in a subject in need thereof comprising administering to said subject an indazolamide of formula I:
wherein
X is an NHC(O) or C(O)NH group,
R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C1-3 alkyl or C1-3 alkoxy group,
R2 is a hydrogen atom or a linear or branched C1-6 alkyl group or an aryl(C1-3)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C1-3 alkyl and C1-3 alkoxy,
R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C1-3 alkyl, C1-3 alkoxy, di(C1-3)alkylamino, acetylamino or O-(C1-3)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O,
R5, R6, R7 and R8, which may be identical or different, are H or methyl;
and acid-addition salts thereof with pharmaceutically acceptable organic and mineral acids.
37. The method according to claim 36, wherein said chronic pain is a disorder selected from the group consisting of rheumatoid arthritis, osteoarthritis, fibromyalgia, oncology pain, and neuropathic pain.

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 continuous extracorporeal blood filtration system comprising:
a line for the continuous circulation of blood for filtration comprising an outlet line portion and an inlet line portion for the circulation of blood for filtration;
a plurality of intermediate lines connected in parallel between said outlet line portion and said inlet line portion;
a filter connected to each of said parallel lines, one of said filters being operable at a particular time to permit the flow of blood therethrough;
a valve connected in each parallel line upstream of the corresponding filter to permit blood flow through a single filter at one time; and
control means coupled to each valve to serially activate such valves switching the blood flow to another filter and closing the flow to the previously active filter.
2. A continuous blood filtration system in accordance with claim 1 wherein:
the filters comprise multiple different types of blood filters and the system further includes means to change said filters at any time and in any sequence.
3. A continuous blood filtration system in accordance with claim 1 wherein:
the filters comprise one or more leukocyte filters andor biochemical filters and wherein the filters can be independently or in any combination switched on and off line at any desired interval.
4. A continuous blood filtration system in accordance with claim 1 wherein:
the control means comprises a timer and the valves comprise timer controlled solenoid valves.
5. A continuous blood filtration system in accordance with claim 1 wherein:
the filters comprise means for removing cellular components of blood and removing biochemicals.
6. A continuous blood filtration system in accordance with claim 1 further including:
a timer or other control switching mechanism including manual, pressure, flow or particulate buildup sensing; and
a one-way valve in each flow line, and controlled by said timing or other control mechanism.
7. A continuous blood filtration system in accordance with claim 6 further including:
a plurality of line clamps manually placed both proximal and distal to the individual arterial filters.
8. A continuous extracorporeal blood filtration system comprising:
a line for the continuous circulation of blood for filtration comprising an outlet line portion and an inlet line portion for the circulation of blood for filtration;
a plurality of intermediate lines connected in parallel between said outlet line portion and said inlet line portion;
a filter connected to each of said parallel lines, one of said filters being operable at a particular time to permit the flow of blood therethrough;
a multiple position valve, having an input connected in the outlet line portion and an outlet connected to each of the parallel lines; and,
control means coupled to said valve to activate said valve switching the blood flow to another filter and closing the flow to the previously active filter.
9. A continuous extracorporeal blood filtration system comprising:
two eccentric and offset input and output lines;
a plurality of filters fixedly disposed relative to each other and selectively positionable in said lines; and
means for switching to a clean filter so that full surface filtration area is available to maintain predetermined pressure and flow.
10. A continuous blood filtration system in accordance with claim 9 wherein said system is operable with a heart lung machine.
11. A continuous blood filtration system in accordance with claim 10 wherein said heart lung machine comprises a roller pump based heart lung machine.
12. A continuous extracorporeal blood filtration system for use with a carrier having a plurality of filters fixedly arrayed relative to each other thereon, said system comprising:
a line for the continuous circulation of blood for filtration comprising a first fixed input line and output line pair for the circulation of blood for filtration; and
means for releasably connecting the line to the carrier having the plurality of filters and moving the carrier with respect to the first input and output line pair so as to selectively position individual ones of the filters in sealing engagement with the first input and output lines so as to permit blood to flow through a selected filter.
13. A continuous extracorporeal blood filtration system for use with a plurality of filters ,said system comprising:
two eccentric and offset input and output lines for filtration; and
means for releasably connecting the line to the carrier having the plurality of filters and moving the carrier with respect to the first input and output line pair so as to selectively position individual ones of the filters in sealing engagement with the first input and output lines so as to permit blood to flow through a selected filter.

