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WO1997007798A1 - Composes pharmaceutiques - Google Patents

Composes pharmaceutiques Download PDF

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Publication number
WO1997007798A1
WO1997007798A1 PCT/US1996/013855 US9613855W WO9707798A1 WO 1997007798 A1 WO1997007798 A1 WO 1997007798A1 US 9613855 W US9613855 W US 9613855W WO 9707798 A1 WO9707798 A1 WO 9707798A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
alkyl
cryptophycin
hydrogen
Prior art date
Application number
PCT/US1996/013855
Other languages
English (en)
Inventor
Richard E. Moore
Vinod F. Patel
James E. Ray
John E. Toth
Original Assignee
Eli Lilly And Company
University Of Hawaii
Wayne State University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company, University Of Hawaii, Wayne State University filed Critical Eli Lilly And Company
Priority to EP96929780A priority Critical patent/EP0850057A4/fr
Priority to BR9610214A priority patent/BR9610214A/pt
Priority to JP9510549A priority patent/JP2000501067A/ja
Priority to AU69048/96A priority patent/AU6904896A/en
Publication of WO1997007798A1 publication Critical patent/WO1997007798A1/fr
Priority to JP10511080A priority patent/JP2001502297A/ja
Priority to AU43300/97A priority patent/AU4330097A/en
Priority to EP97941379A priority patent/EP0957912A1/fr
Priority to PCT/US1997/015245 priority patent/WO1998008506A1/fr
Priority to CA002263420A priority patent/CA2263420A1/fr
Priority to MXPA/A/1998/001604A priority patent/MXPA98001604A/xx

