1. a quinazolinone of formula:
wherein
R1 is hal;
X is N or CR8;
R2 is hal; nitro; C1-C8alkylcarbonyl; C1-C6alkyl or C3-C8cycloalkyl;
R3 is C1-C6alkyl; C1-C6alkoxy or amino:
R4 is H; hal; hydroxy; amino; C1-C6alkyl-amino di(C1-C6alkyl)-amino, C1-C6alkyl; C1-C6alkoxy which is unsubstituted or mona, di- or trisubstituted by halogen or hydroxy; C1-C6alkoxyC1-C6alkoxy; C1C6alkoxyC1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkyl; C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkoxy that may be substituted at the cycloalkyl residue by C1-C6alkyl C1-C6alkoxycarbonyl; C3-C6alkenyloxy; (C1-C6alkyl)2N-C1-C6alkoxy; C1-C6alkyl-sulfanylC1-C8alkoxy,
or
\u2014O\u2014CH2n-A wherein A represents
Y represents O or NR13,
and n is 0, 1, 2, 3, 4, 5 or 6;
R5 and R6, independently, are H; hal; C1-C6alkoxy; or C1-C6alkyl;
R7 and R8a independently are H or C1-C6alkyl;
R9 and R10, independently, are H or hal;
R11 is H; hal, C1-C6alkoxy; or C1-C6alkyl
R12 is H; hal; C1-C6alkoxy; or C1-C6alkyl;
R13 is H or C1-C6alkyl;
R14 is H; hal;: C1-C6alkoxy; or C1-C6alkyl; and
R15 and R16, independently, are H; hal; or C1-C6alkyl;
with the exception of the compound of formula I wherein R1 and R2 are both iodo or chloro and
R3 is methyl, and of the compound of formula I wherein R1 and R2 are both selected from fluoro and bromo and R3 is butyl,
in free base or acid addition salt form.
2. A quinazolinone of formula I according to claim 1 wherein
R1 is hal;
X is N or CR8;
R2 is C1-C6alkyl;
R3 is C1-C6alkyl or amino;
R4 is hal; hydroxy; amino; C1-C6alkyl-amino, C1-C6alkyl; C1-C6alkoxy which is unsubstituted or monosubstituted by halogen or hydroxy; C1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkyl; C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkoxy that may be substituted at the cycloalkyl residue by C1-C6alkyl; C1-C6alkoxycarbonyl; C3-C6alkenyloxy; (C1-C6alkyl)2N-C1-C6alkoxy; C1-C6alkyl-sulfanyl; C1-C6alkyl-sulfanylC1-C6alkoxy,
or
\u2014O\u2014CH2n-A wherein A represents
Y represents O or NR13,
and n is 0, 1 or 2;
R5 and R6, independently, are H; hal; or C1-C6alkoxy;
R7 and R8, independently, are H or C1-C6alkyl;
R9 and R10, independently, are H or hal;
R11 is H; hal; C1-C6alkoxy; or C1-C6alkyl;
R12 is H;
R13 is C1-C6alkyl;
R14 is H; or C1-C6alkoxy; and
R15 and R16 are H; hal; or C1-C6alkyl;
in free base or acid addition salt form.
3. A quinazolinone of formula I according to claim 1 wherein
R1 is hal;
X is N or CR8;
R2 is C1-C6alkyl;
R3 is C1-C6alkyl or amino;
R4 is hal; hydroxy; amino; C1-C6alkyl-amino, C1-C6alkyl; C1-C6alkoxy which is unsubstituted or monosubstituted by halogen or hydroxy; C1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkyl; C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkoxy that may be substituted at the cycloalkyl residue by C1-C6alkyl; C1-C6alkoxycarbonyl; C3-C6alkenyloxy; (C1-C6alkyl)2N-C1-C6alkoxy; C1-C6alkyl-sulfanyl; C1-C6alkyl-sulfanylC1-C6alkoxy, or \u2014O\u2014CH2n-A wherein A represents
Y represents O or NR13,
and n is 0, 1 or 2;
R5 and R6, independently, are H; hal; or C1-C6alkoxy;
R7 and R8, independently, are H or C1-C6alkyl;
R9 and R10, independently, are H or hal;
R12 is H;
R13 is C1-C6alkyl;
R14 is H; or C1-C6alkoxy; and
R15 and R16 are H; hal; or C1-C6alkyl;
in free base or acid addition salt form.
