Claims
- 1. A compound of the formula:
- 2. A compound of claim 1 having the structure:
- 3. The compound of claim 1 wherein R1 to R4 are each independently selected from H or halo.
- 4. The compound of claim 1 wherein R5 to R7 are H.
- 5. The compound of claim 1 wherein a is N and the remaining b, c and d substituents are carbon.
- 6. The compound of claim 1 wherein a, b, c, and d are carbon.
- 7. The compound of claim 1 wherein the optional bond between C-5 and C-6 is present.
- 8. The compound of claim 1 wherein the optional bond between C-5 and C-6 is absent.
- 9. The compound of claim 1 wherein R8 is group 2.0, or 4.0.
- 10. The compound of claim 1 wherein one of A or B is H and the other is R9.
- 11. The compound of claim 10 wherein the double bond between C-5 and C-6 is present.
- 12. The compound of claim 1 wherein the double bond between C-5 and C-6 is present, A is H and B is R9.
- 13. The compound of claim 1 wherein R9 is selected from the group consisting of:
(1) heterocycloalkylalkyl of the formula —(CH2)n-heterocycloalkyl; (2) substituted heterocycloalkylalkyl of the formula —(CH2)n-substituted heterocycloalkyl; (3) unsubstituted heteroarylalkyl of the formula —(CH2)n-heteroaryl; and (4) substituted heteroarylalkyl of the formula —(CH2)n-substituted heteroaryl; wherein n is 1, 2, or 3 and the substituents for said substituted R9 groups are each independently selected from the group consisting of: (1) —OH; (2) —CO2R14; (3) —CH2OR14, (3) halo, (4) alkyl; (5) amino; (6) trityl; (7) heterocycloalkyl; (8) arylalkyl; (9) heteroaryl and (10) heteroarylalkyl. wherein R14 is independently selected from the group consisting of: H and alkyl.
- 14. The compound of claim 1 wherein:
(1) R11 is selected from the group consisting of: alkyl, cycloalkyl and substituted cycloalkyl wherein the substituents are selected from the group consisting of: halo, alkyl and amino; (2) R11a is selected from: alkyl, unsubstituted aryl, substituted aryl, cycloalkyl or substituted cycloalkyl, wherein the substituents on said substituted groups are are selected from the group consisting of: halo, —CN or CF3; (3) R12, R21, and R22 are H; and (4) R46 is selected from the group consisting of: unsubstituted aryl, 3432substituted aryl wherein the substituents are selected from the group consisting of: alkyl, alkylcarbonyl and haloalkyl, and wherein R44 is selected from the group consisting of: H or —C(O)NH2.
- 15. The compound of claim 1 wherein:
(1) R1 to R4 are each independently selected from the group consisting of: H and halo; (2) R5, R6, R7, and R7 are H; (3) a is N and the remaining b, c and d substituents are carbon; (4) the optional bond between C5 and C6 is present; (5) A is H; (6) B is R9 (7) R8 is group 2.0 or 4.0; (8) R11 is selected from the group consisting of: alkyl, cycloalkyl and substituted cycloalkyl wherein the substituents are selected from the group consisting of: halo, alkyl and amino; (9) R11a is selected from the group consisting of: alkyl, unsubstituted aryl, substituted aryl, cycloalkyl or substituted cycloalkyl, wherein the substituents on said substituted groups are are selected from the group consisting of: halo, —CN and CF3; (10) R12 is H; (11) R9 is selected from the group consisting of:
(a) —(CH2)n-heterocycloalkyl; (b) —(CH2)n-substituted heterocycloalkyl; (c) —(CH2)n-heteroaryl, and (d) —(CH2)n-substituted heteroaryl; wherein n is 1, 2, or 3 and the substituents for said substituted R9 groups are each independently selected from the group consisting of:
(1) —OH; (2) —CO2R14; (3) —CH2OR14, (4) halo. (5) alkyl; (6) amino; (7) trityl; (8) heterocycloalkyl; (9) arylalkyl; (10) heteroaryl and (11) heteroarylalkyl; wherein R14 is independently selected from the group consisting of: H and alkyl; and (12) X is N or CH.