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione

Definitions

  • This invention relates to the fields of pharmaceutical and organic chemistry and provides novel cryptophycin compounds useful as anti-microtubule agents.
  • 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 and other mammals.
  • Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases.
  • drugs which disrupt the microtubule system of the cytoskeleton can be effective in inhibiting the proliferation of neoplastic cells.
  • the microtubule system of eucaryotic cells is a major component of the cytoskeleton and is a dynamic assembly and disassembly. Thus heterodimers of tubulin are polymerized and form microtubule.
  • Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The dynamic state of microtubules is critical to their normal function.
  • tubulin is polymerized into microtubles that form the mitotic spindle.
  • the microtubules are then depolymerized when the mitotic spindle's use has been fulfilled.
  • agents which disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis comprise, some of the most effective cancer chemotherapeutic agents in clinical use.
  • the compounds claimed herein possess fungicidal properties. Further, such agents having the ability to disrupt the microtubule system can be useful for research purposes.
  • cryptophycin compounds are known in the literature; however, cryptophycin compounds having even greater solubility, robust potency are desired for most pharmaceutical uses and a broader library of cryptophycin compounds could provide additional treatment options.
  • novel compounds providing such desired solubility as well compounds having the ability to disrupt the microtubule system.
  • Such compounds can be prepared using total synthetic methods and are therefore well suited for development as pharmaceutically useful agents.
  • the presently claimed invention provides novel cryptophycin compounds of Formula I
  • Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C_-C_ 2 alkyl, C_-C_ 2 alkyne;
  • R 1 is halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, or phosphate;
  • R 2 is OH or SH; or R 1 and R 2 may be taken together to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, a cyclopropyl ring, or monoalkylphosphate ring; or R 1 and R 2 may be taken together to form a second bond between Cis and C 19 ;
  • R 3 is a lower alkyl group;
  • R 4 is H;
  • R 5 is H;
  • R 4 and R 5 may be taken together to form a second bond between Ci 3 and Ci 4 ,- R 6 is a substituent selected from the group consisting of B- ring heteroaromatic, substituted heteroaromatic, B-ring (C_-C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, substituted C 3 -C 8 cycloalkyl, substituted (C_-C 6 ) alkyl, a group of the formula III":
  • R 7 is selected from the group consisting of NR 51 R 52 , R 53 NR 5 l R 52 OR 53 , H and a lower alkyl group;
  • R 51 and R 52 are independently selected from the group consisting of C 1 -C 3 alkyl;
  • R 53 is C 1 -C 3 alkyl;
  • R 8 is H or a lower alkyl group;
  • R 7 and R 8 can optionally form a cyclopropyl ring;
  • R 9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, and lower alkyl-C 3 -C5 cycloalkyl;
  • R 10 is H or a lower alkyl group; R 9 and R 10 together optionally form a cyclopropyl ring;
  • R 11 is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl;
  • R 14 is H or a lower alkyl group
  • R 15 , R 16 , and R 17 are each independently selected from the group consisting of hydrogen, (C_-C 6 )alkyl, OR 18 , halo,
  • R 18 is selected from the group consisting of hydrogen, aryl, and C_-C 6 alkyl
  • R 18 ' is selected from the group consisting of hydrogen and
  • R 19 is C1-C6 alkyl
  • R 19 ' is selected from the group consisting of hydrogen and (Ci-C ⁇ )alkyl
  • R 23 is selected from the group consisting of hydrogen and (C_-
  • R 30 is hydrogen or Ci-C ⁇ alkyl; n is 0, 1, or 2 p is 0, 1, or 2 . m is 0, 1, or 2 .
  • X is selected from the group consisting of 0, NH and alkylamino
  • Y is selected from the group consisting of 0, NH, and alkylamino
  • Z is selected from the group consisting of -(CH 2 ) n _ ,
  • ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof; provided that when R 6 is a group of Formula III" and n is 1, then at least one of the group consisting of R 15 , R l ⁇ and R 17 ust be a non-hydrogen group and if only one of R 15 , R 16 and R 17 is OH or OR 29 and one of the group consisting of R 15 , R 16 and R 17 is halo then the remaining member of the group consisting of R 15 , R 16 and R 17 must not be hydrogen or halo; R 29 is (C 1 -C 5 )alkyl; further provided that the compound is not a cryptophycin selected from the group consisting of cryptophycins:
  • the present invention provides pharmaceutical formulations, a method for disrupting a microtubulin system using an effective amount of a compound of Formula I, a method for inhibiting the proliferation of mammalian cells comprising administering an effective amount of a compound of Formula I, and a method for treating neoplasia in a mammal comprising administering an effective amount of a compound of Formula I.
  • the term "simple alkyl” shall refer to C 1 -C 7 alkyl wherein the alkyl may be saturated, unsaturated, branched, or straight chain.
  • Example ⁇ include, but are in no way limited to, methyl, ethyl, n-propyl, iso ⁇ propyl, n-butyl, propenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, methylated pentyl groups and the like.
  • B-ring C ⁇ -C 6 alkyl refers to saturated, unsaturated, branched and straight chain alkyl wherein the B-ring C -Cgalkyl group may include up to three (3) non-carbon substituents.
  • non-carbon substituents are most preferredly selected from the group consisting of OH, SCH phenyl, NH 2 , CO, CONH 2 , CO 2 H, PO 3 H 2 , SO 2 R 21 wherein R 21 is selected from hydrogen and C 1 -C 3 alkyl;
  • substituted phenyl shall refer to a phenyl group with from one to three non- hydrocarbon substituents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I.
  • substituted benzyl shall refer to a benzyl group with from one to three non- hydrocarbon substitutents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I wherein such substituents may be attached at any available carbon atom.
  • B-ring heteroaromatic group refers to aromatic rings which contain one or more non-carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur.
  • B-ring heterocyclic groups are selected from, but not limited to, the group consisting of
  • R 20 is selected from hydrogen and C_-C 6 alkyl. It is especially preferred that "B-ring heteroaromatic group” refers to a substituent selected from the group consisting of:
  • cycloalkyl refers to a saturated Ci-Cs cycloalkyl group wherein such group may include from zero to three substituents selected from the group consisting of C 1 -C 3 alkyl, halo, and OR 22 wherein R 22 is selected from hydrogen and C 1 -C 3 alkyl. Such substituents may be attached at any available carbon atom. It is especially preferred that cycloalkyl refers to substituted or unsubstituted cyclohexyl.
  • Lower alkoxy1 group means any alkyl group of one to five carbon atoms bonded to an oxygen atom.
  • lower alkyl group means an alkyl group of one to five carbons and includes linear and non- linear hydrocarbon chains, including for example, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, and methylated pentyl groups.
  • allylically substituted alkene means any alkene having from one to seven carbon atoms which contains an alkyl substitution on it.
  • unsaturated lower alkyl means a lower alkyl group as defined supra , wherein from one to two double bonds are present in the unsaturated lower alkyl substituent.
  • lower alkyl-C 3 ⁇ C 5 cycloalkyl refers to C-C alkyl substituted with a C 3 -C 5 cycloalkyl group.
