1. A method for prevention. treatment andor delay of progression of a hyperproliferative andor angiogenesis related disease comprising the administration of a therapeutically effective amount of at least one kinase inhibitor of formula I
wherein R1 and R5 are independently selected from hydrogen, halogen, cyano, nitro, CF3, optionally substituted linear or branched C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkinyl, optionally substituted C3-C8 cycloalkyl, alkoxy, NR6R7, OR6, SR6, (CH2)nCHR6R7, wherein n is 0, 1, 2, 3, 4 and R6 and R7 are independently selected from hydrogen, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- or 6-membered heterocycle, (CH2)nC(O)OR8, (CH2)nR9, wherein n is as defined above, R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl and Rg is selected from hydrogen, C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, halogen, hydroxyl, NO2, NH2, SO2NH2, cyano, and wherein all optional substituents are selected from the group of methyl, methoxy, halogen, OH, NO2, NH2, \u2014C(O)OMe, cyano;
R2 and R4 are independently selected from hydrogen, optionally substituted linear or branched C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkinyl, optionally substituted C3-C8 cycloalkyl, NR6R7, OR6, SR6, wherein R6 and R7 are independently selected from hydrogen, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- or 6-membered heterocycle, (CH2)nC(O)OR8, (CH2)nR9, wherein n, R8 and R9 are as defined above;
R3 is hydroxyl, halogen, NH2, NO2, cyano, SH, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5- or 6-membered heterocycle,
to a subject in need of such treatment.
2. The method of claim 1 wherein R1 and R5 are independently selected from hydrogen, halogen, cyano, nitro, CF3 and methyl.
3. The method of claim 2 wherein R5 is hydrogen, methyl, or OH.
4. The method of claim 1 wherein either R1 or R5 is hydrogen.
5. The method of claim 1 wherein both R1 and R5 are hydrogen.
6. The method of claim 1 wherein R2 and R4 are independently selected from hydrogen, alkyl or NHR7 with R7 as defined in claim 1.
7. The method of claim 1, wherein R2 is NHR7.
8. The method of claim 7 wherein R7 is optionally substituted aryl.
9. The method of claim 7 wherein R7 is optionally substituted phenyl.
10. The method of claim 7 wherein the substituents are selected from the group consisting, of C1-C6 alkyl, methyl, halogen, methoxy, C(O)OMe, hydroxyl, NO2, and NH2.
11. The method of of claim 8, wherein R7 is mono-halogenated aryl.
12. The method of claim 1 wherein R4 is hydrogen.
13. The method of claim 1, wherein R4 is methyl.
14. The method of claim 1, wherein R4 is NR10R11, wherein R10 and R11 are independently selected from hydrogen, methyl or phenylmethyl.
15. The use method of claim 10, wherein R3 is optionally substituted C1-C6 alkyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocycle.
16. The method of claim 10, wherein R3 is optionally substituted phenyl and R4 is methyl.
17. The method of claim 1, wherein R2 is NHR7 with R7 being optionally substituted phenyl, R3 isoptionally substituted Phenyl and R4 is methyl.
18. The method of claim 1 wherein the disease is a (hyper)proliferative disease.
19. The method of claim 1, wherein the disease is a benign or malignant tumour.
20. The method of claim 1, wherein the disease is a benign or malignant neoplasia.
21. The method of claim 20, wherein the disease is a gastric tumour, colon carcinoma, colorectal adenoma, psoriasis, mammary carcinoma or leukaemia.
22. The method of claim 1, wherein the disease is related to angiogenesis.
23. The method of claim 1 wherein the disease is psoriasis, Kaposi’s sarcoma, restenosis, endometriosis, Crohn’s disease, leukaemia, arthritis, rheumatoid arthritis, hernangioma, angiofibroma, diabetic retinopathy, age-related macular degeneration, neovascular glaucoma, renal diseases, glomenilonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndromes, transplant rejections, glomerulopathy, cirrhosis of the liver, mesangial cell-proliferative diseases, arteriosclerosis, or injuries of the nerve tissue.