- 16. The compound of claim 1 wherein A is H, the double bond between C-5 and C-6 is present and B is the group:
- 17. The compound of claim 16 wherein B is the group:
- 18. The compound of claim 17 wherein R9 is substituted imidazolyl.
- 19. The compound of claim 18 wherein said substituted imidazolyl is:
- 20. The compound of claim 19 wherein: X is N.
- 21. The compound of claim 1 wherein A is H, the double bond between C-5 and C-6 is present and N is the group:
- 22. The compound of claim 21 wherein R9 is substituted imidazolyl.
- 23. The compound of claim 22 wherein said substituted imidazolyl is:
- 24. The compound of claim 23 wherein: X is N.
- 25. The compound of claim 1 wherein B is selected from the group consisting of:
- 26. The compound of claim 1 wherein R8 is selected from the group consisting of:
- 27. A compound of the formula:
- 28. The compound of claim 15 wherein:
(1) a is N; (2) b, c and d are CR1 groups wherein all of said R1 substituents are H, or one R1 substituent is halo and the remaining two R1 substituents are hydrogen; (3) m is 1, and R3A is halo, or m is 2 and each R3A is the same or different halo; (4) R5, R6, R7, and R7a are H; and (5) X is N or CH.
- 29. The compound of claim 28 wherein the optional bond between C-5 and C-6 is present.
- 30. The compound of claim 28 wherein: X is N.
- 31. The compound of claim 30 wherein the optional bond between C-5 and C-6 is present.
- 32. The compound of claim 28 wherein R9 is substituted imidazolyl.
- 33. The compound of claim 32 wherein said substituted imidazolyl is:
- 34. The compound of claim 33 wherein m is 1 and R3A is halo.
- 35. The compound of claim 34 wherein said halo is Cl.
- 36. The compound of claim 35 wherein said Cl is bound to C-8.
- 37. The compound of claim 36 wherein b, c and d are CR1 groups wherein all of said R1 substituents are H.
- 38. The compound of claim 37 wherein R8 is 2.0.
- 39. The compound of claim 38 wherein R11 is alkyl.
- 40. The compound of claim 39 wherein said alkyl is selected from the group consisting of: isopropyl and t-butyl.
- 41. The compound of claim 40 wherein said alkyl is isopropyl.
- 42. A compound of the formula:
- 43. The compound of claim 42 wherein: X is N.
- 44. The compound of claim 43 wherein R9 is substituted imidazolyl.
- 45. The compound of claim 44 wherein said substituted imidazolyl is:
- 46. The compound of claim 45 wherein m is 1 and R3A is halo.
- 47. The compound of claim 46 wherein said halo is Cl.
- 48. The compound of claim 47 wherein said Cl is bound to C-8.
- 49. The compound of claim 47 wherein b, c and d are CR1 groups wherein all of said R1 substituents are H.
- 50. The compound of claim 49 wherein R8 is 2.0.
- 51. The compound of claim 50 wherein R11 is alkyl.
- 52. The compound of claim 51 wherein said alkyl is selected from the group consisting of: isopropyl and t-butyl.
- 53. The compound of claim 52 wherein said alkyl is isopropyl
- 54. The compound of claim 42 wherein R30 is selected from the group consisting of —NH2 or —NHR9b, and R31 is H.
- 55. The compound of claim 51 wherein R30 is selected from the group consisting of —NH2 or —NHR9b, and R31 is H.
- 56. The compound of claim 42 wherein R30 is —NH2, and R31 is H.
- 57. The compound of claim 51 wherein R30 is —NH2, and R31 is H.
- 58. The compound of claim 42 having the structure:
- 59. The compound of claim 42 wherein B is selected from the group consisting of:
- 60. The compound of claim 42 wherein B is selected from the group consisting of:
- 61. The compound of claim 42 wherein B is:
- 62. The compound of claim 42 wherein R8 is selected from the group consisting of:
- 63. The compound of claim 42 wherein R8 is selected from the group consisting of:
- 64. The compound of claim 42 wherein R8 is selected from the group consisting of:
- 65. The compound of claim 42 wherein R8 is selected from the group consisting of:
- 66. A compound of the formula:
- 67. The compound of claim 66 wherein:
(A) in said B group:
(1) p of the —(CH2)p— moiety is 0; (2) p of the 3492 moiety is 1; (3) R30 is selected from the group consisting of: —OH and —NH2, and R31 is C1-C2 alkyl; and (4) R9 is substituted imidazolyl wherein the substituent is an alkyl group, provided that said imidazolyl group is not bound by a ring nitrogen to the adjacent —CR30R31— moiety; (B) R8 is 2.0; (C)R11 is alkyl; (D) X is N; (E) b, c and d are CR1 groups wherein all of said R1 substituents are H; (F) m is 1, and R3A is halo; and (G) the bond between C-5 and C-6 is present.