  • a preferred lower alkyl-C 3 -C 5 cycloalkyl group is -CH 2 -cyclopropyl; wherein the group is attached to the cryptophycin core structure at R 9 via the CH 2 .
  • epoxide ring means a three- membered ring whose backbone consists of two carbons and an oxygen atom.
  • aziridine ring means a three- membered ring whose backbone consists of two carbon atoms and a nitrogen atom.
  • sulfide ring means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom.
  • episulfide ring means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom.
  • sulfate group means a five membered ring consisting of a carbon- carbon-oxygen-sulfur-oxygen backbone with two additional oxygen atoms connected to the sulfur atom.
  • cyclopropyl ring mean ⁇ a three member ring whose backbone consists of three carbon atoms.
  • monoalkylphosphate ring means a five membered ring consisting of a carbon-carbon-oxygen-phosphorous-oxygen backbone with two additional oxygen atoms, one of which bears a lower alkyl group, connected to the phosphorous atom.
  • concise unsubstituted aromatic group refers to common aromatic rings having 4n ⁇ -2 electrons in a monocyclic conjugated system, for example, but not limited to: furyl, pyrrolyl, thienyl, pyridyl and the like, or a bicyclic conjugated system, for example but not limited to indolyl or naphthyl.
  • simple substituted aromatic group refers to a phenyl group substituted with a single group selected from the group consisting of halogen and lower alkyl group.
  • heteromatic group refers to aromatic rings which contain one or more non-carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur.
  • halogen or “halo” refers to those members of the group on the periodic table historically known a ⁇ halogens. Methods of halogenation include, but are not limited to, the addition of hydrogen halides, substitution at high temperature, photohalogenation, etc., and such methods are known to the skilled artisan.
  • the term “mammal” shall refer to the Mammalia class of higher vertebrates.
  • the term “mammal” includes, but is not limited to, a human.
  • the term “treating” as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.
  • the cryptophycin compounds claimed herein can be useful for veterinary health purposes as well as for the treatment of a human patient.
  • R 7 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl;
  • R 7 is H, R 8 is methyl, R 3 is methyl, and X and Y are not both O; D) R 3 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl;
  • R 9 is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl;
  • R 10 is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or i ⁇ opentyl;
  • G a cryptophycin compound wherein at least one of the groups selected from the group consisting of C- 3, C-6, C-7, C-10, C-16, C-17, and C-18 has R stereochemistry (numbering as set forth in Formula I supra . ) ;
  • H a cryptophycin compound wherein at least one of the groups selected from the group consisting of C- 3, C-6, C-7, C-10, C-16, C-17, and C-18 has S stereochemi ⁇ try (numbering a ⁇ set forth in Formula I supra . ) ;
  • Ar is phenyl with a sub ⁇ tituent selected from the group consisting of hydrogen, halogen, and simple alkyl; J) a compound wherein Y is 0; K) a compound wherein Y is 0, R 7 , R 8 , R 9 , and R 10 are each hydrogen; and R 1 and R 2 form an epoxide; L) R 7 , R 8 are each hydrogen;
  • R 7 and R 8 are each selected from hydrogen and CH 3 ; N) Y is O;
  • R is selected from the group consisting of methyl, ethyl, n-propyl, and phenyl; P) R 1 and R 2 form an epoxide ring;
  • R 4 and R 5 form a double bond
  • R 6 is substituted benzyl wherein one substituent is a halogen and one is an OR 12 group wherein R 12 is lower alkyl;
  • R6 is ⁇ elected from the group consisting of
  • Z) Z is -(CH2) n - wherein n is 0; AA) Z is -(CH2) n - wherein n is 2; BB) Z is -(CH2) n - wherein n is 1; CC) R 6 is Formula III';
  • R 6 is Formula III' 1 ; EE) R 6 is C 3 -C 6 cycloalkyl;
  • R 6 is selected from the group consisting of fi ⁇ ring heteroaromatic, substituted heteroaromatic, B-ring alkyl, cycloalkyl, substituted cycloalkyl, Formula III' and Formula III ' ' ;
  • R 15 , R l ⁇ , and R 17 is selected from the group consisting of SCH 2 phenyl, NH 2 , CO, CONH 2 , CO 2 H, PO 3 H 2 , and SO 2 R 21 ' " wherein R 21 is selected from hydrogen and C 1 -C 3 alkyl;
  • HH) Ar is phenyl
  • R 6 i ⁇ a heteroaromatic ring
  • MM R 7 is selected from the group consisting of N ( CH 3 ) 2 , CH 2 N ( CH 3 ) 2; NN) R 7 is CH 2 OCH 3 ;
  • R 9 is CH 2 cyclopropyl
  • R 3 is CH 3 ; R 4 and R 5 together form a second bond;
  • R 14 is hydrogen;
  • R 30 is hydrogen;
  • R 7 and R 8 are each methyl;
  • R 10 is hydrogen;
  • R 9 is -CH 2 CH(CH3) 2 ;
  • X and Y are each O;
  • Ar is phenyl; and Ri R 2 - R-6
  • Ar is instead of phenyl.
  • the present invention provides a method of alleviating a pathological condition caused by hyperproliferating mammalian cells comprising administering to a subject an effective amount of a pharmaceutical or veterinary composition disclo ⁇ ed herein to inhibit proliferation of the cells.
  • the method further comprises administering to the subject at least one additional therapy directed to alleviating the pathological condition.
  • the pathological condition is characterized by the formation of neoplasm ⁇ .
  • the neoplasms are selected from the group consi ⁇ ting of mammary, 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.
  • CNS central nervous system
  • neoplastic refers to a neoplasm, which is an abnormal growth, such growth occurring because of a proliferation of cells not ⁇ ubject to the u ⁇ ual limitations of growth.
  • anti-neopla ⁇ tic agent i ⁇ any compound, compo i ion, admixture, co-mixture, or blend which inhibit ⁇ , eliminate ⁇ , retard ⁇ , or reverses the neoplastic phenotype of a cell.
  • Anti-mitotic agents may be classified into three groups on the basi ⁇ of their molecular mechani ⁇ m of action.
  • the first group consist ⁇ of agents, including colchicine and colcemid, which inhibit the formation of microtubules by sequestering tubulin.
  • the second group consist ⁇ of agents, including vinblastine and vincristine, which induce the formation of paracry ⁇ talline aggregate ⁇ of tubulin.
  • Vinblastine and vincristine are well known anticancer drugs: their action of di ⁇ rupting mitotic ⁇ pindle microtubule ⁇ preferentially inhibit ⁇ hyperproliferative cells.
  • the third group consists of agents, including taxol, which promote the polymerization of tubulin and thus stabilizes microtubules.
  • composition ⁇ containing a therapeutically effective amount of at lea ⁇ t one compound of Formula I, including the non-toxic addition salts thereof, which serve to provide the above recited benefits.
  • compositions can also be provided together with physiologically tolerable liquid, gel, or solid carriers, diluents, adjuvants and excipients.
  • physiologically tolerable liquid, gel, or solid carriers diluents, adjuvants and excipients.
  • Such carriers, adjuvants, and excipients may be found in the U.S. Pharmacopeia, Vol. XXII and National Formulary vol XVII, U.S. Pharmacopeia Convention. Inc. Rockville, MD (1989) . Additional modes of treatment are provided in AHFS Dru ⁇ Information, 1993 e. by the American Hospital Formulary Service, pp. 522-660. Each of these references are well known and readily available to the skilled artisan.
  • the present invention further provides a pharmaceutical composition used to treat neoplastic disease containing at least one compound of Formula I and at least one additional anti-neoplastic agent.
  • Anti-neoplastic agents which may be utilized in combination with Formula I compounds include those provided in the Merck Index 11, pp 16-17, Merck & Co., Inc. (1989) .
  • the Merck Index is widely recognized and readily available to the skilled artisan.
