Small molecule compositions and methods for increasing drug efficiency using compositions thereof

• US 20050148534A1
• Filed: 09/22/2004
• Published: 07/07/2005
• Est. Priority Date: 09/22/2003
• Status: Abandoned Application

• Current Assignee: Acidophil, LLC
• Original Assignee: Acidophil, LLC
• Inventors: Wirsching, Peter, Desharnais, Joel, Ballatore, Carlo, Aspland, Simon Eric, Sun, Chengzao, Castellino, Angelo John, Newman, Michael James
• Application Number:
  US10/948,364
• Publication Number:
  US 20050148534A1
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds

Abstract

In certain embodiments, provided herein are compositions and methods for increasing drug efficiency. The conjugates provided are in certain embodiments, for compositions and methods in treatment of variety of diseases and have the formula 1:
D-L-S  (1) or formula 2:
D-L-S′  (2) wherein D is a drug moiety; L, which may or may not be present, is a non-releasing linker moiety; S is a substrate for a kinase, other than a hexokinase, a protein kinase or a lipid kinase; and S′ is a substrate for a phosphotransferase, other than a hexokinase, a protein kinase or a lipid kinase.

Claims

1. A conjugate, comprising a drug and a substrate for a protein kinase or a lipid kinase non-releasably linked thereto, optionally via a non-releasable linker.

2. The conjugate of claim 1, wherein a significant fraction of a biological activity of the drug is retained in the conjugate.

3. The conjugate of claim 1, wherein more than 50% of the biological activity is retained in the conjugate.

4. The conjugate of claim 1, wherein more than 20% of the biological activity is retained in the conjugate.

5. The conjugate of claim 1, wherein more than 5% of the biological activity is retained in the conjugate.

6. The conjugate of claim 1 that comprises:

(substrate)_t, (Linker)_q, and (drug)_d;

wherein at least one substrate moiety is linked, optinally via a non-releasable linker to at least one drug, t is 1 to 6, q is 0 to 6, and d is 1 to 6.

7. The conjugate of claim 1, wherein the kinase is overexpressed, overactive or that exhibits undesired activity in a target system.

8. The conjugate of claim 1, wherein the kinase is associated with an ACAMPS-related condition.

9. The conjugate of claim 1, wherein the substrate is a substrate for a nucleoside kinase.

10. The conjugate of claim 1, wherein the substrate is a substrate for a thymidine kinase, deoxycytidine kinase or deoxyguanosine kinase.

11. The conjugate of claim 1, wherein the substrate is a substrate for viral thymidine kinase or human thymidine kinase.

12. The conjugate of claim 1, wherein the substrate is a natural or a non-natural nucleoside.

13. The conjugate of claim 1, wherein the substrate is a natural or a non-natural nucleoside that is converted to a substrate of thymidine kinase or deoxycytidine kinase by an action of thymidine phosphorylase or cytidine deaminase.

14. The conjugate of claim 9, wherein the nucleoside is a pyrimidine or a purine nucleoside, or a pharmaceutically acceptable derivative thereof.

15. The conjugate of claim 9, wherein the nucleoside is a pyrimidine nucleoside or a pharmaceutically acceptable derivative thereof.

16. The conjugate of claim 9, wherein the nucleoside is a purine nucleoside or a pharmaceutically acceptable derivative thereof.

17. The conjugate of claim 9, wherein the nucleoside is a pyrimidine covalently linked to a deoxyribose sugar.

18. The conjugate of claim 9, wherein the nucleoside is a pyrimidine covalently linked to a ribose sugar.

19. The conjugate of claim 9, wherein the nucleoside comprises a purine covalently linked to a deoxyribose sugar.

20. The conjugate of claim 9, wherein the nucleoside comprises a purine covalently linked to a ribose sugar.

21. The conjugate of claim 9, wherein the nucleoside comprises a base selected from cytosine, uridine, thymidine, guanosine, adenosine, or a pharmaceutically acceptable derivative thereof.

22. The conjugate of claim 9, wherein the nucleoside is thymidine.

23. The conjugate of claim 1, wherein the substrate is a nucleoside or nucleoside analog substrate for a thymidine kinase.

24. The conjugate of claim 1, wherein the substrate is a nucleoside or nucleoside analog substrate for human thymidine TK-1 or a viral TK.

