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(12) Patent Application Publication (10) Pub. No.: US 2006/0019936A1 Eissigmann Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0019936A1 Eissigmann Et Al US 2006OO19936A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0019936A1 Eissigmann et al. (43) Pub. Date: Jan. 26, 2006 (54) METHODS AND COMPOSITIONS FOR Related U.S. Application Data TREATING CANCER (60) Provisional application No. 60/552,322, filed on Mar. 10, 2004. (75) Inventors: John M. Eissigmann, Cambridge, MA (US); Robert G. Croy, Belmont, MA Publication Classification (US) (51) Int. Cl. Correspondence Address: A61K 3.11573 (2006.01) WOLF GREENFIELD & SACKS, PC (52) U.S. Cl. .............................................................. 514/179 FEDERAL RESERVE PLAZA (57) ABSTRACT 600 ATLANTIC AVENUE BOSTON, MA 02210-2211 (US) The invention provides compounds and methods for treating cancer. Exemplary compounds are multi-functional com pounds with two different moieties connected by a linker. (73) Assignee: Massachusetts Institute of Technology, Compounds of the invention can activate one or more Cambridge, MA pathways that result in the inhibition of cell growth. The invention includes cytostatic and cytotoxic compounds. (21) Appl. No.: 11/078,645 Methods and compositions of the invention are particularly useful for treating cancer cells that are resistant to other (22) Filed: Mar. 10, 2005 chemotherapeutic drugs. Patent Application Publication Jan. 26, 2006 Sheet 1 of 20 US 2006/0019936A1 Patent Application Publication Jan. 26, 2006 Sheet 2 of 20 US 2006/0019936A1 O HO C ( ) s O H -N Cer N-I-O-(CH2)2-N-(CH2)6H O OH C HO H Fig. 1B Patent Application Publication Jan. 26, 2006 Sheet 3 of 20 US 2006/0019936A1 (L) O ? HO |BWEHOS) Patent Application Publication Jan. 26, 2006 Sheet 6 of 20 US 2006/0019936A1 Patent Application Publication Jan. 26, 2006 Sheet 7 of 20 US 2006/0019936A1 5 R S 1S S 5 9-N- - - Z 1S 9. - Z. ?y O O) O N 1S 9. - Z O 1S 9. 5 Patent Application Publication Jan. 26, 2006 Sheet 8 of 20 US 2006/0019936A1 gl|HLIMQB1VB81 TOHINOD(C]BIVBHLNT) —––Loo,3TDIHBA OHOTHDIG-JI—B—?009I 008 BWOWOW?. LWN 96 Patent Application Publication Jan. 26, 2006 Sheet 9 of 20 US 2006/0019936A1 C L) t;O .9) '. o={ l O .. ZC () 8 b --/ : S2-/ S O CS Patent Application Publication Jan. 26, 2006 Sheet 10 of 20 US 2006/0019936A1 arrasaaraaS AXOHIBWIG-JII W/Z5)S19/09 OHOTHDIQ-g?l || | Patent Application Publication Jan. 26, 2006 Sheet 11 of 20 US 2006/0019936A1 11 B- 11 B CHORAMBUCIL DICHLORO DIMETHOXY (h). On 3 69 15 3 6 9 15 3 6 9 15 . .3: -- U O d CC ? VO VO OO CO C tr V. D D 11 B- 11 B DCHLORO DIMETHOXY Patent Application Publication Jan. 26, 2006 Sheet 12 of 20 US 2006/0019936A1 100 2. g 75 it E Z M 50 2 25 O . E . E. E. 5 s se se -" > C N 5 C. 3is EU Uas UE it 9 - F S... ch.Cl I - U Fig.8A 11 B- 11B CHLORAMB . N -- Fig.8B 11 B- 11 B CHORAMBUCL DCHLORO . DMETHOXY (h) 6 9 24 6 9 24 6 9 24 PARP gets assis. Patent Application Publication Jan. 26, 2006 Sheet 13 of 20 US 2006/0019936A1 p70S6K-P 100 Skp2 80 60 40 20 O 2 4 6 8 10 12 14 16 18 20 22 24 TIME (hr) Fig.9 Patent Application Publication Jan. 26, 2006 Sheet 14 of 20 US 2006/0019936A1 100 60 40 O 2 4 6 8 10 12 14 16 18 20 22 24 TIME (hr) Fig. 10 Patent Application Publication Jan. 26, 2006 Sheet 15 of 20 US 2006/0019936A1 p70S6K-P 100 Skp2 80 60 40 O 2 4 6 8 1 0 1 2 4 6 18 20 22 24 TIME (hr) Fig.11 Patent Application Publication Jan. 26, 2006 Sheet 16 of 20 US 2006/0019936A1 ‘61)ZI Patent Application Publication Jan. 26, 2006 Sheet 17 of 20 US 2006/0019936A1 ESTRADOL OH bis(2-CHLOROETHYL) ANILINE H O H (CH2)2CH2)2C HO (CH2)6 -N-(CH2)2 -oil-N-(CH2-()- N -- (CH2)2C LINKER (1) Fig. 13A Patent Application Publication Jan. 26, 2006 Sheet 18 of 20 US 2006/0019936A1 WWAS INDS US 2006/0019936A1 Jan. 26, 2006 METHODS AND COMPOSITIONS FOR TREATING nucleic acid from repair due to the binding of the ligand to CANCER a specific intracellular molecule. Alternatively, or in addi tion, without wishing to be bound by theory, it is thought that RELATED APPLICATIONS compositions of the invention may act as "sinks' by binding 0001) This application claims benefit under 35 U.S.C. a specific important intracellular molecule thereby decreas 119(e) of the filing date of U.S. Ser. No. 60/552,322 filed on ing its effective intracellular concentration. However, Appli Mar. 10, 2004, the entire disclosure of which is incorporated cants have found Surprisingly that certain compounds of the herein by reference. invention are cytotoxic and induce apoptosis in diseased cells (e.g., cancer cells) that do not express or over-express FEDERALLY SPONSORED RESEARCH the intracellular molecule (e.g., a receptor) that the ligand is 0002 This invention was made with Government support known to bind to. In addition, Applicants have found that under grant R01 CA077743 from the National Cancer certain compounds that contain a mono- or di-Substituted Institute. The Government may have certain rights to this bi-functional alkylating moiety may be cytostatic and/or invention. cause cell cycle arrest. 