  • antineoplastic agents may be antimetabolites which may include but are in no way limited to those selected from the group consisting of methotrexate, 5-fluorouracil, 6- mercaptopurine, cytosine, arabinoside, hydroxyurea, and 2- chlorodeoxyadeno ⁇ ine.
  • the anti-neoplastic agents contemplated are alkylating agents which may include but are in no way limited to those ⁇ elected from the group consisting of cyclopho ⁇ phamide, mephalan, busulfan, paraplatin, chlorambucil, and nitrogen mustard.
  • the anti-neoplastic agents are plant alkaloids which may include but are in no way limited to those selected from the group consisting of vincristine, vinblastine, taxol, and etoposide.
  • the anti-neoplastic agents contemplated are antibiotic ⁇ which may include, but are in no way limited to tho ⁇ e ⁇ elected from the group consisting of doxorubicin, daunorubicin, mitomycin C, and bleomycin.
  • the anti-neoplastic agents contemplated are hormones which may include, but are in no way limited to those selected from the group consisting of calusterone, diomostavolone, propionate, epitiostanol, mepitiostane, testolactone, tamoxifen, polyestradiol phosphate, megesterol acetate, flutamide, nilutamide, and trilotane.
  • the anti-neoplastic agents contemplated include enzymes which may include, but are in no way limited to tho ⁇ e ⁇ elected from the group con ⁇ i ⁇ ting of L- A ⁇ pargina ⁇ e and aminoacridine derivative ⁇ ⁇ uch as, but not limited to, amsacrine.
  • Additional anti-neoplastic agents include those provided by Skeel, Roland T., "Antineoplastic Drugs and Biologic Response Modifier: Classification, Use and Toxicity of Clinically Useful Agents" Handbook of Cancer Chemotheranv (3rd ed. ) , Little Brown & Co. (1991) . These compounds and compositions can be administered to mammals for veterinary use.
  • the dosage required for therapeutic effect will vary according to the type of use, mode of administration, as well as the particularized requirements of the individual hosts. Typically, dosages will range from about 0.001 to 1000 mg/kg, and more usually 0.01 to 10 mg/kg of the host body weight. Alternatively, dosages within these ranges can be administered by constant infusion over an extended period of time, usually exceeding 24 hours, until the desired therapeutic benefits are obtained.
  • drug dosage as well as route of administration, must be selected on the basis of relative effectivenes ⁇ , relative toxicity, growth characteristics of tumor and effect of Formula I compound on cell cycle, drug pharmacokinetics, age, sex, physical condition of the patient and prior treatment, which can be determined by the skilled artisan.
  • the compound of Formula I may be formulated into therapeutic compositions as natural or salt forms.
  • Pharmaceutically acceptable non-toxic salts include base addition salts which may be derived from inorganic bases such as for example, ⁇ odium, potassium, ammonium, calcium, or ferric hydroxides, and such organic base ⁇ a ⁇ isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as for example, hydrochloric or phosphoric acids or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Additional excipients which further the invention are provided to the skilled artisan for example in the U.S. Pharmacopeia .
  • anti- neoplastic compositions may be formulated for oral administration. Such compositions are typically prepared as liquid solution or suspen ⁇ ions or in solid forms. Oral formulation usually include such additives as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions may take the form of solution ⁇ , suspension ⁇ , tablet ⁇ , pills, capsules, ⁇ u ⁇ tained relsease formulations, or powders, and typically contain 1% to 95% of active ingedient.
  • compositions of the present invention may be prepared as injectables, either as liquid solutions, suspensions, or emulsion ⁇ ; ⁇ olid form ⁇ suitable for solution in or suspension in liquid prior to injection. Such injectables may be administered subcutaneously, intravenously, intraperitoneally, intramuscularly, intrathecally, or intrapleurally.
  • the active ingredient or ingredients are often mixed with diluents, carriers, or excipients which are physiologically tolerable and compatible with the active ingredient (s) .
  • Suitable diluent ⁇ and excipients are for example, water, saline, dextrose, glycerol, or the like and combinations thereof.
  • the compositions may contain minor amounts of auxilary ⁇ ubstances such as wetting or emulsifying agents, stabilizing or pH buffering agents.
  • the invention further provides methods for using
  • a preferred embodiment i ⁇ a method to inhibit the proliferation of hyperproliferative mammalian cell ⁇ .
  • hyperproliferative mammalian cells are mammalian cells which are not subject to the characteristic limitations of growth (programmed cell death for example) .
  • a further preferred embodiment is when the mammalian cell is human.
  • the invention further provides contacting the mammalian cell with at least one Formula I compound and at least one anti-neoplastic agent. The types of anti-neopla ⁇ tic agents contemplated are discussed supra .
  • the invention further provides methods for using a compound of Formula I to inhibit the proliferation of hyperproliferative cell ⁇ with drug-resistant phenotypes, including those with multiple drug-resi ⁇ tant phenotypes, by contacting said cell with a compound of Formula I in an amount sufficient to inhibit the proliferation of a hyperproliferative mammalian cell.
  • a preferred embodiment is when the mammalian cell is human.
  • the invention further provides contacting a Formula I compound and at least one additional anti-neoplastic agent, discussed supra .
  • the invention provides a method for alleviating pathological conditions caused by hyperproliferating mammalian cells for example, neoplasia, by administering to a subject an effective amount of a pharmaceutical composition containing Formula I compound to inhibit the proliferation of the hyperproliferating cell ⁇ .
  • pathological condition refers to any pathology arising from the proliferation of mammalian cells that are not subject to the normal limitations of growth. Such proliferation of cells may be due to neoplasms as discussed supra .
  • the neoplastic cells are human.
  • the present invention provides methods of alleviating ⁇ uch pathological conditions utilizing a compound of Formula I in combination with other therapies, as well as other anti-neoplastic agents.
  • Twofold dilution ⁇ are made with sterile distilled water/10 percent DMSO to obtain final drug concentrations in the agar dilution assay plates ranging from 0.008 ⁇ g/ml to 16.0 ⁇ g/ml against an expanded panel of 84 Cryptococcus neoformans strains.
  • Cryptococcus neoformans isolates is determined to illustrate the desired antifungal activity.
  • the compounds are screened for minimum inhibitory concentrations against KB, a human nasopharyngeal carcinoma cell line, LoVo, a human colorectal adenocarcinoma cell line using The Corbett assay, see Corbett, T.H. et al. Cvtotoxic Anticancer Dru ⁇ s: Models and Concepts for Dru ⁇ Discovery and Developmen . pp 35-87, Kluwer Academic Publisher ⁇ : Norwell, 1992. see also, Valeriote, et al. Discovery and Development of Anticancer Agents; Kluwer Academic Publisher ⁇ , Norwell, 1993 i ⁇ used for the evaluation of compounds.
  • the most active compounds are further evaluated for cytotoxicity against four different cell types, for example a murine leukemia, a murine solid tumor, a human solid tumor, and a low malignancy fibroblast using the Corbett assay.
  • the compounds are further evaluated against a broad spectrum of murine and human tumors implanted in mice, including drug resi ⁇ tant tumors.
  • Tumor burden (mean tumor burden in treated animals versus mean tumor burden in untreated animals) are used as a further as ⁇ essment. T/C values that are less than 42% are considered to be active by National Cancer Institute Standards; T/C values less than 10% are considered to have excellent activity and potential clinical activity by National Cancer Institute standards. Materials