- 68. The compound of claim 67 wherein:
(A) in said B group:
(1) R30 is —OH, and R31 is methyl; and (2) R9 is substituted imidazolyl wherein the substituent is a methyl group, provided that said imidazolyl group is not bound by a ring nitrogen to the adjacent —CR30R31— moiety; and (B) R3A is Cl.
- 69. The compound of claim 68 wherein R9 is
- 70. The compound of claim 69 wherein R11 is t-butyl.
- 71. The compound of claim 69 wherein R11 is isopropyl.
- 72. The compound of claim 66 having the formula:
- 73. The compound of claim 1 selected from the group consisting of the final compounds of Examples 1 to 4618.
- 74. The compound of claim 1 selected from the group consisting of:
- 75. The compound of claim 1 selected from the group consisting of:
- 76. A compound of claim 1 selected from the group consisting of:
- 77. The compound of claim 1 selected from the group consisting of:
- 78. The compound of claim 1 selected from the group consisting of:
- 79. The compound of claim 1 selected from the group consisting of
- 80. The compound of claim 1 having the formula:
- 81. The compound of claim 1 having the formula:
- 82. The compound of claim 1 selected from the group consisting of:
- 83. The compound of claim 1 having the formula:
- 84. The compound of claim 1 having the formula:
- 85. The compound of claim 1 selected from the group consisting of:
- 86. The compound of claim 1 having the formula:
- 87. The compound of claim 1 having the formula:
- 88. The compound of claim 1 selected from the group consisting of:
- 89. The compound of claim 1 having the formula:
- 90. The compound of claim 1 having the formula:
- 91. The compound of claim 1 selected from the group consisting of:
- 92. The compound of claim 1 having the formula:
- 93. The compound of claim 1 having the formula:
- 94. A pharmaceutical composition comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier.
- 95. A pharmaceutical composition comprising an effective amount of compound of claim 42 in combination with a pharmaceutically acceptable carrier.
- 96. A method for treating the abnormal growth of cells in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of claim 1.
- 97. A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of claim 1.
- 98. A method of treating tumors expressing an activated ras oncogene in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of claim 1.
- 99. A method of treating cancer in a patient in need of such treatment, wherein said cancer is selected from the group consisting of: pancreatic cancers, lung cancers, myeloid leukemias, thyroid follicular tumors, myelodysplastic syndrome, head and neck cancers, melanomas, breast cancers, prostate cancers, ovarian cancers, bladder cancers, gliomas, epidermal cancers, colon cancers, non-Hodgkin's lymphomas, and multiple myelomas comprising administering to said patient an effective amount of a compound of claim 1
- 100. A method of inhibiting ras farnesyl protein transferase in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of claim 1.
- 101. A method of treating cancers, wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of claim 1.
- 102. A method of treating cancers in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of claim 1 in combination with an effective amount of at least one chemotherapeutic agent and/or radiation.
- 103. The method of claim 102 wherein the cancer treated is lung cancer and the chemotherapeutic agent is selected from the group consisting of: carboplatin, taxol and taxotere.
- 104. The method of claim 102 wherein the cancer treated is lung cancer and the chemotherapeutic agent is selected from the group consisting of: gemcitabine and cisplatin.
- 105. The method of claim 102 wherein the chemotherapeutic agent is Taxol.
- 106. A method of treating cancers in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of claim 1 in combination with an effective amount of at least one signal transduction inhibitor.
- 107. The method of 106 wherein the signal transduction inhibitor is selected from the group consisting of: Gleevec, Iressa, OSI-774, Imclone C225, Abgenix ABX-EGF, and Herceptin.