25. The conjugate of claim 1, wherein the drug is a cytotoxic agent.

26. The conjugate of claim 1, wherein the drug is a label.

27. The conjugate of claim 1, wherein the drug is an anti-infective agent, antihelminthic agent, antiprotozoal agent, antimalarial agent, antiamebic agent, antileiscmanial agent, antitrichomonal agent, antitrypanosomal agent, sulfonamide, antimycobacterial agent, or antiviral agent.

28. The conjugate of claim 1, wherein the drug is an alkylating agent, plant alkaloid, antimetabolite, antibiotic, microtubue or tubulin binding agent.

29. The conjugate of claim 1, wherein the drug is a central nervous system depressant and stimulant, respiratory tract drug, pharmacodynamic agent, cardiovascular agent, blood or hemopoietic system agent, gastrointestinal tract agent, or locally acting chemotherapeutic agent.

30. The conjugate of claim 1, wherein the drug is selected from among the following classes of drugs:

a) anthracycline family of drugs,

b) vinca alkaloid drugs,

c) mitomycins,

d) bleomycins,

e) cytotoxic nucleosides,

f) pteridine family of drugs,

g) diynenes,

h) estramustine,

i) cyclophosphamide,

j) taxanes,

k) podophyllotoxins,

l) maytansanoids,

m) epothilones, and

n) combretastatin and analogs,

or pharmaceutically acceptable derivatives thereof.

31. The conjugate of claim 1, wherein the drug is selected from among the following drugs:

a) doxorubicin,

b) carminomycin,

c) daunorubicin,

d) aminopterin,

e) methotrexate,

f) methopterin,

g) dichloromethotrexate,

h) mitomycin C,

i) porfiromycin,

j) 5-fluorouracil,

k) 6-mercaptopurine,

l) cytosine arabinoside,

m) podophyllotoxin,

n) etoposide,

o) etoposide phosphate,

p) melphalan,

q) vinblastine, r) vincristine,

s) leurosidine,

t) vindesine,

u) estramustine,

v) cisplatin,

w) cyclophosphamide,

x) paclitaxel,

y) leurositte,

z) 4-desacetylvinblastine,

aa) epothilone B,

bb) docetaxel,

cc) maytansanol,

dd) epothilone A, and

ee) combretastatin and analogs;

or a pharmaceutically acceptable derivative thereof.

32. The conjugate of claim 1 comprising a non-releasable linker.

33. The conjugate of claim 1, wherein the linker comprises linear or acyclic portions, cyclic portions, aromatic rings or combinations thereof.

34. The conjugate of claim 1, wherein the linker comprises linear or acyclic portions.

35. The conjugate of claim 1, wherein the linker comprises up to 50 main chain atoms.

36. The conjugate of claim 1, wherein the linker comprises up to 30 main chain atoms.

37. The conjugate of claim 1, wherein the linker comprises up to 20 main chain atoms.

38. The conjugate of claim 1, wherein the linker comprises up to 10 main chain atoms.

39. The conjugate of claim 1, wherein the linker comprises up to 5 main chain atoms.

40. The conjugate of claim 1, wherein the linker comprises oligomers of ethylene glycol or straight alkelene chains or mixtures thereof.

41. The conjugate of claim 1, wherein the linker comprises polyethylene glycol.

42. The conjugate of claim 41, wherein the polyethylene glycol comprises 5, 11, 13, 14, 22 or 29 atoms in the chain.

43. The conjugate of claim 41, wherein the polyethylene glycol comprises 5, 11, 13 or 29 atoms in the chain.

44. The conjugate of claim 41, wherein the linker comprises straight alkelene chain containing from 1 up to 50 carbon atoms in the chain.

45. The conjugate of claim 1, wherein the linker comprises straight alkelene chain containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in the alkelene chain.

46. The conjugate of claim 1, wherein the linker comprises straight alkelene chain containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms in the alkelene chain.

47. The conjugate of claim 1 having formula

(D)-(L)-(S), or a pharmaceutically acceptable derivative thereof, wherein

D is a drug moiety;

L is a non-releasable linker; and

S is a substrate for a kinase other than a hexokinase, a protein kinase or a lipid kinase.

48. The conjugate of claim 47 having formula

(D)-(L)-(N), or a pharmaceutically acceptable derivative thereof, wherein

D is a drug moiety;

L is a non-releasable linker; and

N is a natural or non-natural nucleoside.