1. A robust micromachined thermal mass flow sensor comprising: a suspending polyimide membrane with double side passivation layers on both top and bottom surfaces of the polyimide membrane which is suspended on a silicon substrate;
a heating element thermistor being connected to a microcontroller circuit with an ambient temperature sensing thermistor;
a temperature sensing thermistor being disposed on upstream flow side of the heating element thermistor with an open slot on the suspending polyimide membrane;
a temperature sensing thermistor being disposed on downstream flow side of the heating element thermistor with an open slot on the suspending membrane;
wherein the passivation layer on the bottom surface of the polyimide layer contains silicon nitride;
wherein the ambient temperature sensing thermistor being disposed in a region of no polyimide layer on the silicon substrate; and
wherein the open slots on the suspending polyimide membrane between the heating element thermistor and the temperature sensing thermistors isolates transverse heat conduction from the heating element thermistor to the temperature sensing thermistors.
2. The robust micromachined thermal mass flow sensor of claim 1 wherein:
the open slots on the suspending polyimide membrane are disposed in the direction perpendicular to the flow direction wherein the dimension of the open slots are 20 to 40 um wide and 400 to 600 um long.
3. The robust micromachined thermal mass flow sensor of claim 1 wherein:
the open slots are utilized to balance the pressure difference between flow passage above the suspending membrane and a cavity underneath the suspending membrane, which could increase stability and endurance of the polyimide membrane and enhance sensor accuracy under high pressure operation.
4. The robust micromachined thermal mass flow sensor of claim 1 wherein:
the ambient temperature sensing thermistor is positioned on an upstream location related to the heating element thermistor;
wherein the ambient temperature sensing thermistor is at least 500 um away from the heating element thermistor to reduce heating effects from the heating element thermistor.
5. The robust micromachined thermal mass flow sensor of claim 1 wherein: a silicon dioxide layer is applied as an adhesion enhancement layer to improve the long term reliability and the adhesion between the passivation layer and the polyimide layer membrane.
6. The robust micromachined thermal mass flow sensor of claim 5 wherein:
the thickness of the dielectric silicon dioxide layer is from 500 A to 1000 A; the thickness of the dielectric silicon nitride layer is from 3000 A to 5000 A.

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 atom probe tomography (APT) sample preparation from a three-dimensional (3D) field effect transistor device formed within a semiconductor structure, the method comprising:
identifying, based on a measured capacitance-voltage (C-V) characteristic, a defect associated with a Fin structure corresponding to the 3D field effect transistor device;
detaching, using a nanomanipulator, the Fin structure from the 3D field effect transistor device based on the measured capacitance-voltage (C-V) characteristic identifying the defect associated with the 3D field effect transistor device; and
welding the detached Fin having the identified defect to the nanomanipulator probe tip using an incident focused ion beam.
2. The method of claim 1, further comprising:
applying the incident focused ion beam having a voltage of less than about 1000 eV to a tip of the Fin that is welded to the nanomanipulator probe tip, wherein the tip of the Fin is sharpened by the focused ion beam; and
applying an atomic probe tomography measurement on the Fin that is sharpened by the focused ion beam.
3. The method of claim 2, wherein the tip of the Fin is sharpened to a diameter in the range of about 20 nm-100 nm.
4. The method of claim 1, wherein the measuring of the capacitance-voltage (C-V) characteristic for the 3D field effect transistor device comprises:
exposing first and second contact regions associated with the 3D field effect transistor device;
coupling a high-frequency impedance probe having a frequency range of about 5 Mhz to about 110 Mhz to an impedance analyzer;
coupling the high-frequency impedance probe to a first and a second atomic force probe tip;
coupling, using an atomic force microscope, the first atomic force probe tip to the exposed first contact region;
coupling, using the atomic force microscope, the second atomic force probe tip to the exposed second contact region; and
measuring the C-V characteristic for the 3D field effect transistor device on the impedance analyzer, the impedance analyzer applying an operating frequency corresponding to the frequency range of about 5 Mhz to about 110 Mhz to the first and second contact regions of the 3D field effect transistor device using the high-frequency impedance probe.
