1. A compound according to formula I:
wherein:
D represents oxygen or sulfur;
E represents a single bond, oxygen, sulfur, or NR1;
Ar1 is selected from an ortho-halo-substituted 5- or 6-membered aromatic or heteroaromatic ring having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, or selected from an ortho-halo-substituted 8-, 9- or 10-membered fused aromatic or heteroaromatic ring system having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms;
Ar2 is selected from a 5- or 6-membered aromatic or heteroaromatic ring having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms;
where Ar2 is unsubstituted or has 1, 2 or 3 substituents independently selected from \u2014R2, \u2014C1-C6alkyl, \u2014C2-C6alkenyl, \u2014C2-C6alkynyl, halogen, \u2014CN, \u2014NO2, \u2014CF3, \u2014S(O)nR2, \u2014NR2R3, \u2014CH2NR2R3, \u2014OR2, \u2014CH2OR2 or \u2014CO2R4;
R2 and R3 are independently selected at each occurrence from hydrogen, \u2014C1-C4alkyl, aryl, heteroaryl, \u2014C(O)R4, \u2014C(O)NHR4, \u2014CO2R4 or \u2014SO2R4, or
R2 and R3 in combination is \u2014(CH2)jG(CH2)k\u2014 wherein G is oxygen, sulfur, NR4, or a bond;
j is 2, 3 or 4;
k is 0, 1 or 2;
n is 0, 1 or 2, and
R4 is independently selected at each occurrence from hydrogen, \u2014C1-C4alkyl, aryl, or heteroaryl, and
stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically-acceptable salts thereof.
2. A compound according to claim 1 being an R-isomer of a compound of formula I in accord with formula II,
wherein D, Ar1, E and Ar2 are as defined for compounds of formula I.
3. A compound according to claim 1, wherein:
D represents oxygen or sulfur;
E represents a single bond, oxygen, sulfur, or NR1;
Ar1 is selected from an ortho-fluoro-substituted 5- or 6-membered aromatic or heteroaromatic ring having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, or selected from an ortho-fluoro-substituted 8-, 9- or 10-membered fused aromatic or heteroaromatic ring system having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms;
Ar2 is selected from a 5- or 6-membered aromatic or heteroaromatic ring having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms;
where Ar2 is unsubstituted or has 1, 2 or 3 substituents independently selected from \u2014R2, \u2014C1-C6alkyl, \u2014C2-C6alkenyl, \u2014C2-C6alkynyl, halogen, \u2014CN, \u2014NO2, \u2014CF3, \u2014S(O)nR2, \u2014NR2R3, \u2014CH2NR2R3, \u2014OR2, \u2014CH2OR2 or \u2014CO2R4;
R2 and R3 are independently selected at each occurrence from hydrogen, \u2014C1-C4alkyl, aryl, heteroaryl, \u2014C(O)R4, \u2014C(O)NHR4, \u2014CO2R4 or \u2014SO2R4, or
R2 and R3 in combination is \u2014(CH2)jG(CH2)k\u2014 wherein G is oxygen, sulfur, NR4, or a bond;
j is 2, 3 or 4;
k is 0, 1 or 2;
n is 0, 1 or 2, and
R4 is independently selected at each occurrence from hydrogen, \u2014C1-C4alkyl, aryl, or heteroaryl, and
stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically-acceptable salts thereof.
4. A compound according to claim 1, wherein:
D represents oxygen;
E represents a single bond;
Ar1 is selected from an ortho-fluoro-substituted 5- or 6-membered aromatic or heteroaromatic ring having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atom;
Ar2 is selected from a 5- or 6-membered aromatic or heteroaromatic ring having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, and
stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically-acceptable salts thereof.
5. A compound according to claim 1, wherein:
D represents oxygen;
E represents a single bond;
Ar1 is selected from an ortho-fluoro-substituted 5- or 6-membered aromatic or heteroaromatic ring having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atom;
Ar2 is selected from phenyl or pyridyl, and
stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically-acceptable salts thereof.
6. A compound according to claim 1, wherein:
D is O; or an enantiomer thereof, and pharmaceutically-acceptable salts thereof.
7. A compound according to claim 1, wherein:
Ar1 is selected from 2-fluoro-phenyl or 2-linked 3-fluoro-thiophenyl.
8. A compound according to claim 1, wherein:
Ar1 is selected from phenyl or thiophenyl and Ar2 is selected from phenyl, pyridyl, furanyl or thiophenyl having optional substituents as defined herein.
9. A compound according to claim 1 having a low P-glycoprotein-mediated efflux from the brain.
10. A method of treatment or prophylaxis of a disease or condition in which activation of the \u03b17 nicotinic receptor is beneficial which method comprises administering a therapeutically-effective amount of a compound according to claim 1 to a subject suffering from said disease or condition.
11. The method of claim 10, wherein said disease or condition is anxiety, schizophrenia, mania or manic depression.
12. A method of treatment or prophylaxis of neurological disorders, psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a compound according to claim 1.