4. A compound of formula I according to claim 1 wherein
R1 is hal;
R2 is hal; nitro; C1-C6alkylcarbonyl; C1-C6alkyl or C3-C6cycloalkyl;
R3 is C1-C6alkyl; C1-C6alkoxy or amino;
R4 is hal; hydroxy; amino; C1-C6alkyl-amino, C1-C6alkyl; C1-C6alkoxy which is unsubstituted or monosubstituted by halogen or hydroxy; C1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkyl; C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkoxy that may be substituted at the cycloalkyl residue by C1-C6alkyl; C1-C6alkoxycarbonyl; C3-C6alkenyloxy; (C1-C6alkyl)2N-C1-C6alkoxy; C1-C6alkyl-sulfanyl; C1-C6alkyl-sulfanylC1-C6alkoxy,
wherein n is 0, 1, 2, 3, 4, 5 or 6;
R5, R6, R11 and R14, independently, are H hal; C1-C6alkoxy; or C1-C6alkyl;
R12 is H or C1-C6alkyl; and
R9 and R10, independently are H or hal;
with the exception of the compound of formula I wherein R1 and R2 are both iodo or chloro and R3 is methyl, and of the compound of formula I wherein R1 and R2 are both selected from fluoro and bromo and R3 is butyl,
in free base or acid addition salt form.
5. A compound of formula II
wherein
R1 is hal;
and
R2 is hal; nitro; C1-C6alkylcarbonyl; C1-C6alkyl or C3-C6cycloalkyl.
6. A process for the preparation of a compound of formula I
wherein
R1 is hal;
X is N or CR8;
R2 is hal; nitro; C1C6alkylcarbonyl; C1-C6alkyl or C3-C8cycloalkyl;
R3 is C1-C6alkoxy or amino;
R4 is hal; hydroxy; amino; C1-C6alkyl-amino, C1-C6alkyl; C1-C6alkoxy which is unsubstituted or monosubstituted by halogen or hydroxy; C1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkyl; C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkoxy that may be substituted at the cycloalkyl residue by C1-C6alkyl; C1-C6alkoxycarbonyl; C3-C6alkenyloxy; (C1-C6alkyl)2N-C1-C6alkoxy; C1-C6alkyl-sulfanyl; C1-C6alkyl-sulfanylC1-C6alkoxy,
or
\u2014O\u2014CH2n-A wherein A represents
Y represents O or NR13,
and n is 0, 1 or 2;
R5 and R6, independently, are H; hal; or C1-C6alkoxy;
R7 and R8, independently, are H or C1-C6alkyl;
R9 and R10, independently, are H or hal;
R11 is H; hal; C1-C6alkoxy; or C1-C6alkyl;
R12 is H;
R13 is C1-C6alkyl;
R14 is H; or C1-C6alkoxy; or C1-C6alkyl; and
R15 and R16 independently, are H; hal; or C1-C6alkyl; with the exception of the compound of formula I where R1 and R2 are both selected from fluor and bromo and R3 is butyl,
or a salt thereof, comprising the step of
a) for the production of a compound of formula I wherein R3 is not NH2, reacting a compound of formula II
wherein
R1 and R2 are as defined above, with a compound of formula III
N\u2261C\u2014R3\u2003\u2003(III)
wherein R3 is as defined in claim 1; or
b) for the production of a compound of formula I wherein R3 is NH2, reacting a compound of formula IV
wherein R1 and R2 is as defined above,
with 2-ethyl-2-thiopseudourea hydrobromide;
and recovering the obtained compound, in free or in salt form.
7. (canceled)
8. (canceled)
9. A pharmaceutical composition comprising a compound of claim 1 in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
10. (canceled)
11. (canceled)
12. A method for treating or preventing a disease or condition in which vanilloid receptor activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of a quinazolinone of formula I
wherein
R1 is hal;
X is N or CR8;
R2 is hal; nitro; C1-C6alkylcarbonyl; C1-C6alkyl or C3-C8cycloalkyl;
R3 is C1-C6alky; C1-C6alkoxy or amino;
R4 is hal; hydroxy; amino; C1-C6alkyl-amino, C1-C6alkyl; C1-C6alkoxy which is unsubstituted or monosubstituted by halogen or hydroxy; C1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkyl; C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkoxy that may be substituted at the cycloalkyl residue by C1-C6alkyl; C1-C6alkoxycarbonyl; C3-C6alkenyloxy; (C1-C6alkyl)2N-C1-C6alkoxy; C1-C6alkyl-sulfanyl; C1-C6alkyl-sulfanylC1-C6alkoxy,
or
\u2014O\u2014CH2n-A wherein A represents
Y represents O or NR13,
and n is 0, 1 or 2;
R5 and R6, independently, are H; hal; or C1-C6alkoxy;
R7 and R8, independently, are H or C1-C6alkyl;
R9 and R10, independently, are H or hal;
R11 is H; hal; C1-C6alkoxy; or C1-C6alkyl;
R12 is H; hal; C1-C6alkoxy; or C1-C6alkyl;
R13 is C1-C6alkyl;
R14 is H; or C1-C6alkoxy; and
R15 and R16, independently, are H; hal; or C1-C6alkyl;
in free base or acid addition salt form.