0008 Accordingly, in one aspect the invention provides BACKGROUND OF INVENTION a method for killing androgen receptor negative cells by 0.003 Cytotoxic agents that act by covalent modification contacting the cells with an effective amount of a compound of DNA were the first modern anticancer chemotherapeutics that includes a bifunctional DNA damaging moiety that is and remain major components of combination chemo linked by a linker Stable under intracellular conditions to a therapy regimens. In combination with drugs that act by ligand for an androgen receptor. The androgen may be other mechanisms, alkylating antitumor drugs have pro testosterone (e.g., dihydroxy-testosterone). In one embodi duced impressive and even curative responses in the treat ment, the ligand may be estradienone. In one embodiment, ment of Some cancers (e.g., cisplatin in testicular cancer). the compound is 11 B-N-(2-(N-((N.N-bis-2-chloroethy Frequently, however, tumors are found to have inherent laminophenyl)propyl)-carbamoyloxy) ethyl)aminohexyl)- resistance to these compounds or to develop resistance 17 B-hydroxy-estra-A4(5).9(10)-3-one. In one embodiment, during the course of treatment. The rapid evolution of the androgen receptor negative cells are cancer cells. The resistance makes it important to develop new agents that can cancer cells may be breast, ovarian, endometrial, colon, defeat the molecular barriers responsible for clinical failure. melanoma, lymphoma and/or pancreatic cancer cells. 0009. In another aspect, the invention provides a method SUMMARY OF THE INVENTION for killing estrogen receptor negative cells by contacting the 0004 Aspects of the invention provide methods and cells with an effective amount of a compound that includes compositions (including cytotoxic and cytostatic composi a bifunctional DNA damaging moiety that is linked by a tions) useful for treating cancer and other diseases. In one linker that is stable under intracellular conditions to a ligand aspect, cytotoxic compositions of the invention may be for an estrogen receptor. The estrogen may be progesterone. apoptosis inducing agents and may be useful to treat dis In one embodiment, the ligand may be 2-phenyl-indole. In eases or conditions that are currently treated with alkylating one embodiment, the ligand may be estradiol. In one agents. In one aspect, embodiments of the invention are embodiment, the compound is 1-6{N-2-(N-((N,N-bis-2- multifunctional compounds that disrupt multiple biochemi chloroethylaminophenyl)propyl)-carbamoyl oxy)ethylami cal pathways responsible for tumor growth and Survival. nohexyl-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl indole. Certain compounds of the invention incorporate Several In one embodiment, the compound is 7c-N-(2-(N-((N.N- bis-2-chloroethylaminophenyl)propyl)-carbamoyloxy) mechanisms of action into a single anticancer agent. ethyl)aminohexyl)-3,17B-dihydroxyestra-1,3,5(10)-triene. 0005. In one aspect, compounds of the invention may In one embodiment, the estrogen receptor negative cells are include a bi-functional alkylating moiety. In another aspect, cancer cells. The cancer cells may be prostate, colon, compounds of the invention may include a variant of the melanoma, lymphoma and/or pancreatic cancer cells. bi-functional alkylating moiety that is mono-Substituted in that one of the alkylating arms of the bi-functional alkylating 0010. In yet another aspect, the invention provides a moiety is Substituted with a non-alkylating group. In yet a method for killing Vitamin D receptor negative cells by further aspect, compounds of the invention may include a contacting the cells with an effective amount of a compound variant of the bi-functional alkylating moiety that is di that includes a bifunctional DNA damaging moiety that is substituted in that both of the alkylating arms of the bi linked by a linker that is stable under intracellular conditions functional alkylating moiety are Substituted with a non to a ligand for a vitamin D receptor. In one embodiment, the alkylating group(s). ligand may be vitamin D. In one embodiment, in the compound may be 11 B-N-(2-(N-((N.N-bis-2-chloroethy 0006 According to aspects of the invention, the bi laminophenyl)propyl)-carbamoyloxy) ethyl)aminohexyl)- functional alkylating moiety may be linked by a linker that 17 B-hydroxy-estra-A4(5).9(10)-3-one. In one embodiment, is stable and/or Soluble under intracellular conditions to a the compound may be (3-4-Bis-(2-chloro-ethyl)-amino ligand that binds to one or more intracellular molecules (e.g., phenyl-propyl)-carbamic acid 2-3-(4-4-2-(3,5-dihy nucleic acid, lipid, or protein).
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