  • Vinblastine Vinblastine, cytochalasin B, tetramethylrhodamine isothiocyanate (TRITC) -phalloidin, sulforhodamine B (SRB) and antibodies against ⁇ -tubulin and vimentin are commercially available from recognized commercial vendors.
  • BME Basal Medium Eagle containing Earle ' s salts
  • FBS Fetal Bovine Serum
  • the Jurkat T cell leukemia line and A-10 rat aortic smooth muscle cells are obtained from the American Type Culture Collection and are cultured in BME containing 10% FBS and 50 ⁇ g/mL gentamycin sulfate.
  • Human ovarian carcinoma cell ⁇ (SKOV3) and a sub-line which has been selected fro re ⁇ i ⁇ tance to vinbla ⁇ tine (SKVLBl) were a generou ⁇ gift from Dr. Victor Ling of the Ontario Cancer Institute. Both cell lines are maintained in BME containing 10% FBS and 50 ⁇ g/mL gentamycin sulfate.
  • Vinblastine is added to a final concentration of l ⁇ g/mL to SKVLBl cells 24 hours after pas ⁇ age to maintain selection pressure for P-glycoprotein- overexpressing cells.
  • Cell proliferation as ⁇ ay ⁇ are performed as described by Skehan et al .
  • cultures are treated with the indicated drugs as described in Skehan and total cell numbers are determined by counting the cells in a hemacytometer.
  • the percentage of cells in mitosis are determined by staining with 0.4% Giemsa in PBS followed by rapid wa ⁇ he ⁇ with PBS.
  • At least 1000 cells per treatment are scored for the presence of mitotic figures and the mitotic index is calculated as the ration of the cells with mitotic figures to the total number of cells counted.
  • A-10 cells are grown to near-confluency on glass coverslips in BME/10% FBS. Compounds in PBS are added to the indicated final concentrations and cells are incubated for an additional 24 hours. For the staining of microtubules and intermediate filaments, the cells are fixed with cold methanol and incubated with PBS containing 10% calf serum to block nonspecific binding sites. Cells are then incubated at 37"C for 60 min. with either monoclonal anti- ⁇ -tubulin or with monoclonal anti-vimentin at dilutions recommended by the manufacturer. Bound primary antibodies are subsequently visualized by a 45-minute incubation with fluorescein- conjugated rabbit antimouse IgG.
  • the coverslips are mounted on microscope slides and the fluorescence patterns are examined and photographed using a Zeiss Photomicroscope 111 equipped with epifluorescence optics for fluore ⁇ cein.
  • a Zeiss Photomicroscope 111 equipped with epifluorescence optics for fluore ⁇ cein.
  • cells are fixed with 3% paraformaldehyde, permeabilized with 0.2% Triton X-100 and chemically reduced with sodium borohydride (Img/ML) .
  • PBS containing lOOnM TRITC-phalloidin is then added and the mixture is allowed to incubate for 45 min. at 37 'C.
  • the cells are washed rapidly with PBS before the coverslips are mounted and immediately photographed a ⁇ de ⁇ cribed above.
  • Dose-re ⁇ pon ⁇ e curve ⁇ for the effect ⁇ of cryptophycin compounds and vinblastine on cell proliferation and the percentage of cells in mitosis are determined.
  • Aortic smooth muscle (A-10) cells are grown on glass coverslip ⁇ and treated with PBS, 2 ⁇ M cytochala ⁇ in B, lOOnM vinbla ⁇ tine or lOnM cryptophycin compounds . After 24 hours, microtubules and vimentin intermediate filaments are visualized by indirect immunofluorescence and microfilaments are stained using TRITC - phalloidin. The morphological effects of each drug is examined. Untreated cells displayed extensive microtubule networks complete with perinuclear microtubule organizing centers. Vimentin intermediate filaments were also evenly distributed throughout the cytoplasm, while bundles of microfilaments were concentrated along the major axis of the cell.
  • Cytochalasin B cau ⁇ ed complete depolymerization of microfilaments along with the accumulation of paracrystalline remnants. This compound did not affect the distribution of either microtubules or intermediate filaments. The cryptophycin treated microtubules and vimentin intermediates are observed for depletion of microtubules, and collapse of rimentin intermediate filaments.
  • A-10 cells are treated for 3 hours with 0 or 10 ⁇ M taxol before the addition of PBS, lOOnM vinblastine or lOnM cryptophycin compound.
  • microtubule organization i ⁇ examined by immunofluorescence as described above.
  • microtubule ⁇ in taxol-treated cell ⁇ were extensively bundled, especially in the cell polar regions.
  • vinblastine caused complete depolymerization of microtubules non-pretreated cells.
  • pretreatment with taxol prevented microtubule depolymerization in respon ⁇ e to vinblastine.
  • microtubules pretreated with taxol are observed with cryptophycin treatment.
  • A-10 cells are treated with either lOOnM vinblastine or lOnM cryptophycins for 24 hr., re ⁇ ulting in complete microtubule depolymerization.
  • the cell ⁇ are then wa ⁇ hed and incubated in drug-free medium for period ⁇ of 1 hour or 24 hour ⁇ .
  • Microtubule ⁇ repolymerized rapidly after the removal of vinbla ⁇ tine, ⁇ howing significant levels of microtubules after 1 hour and complete morphological recovery by 24 hour.
  • Cells are visualized for microtubule state after treatment with a cryptophycin compound of this invention at either 1 hour or 24 hours after removal of the cryptophycin compounds.
  • SKOV3 cells are treated with combinations of cryptophycins and vinblastine for 48 hours. The percentages of surviving cells are then determined and the IC 50 S for each combination is calculated.
  • SKVLBl cells are resistant to natural product anticancer drugs because of their over expression of P-glycoprotein.
  • Taxol caused dose-dependent inhibition of the proliferation of both cell lines with IC 50 S for SKOV3 and SKVLBl cells of 1 and 8000nM, respectively.
  • Vinblastine also inhibited the growth of both cell lines, with IC 50 S of 0.35 and 4200nM for SKOV3 and SKVLBl cells, re ⁇ pectively.
  • Cryptophycin ⁇ compounds of this invention demonstrate activity with an IC 50 S of from about 1 to about 1000pm for SKOV3 and SKVLBl cell ⁇ .
  • the present invention provides novel cryptophycin compounds which are potent inhibitors of cell proliferation, acting by disruption of the microtubule network and inhibition of mitosis.
  • These studie ⁇ can illustrate that cryptophycin compounds disrupt microtubule organization and thus normal cellular functions, including those of mitosi ⁇ .
  • Cla ⁇ sic anti-microtubule agents such as colchicine and
  • Vinca alkaloids arrest cell division at mitosi ⁇ . It seems appropriate to compare the effect of one of these agent ⁇ on cell proliferation with the cryptophycin compounds.
  • Vinca alkaloid vinblastine was selected as representative of the classic anti-microtubule agents. Accordingly, the effect of cryptophycin compounds and vinblastine on the proliferation and cell cycle progression of the Jurkat T-cell leukemia cell line is compared.
  • GC3 human colon carcinoma cells (1x10 cells in lOO ⁇ l as ⁇ ay medium/well) twenty four hour ⁇ prior to test compound addition.
  • Cell free assay medium was added to other select wells of the 96 well plate.
  • the assay medium (RPMI-1640 was the medium used; however, any medium that will allow the cells to survive would be acceptable) was supplemented with 10% dialyzed fetal bovine serum and 25 mM HEPES buffer.
  • test compound was stored in an amber bottle prior to testing.
  • Fresh dimethylsulfoxide stock solution 200 ⁇ g/ml was prepared immediately prior to preparation of test sample dilutions in phosphate-buffered saline (PBS) .
  • a dilution of 1:20 dimethylsulfoxide solution in PBS was prepared such that the final concentration was 10 ⁇ g/ml.
