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1. WO1996039829 - NEW CRYPTOPHYCINS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

What is claimed is:
1. A cryptophycin represented by the structure:


Wherein
R, is H or a halogen;
R2 is H, an oxygen of a ketone or OH; or
R, and R2 may be taken together to form an epoxide ring; or R, and R2 may be taken together to form an episulfide ring;
R3 is H, or a lower alkyl group;
R4 is H or OH;
R5 is H or OH; or
R4 and R5 may be taken together to form a second bond;
Rt is H or a halogen;
With the following proviso
when R, and R2 are taken together to form an epoxide group, R4 and R3 are taken together to form a second bond and R« is chlorine, R3 is not methyl.

2. A method for producing a cryptophycin of the following structure:


Wherein
R, is H or a halogen;
R2 is H, an oxygen of a ketone or OH; or R, and R2 may be taken together to form an epoxide ring; or R, and R2 may be taken together to form an episulfide ring;
R3 is H, or a lower alkyl group;
R4 is H or OH;
R5 is H or OH; or
R4 and R3 may be taken together to form a second bond;
Re is H or a halogen;
With the following proviso
when R, and R2 are taken together to form an epoxide group, R4 and R3 are taken together to form a second bond and R^ is chlorine, R3 is not methyl.

3. A pharmaceutical composition useful for inhibiting the proliferation of a hyperproliferative mammalian cell comprising an effective amount of a compound with the following structure:


Wherein
R, is H or a halogen;
R2 is H, an oxygen of a ketone or OH; or
R, and R2 may be taken together to form an epoxide ring; or R, and R2 may be taken together to form an episulfide ring;
R3 is H, or a lower alkyl group;
R4 is H or OH;
R3 is H or OH; or
R4 and R3 may be taken together to form a second bond;
Re is H or a halogen;
With the following proviso
when R, and R2 are taken together to form an epoxide group, R4 and R3 are taken together to form a second bond and R« is chlorine, R3 is not methyl;
together with a pharmaceutically acceptable carrier.

SUBSTIΓ : SHEET (RULE 26)

4. The pharmaceutical composition of claim 3 further comprising at least one additional antineoplastic agent.

5. A method for inhibiting the proliferation of a mammalian cell comprising contacting the mammalian cell with the cryptophycin compound of claim 1 in an amount sufficient to disrupt the dynamic state of microtubule polymerization and depolymerization to arrest cell mitosis, thereby inhibiting the proliferation of the cell

6. The method of claim 5 further comprising contacting the cell with at least one additional anti-neoplastic agent.

7. The method of claim 5, wherein the mammalian cell is hyperproliferative.

8. The method of claim 8, wherein the hyperproliferative cell is human.

9. A method of alleviating a pathological condition caused by hyperproliferating mammalian cells comprising administering to a subject an effective amount of the pharmaceutical composition of claim 3 to inhibit proliferation of the cells.

10. The method of claim 9, wherein the mammalian cells are human.

11. The method of claim 10 further comprising administering to the subject at least one additional therapy directed to alleviating the pathological condition.

12. The method of claim 9, wherein the pathological condition is characterized by the formation of neoplasms.

13. The method of claim 12, wherein the neoplasms are selected from the group consisting of mammory, small-cell lung, non-small-cell lung, colorectal, leukemia, melanoma, pancreatic adenocarcinoma, central nervous system (CNS), ovarian, prostate, sarcoma of soft tissue or bone, head and neck, gastric which includes pancreatic and esophageal, stomach, myeloma, bladder, renal, neuroendocrine which includes thyroid and non-Hodgkin's disease and Hodgkin's disease neoplasms.