US 2005/0239777 A1 · Quinazoline derivatives and pharmaceutical compositions containing them

Abstract

The invention relates to quinazoline derivatives of formula (1) wherein m is an integer from 1 to 2; R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl); R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X1 represents —O—, —CH2—, —S—, —SO—, —SO2—, —NR7CO—, —CONR8—, —SO2NR9—, —NR10SO2— or —NR11— (wherein R7, R8, R9, R10 and R11 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl); R4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Claims7

Dependent claims

1-16. (canceled)

A method for producing an anti-cancer effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of formula I:

wherein:
m is an integer from 1 to 2;
R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl);
R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;
R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X1 represents —O—;
R4 is selected from one of the following twelve groups:
1) C1-5alkylR12 (wherein R12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or C1-5alkylR13 (wherein R13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
2) C2-5alkenylR14 (wherein R14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
3) C2-5alkynylR15 (wherein R15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each —O—, —S—, —SO—, —SO2—, —NR17CO—, —CONR18—, —SO2NR19—, —NR20SO2— or —NR21— (wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl) with the proviso that X1 cannot be —CH2— when R4 is C1-5alkylX2C1-5alkylX3R16;
5) C1-5alkylX4COR22 (wherein X4 represents —O— or —NR23— (wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents —NR24R25 or —OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
6) C1-5alkylX5R27 (wherein X5 represents —O—, —S—, —SO—, —SO2—, —OCO—, —NR28CO—, —CONR29, —SO2R30—, —NR31SO2— or —NR32— (wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) or X5 is carbonyl, and R27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl or R27 is C1-3alkyl with the proviso that when R27 is C1-3alkyl, X5 is —S—, —SO—, —SO2—, —SO2NR30— or —NR31SO2— and X1 is not —CH2—);
7) C1-3alkoxyC2-4alkyl provided that X1 is —S—, —SO— or —SO2—;
8) C1-5alkylX6C1-5alkylR33 (wherein X6 represents —O—, —S—, —SO—, —SO2—, —NR34CO—, —CONR35—, —SO2NR36—, —NR37SO2— or —NR38— (wherein R34, R35, R36, R37 and R38 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
9) R39 (wherein R39 is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
10) C1-5alkylR40 (wherein R40 is piperazin-1-yl which bears at least one substituent selected from C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4hydroxyalkyl and —CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-4alkyl);
11) C1-5alkylR43 (wherein R43 is morpholino which may bear one or two substituents selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) with the proviso that when R4 is C1-5alkylR43, X1 is —S—, —SO—, —SO2—, —SO2NR9— or —NR10SO2—;
and
12) C1-5alkylR44 (wherein R44 is morpholino which bears at least one and optionally two substituents selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
or a pharmaceutically acceptable salt thereof.

18 more elements

A method for inhibiting the effects of VEGF in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I:

wherein:
m is an integer from 1 to 2;
R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR R (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl);
R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;
R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X1 represents —O—;
R4 is selected from one of the following twelve groups:
1) C1-5alkylR12 (wherein R12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or C1-5alkylR3 (wherein R13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
2) C2-5alkenylR14 (wherein R14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
3) C2-5alkynylR15 (wherein R15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each —O—, —S—, —SO—, —SO2—, —NR17CO—, —CONR18—, —SO2NR19—, —NR2SO2— or —NR21— (wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl) with the proviso that X1 cannot be —CH2— when R4 is C1-5alkylX2C1-5alkylX3R16;
5) C1-5alkylX4COR22 (wherein X4 represents —O— or —NR23— (wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents —NR24R25 or —OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
6) C1-5alkylX5R27 (wherein X5 represents —O—, —S—, —SO—, —SO2—, —OCO—, —NR28CO—, —CONR29—, —SO2NR30—, —NR31SO2— or —NR32— (wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) or X5 is carbonyl, and R27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl or R27 is C1-3alkyl with the proviso that when R27 is C1-3alkyl, X5 is —S—, —SO—, —SO2—, —SO2NR30— or —NR31SO2— and X1 is not —CH2—);
7) C1-3alkoxyC2-4alkyl provided that X1 is —S—, —SO— or —SO2—;
8) C1-5alkylX6C1-5alkylR33 (wherein X6 represents —O—, —S—, —SO—, —SO2—, —NR34CO—, CONR35—, —SO2NR6, NR37SO2— or —NR38— (wherein R34, R35, R36, R37 and R38 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
9) R39 (wherein R39 is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
10) C1-5alkyl40 (wherein R40 is piperazin-1-yl which bears at least one substituent selected from C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4hydroxyalkyl and —CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-4alkyl);
11) C1-5alkylR43 (wherein R43 is morpholino which may bear one or two substituents selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) with the proviso that when R4 is C1-5alkylR43, X1 is —S—, —SO—, —SO2—, —SO2NR9— or —NR10SO2—;
and
12) C1-5alkylR44 (wherein R44 is morpholino which bears at least one and optionally two substituents selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
or a pharmaceutically salt thereof.