49. The conjugate of claim 48 having formula

S_c-P¹-L-D,

or a pharmaceutically acceptable derivative thereof, wherein S_c is ribose, deoxyribose or analog thereof and P¹ is a purine, pyrimidine or analog thereof.

50. The conjugate of claim 48 having formula

P¹-S_c-L-D,

or a pharmaceutically acceptable derivative thereof, wherein S_c is ribose, deoxyribose or analog thereof, P¹ is a purine, pyrimidine or analog thereof.

51. The conjugate of claim 48 having formula

52. The conjugate of claim 51, wherein R¹ is Y, H, hydroxy, halo, azido, C1-6 alkyl and optionally containing a heteroatom, C2-6 alkenyl or C2-6 alkynyl.

53. The conjugate of claim 51, wherein R¹ is OH.

54. The conjugate of claim 51, wherein R³ is hydroxy.

55. The conjugate of claim 51, wherein R³ is Y.

56. The conjugate of claim 51, wherein R⁴ is hydroxy.

57. The conjugate of claim 51, wherein R⁴ is H.

58. The conjugate of claim 51, wherein R⁴ is Y.

59. The conjugate of claim 51, wherein R⁵ is H.

60. The conjugate of claim 51, wherein R⁵ is hydroxy.

61. The conjugate of claim 51, wherein R⁵ is Y.

62. The conjugate of claim 51, wherein R² is H.

63. The conjugate of claim 51, wherein R² is C1-6 alkyl.

64. The conjugate of claim 51, wherein R² is methyl.

65. The conjugate of claim 51, wherein R² is Y.

66. The conjugate of claim 51, wherein R² is halo

67. The conjugate of claim 51, wherein R is C1-6 alkyl.

68. The conjugate of claim 51, wherein R is Y.

69. The conjugate of claim 51, wherein W is CR^eR^f or O.

70. The conjugate of claim 51, wherein W is O.

71. The conjugate of claim 51, wherein W is CR^eR^f.

72. The conjugate of claim 51, wherein R^e and R^f are each H.

73. The conjugate of claim 51, wherein Y is -L-D

74. The conjugate of claim 51, wherein Y is D.

75. The conjugate of claim 51, wherein -L- is selected from a bifunctional alkelene chain or bifunctional polyethylene glycol chain.

76. The conjugate of claim 51, wherein -L- is —

O-(L₁)-, where L₁ is non-releasable linker.

77. The conjugate of claim 51, wherein -L₁- is selected from a bifunctional alkelene chain or bifunctional polyethylene glycol chain.

78. The conjugate of claim 51, wherein the conjugate has formula:

79. The conjugate of claim 51, wherein the conjugate has formula:

80. The conjugate of claim 1, wherein the conjugate has formula:

81. The conjugate of claim 80, wherein R^1a is OH and W=O.

82. The conjugate of claim 1, wherein the conjugate has formula:

83. The conjugate of claim 1, wherein the conjugate has formula:

84. The conjugate of claim 83, wherein R^1d is OH, W^d is O and R^9d is Y.

85. The conjugate of claim 1, wherein the conjugate has formula:

86. The conjugate of claim 85, wherein R^1e is OH, W^e is O and R^9e is Y.

87. The conjugate of claim 1, wherein the conjugate has formula:

88. The conjugate of claim 1, wherein the conjugate has an improved cytotoxic selectivity index as compared to an unconjugated drug

89. The conjugate of claim 1, wherein the cytotoxic selectivity index is more than about 1.5 folds up to more than about 100 folds improved.

90. A method of treatment of conditions caused by ACAMPS comprising administering to a subject an effective amount of the conjugate of claim 1, or a pharmaceutically acceptable derivative thereof.

91. The method of claim 90, wherein the ACAMPS condition is characterized by undesirable or aberrant activation, migration, proliferation or survival of tumor cells, endothelial cells, B cells, T cells, macrophages, neutrophils, eosinophils, basophils, monocytes, platelets, fibroblasts, other connective tissue cells, osteoblasts, osteoclasts and progenitors of these cell types.

92. The method of claim 91, wherein the ACAMPS condition is a cancer, coronary restenosis, osteoporosis, chronic inflammation or an autoimmunity disease.