  • Serial 1:3 dilutions using PBS (.5ml previous sample of 1ml PBS) were prepared.
  • Falcon 2054 tubes were used for the assay.
  • a lOul sample of each dilution of test compound was added in triplicate to wells of GC3 plates. The plates were incubated for 72 hours at about 37 C. A 10 ⁇ l sample of stock 3- [4, 5-dimethyl-2-yl] -2, 5-diphenyltetrazolium bromide salt ("MTT" 5 mg/ml in PBS) was added to each well. The plates were incubated for about an hour at 37 C. The plates were centrifuged, media was decanted from the wells and lOO ⁇ l acid-isopropanol (0.04 N HCl in i ⁇ opropanol) was added to each well. The plate was read within one hour using a te ⁇ t wavelength of 570nm (SpectraMax reader) .
  • Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 have the meanings set for supra in Formula I.
  • R 13 is selected from the group consi ⁇ ting of t-butylcarbamate (BOC) ;
  • R 24 is selected from the group consi ⁇ ting of
  • N-hydroxy ⁇ uccinimide herein "NHS”
  • N-hydroxysulfosuccinimide and salts thereof, 2-nitrophenyl, 4- nitrophenyl, and 2, 4-dichlorophenyl
  • X i ⁇ O NH or alkylamino
  • Y is 0, NH, or alkylamino.
  • R 25 is an active ester substituent; with an acid of the formula
  • R 27 is ⁇ elected from the group consisting of H, C_-C_2 alkyl, and aryl; and a silylating agent.
  • active ester substituent refers to a sub ⁇ tituent which makes the OR 24 sub ⁇ tituent a good leaving group.
  • Appropriate ⁇ ubstituents can be selected with guidance from standard reference guides, for example, “Protective Groups in Organic Chemistry”, Plenum Press, (London and New York, 1973); Greene, T.W. "Protecting Group ⁇ in Organic Synthesis", Wiley (New York, 1981).
  • An especially preferred R 25 group is N-hydroxy-succinimide. (NHS)
  • Formula I contains an amine, then the amine substituent of the R 6 group must be protected using an amino protecting group.
  • an amino protecting group The artisan can readily select an appropriate amino protecting group using guidance from standard works, including, for example, “Protective Groups in Organic Chemistry”, Plenum Press, (London and New York, 1973); Greene, T.W. "Protecting Groups in Organic Synthesis", Wiley (New York, 1981) .
  • R 27 should be a group that allows for the removal of the -CO 2 R 27 substituent using acidic, neutral, or mild basic conditions.
  • Preferred R 27 groups include, but are in no way limited to, hydrogen, C_-C 6 alkyl, tricholoromethyl, trichloroethyl, and methylthiomethyl. It is especially preferred that R 27 is hydrogen. To provide further guidance for the artisan, the following schemes are provided:
  • R 1 ' is halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, phosphate or a protected OH or protected SH group;
  • R 2 is OH or SH;
  • R 26 i ⁇ an alcohol protecting group introduced during a portion of the ⁇ ynthetic proce ⁇ to protect an alcohol group which might otherwi ⁇ e react in the course of chemical manipulations, and is then removed at a later stage of the synthesis.
  • R 6 has the meaning def ined supra .
  • the ester starting material can be prepared, for example, as follows:
  • R 6 has the meaning def ined supra .
  • the ⁇ cheme for preparing the ester is further explained by the Preparation Section herein which provides one specific application of the scheme for the convenience of the skilled artisan.
  • the Scheme for preparing the ester is applicable to the Ar substituents claimed herein.
  • the scheme illustration is not intended to limited the synthesis scheme only to the phenyl ring illustrated. Rather, the artisan can broadly apply this process to provide desired starting materials for the compounds claimed herein.
  • the necessary reaction time is related to the starting materials and operating temperature.
  • the optimum reaction time for a given process is, as always, a compromise which is determined by considering the competing goals of throughput, which is favored by ⁇ hort reaction times, and maximum yield, which is favored by long reaction times.
  • Step 1 Methyl 5-Phenylpent-2 ( E) -enoate.
  • a solution of trimethyl phosphonoacetate (376 g, 417 mL, 2.07 mol) in THF (750 mL) was stirred at 0 °C in a 3L 3-neck round bottom flask equipped with a mechanical stirrer and N2 inlet.
  • To the chilled solution neat tetramethyl guanidine (239 g, 260 mL, 2.07 mol) was added dropwise via an addition funnel. The chilled clear pale yellow solution was stirred for 25 minute ⁇ at 0 °C.
  • Step 2 5-phenyl-pent-2-en-l-ol.
  • a solution of enoate e ⁇ ter 310.5 g, 1.5 mol
  • THF 1.5 L
  • DIBAL 2.5 L, 1.5 M in toluene, 3.75 mol
  • EIMS m/z 162 (1:M+) 144 (16), 129 (7), 117 (9) 108 (6), 92 (17), 91 (100), 75 (5), 65 (12), HREIMS m/z 162, 1049 (CnHi4 ⁇ , D -0.4 mmu) ; UV lmax (e) 206 (9900), 260 (360); IR nmax 3356, 2924, 1603, 1496, 1454, 970, 746, 700 cm- 1 ; NMR d 7.15-7.3 (Ph-H5;m), 5.70 (3-H;dt, 15.6/6.0), 5.61 (2-H;dt, 15.6/4.8), 4.02 (1-H2;d 4.8) , 2.68 (5-H2; t, 7.2), 2.40 (OH;b ⁇ ), 2.36(4-H2; dt, 6.0/7.2); 13 C NMR dl41.6 (Ph i 1 ), 131.8(3), 129.5 (2), 128.3/128.2
  • the resulting mixture was cooled to -20 °C and treated with Ti(0-i-Pr) 4 (9.2 mL, 0.031 mol), followed by the addition of t-butylhydroperoxide (4.0 M in CH 2 CI 2 , 182 mL, 0.78 mol) at a rate to maintain the temperature ⁇ -20 °C.
  • t-butylhydroperoxide 4.0 M in CH 2 CI 2 , 182 mL, 0.78 mol
  • the reaction mixture was stirred for another 30 min, and then treated with a solution of the allylic alcohol (50 g, 0.31 mol) in CH 2 CI 2 (30 mL) at a rate to maintain the temperature ⁇ -20 °C.
  • the reaction was stirred at the same temperature for 5 h, then filtered into a solution of ferrous sulfate heptahydrate (132 g) and tartaric acid (40 g) in water (400 mL) at 0 °C. The mixture was stirred for 20 min, then transferred to a separatory funnel and extracted with t-BuOMe (2x200 mL) . The combined organic phase was stirred with 30% NaOH solution containing NaCl, for 1 h at 0 °C. The layers were again separated, and the aqueous phase extracted with t-BuOMe. The combined organic phase was washed with brine, dried over MgS0 4 and concentrated to yield 52.8 g as an amber oil.
  • the crude aldehyde from above was dis ⁇ olved in THF (90 mL) and treated with trimethyl phosphonoacetate (9.03 mL, 55.8 mmol) and tetramethylguanidine (7.0 mL, 55.8 mmol) at room temperature under nitrogen.
  • the reaction mixture was stirred for 16 h, then partitioned between EtOAc (200 mL) and water (100 mL) .
  • the aqueous phase was back extracted with EtOAc (100 mL) , and the combined organic phase was washed with water, brine and dried over Na2S ⁇ 4 .
  • Methyl ester (2.673 mmol) was dis ⁇ olved in acetone and then IN aqueous LiOH (26mL) added at room temperature. The cloudy mixture was further diluted with acetone (20mL) and the re ⁇ ulting yellow mixture stirred at room temperature for 23.5h. The reaction was diluted with diethylether (400mL) and the organics washed with IN HCl (120mL) , brine (200mL) and H 2 O (160mL) .
  • Boc amine as prepared by Example 2 (109mg,0.154mmol) was dis ⁇ olved in trfluoracetic acid (5mL,5mM) and ⁇ tirred at room temperature for 2h. The reaction was concentrated in vacuo and dried under high vacuum to give the trifluoroacetate salt of amine as a light brown foam. Crude amine salt (max. 0.154mmol) was dissolved in dry DMF (31mL) and dusopropylethylamine (80uL, 0.462mmol) , followed by pentafluorophenyl diphenyl -phosphinate (77mg, 0.2mmol) added.
  • Styrene prepared as described by Example 3 (42mg, 0.0712mmol) was suspended in dry dichloromethane (2.2mL, 0.035mM) and mCPBA (49mg, 0.285mmol) added in one portion at room temperature. Dry tetrahydrofuran (0.3mL) was added to produce a homogeneous solution. The reaction was stirred under N at room temperture for 21h and then diluted with further CH 2 CI 2 (15mL) . Organics were washed with 10% aq. Na 2 S 2 ⁇ s (lOmL), sat. aq.