- 108. A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor of claim 42 and at least two different antineoplastic agents selected from:
(1) taxanes; (2) platinum coordinator compounds; (3) EGF inhibitors that are antibodies; (4) EGF inhibitors that are small molecules; (5) VEGF inhibitors that are antibodies; (6) VEGF kinase inhibitors that are small molecules; (7) estrogen receptor antagonists or selective estrogen receptor modulators; (8) anti-tumor nucleoside derivatives; (9) epothilones; (10) topoisomerase inhibitors; (11) vinca alkaloids; (12) antibodies that are inhibitors of αVβ3 integrins; and (13) small molecule inhibitors of αVβ3 integrins (14) folate antagonists; (15) ribonucleotide reductase inhibitors; (16) anthracyclines; (17) biologics; (18) Thalidomide (or related Imid); and (19) Gleevec.
- 109. The method of claim 108 wherein two antineoplastic agents are used wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound.
- 110. The method of claim 109 wherein:
(a) said taxane is paclitaxel and said platinum coordinator compound is carboplatin; or (b) said taxane is paclitaxel and said platinum coordinator compound is cisplatin; or (c) said taxane is docetaxel and said platinum coordinator compound is cisplatin; or (d) said taxane is docetaxel and said platinum coordinator compound is carboplatin.
- 111. The method of claim 109 wherein:
(a) said taxane is paclitaxel administered in an amount of about 150 mg to about 250 mg/m2 once every three weeks per cycle, and said platinum coordinator compound is carboplatin administered once every three weeks per cycle in amount of to provide an AUC of about 5 to about 8; or (b) said taxane is docetaxel administered in an amount of about 50 mg to about 100 mg/m2 once every three weeks per cycle, and said platinum coordinator compound is cisplatin administered in amount of about 60 mg to about 100 mg/m2 once every three weeks per cycle.
- 112. The method of claim 111 wherein the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day.
- 113. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 114. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 115. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 116. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 117. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 118. The method of claim 109 wherein said FPT inhibitor is:
- 119. The method of claim 109 wherein said FPT inhibitor is:
- 120. The method of claim 109 wherein said FPT inhibitor is:
- 121. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 122. The method of claim 109 wherein said FPT inhibitor is:
- 123. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 124. The method of claim 109 wherein said FPT inhibitor is selected from the group consisting of:
- 125. The method of claim 109 wherein said FPT inhibitor is:
- 126. The method of claim 109 wherein said FPT inhibitor is:
- 127. The method of claim 109 wherein non small cell lung cancer is treated.
- 128. The method of claim 108 wherein two antineoplastic agents are used wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is an EGF inhibitor that is an antibody.
- 129. The method of claim 108 wherein two antineoplastic agents are used and wherein one antineoplastic agent is an antinucleoside derivative, and the other antineoplastic agent is a platinum coordinator compound.
- 130. The method of claim 108 wherein non small cell lung cancer is being treated in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) said FPT inhibitor; and (b) carboplatin; and (c) paclitaxel.
- 131. The method of claim 130 wherein said FPT inhibitor is administered twice a day, said carboplatin is administered once every three weeks per cycle, and said paclitaxel is administered once every three weeks per cycle, said treatment being given for one to four weeks per cycle.
- 132. The method of claim 131 wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said paclitaxel is administered once every three weeks per cycle in an amount of about 150 to about 250 mg/m2, and wherein said carboplatin and said paclitaxel are administered on the same day.
- 133. The method of claim 108 wherein non small cell lung cancer is being treated in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) said FPT inhibitor; and: (b) cisplatin; and (c) gemcitabine.
- 134. The method of claim 133 wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said cisplatin is administered once every three or four weeks per cycle in an amount of about 60 to about 100 mg/m2, and said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m2, said treatment being given for one to seven weeks per cycle.
- 135. The method of claim 108 wherein non small cell lung cancer is being treated in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) said FPT inhibitor; and (b) carboplatin; and (c) gemcitabine.
- 136. The method of claim 135 wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, and said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m2, said treatment being given for one to seven weeks per cycle
- 137. A method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of claim 42 and an antineoplastic agent selected from the group consisting of:
(1) EGF inhibitors that are antibodies; (2) EGF inhibitors that are small molecules; (3) VEGF inhibitors that are antibodies; or (4) VEGF kinase inhibitors that are small molecules.