24. The method of claim 1 for inhibiting the re-occlusion of vessels after balloon catheter treatment, for holding vessels open in vascular prosthetics or after inserting mechanical devices, including stents, as immunosuppressants, as an aid in scar-free wound healing, and for treating dermatitis.
25. The method of claim 1, wherein the kinase inhibitor is an inhibitor of a member of the ephrin (Eph) family of receptor tyrosine kinases.
26. The method of claim 25, wherein the kinase inhibitor is an inhibitor of a member of the ephrin B family of receptor tyrosine kinases.
27. The method of claim 26, wherein the kinase is an ephrin B2 or ephrin B4 receptor tyrosine kinase.
28. The kinase inhibitor of claim 1, having formula Ia
wherein R12 is hydrogen or methoxy and R13 and R14 are independently selected from Hydrogen, methyl, halogen.
29. The kinase inhibitor of claim 28, wherein R12 is hydrogen and either R13 or R14 is H.
30. The kinase inhibitor of claim 28 or 29 wherein R13 is methyl, Cl, Br, or F.
31. The kinase inhibitor of claim 28, wherein R12 is hydrogen, and R13 and R14 are both either F or Cl.
32. The kinase inhibitor of claim 28 wherein R12 is metlhoxy, R13 is methyl and R14 is hydrogen.
33. The kinase inhibitor of claim 28 wherein R12 is methoxy, R13 is hydrogen and R14 is Cl.
34. The kinase inhibitor of claim 28 wherein R12 is methoxy, R13 is Cl and R14 is hydrogen.
35. The kinase inhibitor of claim 28 wherein R12 is methoxy, R13 is methyl and R14 is hydrogen.
36. (canceled)
37. The compounds as defined in in claim 28.
38. A pharmaceutical composition comprising a compound in claim 28.
39. A pharmaceutical composition comprising a compound as defined in in claim 28 and an acceptable pharmaceutical carrier.
40. A method for inhibiting angiogenesis or treating a vascular anomaly in a mammal comprising administering to the mammal an amount of an Eph receptor inhibitor of the formula I according claim 1 or the formula Ia according to claim 28, which is effective for inhibiting angiogenesis or for treating the vascular anomaly in the mammal.
41. (canceled)
42. (canceled)
43. (canceled)
44. (canceled)
45. The method of claim 20 wherein the benign or malignant neoplasia is selected from tumours of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, ovaries, rectum, prostate pancreas, lung, vagina, thyroid, connective tissue (sarcoma), gastrointestinal tract, tumours of the neck and head, tumours derived from cells of the hematopietic system (including leukemias, lynphomas and multiple myeloma), epidermal hyperproliferation, including for example, and prostate hyperplasia.
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 forming a semiconductor device comprising:
providing a semiconductor substrate;
providing a semiconductor layer of a first conductivity type over the semiconductor substrate;
forming a first region of the first conductivity type in a part of the semiconductor layer;
forming an insulated gate region over part of the semiconductor layer and over part of the first region;
forming a mask layer over the semiconductor layer, the mask layer outlining a first portion of a surface of the semiconductor layer over part of the first region;
providing a dopant of a second conductivity type to the outlined first portion to provide a second region in the semiconductor layer;
driving the first region and second region into the semiconductor layer so as to form a pre-control region of the first conductivity type extending into the semiconductor layer from the surface and under a portion of the insulated gate region and a graded body region of the second conductivity type having a first doping concentration extending into the semiconductor layer under the pre-control region;
providing a dopant of the second conductivity type to the outlined first portion to provide a body region having a second doping concentration extending into the pre-control region; and
forming a current electrode region of the first conductivity type in the body region.
2. The method according to claim 1, wherein the first doping concentration of the graded body region decreases away from the pre-control region.
3. The method according to claim 1, wherein the graded body region extends under the pre-control region to the substrate.