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Abstract

Nouveaux composés de cryptophycine, utiles pour rompre le système de la microtubuline, en tant qu'agents antinéoplasiques, antifongiques, et dans le traitement du cancer. L'invention concerne également une formulation permettant d'administrer les nouveaux composés de cryptophycine.
PCT/US1996/013855 1995-08-30 1996-08-30 Composes pharmaceutiques WO1997007798A1 (fr)

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Application Number Priority Date Filing Date Title
EP96929780A EP0850057A4 (fr) 1995-08-30 1996-08-30 Composes pharmaceutiques
BR9610214A BR9610214A (pt) 1995-08-30 1996-08-30 Compostos farmacéuticos
JP9510549A JP2000501067A (ja) 1995-08-30 1996-08-30 医薬化合物
AU69048/96A AU6904896A (en) 1995-08-30 1996-08-30 Pharmaceutical compounds
JP10511080A JP2001502297A (ja) 1996-08-30 1997-08-29 医薬用化合物
AU43300/97A AU4330097A (en) 1996-08-30 1997-08-29 Pharmaceutical compounds
EP97941379A EP0957912A1 (fr) 1996-08-30 1997-08-29 Composes pharmaceutiques
PCT/US1997/015245 WO1998008506A1 (fr) 1996-08-30 1997-08-29 Composes pharmaceutiques
CA002263420A CA2263420A1 (fr) 1996-08-30 1997-08-29 Composes pharmaceutiques
MXPA/A/1998/001604A MXPA98001604A (en) 1995-08-30 1998-02-27 Farmaceuti compounds

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US60/002,935 1995-08-30

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PCT/US1996/013855 WO1997007798A1 (fr) 1995-08-30 1996-08-30 Composes pharmaceutiques

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Cited By (13)

* Cited by examiner, † Cited by third party
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WO1998009974A1 (fr) * 1996-09-06 1998-03-12 Eli Lilly And Company Procede et nouveaux intermediaires
EP0861838A2 (fr) * 1997-02-26 1998-09-02 Eli Lilly And Company Procédés et intermédiaires pour la préparation de composés de cryptophycine
EP0869786A1 (fr) * 1995-12-22 1998-10-14 Eli Lilly And Company Composes pharmaceutiques
EP0932601A1 (fr) * 1996-08-30 1999-08-04 Eli Lilly And Company Procede de preparation de composes pharmaceutiques
EP0934065A1 (fr) * 1996-08-30 1999-08-11 Eli Lilly And Company Composes pharmaceutiques
EP0957912A1 (fr) * 1996-08-30 1999-11-24 Eli Lilly And Company Composes pharmaceutiques
EP0975610A1 (fr) * 1997-02-26 2000-02-02 Eli Lilly And Company Composes pharmaceutiques a base de tripeptides et de tetrapeptides
US6103913A (en) * 1998-10-16 2000-08-15 Eli Lilly And Company Process for preparing enollactone derivatives
US6376230B1 (en) 1998-10-16 2002-04-23 Eli Lilly And Company Stereoselective process for producing intermediates of cryptophycins
WO2003077906A1 (fr) * 2002-03-18 2003-09-25 Nihon University Derives d'etheramine cyclique servant de medicaments pour les tumeurs malignes
US6680311B1 (en) 1996-08-30 2004-01-20 Eli Lilly And Company Cryptophycin compounds
EP1751279A2 (fr) * 2004-05-05 2007-02-14 Regents Of The University Of Minnesota Acides nucleiques et polypeptides impliques dans la production de cryptophycine
EP2266607A2 (fr) 1999-10-01 2010-12-29 Immunogen, Inc. Des immunoconjugués pour le traitement des cancers.