5. The method of claim 4, further comprising:
an XYZ manipulation stage that holds the high-frequency impedance probe, the XYZ manipulation stage manipulating the XYZ position of the high-frequency impedance probe for optimizing the measured C-V characteristic for the 3D field effect transistor device by controlling both a first physical tension associated with a first electrical conductor coupled to a ground connection of the high-frequency impedance, and a second physical tension associated with a second electrical conductor coupled to a signal conductor of the high-frequency impedance probe.
6. The method of claim 4, wherein the exposing of the first and second contact regions comprises:
applying a voltage in the range of about 50 eV to less than 300 eV to an inductively coupled Argon ion source operating at a radio frequency;
generating, from the Argon ion source, a collimated ion beam incident on a surface corresponding to the first and second contact regions for planar removal of layers of the surface; and
exposing the first and second contact regions underlying the surface using an end-point detector based on the planar removal of the layers.
7. The method of claim 6, wherein the generated collimated ion beam is incident on the surface of the semiconductor structure at an angle of about 3-12 degrees.
8. The method of claim 6, wherein the radio frequency (RF) comprises a 1.4 MHz signal.
9. The method of claim 6, wherein the end-point detector comprises a secondary ion mass spectroscopy (SIMS) detector.
10. The method of claim 6, wherein the planar removal of layers comprises removing layers of silicon nitride using etch selective hexafluoroethane (C2F6) gas.
11. The method of claim 6, wherein the planar removal of layers comprises removing layers of silicon oxide using etch selective tetrafluoromethane (CF4) gas.
12. The method of claim 6, wherein the planar removal of layers comprises removing layers of copper metallization.
13. The method of claim 6, wherein the exposed first and second contact regions comprises tungsten studs coupled to the 3D field effect transistor device.
14. The method of claim 1, wherein the C-V measurement is utilized to determine doping concentration in the Fin structure.
15. The method of claim 4, wherein the high-frequency impedance probe is coupled to a first and a second electrical conductor, the first electrical conductor coupled to the ground connection of the high-frequency impedance probe and the second electrical conductor coupled to the signal conductor of the high-frequency impedance probe.
16. The method of claim 15, wherein the first electrical conductor is coupled to the first atomic force probe tip and the second electrical conductor is coupled to the second atomic force probe tip.
17. A method for atom probe tomography (APT) sample preparation from a three-dimensional (3D) field effect transistor device formed within a semiconductor structure, the method comprising:
applying a voltage in the range of about 50 eV to less than 300 eV to an inductively coupled Argon ion source operating at a radio frequency;
generating, from the Argon ion source, a collimated ion beam incident on a crystalline surface of the semiconductor structure for planar removal of layers of the crystalline surface;
exposing first and second contact regions underlying the crystalline surface associated with the 3D field effect transistor device based on the planar removal of the layers;
coupling a high-frequency impedance probe to an impedance analyzer;
coupling the high-frequency impedance probe to a first and a second atomic force probe tip;
coupling the first atomic force probe tip to the exposed first contact region;
coupling the second atomic force probe tip to the exposed second contact region;
measuring the C-V characteristic for the 3D field effect transistor device on the impedance analyzer, the impedance analyzer applying an operating frequency to the first and second contact regions associated with the 3D field effect transistor device using the high-frequency impedance probe; and
detaching, based on the measured C-V characteristic, a Fin structure from the 3D field effect transistor device.
18. The method of claim 17, wherein the incident focused ion beam is generated by an inductively coupled Gallium ion source having a voltage in the range of about 500 eV-1000 eV.
19. A method for atom probe tomography (APT) sample preparation from a three-dimensional (3D) field effect transistor device formed within a semiconductor structure, the method comprising:
identifying, based on a capacitance-voltage (C-V) characteristic measurement, a defect associated with a Fin structure corresponding to the 3D field effect transistor device;
removing a hardmask layer from a top surface of the Fin structure using a collimated ion beam generated by applying a voltage in the range of about 50 eV to less than 300 eV to an inductively coupled Argon ion source operating at a radio frequency;
applying a metallic coating to the Fin structure having the identified defect;
detaching the coated Fin structure having the identified defect from the 3D field effect transistor device using a nanomanipulator probe tip;
welding the detached coated Fin having the identified defect to the nanomanipulator probe tip using an incident focused ion beam; and
applying the incident focused ion beam to a tip of the Fin that is welded to nanomanipulator probe tip.
20. The method of claim 19, wherein the metallic coating comprises a thickness of about 10 nm-30 nm.