1. An earth-boring tool, comprising:
a steel body;
at least one cutting element support member mounted on the steel body, the at least one cutting element support member having an at least substantially planar support surface at a first end of the at least one cutting element support member and a tapered lateral side surface extending from the support surface to an opposing second end of the at least one cutting element support member; and
at least one polycrystalline diamond compact (PDC) cutting element mounted on the steel body adjacent and rotationally preceding the at least one cutting element support member, the at least one PDC cutting element having a volume of polycrystalline diamond on a first end of a cylindrical substrate, the cylindrical substrate having a cylindrical lateral side surface extending from the first end of the cylindrical substrate to an at least substantially planar back surface at an opposing second end of the cylindrical substrate, the at least substantially planar back surface of the cylindrical substrate abutting the at least substantially planar support surface of the at least one cutting element support member.
2. The earth-boring tool of claim 1, wherein the at least one PDC cutting element has an exposure over an outer surface of the steel body adjacent the at least one cutting element of between about 30% and about 60% of an average diameter of the at least one PDC cutting element.
3. The earth-boring tool of claim 1, wherein the steel body has a plurality of blades defining fluid courses therebetween, the at least one PDC cutting element mounted on a blade of the plurality of blades.
4. The earth-boring tool of claim 1, wherein the tapered lateral side surface of the at least one cutting element support member has a frustoconical shape.
5. The earth-boring tool of claim 1, wherein the at least one cutting element support member comprises a metal alloy.
6. The earth-boring tool of claim 5, wherein the at least one cutting element support member comprises steel.
7. The earth-boring tool of claim 1, wherein the at least one cutting element support member comprises a cemented carbide material.
8. The earth-boring tool of claim 7, wherein the at least one cutting element support member comprises cobalt-cemented tungsten carbide.
9. The earth-boring tool of claim 1, wherein the volume of polycrystalline diamond on the first end of the cylindrical substrate of the at least one PDC cutting element is at least substantially planar.
10. The earth-boring tool of claim 1, wherein a ratio of a total volume of fluid channels to a total volume of a face of the body is between about 0.3 and about 0.6 to 1.
11. The earth-boring tool of claim 10, wherein the ratio of the total volume of fluid channels to the total volume of the face of the body is between about 0.4 and about 0.5.
12. A method of fabricating an earth-boring tool, comprising:
mounting at least one cutting element support member on a steel body, the at least one cutting element support member having an at least substantially planar support surface at a first end of the at least one cutting element support member and a tapered lateral side surface extending from the support surface to an opposing second end of the at least one cutting element support member; and
mounting at least one polycrystalline diamond compact (PDC) cutting element on the steel body adjacent and rotationally preceding the at least one cutting element support member, the at least one PDC cutting element having a volume of polycrystalline diamond on a first end of a cylindrical substrate, the cylindrical substrate having a cylindrical lateral side surface extending from the first end of the cylindrical substrate to an at least substantially planar back surface at an opposing second end of the cylindrical substrate, the at least substantially planar back surface of the cylindrical substrate abutting the at least substantially planar support surface of the at least one cutting element support member.
13. The method of claim 12, wherein mounting the at least one PDC cutting element on the steel body comprises positioning the at least one PDC cutting element on the steel body such that the at least one PDC cutting element has an exposure over an outer surface of the steel body adjacent the at least one cutting element of between about 30% and about 60% of an average diameter of the at least one PDC cutting element.
14. The method of claim 12, further comprising selecting the steel body to comprise a plurality of blades defining fluid courses therebetween, and wherein mounting the at least one PDC cutting element on the steel body comprises mounting the at least one PDC cutting element on a blade of the plurality of blades.
15. The method of claim 12, wherein the tapered lateral side surface of the at least one cutting element support member has a frustoconical shape.
16. The method of claim 12, further comprising selecting the at least one cutting element support member to comprise a metal alloy.
17. The method of claim 16, further comprising selecting the at least one cutting element support member to comprise steel.
18. The method of claim 12, further comprising selecting the at least one cutting element support member to comprise a cemented carbide material.
19. The method of claim 18, further comprising selecting the at least one cutting element support member to comprise cobalt-cemented tungsten carbide.