18 more elements

A method for inhibiting the growth of a solid tumour of the colon, breast, prostate, lung or skin in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I:

wherein:
m is an integer from 1 to 2;
R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl);
R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;
R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X1 represents —O—;
R4 is selected from one of the following twelve groups:
1) C1-5alkylR12 (wherein R12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or C1-5alkylR13 (wherein R13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
2) C2-5alkenylR14 (wherein R14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
3) C2-5alkynylR15 (wherein R15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each —O—, —S—, —SO—, —SO2—, —NR17CO—, —CONR18—, —SO2NR19—, —NR2SO2— or —NR21— (wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl) with the proviso that X1 cannot be —CH2— when R4 is C1-5alkylX2C1-5alkylX3R16;
5) C1-5alkylX4COR22 (wherein X4 represents —O— or —NR23— (wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents —NR24R25 or —OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
6) C1-5alkylX5R27 (wherein X5 represents —O—, —S—, —SO—, —SO2—, —OCO—, —NR23CO—, —CONR21—, —SO2NR31, —NR31SO2— or —NR32— (wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) or X5 is carbonyl, and R27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl or R27 is C1-3alkyl with the proviso that when R27 is C1-3alkyl, X5 is —S—, —SO—, —SO2—, —SO2NR30 or —NR31SO2— and X1 is not —CH2—);
7) C1-3alkoxyC2-4alkyl provided that X1 is —S—, —SO— or —SO2—;
8) C1-5alkylX6C1-5alkylR33 (wherein X6 represents —O—, —S—, —SO—, —SO2—, —NR34CO—, CONR35, SO2NR36—, NR37SO2— or —NR38— (wherein R34, R3, R36, R37 and R3 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
9) R39 (wherein R39 is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
10) C1-5alkylR40 (wherein R40 is piperazin-1-yl which bears at least one substituent selected from C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4hydroxyalkyl and —CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-4alkyl);
11) C1-5alkylR43 (wherein R43 is morpholino which may bear one or two substituents selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) with the proviso that when R4 is C1-5alkylR43, X1 is —S—, —SO—, —SO2—, —SO2NR9— or —NR10SO2—;
and
12) C1-5alkylR44 (wherein R44 is morpholino which bears at least one and optionally two substituents selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
or a pharmaceutically acceptable salt thereof.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application

11/024,840Filed 30 Dec 2004

Priority

EP 96402033.325 Sep 1996

Published

27 Oct 2005

Term ends

Not estimatedThe source records don’t support an estimate.

Classification28 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61F 13/02
Bandages or dressings ; Absorbent pads: adhesive bandages or dressings
A61F 13/023
Adhesive bandages or dressings: wound covering film layers without a fluid retention layer
A61K 31/517
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Family

Application09/269,595Division · filed 25 Mar 1999

Application10/080,716Continuation · filed 25 Feb 2002

Application10/698,388Continuation · filed 3 Nov 2003

Application10/698,388Division · filed 3 Nov 2003

Application11/024,840Continuation · filed 30 Dec 2004

US 2002/0173646 A1Published application

US 2004/0242574 A1Published application

US 6,414,148 B1Related patent

US 6,673,803 B2Related patent

US 6,897,210 B2Related patent

US 2005/0239777 A1This patent