13. A pharmaceutical composition for the treatment or prevention of a diseases or condition in which vanillold receptor activation plays a role or is implicated comprising a quinazolinone of formula I
wherein
R1 is hal;
X is N or CR8;
R2 is hal; nitro; C1-C6alkylcarbonyl; C1-C6alky or C3-C6cycloalkyl;
R3 is C1-C6alkyl; C1-C6alkoxy or amino;
R4 is hal; hydroxy; amino; C1-C6alkyl-amino, C1-C6alkyl; C1-C6alkoxy which is unsubstituted or monosubstituted by halogen or hydroxy; C1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkoxyC1-C6alkoxy; C1-C6alkoxyC1-C6alkyl; C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkoxy that may be substituted at the cycloalkyl residue by C1-C6alkyl; C1-C6alkoxycarbonyl; C3-C6alkenyloxy; (C1-C6alkyl)2N-C1-C6alkoxy; C1-C6alkyl-sulfanyl; C1-C6alkyl-sulfanylC1-C6alkoxy,
or
\u2014O\u2014CH2n-A wherein A represents
Y represents O or NR13,
and n is 0, 1 or 2;
R5 and R6, independently, are H; hal; or C1-C6alkoxy; or C1-C6alkyl;
R7 and R8, independently, are H or C1-C6alkyl;
R9 and R10, independently, are H or hal;
R11 is H; hal; C1-C6alkoxy; or C1-C6alkyl;
R12 is H; C1-C6alkoxy; or C1-C6alkyl;
R13 is C1-C6alkyl;
R14 is H; or C1-C6alkoxy; or C1-C6alkyl; and
R15 and R16, independently, are H; hal; or C1-C6alkyl;
and a carrier.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. A method of manufacturing a workpiece, comprising:
forming a sheet of material having a predetermined shape; and
forming a physical marker on said sheet of material, said physical marker indicating a position on said sheet of material, where said sheet of material is to be bent.
2. A method of manufacturing a workpiece as recited in claim 1, wherein said physical marker is a line where said sheet of material is to be bent along said line.
3. A method of manufacturing a workpiece as recited in claim 1, wherein said physical marker is a shape where said sheet of material is to be bent through said shape.
4. A method of manufacturing a workpiece as recited in claim 3, wherein said shape includes at least two vertices and said sheet of material is to be bent along said at least two vertices.
5. A method of manufacturing a workpiece as recited in claim 4, wherein said shape is a diamond.
6. A method of manufacturing a workpiece as recited in claim 4, wherein said shape is a four-sided arrow.
7. A workpiece, comprising:
a sheet of material having a predetermined shape;
a physical marker on said sheet of material, said physical marker indicating a position on said sheet of material, where said sheet of material is to be bent.
8. A workpiece as recited in claim 7, wherein said physical marker is a line where said sheet of material is to be bent along said line.
9. A workpiece as recited in claim 7, wherein said physical marker is a shape where said sheet of material is to be bent through said shape.
10. A workpiece as recited in claim 9, wherein said shape includes at least two vertices and said sheet of material is to be bent along said at least two vertices.
11. A workpiece as recited in claim 10, wherein said shape is a diamond.
12. A workpiece as recited in claim 10, wherein said shape is a four-sided arrow.
13. A method of determining whether a workpiece has been properly bent, comprising:
forming a sheet of material having a predetermined shape;
forming a physical marker on said sheet of material, said physical marker indicating a position on said sheet of material, where said sheet of material is to be bent;
bending said sheet of material along said position on said sheet of material;
determining whether said sheet of material has been properly bent by comparing said physical marker with a line along which said sheet of material has been bent.
14. A workpiece as recited in claim 13, wherein said physical marker is a line where said sheet of material is to be bent along said line.
15. A workpiece as recited in claim 13, wherein said physical marker is a shape where said sheet of material is to be bent through said shape.
16. A workpiece as recited in claim 15, wherein said shape includes at least two vertices and said sheet of material is to be bent along said at least two vertices.
17. A workpiece as recited in claim 16, wherein said shape is a diamond.
18. A workpiece as recited in claim 16, wherein said shape is a four-sided arrow.