CA2369270A1 - Camptothecin analogs and methods of preparation thereof - Google Patents

Camptothecin analogs and methods of preparation thereof Download PDF

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CA2369270A1
CA2369270A1 CA002369270A CA2369270A CA2369270A1 CA 2369270 A1 CA2369270 A1 CA 2369270A1 CA 002369270 A CA002369270 A CA 002369270A CA 2369270 A CA2369270 A CA 2369270A CA 2369270 A1 CA2369270 A1 CA 2369270A1
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alkynyl
alkenyl
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Dennis P. Curran
David Bom
Thomas G. Burke
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University of Kentucky Research Foundation
University of Pittsburgh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si

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Abstract

Provided are compounds of the formula (see formula 1) which are E-ring expanded camptothecin derivatives/analogues. The method of synthesis of compound (1) and intermediates in the synthesis thereof are provided.
The compounds have anticancer properties.

Claims (57)

1. A compound having the formula -in racemic form, enantiomerically enriched form or enantiomerically pure form;

wherein R1 and R2 are independently the same or different and are hydrogen, -C(O)Rf wherein Rf is an alkyl group, an alkoxy group, an amino group or a hydroxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, -OC(O)OR d, wherein Rd is an alkyl group, -OC (O) NR a R b wherein Ra and Rb are independently the same or different, H, -C(O)Rf, an alkyl group or an aryl group, a halogen, a hydroxy group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an amino group, -SRc, wherein Rc is hydrogen, -C(O)Rf, an alkyl group or an aryl group; or R1 and R2 together form a chain of three or four members selected from the group of CH, CH2, O, S, NH, or NR15, wherein R15 is an C1-C6 alkyl group;

R3 is H, a halogen atom, a nitro group, an amino group, a hydroxy group, or a cyano group; or R2 and R3 together form a chain of three or four members selected from the group of CH, CH2, O, S, NH, or NR15;

R4 is H, F, an amino group, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a trialkylsilyl group or a C1-3 alkoxy group;

R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;

-R6 is -Si (R8R9R10) or - (R7) Si (R8R9R10), wherein R7 is an alkylene group, an alkenylene group, or an alkynylene group;
and R8, R9 and R10 are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, an aryl group or a - (CH2) NR11 group, wherein N is an integer within the range of 1 through 10 and R11 is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, -SR c or a nitro group;

R13 is H, F or -CH3;
R16 is -C (O) R f or H; and pharmaceutically acceptable salts thereof.
2. The compound of Claim 1 wherein R16 is H.
3. The compound of Claim 2 wherein R2 and R3 together form a group of the formula -O(CH2)n O- wherein n represents the integer 1 or 2.
4. The compound of Claim 2 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
5. The compound of Claim 2 wherein R13 is H.
6. The compound of Claim 5 wherein R5 is an ethyl group.
7. The compound of Claim 6 wherein R4 is H.
8. The compound of Claim 7 wherein R8 and R9 are methyl groups, R10 is a tert-butyl group or a methyl group, R1 is H and R3 is H.
9. The compound of Claim 8 wherein R2 is H, NH2 or OH.
10. A method of synthesizing a compound having the formula via a cascade radical 4 + 1 annulation wherein the precursor or the precursor is reacted with an arylisonitrile having the formula wherein X is a radical precursor;

wherein R1 and R2 are independently the same or different and are hydrogen, -C(O)R f wherein R f is an alkyl group, an alkoxy group, an amino group or a hydroxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, -OC(O)OR d, wherein R d is an alkyl group, -OC(O)NR aR b wherein R a and R b are independently the same or different, H, -C(O)R f, an alkyl group or an aryl group, a halogen, a hydroxy group, a vitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an amino group, -SR c, wherein R c is hydrogen, -C(O)R f, an alkyl group or an aryl group; or R1 and R2 together form a chain of three or four members selected from the group of CH, CH2, O, S, NH, or NR15, wherein R15 is an C1-C6 alkyl group;

R3 is H, a halogen atom, a vitro group, an amino group, a hydroxy group, or a cyano group; or R2 and R3 together form a chain of three or four members selected from the group of CH, CH2, O, S, NH, or NR15;