- 138. The method of claim 137 wherein said antineoplastic agent is selected from: Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416, or SU6688.
- 139. The method of claim 109 wherein: said taxane is paclitaxel administered in an amount of about 150 mg to about 250 mg/m2 once a week per cycle, and said platinum coordinator compound is carboplatin administered once a week per cycle in an amount to provide an AUC of about 5 to about 8.
- 140. The method of claim 109 wherein: said taxane is docetaxel administered in an amount of about 50 mg to about 100 mg/m2 once a week per cycle, and said platinum coordinator compound is cisplatin administered in amount of about 60 mg to about 100 mg/m2 once a week per cycle.
- 141. The method of claim 102 wherein said cancer being treated is non small cell lung cancer, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; (b) carboplatin; and (c) gemcitabine.
- 142. The method of claim 102 wherein the cancer being treated is non small cell lung cancer, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; (b) Carboplatin; and (c) Docetaxel.
- 143. The method of claim 102 wherein the cancer being treated is squamous cell cancer of the head and neck, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) one or more antineoplastic agents selected from the group consisting of:
(1) taxanes; and (2) platinum coordinator compounds.
- 144. The method of claim 102 wherein the cancer being treated is squamous cell cancer of the head and neck, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) at least two different antineoplastic agents selected from the group consisting of:
(1) taxanes; (2) platinum coordinator compounds; and (3) anti-tumor nucleoside derivatives.
- 145. The method of claim 102 wherein the cancer being treated is CML, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; (b) Gleevec; and (c) interferon.
- 146. The method of claim 102 wherein the cancer being treated is CML, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; (b) Gleevec; and (c) pegylated interferon.
- 147. The method of claim 102 wherein the cancer being treated is AML, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) an anti-tumor nucleoside derivative.
- 148. The method of claim 102 wherein the cancer being treated is AML, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) an anti-tumor nucleoside derivative; and (c) an anthracycline.
- 149. The method of claim 102 wherein the cancer being treated is non-Hodgkin's lymphoma, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) Rituximab.
- 150. The method of claim 102 wherein the cancer being treated is non-Hodgkin's lymphoma, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; (b) Rituximab; and (c) an anti-tumor nucleoside derivative.
- 151. The method of claim 102 wherein the cancer being treated is non-Hodgkin's lymphoma, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) Genasense.
- 152. The method of claim 102 wherein the cancer being treated is multiple myeloma, and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) a proteosome inhibitor.
- 153. The method of claim 102 wherein the cancer being treated is multiple myeloma and the treatment comprises administering therapeutically effective amounts of:
(a) said compound; and (b) Thalidomide or related imid.
- 154. The method of claim 102 wherein the cancer being treated is multiple myeloma and the treatment comprises administering therapeutically effective amounts of::
(a) said compound; and (b) Thalidomide.
- 155. A final compound of Examples 1-568, 570-573, 575-900, 902-905, 907-913, 915-924, 926-929, 931-937, 939-948, 950-953, 955-961, 963-972, 974-977, 979-985, 987-1141, 1143-1146, 1148-1154, 1156-1165, 1167-1170, 1172-1179, 1180-1334, 1336-1339, 1341-1347, 1349-1358, 1360, 1362-1371, 1373-1531, 1533-1539, 1541-1550, 1552-1555, 1557-1563, 1565-1654, 1656-1745, 1747-1750, 1752-1758, 1760-1845, 1847-1940, 1942-2033, 2035-3027, 3029-3121, 3123-3221, 3223-3923, and 3944-4319.
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of application Ser. No. 10/085,896 filed Feb. 27, 2002 (the disclosure of which is incorporated herein by reference thereto), which in turn is a continuation-in-part of application Ser. No. 08/940,811 filed Aug. 28, 2001 (the disclosure of which is incorporated herein by reference thereto), which in turn claims the benefit of Provisional Application Serial No. 60/229,183 filed Aug. 30, 2000.
Continuation in Parts (2)
|
Number |
Date |
Country |
Parent |
10085896 |
Feb 2002 |
US |
Child |
10325896 |
Dec 2002 |
US |
Parent |
09940811 |
Aug 2001 |
US |
Child |
10325896 |
Dec 2002 |
US |