20. The method of claim 12, wherein mounting at least one cutting element support member on the steel body comprises brazing the at least one cutting element support member to the steel body.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
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25. A particle consisting of a solid dispersion comprising
(a) a compound of formula
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein
-b1=b2-C(R2a)=b3-b4=represents a bivalent radical of formula
\u2014CH\u2550CH\u2014C(R2a)\u2550CH\u2014CH\u2550\u2003\u2003(b-1);
\u2014N\u2550CH\u2014C(R2a)\u2550CH\u2014CH\u2550\u2003\u2003(b-2);
\u2014CH\u2550N\u2014C(R2a)\u2550CH\u2014CH\u2550\u2003\u2003(b-3);
\u2014N\u2550CH\u2014C(R2a)\u2550N\u2014CH\u2550\u2003\u2003(b-4);
\u2014N\u2550CH\u2014C(R2a)\u2550CH\u2014N\u2550\u2003\u2003(b-5);
\u2014CH\u2550N\u2014C(R2a)\u2550N\u2014CH\u2550\u2003\u2003(b-6);
\u2014N\u2550N\u2014C(R2a)\u2550CH\u2014CH\u2550\u2003\u2003(b-7);
q is 0, 1, 2; or where possible q is 3 or 4;
R1 is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl,
C1-6alkyloxycarbonyl, C1-6alkyl substituted with formyl,
C1-6alkylcarbonyl, C1-6alkyloxycarbonyl;
R2a is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl, C1-6alkyl substituted with cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl, C2-6alkenyl substituted with cyano, or C2-6alkynyl substituted with cyano;
each R2 independently is hydroxy, halo, C1-6alkyl optionally substituted with cyano or C(\u2550O)R6, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, \u2014S(\u2550O)pR6, \u2014NH\u2014S(\u2550O)pR6,
\u2014C(\u2550O)R6, \u2014NHC(\u2550O)H, \u2014C(\u2550O)NHNH2, \u2014NHC(\u2550O)R6, \u2014C(\u2550NH)R6 or a radical of formula
wherein each A independently is N, CH or CR6;
B is NH, O, S or NR6;
p is 1 or 2; and
R6 is methyl, amino, mono- or dimethylamino or polyhalomethyl;
L is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, whereby each of said aliphatic group may be substituted with one or two substituents independently selected from
C3-7cycloalkyl,
indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, hydroxy, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C1-6alkylcarbonyl,
phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R2; or
L is \u2014X\u2014R3 wherein
R3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R2; and
X is \u2014NR1\u2014, \u2014NH\u2014NH\u2014, \u2014N\u2550N\u2014, \u2014O\u2014, \u2014C(\u2550O)\u2014, \u2014CHOH\u2014, \u2014S\u2014, \u2014S(\u2550O)\u2014 or \u2014S(\u2550O)2\u2014;
Q represents hydrogen, C1-6alkyl, halo, polyhaloC1-6alkyl or NR4R5; and
R4 and R5 are each independently selected from hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl wherein each of the aforementioned C1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, \u2014S(\u2550O)pR6,
\u2014NH\u2014S(\u2550O)pR6, \u2014C(\u2550O)R6, \u2014NHC(\u2550O)H,
\u2014C(\u2550O)NHNH2, \u2014NHC(\u2550O)R6, \u2014C(\u2550NH)R6, aryl and Het; or
R4 and R5 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-12alkyl)aminoC1-4alkylidene;
Y represents hydroxy, halo, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms, C2-6alkynyl optionally substituted with one or more halogen atoms, C1-6alkyl substituted with cyano or C(\u2550O)R6, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, \u2014S(\u2550O)pR6, \u2014NH\u2014S(\u2550O)pR6, \u2014C(\u2550O)R6, \u2014NHC(\u2550O)H, \u2014C(\u2550O)NHNH2, \u2014NHC(\u2550O)R6, \u2014C(\u2550NH)R6 or aryl;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy;
Het is an aliphatic or aromatic heterocyclic radical; said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy;
and
(b) one or more pharmaceutically acceptable water-soluble polymers.
26. A particle according to claim 25 wherein the compound of formula (I-B) is a compound wherein -b1=b2-C(R2a)=b3-b4=is a radical of formula (b-1); q is 0; R2a is cyano or \u2014C(\u2550O)NH2; Y is cyano, \u2014C(\u2550O)NH2 or a halogen; Q is hydrogen or \u2014NR4R5; L is \u2014X\u2014R3 wherein R3 is substituted phenyl.