13. The method of claim 12, wherein said disorder is Alzheimer’s disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, neurodegenerative disorders in which there is loss of cholinergic synapses, jetlag, nicotine addiction, craving, pain, or ulcerative colitis.
14. A method for inducing the cessation of smoking comprising administering an effective amount of a compound according to claim 1.
15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically-acceptable diluent, lubricant or carrier.
16. A method of treatment or prophylaxis of a disease or condition in which activation of the \u03b17 nicotinic receptor is beneficial which method comprises administering a therapeutically-effective amount of a pharmaceutical composition according to claim 15 to a subject suffering from said disease or condition.
17. The method of claim 16, wherein said disease or condition is anxiety, schizophrenia, mania or manic depression.
18. A method of treatment or prophylaxis of neurological disorders, psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a pharmaceutical composition according to claim 15.
19. The method of claim 18, wherein said disorder is Alzheimer’s disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, neurodegenerative disorders in which there is loss of cholinergic synapses, jetlag, nicotine addiction, craving, pain, and for ulcerative colitis.
20. A method for inducing the cessation of smoking comprising administering an effective amount of a pharmaceutical composition according to claim 15.
21. (canceled)
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 of heating at least a part of a subsurface hydro carbonaceous earth formation, comprising
forming a borehole into or adjacent to said formation,
placing elongated coaxial inner and outer conductors into the borehole with said inner and outer conductors electrically connected to each other at a depth below the top of said formation,
connecting an AC power source to at least said outer conductor to produce heat in at least one of said conductors, said AC output having a controlled frequency, said outer conductor comprising a standard oil well component made of a ferromagnetic material that conducts current from said AC power source in only a surface region of the conductor due to the skin effect phenomenon, and
dissipating more heat from portions of said conductors that are within the depth range of said formation than from other portions of said conductors.
2. The method of claim 1 wherein said outer conductor has a ratio of AC impedance to DC impedance that is at least about 3 to 1.
3. The method of claim 2 wherein said ratio is at least about 10 to 1.
4. The method of claim 1 wherein said outer conductor is a standard commercially available pipe for oil field applications.
5. The method of claim 1 wherein said portions of said conductors that are within the depth range of said formation have a geometry that is different from that of said other portions of said conductors, to cause more heat to be dissipated from said portions of said conductors that are within the depth range of said formation than from said other portions of said conductors.
6. The method of claim 1 wherein said portions of said conductors that are within the depth range of said formation are made of a material that is different from that of said other portions of said conductors, to cause more heat to be dissipated from said portions of said conductors that are within the depth range of said formation than from said other portions of said conductors.
7. The method of claim 1 wherein thermal insulation is provided around said portions of said conductors that are within the depth range of said formation, to cause more heat to be dissipated from said portions of said conductors that are within the depth range of said formation than from said other portions of said conductors.
8. The method of claim 7 which includes recovering reactive power dissipated from said ferromagnetic material.
9. The method of claim 8 in which said reactive power is determined from measurements of the applied voltage and the resulting current and the relationship between them.
10. The method of claim 7 which includes recovering energy dissipated from harmonics of said AC output.
11. The method of claim 1 which includes varying at least one of the amplitude and waveform of said AC output to control the input impedance presented by said conductors to said power supply, so that said input impedance is within the operating range of the currents and voltages of said power supply.
12. The method of claim 1 wherein liquid from said formation is withdrawn from said borehole through said tubular conductor.
13. The method of claim 1 wherein said outer conductor is directly adjacent the earth wall of said borehole.
14. The method of claim 11 wherein liquid from said formation is withdrawn from said borehole through said outer conductor.
15. The method of claim 1 wherein at least one of said inner and outer conductors is made of standard carbon steel.
16. The method of claim 1 wherein longitudinal segments of at least one of said inner and outer conductors vary in at least one of geometry, chemical composition or heat treatment, and sequentially varying the amplitude and frequency of said AC output to preferentially heat selected ones f said longitudinal segments.
17. The method of claim 1 wherein longitudinal segments of at least one of said inner and outer conductors vary in at least one of geometry, chemical composition or heat treatment, and simultaneously using at least two frequencies in said AC output to preferentially heat selected ones f said longitudinal segments.
18. The method of claim 1 wherein at least one of said inner and outer conductors is made of aluminum having an anodized surface to control corrosion.
19. The method of claim 1 wherein at least one of said inner and outer conductors is made of aluminum, and electrolytic corrosion of said aluminum is controlled by using a capacitor to block DC current paths.
20. A method of heating at least a part of a subsurface hydro carbonaceous earth formation, comprising
forming a borehole into or adjacent to said formation,
placing elongated coaxial inner and outer conductors into the borehole with said inner and outer conductors electrically connected to each other at a depth below the top of said formation,
connecting an AC power source to at least said outer conductor to produce heat in at least one of said conductors, said AC output having a controlled frequency, said inner conductor comprising a standard tubular oil well component made of a ferromagnetic material that conducts current from said AC power source in only a surface region of the conductor due to the skin effect phenomenon, and
dissipating more heat from portions of said conductors that are within the depth range of said formation than from other portions of said conductors.