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Cryptophycins Cryptophycine Cryptophycines Europäisches Patentamt *EP000735819B1* (19) European Patent Office Office européen des brevets (11) EP 0 735 819 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07D 273/00, C07D 307/20, of the grant of the patent: C07D 413/06, C07C 237/22, 11.07.2001 Bulletin 2001/28 A61K 31/395, A61K 31/34, (21) Application number: 95906059.1 A61K 31/38, A61K 31/335, C12P 17/00, C12P 13/04 (22) Date of filing: 21.12.1994 (86) International application number: PCT/US94/14740 (87) International publication number: WO 95/17093 (29.06.1995 Gazette 1995/27) (54) CRYPTOPHYCINS CRYPTOPHYCINE CRYPTOPHYCINES (84) Designated Contracting States: (74) Representative: Baldock, Sharon Claire et al AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL BOULT WADE TENNANT, PT SE Verulam Gardens 70 Gray’s Inn Road (30) Priority: 21.12.1993 US 172632 London WC1X 8BT (GB) 27.05.1994 US 249955 (56) References cited: (43) Date of publication of application: US-A- 4 845 085 US-A- 4 845 086 09.10.1996 Bulletin 1996/41 US-A- 4 868 208 US-A- 4 946 835 (73) Proprietors: • CHEMICAL & PHARMACEUTICAL BULLETIN, • UNIVERSITY OF HAWAII vol. 42, no. 11, November 1994, TOKYO JP, Honolulu, HI 96822 (US) pages 2394-6, XP002022693 M. KOBAYASHI ET • WAYNE STATE UNIVERSITY AL.: "A total synthesis of arenastatin A, an Detroit, MI 48202 (US) extremely potent cytotoxic depsipeptide, from the Okinawan marine sponge Dysidea Arenaria" (72) Inventors: • CHEMICAL & PHARMACEUTICAL BULLETIN, • MOORE, Richard, E. vol. 42, no. 10, October 1994, TOKYO JP, pages Honolulu, HI 98816 (US) 2196-8, XP002022694 M. KOBAYASHI ET AL.: • SMITH, Charles, D. "The absolute stereostructure of Arenastatin A, Feasterville, PA 19053 (US) a potent cytotoxic depsipeptide from the • PATTERSON, Gregory M. L. Okinawan marine sponge Dysidea Arenaria" Honolulu, HI 96734 (US) • CHEMICAL ABSTRACTS, Volume 121, SMITH et • MOOBERRY, Susan, L. al., "Cryptophycin: A New Antimicrotuble Agent Honolulu, HI 96734 (US) Active Against Drug-Resistant Cells", Abstract • CORBETT, Thomas, H. No. 99272; & CANCER RESEARCH 54(14), Grosse Point, MI 48230 (US) issued 1994, pages 3779-84. • VALERIOTE, Frederick, A. Shelby Township, MI 48316 (US) • GOLAKOTI, Trimurtulu Honolulu, HI 96822 (US) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 735 819 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 0 735 819 B1 • CHEMICAL ABSTRACTS, Volume 121, • CHEMICAL ABSTRACTS, Volume 114, TRIMURTULU et al., "Total Structures of SCHWARTZ et al., "Pharmaceuticals from Cryptophycins, Potent Antitumor Depsipeptides Cultured Algae", Abstract No. 12039; & from the Blue-Green Alga Nostoc sp. Strain GSV JOURNAL OF INDUSTRIAL MICROBIOLOGY 224", Abstract No. 4625; & JOURNAL OF THE 5(2-3), pages 113-123, issued 1990. AMERICAN CHEMICAL SOCIETY 116(11), issued • CHEMICAL ABSTRACTS, Volume 113, Abstract 1994, pages 4729-37. No. 22216; & GB,A,2 220 657 (HIRSCH et al.), 17 January 1990. 2 EP 0 735 819 B1 Description Background of the Invention 5 [0001] Neoplastic diseases, characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans. Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases. Such clinical experience has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton can be effective in inhibiting the proliferation of neoplastic cells. [0002] The microtubule system of eucaryotic cells is a major component of the cytoskeleton and is in a dynamic state 10 of assembly and disassembly; that is, heterodimers of tubulin are polymerized and form microtubules. These microtu- bules play a key role in the regulation of cell architecture, metabolism, and division and their dynamic character is essential to their normal function in the cell. For example, with respect to cell division, microtubules are created, that is, polymerized from tubulin, to form the mitotic spindle. When the mitotic spindle's use has been fulfilled, the microtu- bules contained in it are subsequently depolymerizd. Disrupting either the polymerization or depolymerization of mi- 15 crotubules in the cell can inhibit mitosis, and thereby cell proliferation. [0003] An agent which could prevent a cell from proliferating by inhibiting a cells' microtubule dynamic state would be useful in treating cancer, a disease characterized by cells proliferating at abnormally high rates. Indeed, such agents comprise some of the most effective cancer chemotherapeutic agents in clinical use today. [0004] These anti-mitotic agents or poisons are classified into three groups based on their molecular mechanism of 20 action. The first group, including colchicine and colcemid, inhibit the formation of microtubules by sequestering tubulin. The second group, including vinblastine and vincristine, induce the formation of paracrystalline aggregates of tubulin. These two agent's action preferentially inhibits the proliferation of hyperproliferating cells by disrupting mitotic spindle microtubules. The third group, including taxol, promotes the polymerization of tubulin, thereby disrupting the dyanmic state of microtubule polymerization and depolymerization. 