27. A particle according to claim 25 wherein the compound of formula (I-B) is a compound wherein R2a is cyano; Y is halo; Q is NH2; L is X\u2014R3 wherein X is NR1, O or S, and R3 is phenyl substituted with C1-6alkyl, halogen or cyano.
28. A particle according to claim 25 wherein the compound of formula (I-B) is a compound wherein L is \u2014X\u2014R3 wherein R3 is 2,4,6-trisubstituted phenyl, each substituent independently selected from chloro, bromo, fluoro, cyano or C1-4alkyl.
29. A particle according to claim 25 wherein the compound of formula (I-B) is a compound wherein Y is chloro or bromo and Q is hydrogen or amino
30. A particle according to claim 25 wherein the compound of formula (I-B) is a compound wherein the moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilino group.
31. A particle according to claim 25 wherein the compound of formula (I-B) is a compound wherein the moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilino group, L is \u2014X\u2014R3 wherein R3 is a 2,4,6-trisubstituted phenyl, Y is a halogen and Q is hydrogen or NH2.
32. A particle according to claim 25 wherein the compound of formula (I-B) is selected from
4-4-amino-5-chloro-6-(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-5-chloro-4-(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinylaminobenzonitrile;
4-4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyl)amino-2-pyrimidinylamino-benzonitrile;
4-5-bromo-6-(4-cyano-2,6-dimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinylaminobenzonitrile; and
a N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine thereof.
33. A particle according to claim 25 wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPa\xb7s when dissolved at 20\xb0 C. in an aqueous solution at 2% (wv).
34. A particle according to claim 25 wherein the water-soluble polymer is selected from the group comprising
alkylcelluloses,
hydroxyalkylcelluloses,
hydroxyalkyl alkylcelluloses,
carboxyalkylcelluloses,
alkali metal salts of carboxyalkylcelluloses,
carboxyalkylalkylcelluloses,
carboxyalkylcellulose esters,
starches,
pectines,
chitosan,
di-, oligo- or polysaccharides,
polyacrylic acids and the salts thereof,
polymethacrylic acids, the salts and esters thereof, methacrylate copolymers,
polyvinylalcohol,
polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.
35. A particle according to claim 34 wherein the water-soluble polymer is selected from the group comprising methylcellulose; hydroxymethylcellulose; hydroxyethylcellulose; hydroxypropylcellulose; hydroxybutylcellulose; hydroxyethyl methylcellulose; hydroxypropyl methylcellulose; carboxymethylcellulose; sodium carboxymethylcellulose; carboxymethylethylcellulose; sodium carboxymethylamylopectine; chitosan; trehalose; cyclodextrins; alginic acid, alkali metal and ammonium salts thereof; carrageenans; galactomannans; tragacanth; agar-agar; gummi arabicum; guar gummi; xanthan gummi; polyethylene oxide; polypropylene oxide; and copolymers of ethylene oxide and propylene oxide.
36. A particle according to claim 34 wherein the water-soluble polymer is selected from Eudragit E\xae and hydroxypropyl methylcellulose.
37. A particle according to claim 34 wherein the water-soluble polymer is an aminoalkyl methacrylate copolymer.
38. A particle according to claim 34 wherein the water-soluble polymer is hydroxypropyl methylcellulose.
39. A particle according to claim 38 wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 1 to about 100 mPa\xb7s when dissolved at 20\xb0 C. in an aqueous solution at 2% (wv).
40. A particle according to claim 38 wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 3 to about 15 mPa\xb7s when dissolved at 20\xb0 C. in an aqueous solution at 2% (wv).
41. A particle according to claim 38 wherein the hydroxypropyl methylcellulose has an apparent viscosity of about 5 mPa\xb7s when dissolved at 20\xb0 C. in an aqueous solution at 2% (wv).
42. A particle according to claim 38 wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose HPMC 2910 5 mPa\xb7s.
43. A particle according to claim 25 wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:899.
44. A particle according to claim 43 wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:100.
45. A particle according to claim 44 wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:5.
46. A particle according to claim 42 wherein the weight-by-weight ratio of (a):(b) is in the range of from about 1:1 to about 1:3.