R4 is H, F, an amino group, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a trialkylsilyl group or a C1-3 alkoxy group;

R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;

R13 is H, F or -CH3; and R6 is H, an alkyl group, -Si (R8R9R10) or - (R7) Si (R8R9R10), wherein R7 is an alkylene group, an alkenylene group, or an alkynylene group; and R8, R9 and R10 are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, an aryl group or a - (CH2)NR11 group, wherein N is an integer within the range of 1 through 10 and R11 is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, -SR c or a vitro group.
11. The method of Claim 10 wherein R2 and R3 together form a group of the formula -O(CH2)n O- wherein n represents the integer 1 or 2.
12. The method of Claim 10 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
13. The method of Claim 10 wherein X is Br or I.
14. The method of Claim 13 wherein R13 is H.
15. The method of Claim 14 wherein R5 is an ethyl group.
16. The method of Claim 15 wherein R4 is H.
17. The method of Claim 16 wherein R8 and R9 are methyl groups, R10 is a tert-butyl group or a methyl group, R1 is H and R3 is H.
18. The method of Claim 17 wherein R2 is H, NH2 or OH.
19. A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form;
wherein R1 and R are independently the same or different and are hydrogen, -C(O)R f wherein R f is an alkyl group, an alkoxy group, an amino group or a hydroxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, -OC (O) OR d, wherein R d is an alkyl group, -OC (O) NR a R b wherein R a and R b are independently the same or different, H, -C(O)R f, an alkyl group or an aryl group, a halogen, a hydroxy group, a nitro group, a cyano group, an amino group, a formyl group, a hydrazino group, an amino group, -SR c, wherein R c is hydrogen, -C(O)R f, an alkyl group or an aryl group; or R1 and R2 together form a chain of three or four members selected from the group of CH, CH2, O, S, NH, or NR15, wherein R15 is an C1-C6 alkyl group;

R3 is H, a halogen atom, a nitro group, an amino group, a hydroxy group, or a cyano group; or R2 and R3 together form a chain of three or four members selected from the group of CH, CH2, O, S, NH, or NR15, wherein R15 is an C1-C6 alkyl group;

R4 is H, F, an amino group, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a trialkylsilyl group or a C1-3 alkoxy group;

R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;

R6 is -Si (R8R9R10) or - (R7) Si (R8R9R10), wherein R7 is an alkylene group, an alkenylene group, or an alkynylene group;
and R8, R9 and R10 are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, an aryl group or a - (CH2)NR11 group, wherein N is an integer within the range of 1 through 10 and R10 is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, -SR c or a nitro group;
R12 is H or -C(O)R f, -C (O) OR d or -C (O) NR aR b;
R13 is H, F or -CH3; and pharmaceutically acceptable salts thereof.
20. The compound of Claim 19 wherein R2 and R3 together form a group of the formula -O(CH2)n O- wherein n represents the integer 1 or 2.
21. The compound of Claim 19 wherein R 5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
22. The compound of Claim 19 wherein R13 is H.
23. The compound of Claim 22 wherein R5 is an ethyl group.
24. The compound of Claim 23 wherein R4 is H.
25. The compound of Claim 24 wherein R8 and R9 are methyl groups, R10 is a tert-butyl group or a methyl group , R1 i s H and R3 is H.
26. The compound of Claim 25 wherein R2 is H, NH2 or OH.
27. A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form;
wherein X is a radical precursor;
R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;

R6 is an alkyl group, -Si (R8R9R10) or - (R7) Si (R8R9R10), wherein R7 is an alkylene group, an alkenylene group, or an alkynylene group; and R8, R9 and R10 are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group , an aryl group or a - (CH2) NR11 group , wherein N i s an integer within the range of 1 through 10 and R11 is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, -SR c or a nitro group; and R13 is H, F or -CH3.
28. The compound of Claim 27 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
29. The compound of Claim 27 wherein X is Br or I.
30. The compound of Claim 29 wherein R13 is H.
31. The compound of Claim 30 wherein R5 is an ethyl group.
32. A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form;
wherein X is a radical precursor; and R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group; and R13 is H , F or -CH3.
33. The compound of Claim 32 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
34. The compound of Claim 33 wherein X is Br or I.
35. The compound of Claim 32 wherein R13 is H.
36. The compound of Claim 35 wherein R5 is an ethyl group.
37. A compound having the formula wherein R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;
R12 is H or -C (O) R f, -C (O) OR d or -C (O) NR aR b.
38. The compound of Claim 37 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
39. The compound of Claim 38 wherein R5 is an ethyl group.
40. A compound having the formula wherein R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;
R13 is H, F or -CH3; and R15 is a C1-C6 alkyl group.
41. The compound of Claim 40 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
42. The compound of Claim 41 wherein R13 is H.
43. The compound of Claim 42 wherein R5 is an ethyl group.
44. A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form;
wherein R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;
wherein R13 is H, F or -CH3; and R14 is SiMe3, I, or Br.
45. A method of synthesizing a compound having the following formula:

wherein Y is C1, Br or I;
R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;
R6 is an alkyl group, -Si (R8R9R10) or - (R7) Si (R8R9R10), wherein R7 is an alkylene group, an alkenylene group, or an alkynylene group; and R8, R9 and R10 are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, an aryl group or a - (CH2)N R11 group, where in N is an integer within the range of 1 through 10 and R11 is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, -SR c or a nitro group; and R13 is H, F or -CH3, comprising the steps of (a) treating an enol ether of the structure:

under suitable oxidative cleavage conditions to form a compound having the structure:

(b) treating the compound formed in step (a) with an organometallic reagent having the structure:

MC(R 13)(R13)CO2R15 wherein M is Li, Na, K, MgY, or ZnY, and R15 is a C1-C6 alkyl group under suitable conditions to form a compound having the structure:

(c) treating the compound formed in step (b) under suitable conditions with acid to form a compound having the structure:

(d) treating the compound formed in step (c) under suitable conditions of halogenative desilylation to form a compound having the structure:

(e) treating the compound in step (d) with acid or iodotrimethylsilane under suitable conditions for demethylation to provide a compound of the following structure:

(f) treating the compound in step (e) with a lithium base or a sodium base in the presence of an inorganic lithium salt to deprotonate the nitrogen atom, (g) reacting of the resulting deprotonated species of step (f) with a compound of the following structure:

wherein Z is I, Br, Cl, a mesylate group, or a tosylate group, and under suitable conditions to cause the formation of the compound of the following structure:

46. The method of Claim 45 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
47. The method of Claim 46 wherein R13 is H.
48. The method of Claim 47 wherein R5 is an ethyl group.
49. A method of treating a patient for cancer or leukemia, comprising the step of administering a pharmaceutically effective amount of a compound of Claim 1.
50. The method of Claim 49, wherein the patient is treated for brain cancer, breast cancer or leukemia.
51. A method of treating a patient for cancer or leukemia, comprising the step of administering a pharmaceutically effective amount of a compound of Claim 18 or a pharmaceutically acceptable salt thereof.
52. The method of Claim 51, wherein the patient is treated for brain cancer, breast cancer or leukemia.
53. A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form;

wherein X is a radical precursor;

R5 is a C1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group;

R6 is an alkyl group, -Si (R8R9R10) or - (R7)Si(R8R9R10), wherein R7 is an alkylene group, an alkenylene group, or an alkynylene group; and R8, R9 and R10 are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, an aryl group or a -(CH2)NR11 group, where in N is an integer within the range of 1 through 10 and R11 is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, -SRc or a nitro group; and R13 is H, F or -CH3.
54. The compound of Claim 53 wherein R5 is an ethyl group, an allyl group, a benzyl group or a propargyl group.
55. The compound of Claim 54 wherein X is Br or I.
56. The compound of Claim 55 wherein R13 is H.
57. The compound of Claim 56 wherein R5 is an ethyl group.
CA2369270A 1999-04-09 2000-04-07 Camptothecin analogs and methods of preparation thereof Expired - Fee Related CA2369270C (en)

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US09/290,019 US6207832B1 (en) 1999-04-09 1999-04-09 Camptothecin analogs and methods of preparation thereof
US09/290,019 1999-04-09
PCT/US2000/009401 WO2000061146A1 (en) 1999-04-09 2000-04-07 Camptothecin analogs and methods of preparation thereof

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