25 [0005] However, an agent's having activity as an antimitotic poison does not lead to the concluaion that this agent would evince such activity in a tumor cell nor in a tumor cell with a drug-resistant phenotype. For example, vinca alkaloids such as vinblastine and vincristine are effective against some neoplastic cells and tumors, yet they lack activity against some drug-resistant tumors and cells. One basis for a neoplastic cell displaying drug resistance (DR) or multiple- drug resistance (MDR) is through the over-expression of P-glycoprotein. Compounds which are poor substrates for 30 transport of P-glycoprotein should be useful in circumventing such a MDR phenotype. [0006] Accordingly, the exhibition of the DR or MDR phenotype by many tumor cells and the clinically proven mode of action of anti-microtubule agents against neoplastic cells necessitates the development of anti-microtubule agents cytotoxic to non-drug resistant neoplastic cells as well as cytotoxic to neoplastic cells with a drug resistant phenotype. 35 Background Art [0007] Selected cryptophycin compounds, dioxa-diazacyclohexadecenetetrones isolated or synthesized from iso- lates from the blue-green algae (cyanobacteria) of the genus Nostoc, were characterized as antifungal agents with activity toward filamentous fungi, specifically the Aspergillus, Penicillium and 40 Phoma species thereof; however, their mechanism of action was unknown. Five cryptophycin compounds, herein des- ignated Cryptophycins 1, 3, 5, 13 and 15, were disclosed in U.S. Patent Nos. 4,946,835, 4,845,085, 4,845,086, and 4,868,208, such compounds either having been isolated from a strain of Nostoc sp. designated MB 5357 or having been synthesized from such an isolated compound. 45 Summary of the Invention [0008] The present invention provides novel cryptophycin compounds having the following structure: 50 55 3 EP 0 735 819 B1 5 10 Wherein 15 R1 is H, OH, a halogen, O of a ketone group, NH2, SH, a lower alkoxyl group or a lower alkyl group; R2 is H, OH, O of a ketone group, NH2, SH, a lower alkoxyl group or a lower alkyl group; or R1 and R2 may be taken together to form an epoxide ring, an aziridene ring, a sulfide gring or a second bond between C10 and C11; or R1 and R4 may be taken together to form a tetrahydrofuran ring; 20 R3 is H or a lower alkyl group; R4 is OH, a lower alkanoyloxy group or a lower α-hydroxy alkanoyloxy group; R5 is H or an OH group; R6 is H; or R5 and R6 may be taken together to form a second bond between C5 and C6; 25 R7 is a benzyl, hydroxybenzyl, methoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, halomethoxybenzyl, or dihalomethoxybenzyl group; R8 is OH, a lower β-amino acid wherein C1 is bonded to N of the β-amino acid, or an esterified lower β-amino acid wherein C1 is bonded to N of the esterified lower β-amino acid group; R4 and R8 may be taken together to form a didepsipeptide group consisting of a lower β-amino acid bonded to a 30 lower α-hydroxy alkanoic acid; or R5 and R8 may be taken together to form a didepsipeptide group consisting of a lower β-amino acid bonded to a lower α-hydroxy alkanoic acid; with the following provisos: 35 R1 is H, a lower alkyl group, or a lower alkoxyl group only if R2 is OH, O of a ketone group, NH2, SH; R2 is H, a lower alkyl group, or a lower alkoxyl group only if R1 is OH, O of a ketone group, NH2, SH; when R1 is OH, R2 is OH, R3 is methyl, R5 and R6 are taken together to form a second bond between C5 and C6, R4 and R8 are taken together to form the didepsipeptide group with the structure X: 40 45 50 wherein O1 of X corresponds to R4, N8 of X corresponds to R8, R9 is methyl, and R10 is isobutyl, R7 is not 3-chloro-4-methoxybenzyl; when R1 and R2 are taken together to form an epoxide ring, R3 is methyl, R5 and R6 are taken together to form a second bond between C5 and C6,R4and R8 are taken together to form a didepsipeptide with the structure X, R9 is methyl, and R10 is isobutyl, R7 is not 3-chloro-4-methoxybenzyl; 55 when R1 and R2 are taken together to form a second bond between C10 and C11,R3is methyl, R5 and R6 are taken together to form a second bond between C5 and C6, R4 and R8 are taken together to form a didepsipeptide with the structure X, R9 is methyl, and R10 is isobutyl, R7 is not 3-chloro-4-methoxybenzyl; and 4 EP 0 735 819 B1 when R1 and R2 are taken together to form an epoxide group, R3 is methyl, R5 and R6 are taken together to form a second bond between C5 and C6,R4is bonded to the carboxy terminus of leucic acid, and R8 is bonded to the nitrogen terminus of either 3-amino-2-methylpropionic acid or 3-amino-2-methylpropionic acid methyl ester, R7 is not 3-chloro-4-methoxybenzyl.
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