WO2005117894A1 - Leptomycin compounds - Google Patents
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- WO2005117894A1 WO2005117894A1 PCT/US2005/019591 US2005019591W WO2005117894A1 WO 2005117894 A1 WO2005117894 A1 WO 2005117894A1 US 2005019591 W US2005019591 W US 2005019591W WO 2005117894 A1 WO2005117894 A1 WO 2005117894A1
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- cancer
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- alkenyl
- alkynyl
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- WLADQYKRYSPMME-UHFFFAOYSA-N CC(C1=O)=C(C)N(C(CN)=C2C)N1C2=O Chemical compound CC(C1=O)=C(C)N(C(CN)=C2C)N1C2=O WLADQYKRYSPMME-UHFFFAOYSA-N 0.000 description 1
- 0 CCC(C=C[C@@]([C@@](C)C=C1)OC1=O)=C[C@](C)CC=CC(C)=C[C@@](C)C([C@@](C)[C@@]([C@@](C)CC(C)=CC(NC*)=O)O)=O Chemical compound CCC(C=C[C@@]([C@@](C)C=C1)OC1=O)=C[C@](C)CC=CC(C)=C[C@@](C)C([C@@](C)[C@@]([C@@](C)CC(C)=CC(NC*)=O)O)=O 0.000 description 1
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- This invention relates to leptomycin compounds and methods for making and using them.
- LMB Leptomycin B
- LMB is the archetype of a natural product family referred to as the leptomycin family, characterized by a 2,3-dehydro- ⁇ -valerolactone ring at one end of the molecule (C ⁇ ;-C 5 ) and an extended carbon chain having a 6E,8Z and a 12E,14E diene system located off C 5 .
- a nitromethyl valerolactone LMB analog has been found to be inactive, whereas biotinylated LMB has been found to be active, suggesting that the 2,3-dehydro- ⁇ -valerolactone structure is a crucial pharmacophore.
- leptomycin A ratjadone
- angui- nomycins A-D callystatin A
- kazusamycin A also l ⁇ iown as CL-1957B
- kazusamycin B also known as CL-1957E
- leptolstatin and leptofuranins A-D.
- the formulae of the other family members most structurally similar to leptomycin B are shown:
- LMB acts by arresting cells at the end of the Gl and G2 phases of the cell cycle.
- LMB acts as an inhibitor of the nuclear export receptor CRM1, which binds to and affects the nuclear translocation of "cargo proteins" such as P53, P73, STAT1, (i)ADARl, Rev, actin, and Bcr-abl.
- LMB exhibits remarkable cytotoxicity towards mammalian cells
- LMB was subjected to a bioconversion screening with a number of bacteria and fungi, from which a number of derivatives were isolated (Kuhnt et al, Applied Environ. Microbiol. 1998, 64 (2), 714-720): 26-hydroxyleptomycin B, 4,11- dihydroxyleptomycin B, 2,3-dihydroleptomycin B, and leptomycin B glutaminamide.
- this invention provides a compound having a structure according to formula I
- R° is H, C1-C5 alkyl, C 2 -C 5 alkenyl, or C 2 -C 5 alkynyl; each R is independently H, C1-C 5 alkyl, C 2 -C 5 alkenyl, or C 2 -C 5 alkynyl; R 2 is H, aryl, cycloalkyl, a heterocyclic moiety, wherein R 3 is H, Ci-C 5 alkyl, C 2 -C 5 alkenyl, or C 2 -C 5 alkynyl, provided that R 3 is not H when m is 0; R 4 is H, C1-C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, aryl, cycloalkyl, or a heterocyclic moiety; R 5 is H, C1-C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, aryl, cycl
- a method of inhibiting the proliferation of a target cell comprising contacting the target cell with an effective amount of a compound of this invention.
- the target cell can be a cancer cell, especially a human breast cancer, lung cancer, ovarian cancer, prostate cancer, or leukemia cell.
- the target cell can be a human papilloma virus (HPV)-associated cervical cancer cell or a bladder cancer cell.
- HPV human papilloma virus
- a method of treating a hyperproliferative disease comprising administering to a patient suffering from such hyperproliferative disease a therapeutically effective amount of a compound of this invention.
- the hyperproliferative disease so treated may be cancer, especially breast cancer, lung cancer, ovarian cancer, prostate cancer, or leukemia.
- the hyperproliferative disease can be HPV-associated cervical cancer or bladder cancer.
- the patient preferably is a mammal, especially a human.
- a compound of this invention for the preparation of a medicament for treating a hyperproliferative disease, which can be cancer, especially breast cancer, lung cancer, ovarian cancer, prostate cancer, or leukemia.
- the cancer can be HPV-associated cervical cancer or bladder cancer.
- a pharmaceutical formulation comprising a compound of this invention and an excipient.
- a method of inhibiting the export of a protein from the nucleus of a cell via a CRMl-mediated process comprising contacting said cell with an inhibitory amount of a compound according to this invention.
- a method of treating bladder cancer comprising administering to a patient suffering from bladder cancer a therapeutically effective amount of leptomycin B.
- Alkyl means an optionally substituted straight or branched chain hydrocarbon moiety having the specified number of carbon atoms in its longest chain portion (e.g., as in “C 3 alkyl,” “C1-C 5 alkyl,” or “ to C 5 alkyl,” the latter two phrases referring to an alkyl group having from 1 to 5 carbon atoms in the longest chain portion) or, where the number of carbon atoms is not specified, from 1 to 4 carbon atoms in the longest chain portion.
- Alkenyl means an optionally substituted straight or branched chain hydrocarbon moiety having at least one carbon-carbon double bond and the specified number of carbon atoms in its longest chain portion (e.g., as in “C 3 alkenyl,” “C 2 -C 5 alkenyl,” or “C 2 to C 5 alkenyl,” the latter two phrases referring to an alkenyl group having from 2 to 5 carbon atoms in the longest chain portion) or, where the number of carbon atoms is not specified, from 2 to 4 carbon atoms in the longest chain portion.
- Alkynyl means an optionally substituted straight or branched chain hydrocarbon moiety having at least one carbon-carbon triple bond and the specified number of carbon atoms in its longest chain portion (e.g., as in “C 3 alkenyl,” “C 2 -C 5 alkynyl,” or “C 2 to C 5 alkynyl,” the latter two phrases referring to an alkynyl group having from 2 to 5 carbon atoms in the longest chain portion) or, where the number of carbon atoms is not specified, from 2 to 4 carbon atoms in the longest chain portion.
- Aryl means an optionally substituted aromatic monocyclic, fused bicyclic, or fused polycyclic hydrocarbon or heterocyclic group having 1 to 20 carbon atoms in the ring portion(s), such as phenyl, naphthyl, pyrrolyl, indolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrazinyl, triazinyl, triazolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, quinolinyl-N- oxide, isoquinolinyl, benzo
- Cycloalkyl means an optionally substituted, saturated or unsaturated, non-aro- matic cyclic hydrocarbon ring system, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with a saturated or unsaturated C 3 -C carbocy-hack ring.
- Exemplary cycloalkyl ring systems include cyclopropyl, cyclobutyl, cyclo- pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl.
- Arylalkyl means an alkyl moietysubstituted with an aryl moiety, with the open (unsatisfied) valence at the alkyl moiety, for example as in benzyl, phenethyl, N- imidazoylethyl, N-morpholinoethyl, ethylpyridinyl, and the like.
- Heterocycle means an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic ring system, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom- containing ring.
- Heteroaryl means a heterocycle in which the ring system is aryl.
- Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from N, O and S, where the N and S optionally may be oxidized and the N optionally may be quarternized.
- Exemplary monocyclic heterocyclic ring systems include pyrrolidinyl, pyrrolyl, biotinyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thizaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopi ⁇ erazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridinyl, N-o
- Preferred heterocyclo groups include pyridinyl, morpholinyl, pyrazinyl, pyrimidinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, piperazinyl, and piperidinyl.
- a group may be substituted, for example by use of "substituted or unsubstituted” or “optionally substituted” phrasing, such group may have one or more independently selected substituents, preferably one to five in number, more preferably one or two in number. It is understood that substituents and substitution patterns can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art as well as the methods set forth herein.
- substituents include alkyl, alkenyl, alkynyl, aryl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino quarternary ammonium, aralkylamino, heterocycloalkyl, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thio, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, caroboxylalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkylsulfonyl, sulfonamindo, aryloxy, and the like, in addition to those specified herein.
- the substituent(s) for alkyl, alkenyl, and alkynyl moieties are from one to three in number and are independently selected from N-pyrrolidinyl, N-morpholinyl, N- azetidinyl, hydroxyl, halo, alkoxyl, cyano, amino, alkylamino, and dialkylamino.
- the substituent(s) for aryl, cycloalkyl, and heterocycloalkyl moieties are from one to three in number and are independently selected from alkyl, alkenyl, alkynyl, hydroxy alkyl, haloalkyl, hydroxyl, halo, alkoxyl, cyano, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino, and dialkylamino.
- stereoisomers are specifically indicated (e.g., by a bolded or dashed bond at a relevant stereocenter in a structural formula, by depiction of a double bond as having E or Z configuration in a structural formula, or by use stereochemistry- designating nomenclature), all stereoisomers are included within the scope of the invention, as pure compounds as well as mixtures thereof. Unless otherwise indicated, individual enantiomers, diastereomers, geometrical isomers, and combinations and mixtures thereof are all encompassed by the present invention. Polymorphic crystalline forms and solvates are also encompassed within the scope of this invention.
- “Pharmaceutically acceptable ester” means an ester that hydrolyzes in vivo (for example in the human body) to produce the parent compound or a salt thereof or has per se activity similar to that of the parent compound.
- Suitable ester groups include, without limitation, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety preferably has no more than six carbon atoms.
- Illustrative esters include formates, acetates, propionates, butyrates, acrylates, citrates, succinates, and ethylsuccinates.
- “Pharmaceutically acceptable salts” means salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
- an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen-carbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohy-drogen-sulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, ascorbic, propionic, isobutyric, maleic, malonic, lactic, malic, glutamic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, lactobionic, and the like.
- inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen-carbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric,
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Where a compound contains both basic and acidic functionalities, they can be converted into either a base or an acid addition salt.
- the present invention includes within its scope prodrugs of the compounds of this invention.
- prodrugs are in general functional derivatives of the compounds that are readily convertible in vivo into the required compound.
- the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a subject in need thereof.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Wermuth, "Designing Prodrugs and Bioprecursors," in Wermuth, ed., The Practice of Medicinal Chemistry, 2nd Ed., pp.
- Prodrugs include esters that hydrolyze in vivo (for example in the human body) to produce a compound of this invention or a salt thereof.
- Suitable ester groups include, without limitation, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety preferably has no more than six carbon atoms.
- Illustrative esters include but are not limited to formates, acetates, propionates, butyrates, acrylates, citrates, succinates, and ethylsuccinates.
- “Therapeutically effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. Where a range is stated, as in “C ⁇ to C 5 alkyl” or “5 to 10%,” such range includes the end points of the range.
- R° is H
- R 10 is CH 3
- R 11 is H
- R 12 is CH 3
- R 13 is CH 3
- R 14 is H
- R 1 , R 2 , and m retain the meanings assigned in the BRIEF SUMMARY OF THE INVENTION section above.
- R° is H
- R 10 is CH 3
- R 11 is H
- R 12 is CH 3 or CH 2 CH 3
- R 13 is H
- R 14 is H
- R 1 , R 2 , and m retain the meanings assigned in the BRIEF SUMMARY OF THE INVENTION section above.
- R° is H
- R 10 is CH 2 OH
- R 11 is H
- R 12 is CH 3 or CH 2 CH 3
- R 13 is CH 3
- R 14 is H
- R 1 , R 2 , and m retain the meanings assigned in the BRIEF SUMMARY OF THE INVENTION section above.
- R° is H
- R 10 is CH 3
- R 11 is H
- R 12 is CH 2 CH 3
- R 13 is CH 3
- R 14 is H, corresponding to a compound having a structure according to formula la. (R , R and m retain the meanings assigned in the BRIEF SUMMARY OF THE INVENTION section above.)
- R .2 i •s a heterocyclic moiety, it preferably is
- n 2, 3, or 4.
- R 3 i • appearss other than H
- R fluorescent moieties include
- R 6 preferably is other than a fluorescent moiety.
- cancers of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; cancers of the liver and biliary tree, particularly hepatocellular carcinoma; intestinal cancers, particularly colorectal cancer; treat ovarian cancer; small cell and non-small cell lung cancer; breast cancer sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma; neoplasms of the central nervous systems, particularly brain
- compositions described herein will result in a reduction in the size or number of the cancerous growth and/ or a reduction in associated symptoms (where applicable).
- Pathologically practice of the method and use of compositions described herein will produce a pathologically relevant response, such as: inhibition of cancer cell proliferation, reduction in the size of the cancer or tumor, prevention of further metastasis, and inhibition of tumor angiogenesis.
- the method of treating such diseases comprises administering a therapeutically effective amount of an inventive combination to a subject. The method may be repeated as necessary.
- the cancer can be prostate cancer, human papilloma virus (HPV)-associated cervical cancer, leukemia (especially chronic myeloid leukemia or CML), and bladder cancer.
- HPV human papilloma virus
- Non-cancer disorders that are characterized by cellular hyperproliferation can also be treated by compounds of this invention.
- Illustrative examples of such disorders include but are not limited to: atrophic gastritis, inflammatory hemolytic anemia, graft rejection, inflammatory neutropenia, bullous pemphigoid, coeliac disease, demyelinating neuropathies, dermatomyositis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), multiple sclerosis, myocarditis, myositis, nasal polyps, chronic sinusitis, pemphigus vulgaris, primary glomerulonephritis, psoriasis, surgical adhesions, stenosis or restenosis, scleritis, scleroderma, eczema (including atopic dermatitis, irritant dermatitis, allergic dermatitis), periodontal disease (i.e., periodontitis), polycystic kidney
- vasculitis e.g., Giant cell arteritis (temporal arteritis, Takayasu's arteritis), polyarteritis nodosa, allergic angiitis and granulomatosis (Churg-Strauss disease), polyangitis overlap syndrome, hypersensitivity vasculitis (Henoch-Schonlein purpura), serum sickness, drug-induced vasculitis, infectious vasculitis, neoplastic vasculitis, vasculitis associated with connective tissue disorders, vasculitis associated with congenital deficiencies of the complement system, Wegener's granulomatosis, Kawasaki's disease, vasculitis of the central nervous system, Buerger's disease and systemic sclerosis); gastrointestinal tract diseases (e.g., pancreatitis, Crohn's disease, ulcerative colitis, ulcerative proctitis, primary sclerosing cholangitis, benign strictures of any cause including ideopathic (e.g., ide
- Compounds of this invention can be administered in combination with other anti- cancer or cytotoxic agents, including alkylating agents, angiogenesis inhibitors, antime- tabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors.
- alkylating agents including alkylating agents, angiogenesis inhibitors, antime- tabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome
- Specific anti-cancer or cytotoxic agents include ⁇ -lapachone, ansamitocin P3, auristatin, bicalutamide, bleomycin, bleomycin, bortezomib, busulfan, calicheamycin, callistatin A, camptothecin, capecitabine, CC-1065, cisplatin, cryptophycins, daunorubicin, discodermolide, disorazole, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, floxuridine, fludarabine, fluoruracil, gefitinib, geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), 17-(2- dimethylaminoethyl)aminol7-demethoxygeldanamycin (17-DMAG), gemcitabine, hydroxyurea, im
- compounds of this invention are provided in a purified and isolated form, for example following column chromatography, high-pressure liquid chromatography, recrystallization, or other purification technique.
- stereoisomers of compounds of this invention are denoted, such stereoisomers preferably are substantially free of other stereoisomers.
- Compounds of this invention may be used in a pharmaceutical formulation comprising a compound of this invention and an excipient.
- Excipients that may be used include carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and combinations thereof.
- the selection and use of suitable excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins 2003), the disclosure of which is incorporated herein by reference.
- composition may be in any suitable form such as solid, semisolid, or liquid form.
- the pharmaceutical preparation will contain one or more of the compounds of the invention as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application.
- the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, pessaries, solutions, emulsions, suspensions, and any other form suitable for use.
- the carriers that can be used include water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and other carriers suitable for use in manufacturing preparations, in solid, semi-solid, or liquified form.
- auxiliary stabilizing, thickening, and coloring agents and perfumes may be used.
- Preferred modes of administration include intravenously and, in the case of certain indications such a cervical cancer, bladder cancer, or plantar warts, topically. Where applicable, compounds of this invention may be formulated as microcapsules and nanoparticles.
- Dosage levels of the compounds of the present invention are of the order from about 0.1 mg to about 100 mg per kilogram of body weight per day, preferably from about 1 mg to about 50 mg per kilogram of body weight per day. More preferably, the dosage levels are from about 5 mg to about 20 mg per kilogram of body weight per day, corresponding to 350 mg to 1400 mg per patient per day, assuming a 70 kg patient.
- the compounds of the present invention may be administered on an intermittent basis, i.e., at semi- weekly, weekly, semi-monthly, or monthly intervals.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for oral administration to humans may contain carrier material, which may vary from about 5 percent to about 95 percent of the total composition.
- Dosage unit forms will generally contain from about 5 mg to about 500 mg of active ingredient.
- the specific dose level for any particular patient will depend on a variety of factors. These factors include the activity of the specific compound employed; the age, body weight, general health, sex, and diet of the subject; the time and route of administration and the rate of excretion of the drug; whether a drug combination is employed in the treatment; and the severity of the particular disease or condition for which therapy is sought.
- compounds of this invention having a primary or secondary amine group such as compounds 15-17, can be used in therapeutic conjugates comprising a targeting moiety, a linker moiety, and an active agent.
- the leptomycin compound is the active agent, or warhead, that is delivered to a target cell by the action of the targeting moiety.
- the targeting moiety can be an antibody (especially a monoclonal antibody) that has affinity for a characteristic molecule on the target cell.
- the characteristic molecule can be a tumor-associated antigen recognized by the monoclonal antibody.
- the linker moiety is designed to cleave when the conjugate is internalized by the cancer cell or in proximity thereof, releasing the leptomycin compound as an anti-cancer drug.
- the primary or secondary amine serves as a convenient attachment point for the leptomycin compound to the linker moiety, in particular a "self -immolating" group such as a p- aminobenzyloxycarbonyl (PABC) group.
- PABC p- aminobenzyloxycarbonyl
- cancer cells have mutations resulting in the loss of function of the apoptosis-inducing, tumor suppressor protein p53. Vousden et al, Nat. Rev. Cancer 2002, 2, 594-504. Examples of such cancers include prostate cancer and human papilloma virus (HPV) associated cervical cancer. It has been shown that LMB causes the accumulation of p53 protein in the nucleus of cervical cancer cells. Lane et al. , Proc. Nat'lAcad. Sci. (USA) 2000, 97, 8501-8506. In prostate cancers characterized by defective up-regulation of p53 due to DNA damage, the cell nucleus is deficient in p53. LMB has been shown to trap p53 in the nucleus and induce apopotosis. Hence, prostate cancer cells are highly sensitive to LMB. Peehl et al, Prostate 2003, 54, 258-267.
- compounds of this invention can be used synergistically with other anticancer agents, in particular tyrosine kinase inhibitors such as imatinib (whose mesylate is known by the proprietary name GleevecTM).
- tyrosine kinase inhibitors such as imatinib (whose mesylate is known by the proprietary name GleevecTM).
- Some cancers such as chronic myelogenous leukemia (CML) are characterized by expression of the fusion protein Bcr-Abl. While normally Bcr-Abl is not imported into the nucleus, the Bcr-Abl/imatinib complex is imported into the nucleus. If LMB is also present, it prevents the export of Bcr-Abl out of the nucleus.
- compounds of this invention can be used to inhibit the nuclear export of proteins such as p53, p73, Bcr-Abl, STATl, (i)ADARl, Rev, and actin from the nucleus of a cell, by forming a covalent adduct with CRM1 and interfering with the CRM1 mediated export process for such proteins.
- the inhibited protein is p53.
- the inhibited protein is Bcr-Abl. While a certain variability is to be expected depending on the cell type and the target protein, generally the inhibitory amount used will be in the range of 0.3 to 740 nM, preferably 0.3 to 20 nM, more preferably 0.3 to 2.0 nM.
- Example 1 General procedure for solution-phase synthesis Compounds of this invention can be synthesized by a solution phase method, per the equation below, using LMB as the archetype.
- LMB was obtained by fermentation of Streptomyces sp. ATCC 39366 from the
- solid-phase synthesis may be used to make compounds of this invention, as depicted in the following equation:
- Compound 8 was made following the procedure of Example 1 using 4-(3- aminopropyl)morpholine (Sigma-Aldrich).
- 13 C NMR 100 MHz, CDC1 3 ) ⁇ 8.61, 12.28, 12.84, 12.99, 13.56, 16.11, 17.86, 20.84, 25.16, 26.47, 32.17, 33.22, 33.49, 38.17, 40.76, 45.03, 45.52, 46.01, 46.95, 53.43, 57.15, 66.61, 73.72, 81.46, 119.94, 120.03, 122.62, 127.94, 128.14, 130.09, 135.12, 135.42, 136.31, 136.90, 151.57, 215.27; LRMS calculated for C 40 H 62 N 2 O 6 : 666.5; found 667.5 (M+H).
- Compound 11 was made following the procedure of Example 1 using 2-(2- aminoethyl)-l,3-dioxolane, available from TCI-America.
- 13 C NMR 100 MHz, CDC1 3 ) ⁇ 12.28, 12.65, 12.98, 13.52, 13.58, 16.07, 17.84, 20.82, 26.47, 32.14, 32.75, 33.24, 33.48, 34.27, 40.74, 44.95, 45.51, 46.81, 64.85, 74.02, 81.43, 103.67, 119.95, 120.08, 122.64, 127.93, 128.14, 130.06, 135.11, 135.41, 136.29, 136.88, 151.40, 151.52, 164.27, 166.68, 215.20; LRMS calculated for C 38 H 57 NO 7 : 639.4; found 641.0 (M+H).
- Compound 18 was prepared using the general procedure of Example 1, with a reaction time of 12 h at room temperature.
- the crude activated LMB was added dropwise to a solution of glycine (3.2 mg, 0.042 mmol, 1.1 eq) in 50 mM Na 2 HPO 4 (100 ⁇ L), EtOH (50 ⁇ L), and EtOAc (50 ⁇ L).
- the reaction mixture was stirred at room temperature for 1.5 hours, with occasional o additions of concentrated aqueous KOH in order to maintain a pH of approximately 9.
- the reaction mixture was acidified to pH 2 with 2N HC1 and then partitioned between EtOAc (2 mL) and saturated NH 4 CI (2 mL). The aqueous layer was extracted with EtOAc (2 mL, 2x). The combined organic portions were washed with brine (5 mL, lx), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to yield a light-yellow oil.
- The5 crude product was applied to a silica flash column (0.5 x 3 cm), eluting with 0, 5, and 10% (+0.1%) AcOH) MeOH/CH 2 Cl 2 .
- MCF-7, A549, and0 SKOV-3 are human breast, lung, and ovary cancer cell lines, respectively.
- NCI/ ADR is a multi-drug resistant breast cancer cell line.
- CCRF-CEM and CCRF-CEM/PTX are human leukemia cell lines, the latter being a paclitaxel-resistant subline.
- LNCaP is a prostate cancer cell line.
- Table 2 Cytotoxicity Against Various Cells Lines Tumor Cell Line (IC 50 , nM) Compound CCRF- CCRF- MCF-7 NCI/ADR A549 SKOV-3 LNCaP CEM CEM/PTX LMB 0.29 1.0 0.30 1.5 0.65 0.41 0.3 1 0.27 2.1 0.36 1.7 0.69 .
- mice The maximum tolerated dose (MTD) in mice, upon single dose intravenous administration was determined for a representative selection of compounds.
- the data are summarized in Table 4, with comparative data for LMB included.
- Table 5 presents data on the cytotoxicity of LMB and selected compounds of this invention against MB 49 cells, a line of murine bladder cancer cells.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0511066-1A BRPI0511066A (en) | 2004-06-03 | 2005-06-03 | leptomycin-like compounds, pharmaceutical compositions comprising them and uses |
AU2005249555A AU2005249555A1 (en) | 2004-06-03 | 2005-06-03 | Leptomycin compounds |
EP05758823A EP1765354A4 (en) | 2004-06-03 | 2005-06-03 | Leptomycin compounds |
CA002568341A CA2568341A1 (en) | 2004-06-03 | 2005-06-03 | Leptomycin compounds |
JP2007515625A JP2008501710A (en) | 2004-06-03 | 2005-06-03 | Leptomycin compounds |
MXPA06014045A MXPA06014045A (en) | 2004-06-03 | 2005-06-03 | Technical field of the invention. |
IL179772A IL179772A0 (en) | 2004-06-03 | 2006-11-30 | Leptomycin compounds |
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US57725304P | 2004-06-03 | 2004-06-03 | |
US60/577,253 | 2004-06-03 | ||
US60998104P | 2004-09-14 | 2004-09-14 | |
US60/609,981 | 2004-09-14 | ||
US11/142,482 US7446196B2 (en) | 2004-06-03 | 2005-06-01 | Leptomycin compounds |
US11/142,482 | 2005-06-01 |
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PCT/US2005/019591 WO2005117894A1 (en) | 2004-06-03 | 2005-06-03 | Leptomycin compounds |
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US (2) | US7446196B2 (en) |
EP (1) | EP1765354A4 (en) |
JP (1) | JP2008501710A (en) |
KR (1) | KR20070047276A (en) |
AU (1) | AU2005249555A1 (en) |
BR (1) | BRPI0511066A (en) |
CA (1) | CA2568341A1 (en) |
IL (1) | IL179772A0 (en) |
MX (1) | MXPA06014045A (en) |
WO (1) | WO2005117894A1 (en) |
Cited By (6)
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EP1864682A1 (en) * | 2006-06-09 | 2007-12-12 | Sanofi-Aventis | Leptomycin derivatives |
WO2007144423A1 (en) * | 2006-06-16 | 2007-12-21 | Pharma Mar, S.A. | Antitumoral dihydropyran-2-one compounds |
WO2009080761A1 (en) | 2007-12-20 | 2009-07-02 | Pharma Mar, S.A. | Antitumoral compounds |
AU2012216670B2 (en) * | 2007-12-20 | 2013-11-21 | Pharma Mar S.A. | Antitumoral compounds |
WO2019030284A1 (en) | 2017-08-09 | 2019-02-14 | Helmholtz-Zentrum für Infektionsforschung GmbH | New targeted cytotoxic ratjadone derivatives and conjugates thereof |
US10538535B2 (en) | 2017-04-27 | 2020-01-21 | Pharma Mar, S.A. | Antitumoral compounds |
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US7446196B2 (en) * | 2004-06-03 | 2008-11-04 | Kosan Biosciences, Incorporated | Leptomycin compounds |
US20060099235A1 (en) * | 2004-11-11 | 2006-05-11 | Medtronic Vascular, Inc. | Medical devices and compositions useful for treating or inhibiting restenosis |
EP2124927A2 (en) * | 2007-02-26 | 2009-12-02 | Kosan Biosciences Incorporated | Carbamate compounds |
EP2533810B1 (en) | 2010-02-10 | 2016-10-12 | ImmunoGen, Inc. | Cd20 antibodies and uses thereof |
EP2431364A1 (en) | 2010-09-16 | 2012-03-21 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz | Nuclear export inhibitors |
PT3122358T (en) | 2014-03-26 | 2021-03-04 | