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.