93. The method of claim 92, wherein the autoimmune disease is rheumatoid arthritis, asthma, psoriasis, inflammatory bowel disease, systemic lupus erythematosus, systemic dermatomyositis, inflammatory ophthalmic diseases, autoimmune hematologic disorders, multiple sclerosis, vasculitis, idiopathic nephrotic syndrome, transplant rejection or graft versus host disease.

94. The method of claim 92, wherein the cancer is non-small cell lung cancer, small cell lung cancer, head squamous cancer, neck squamous cancer, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin'"'"'s lymphoma, brain tumor, cervical cancer, childhood cancer, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin cancer or small-cell lung cancer.

95. The method of claim 92, wherein the cancer is brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, Ewing'"'"'s sarcoma, germ cell tumor, Hodgkin'"'"'s disease, ALL, AML, liver cancer, medulloblastoma, neuroblastoma, non-Hodgkin'"'"'s lymphoma, osteosarcoma, malignant fibrous histiocytoma of bone, retinoblastoma, rhabdomyosarcoma, soft tissue sarcoma, supratentorial primitive neuroectodermal and pineal tumors, visual pathway and hypothalamic glioma, Wilms'"'"' tumor, or other childhood kidney tumor.

96. The method of claim 92, wherein the cancer is originated from or have metastasized to the bone, brain, breast, digestive and gastrointestinal system, endocrine system, blood, lung, respiratory system, thorax, musculoskeletal system, or skin.

97. The method of claim 92, wherein the cancer is selected from breast cancer, lung cancer, prostate cancer, ovarian cancer, esophageal cancer, bladder cancer, hepatoma, neuroblastoma, lymphoma, testicular cancer, renal cancer, leukemia, colorectal cancer and head and neck cancer.

98. A method for identifying kinase substrates capable of selectively accumulating in a target system, comprising the steps of:

a) contacting one or more conjugate of claim 1 with a kinase that is overexpressed, overactive or that exhibits undesired activity in a target system;

b) determining kinase activity on the one or more conjugate.

99. A method of claim 98 further comprising the steps of

c) determining a first amount or a plurality of first amounts of the conjugates in the target system;

d) determining a second amount or a plurality of second amounts of the one or more conjugates in a non-target system.

100. The method of claim 98, wherein the one or more conjugates comprises a detectable label.

101. The method of claim 100, wherein the label is a radioactive or fluorescent label.

102. The method of claim 98, wherein the target system is associated with an ACAMPS condition.

103. The method of claim 98, wherein the target system is associated cancer, inflammation, angiogenesis, autoimmune syndromes, transplant rejection or osteoporosis.

104. The method of claim 98, wherein the target system is a cell.

105. The method of claim 104, wherein the cell is a tumor cell or a tumor-associated endothelial cell.

106. A method for identifying conjugates capable of exhibiting selective toxicity against a target system, comprising:

a) contacting one or more conjugates of claim 1 with a target system; and

b) determining the cytotoxicity of the one or more conjugates against the target system.

107. The method of claim 106, wherein the target system is associated with cancer, inflammation, angiogenesis, autoimmune syndromes, transplant rejection or osteoporosis.

108. The method of claim 107, wherein the target system is a cell.

109. The method of claim 107, wherein the cell is a tumor cell or a tumor-associated endothelial cell.

110. The method of claim 107, wherein the drug moiety is an anti-cancer drug.

111. A method of enhancing drug efficiency, comprising administering to a target system, or organism a therapeutically effective amount of the conjugate of claim 1, thereby improving drug efficiency as compared to an unconjugated drug.

112. The conjugate of claim 1 having formula:

113. The conjugate of claim 1 having formula:

114. The conjugate of claim 1 having formula:

115. The conjugate of claim 1 having formula:

116. The conjugate of claim 1 having formula:

117. The conjugate of claim 1 having formula:

118. The conjugate of claim 1 selected from Tables 4-6.

119. An article of manufacture, comprising packaging material, the conjugate of claim 1, or a pharmaceutically acceptable derivative thereof, contained within packaging material, which is used for treatment, prevention or amelioration of one or more symptoms associated with ACAMPS, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for treatment, prevention or amelioration of one or more symptoms associated with ACAMPS.

120. A pharmaceutical composition comprising a conjugate of claim 1 in a pharmaceutically acceptable carrier.

121. The conjugate of claim 1, wherein the substrate is a natural or a non-natural nucleoside base that is converted to a substrate of thymidine kinase or deoxycytidine kinase by an action of thymidine phosphorylase or cytidine deaminase.