47. A particle according to claim 46 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1.5.
48. A particle according to claim 25 wherein the compound of formula (I-B) is in a non-crystalline phase.
49. A particle according to claim 25 wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b).
50. A particle according to claim 25 having a particle size of less than 1500 \u03bcm.
51. A particle according to claim 25 having a particle size of less than 250 \u03bcm.
52. A particle according to claim 25 having a particle size of less than 125 \u03bcm.
53. A particle according to claim 25 further comprising one or more pharmaceutically acceptable excipients.
54. A solid dispersion comprising
(a) a compound of formula (I-B) as defined in claim 25; and
(b) one or more pharmaceutically acceptable water-soluble polymers.
55. A solid dispersion according to claim 54 wherein the water soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPa\xb7s when dissolved at 20\xb0 C. in an aqueous solution at 2% (wv).
56. A solid dispersion according to claim 54 wherein the weight-by-weight ratio of components (a):(b) is 1:1 to 1:5.
57. A solid dispersion according to claim 54 which is in the form of a solid solution comprising (a) and (b).
58. A solid dispersion according to claim 54 wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b).
59. A pharmaceutical dosage form comprising a therapeutically effective amount of particles as claimed in claim 25.
60. A dosage form according to claim 59 which is a tablet.
61. A dosage form according to claim 60 for immediate release of a compound of formula (I-B) upon oral ingestion wherein said particles are homogeneously distributed throughout a mixture of a diluent and a disintegrant.
62. A dosage form according to claim 59 surrounded by a film-coat comprising a film-forming polymer, a plasticizer and optionally a pigment.
63. A dosage form according to claim 61 wherein the diluent is a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), and the disintegrant is crospovidone or croscarmellose.
64. A dosage form according to claim 59 wherein the weight of said particles is at least 40% of the total weight of the dosage form.
65. A dosage form according to claim 59 containing from 200 to 400 mg of a compound of formula (I-B) per unit dosage form.
66. A dosage form according to claim 59 containing from 5 to 200 mg of a compound of formula (I-B) per unit dosage form.
67. A process of preparing a particle according to claim 25 comprising spray-drying of a solution of the components (a) and (b).
68. A process of preparing a particle according to claim 25 comprising blending the components (a) and (b), extruding said blend at a temperature in the range of 20-300\xb0 C. and grinding the extrudate, and optionally sieving the particles.
69. A process of preparing a particle according to claim 25 comprising milling or grinding a solid dispersion comprising (a) a compound of formula (I-B); and (b) one or more pharmaceutically acceptable polymers.
70. A particle according to claim 25 consisting of a solid solution comprising two parts by weight of a compound of formula (I-B) and three parts by weight of hydroxypropyl methylcellulose HPMC 2910 5 mPa\xb7s, obtainable by blending said components, extruding the blend at a temperature in the range of 20\xb0 C.-300\xb0 C., grinding the extrudate, and optionally sieving the thus obtained particles.
71. A process of preparing a solid dispersion according to claim 54 characterized by
(a) spray-drying of a solution of the components (a) and (b);
(b) preparing a solution of the components (a) and (b), pouring said solution onto a large surface so as to form a thin film, and evaporating the solvent therefrom; or
(c) melt-extruding the components (a) and (b).
72. A process of preparing a pharmaceutical dosage form characterized by blending a therapeutically effective amount of particles according to claim 25 with pharmaceutically acceptable excipients and compressing said blend into tablets or filling said blend in capsules.
73. Particles according to claim 25 for use in preparing a pharmaceutical dosage form for oral administration to a mammal suffering from a viral infection.
74. Particles according to claim 25 for use in preparing a pharmaceutical dosage form for oral administration to a mammal suffering from a viral infection, wherein a single such dosage form can be administered once daily to said mammal
75. A pharmaceutical package suitable for commercial sale comprising a container, an oral dosage form of a compound of formula (I-B) as claimed in claim 60, and associated with said package written matter.
76. A particle according to claim 31 wherein the water-soluble polymer is hydroxypropyl methylcellulose.
77. A particle according to claim 76 wherein the weight-by-weight ratio of (a):(b) is in the range of from about 1:1 to about 1:3.