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CA2246117A1 (fr) * 1995-08-30 1997-03-06 University Of Hawai'i Cryptophycines obtenues a partir d'une biosynthese aberrante
EP0870501A1 (fr) * 1997-04-11 1998-10-14 Eli Lilly And Company Utilisation de dérivés spécifiques de la cryptophycine dans la fabrication d'un médicametn destiné au traitement des mycoses
EP0870506A1 (fr) * 1997-04-11 1998-10-14 Eli Lilly And Company Compositions comprenant un dérivé de la cryptophycine associé à un agent de synchronisation ou d'activation pour le traitement du cancer
US6180679B1 (en) * 1998-04-07 2001-01-30 Eli Lilly And Company Method for treating fungal infections
JPWO2007000994A1 (ja) * 2005-06-28 2009-01-22 中外製薬株式会社 抗ｈｃｖ作用を有する化合物の製造方法
CN103724290B (zh) * 2013-11-15 2015-04-29 浙江大学 一种环肽化合物clavatustide A及其产生菌、制备方法和应用

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US5952298A (en) * 1993-12-21 1999-09-14 The University Of Hawaii Cryptophycins
NZ305571A (en) * 1995-03-07 1999-02-25 Univ Hawaii Cryptophycin derivatives, use in pharmaceutical compositions to inhibit mammalian cell proloferation and treat neoplasia
CA2246117A1 (fr) * 1995-08-30 1997-03-06 University Of Hawai'i Cryptophycines obtenues a partir d'une biosynthese aberrante

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SMITH ET AL.: "Cryptophycin: A new antimicrotubule agent active against Drug-resistant Cells.", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 54, 15 July 1994 (1994-07-15), US, pages 3779 - 3784, XP002153401, ISSN: 0008-5472 *
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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0869786A1 (fr) * 1995-12-22 1998-10-14 Eli Lilly And Company Composes pharmaceutiques
EP0869786A4 (fr) * 1995-12-22 1999-04-14 Lilly Co Eli Composes pharmaceutiques
EP0932601A4 (fr) * 1996-08-30 2000-02-02 Lilly Co Eli Procede de preparation de composes pharmaceutiques
US6680311B1 (en) 1996-08-30 2004-01-20 Eli Lilly And Company Cryptophycin compounds
US6133457A (en) * 1996-08-30 2000-10-17 Eli Lilly And Company Process for preparing pharmaceutical compounds
EP0934065A4 (fr) * 1996-08-30 2000-10-11 Lilly Co Eli Composes pharmaceutiques
EP0932601A1 (fr) * 1996-08-30 1999-08-04 Eli Lilly And Company Procede de preparation de composes pharmaceutiques
EP0934065A1 (fr) * 1996-08-30 1999-08-11 Eli Lilly And Company Composes pharmaceutiques
EP0957912A1 (fr) * 1996-08-30 1999-11-24 Eli Lilly And Company Composes pharmaceutiques
EP0957912A4 (fr) * 1996-08-30 1999-12-22
EP0929556A4 (fr) * 1996-09-06 2001-04-18 Lilly Co Eli Procede et nouveaux intermediaires
US6020512A (en) * 1996-09-06 2000-02-01 Eli Lilly And Company Process and novel intermediates
EP0929556A1 (fr) * 1996-09-06 1999-07-21 Eli Lilly And Company Procede et nouveaux intermediaires
WO1998009974A1 (fr) * 1996-09-06 1998-03-12 Eli Lilly And Company Procede et nouveaux intermediaires
EP0975610A1 (fr) * 1997-02-26 2000-02-02 Eli Lilly And Company Composes pharmaceutiques a base de tripeptides et de tetrapeptides
EP0975610A4 (fr) * 1997-02-26 2000-05-17 Lilly Co Eli Composes pharmaceutiques a base de tripeptides et de tetrapeptides
EP0861838A2 (fr) * 1997-02-26 1998-09-02 Eli Lilly And Company Procédés et intermédiaires pour la préparation de composés de cryptophycine
EP0861838A3 (fr) * 1997-02-26 1998-12-09 Eli Lilly And Company Procédés et intermédiaires pour la préparation de composés de cryptophycine
US6143909A (en) * 1997-02-26 2000-11-07 Eli Lilly And Company Selective epoxidation process for preparing pharmaceutical compounds
US6376230B1 (en) 1998-10-16 2002-04-23 Eli Lilly And Company Stereoselective process for producing intermediates of cryptophycins
US6103913A (en) * 1998-10-16 2000-08-15 Eli Lilly And Company Process for preparing enollactone derivatives
EP2266607A2 (fr) 1999-10-01 2010-12-29 Immunogen, Inc. Des immunoconjugués pour le traitement des cancers.
EP2289549A2 (fr) 1999-10-01 2011-03-02 Immunogen, Inc. Des immunoconjugués pour le traitement des cancers.
WO2003077906A1 (fr) * 2002-03-18 2003-09-25 Nihon University Derives d'etheramine cyclique servant de medicaments pour les tumeurs malignes
EP1751279A2 (fr) * 2004-05-05 2007-02-14 Regents Of The University Of Minnesota Acides nucleiques et polypeptides impliques dans la production de cryptophycine
EP1751279A4 (fr) * 2004-05-05 2008-03-19 Univ Minnesota Acides nucleiques et polypeptides impliques dans la production de cryptophycine
US7662599B2 (en) 2004-05-05 2010-02-16 Regents Of The University Of Minnesota Nucleic acids and polypeptides involved in the production of cryptophycin

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EP0850316A4 (fr) 2000-08-23
JP2000501067A (ja) 2000-02-02
JP2000507805A (ja) 2000-06-27
EP0850057A1 (fr) 1998-07-01
CA2246117A1 (fr) 1997-03-06
AU6904896A (en) 1997-03-19
CA2230540A1 (fr) 1997-03-06
AU7109096A (en) 1997-03-19
BR9610214A (pt) 1999-06-15
EP0850316A1 (fr) 1998-07-01
AU709828B2 (en) 1999-09-09
WO1997008334A1 (fr) 1997-03-06

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