4. The method according to claim 1, wherein the second doping concentration of the second conductivity type is greater than the first doping concentration of the second conductivity type.
5. The method according to claim 1, wherein the semiconductor layer has a first doping concentration of the first conductivity type and the pre-control region has a second doping concentration of the first conductivity type, wherein the second doping concentration is greater than the first doping concentration.
6. The method according to claim 1, wherein the substrate is of the first conductivity type and forms another current electrode region, and wherein in operation when the semiconductor device is in an on state, current flows in a current path between the current electrode region and the another current electrode region substantially through the body region, the pre-control region and the semiconductor layer, wherein the current paths of adjacent current electrode regions form a V shape to the another current electrode region.
7. The method according to claim 1, wherein the step of forming a first region comprises implanting a dopant of the first conductivity type into the semiconductor layer.
8. The method according to claim 1, wherein the driving step comprises a first thermal drive operation at a first temperature and wherein the step of providing a body region comprises performing a second thermal drive operation at a second temperature to drive the dopant of the second conductivity type into the pre-control region, wherein the first temperature is greater than the second temperature.
9. The method according to claim 1, wherein the step of forming a current electrode region comprises providing a dopant of the first conductivity type to a portion of the outlined first portion and into the body region.
10. The method according to claim 1, wherein the step of forming a mask layer comprises forming a dielectric layer over the insulated gate region and removing a portion of the dielectric layer and the insulated gate region to provide an opening which extends through the dielectric layer and the insulated gate region, and wherein the outlined first portion comprises the opening.
11. The method according to claim 1, wherein the step of forming a first region comprises providing a dopant of the first conductivity type in the semiconductor layer having a doping dose in the range of 1-3e12 cm\u22122, wherein the step of providing a dopant of a second conductivity type to provide the second region comprises providing a dopant to the outlined first portion having a doping dose in the range of 1-2e13 cm\u22122 and wherein the semiconductor layer has a doping concentration of approximately 1.5e16 cm\u22123.
12. The method according to claim 1, wherein the doping concentration in the semiconductor layer increases across the semiconductor layer away from the surface.
13. A semiconductor device comprising:
a semiconductor substrate of a first conductivity type;
a semiconductor layer of the first conductivity type formed over the semiconductor substrate;
an insulated gate region formed over part of a surface of the semiconductor layer;
a pre-control region of the first conductivity type extending into the semiconductor layer from the surface of the semiconductor layer and under a portion of the insulated gate region;
a graded body region of the second conductivity type and having a first doping concentration formed in the semiconductor layer and extending into the semiconductor layer under the pre-control region;
a body region having a second doping concentration formed in the pre-control region and extending into the pre-control region from the surface; and
current electrode region of the first conductivity type formed in the body region and extending into the body region from the surface, and
wherein the substrate forms another current electrode region, and wherein in operation when the semiconductor device is in an on state, current flows in a current path between the current electrode region and the another current electrode region substantially through the body region, the pre-control region and the semiconductor layer, wherein the current paths of adjacent current electrode regions form a V shape to the another current electrode region.
14. The semiconductor device according to claim 13, wherein the first doping concentration of the graded body region decreases away from the pre-control region.
15. The semiconductor device according to claim 13, wherein the graded body region extends under the pre-control region to the substrate.
16. The semiconductor device according to claim 13, wherein the second doping concentration of the second conductivity type is greater than the first doping concentration of the second conductivity type.
17. The semiconductor device according to claim 13, wherein the semiconductor layer has a first doping concentration of the first conductivity type and the pre-control region has a second doping concentration of the first conductivity type, wherein the second doping concentration is greater than the first doping concentration.
18. The semiconductor device according to claim 13, wherein the doping concentration in the semiconductor layer increases across the semiconductor layer away from the surface.
19. The method according to claim 2, wherein the graded body region extends under the pre-control region to the substrate.
20. The method according to claim 2, wherein the second doping concentration of the second conductivity type is greater than the first doping concentration of the second conductivity type.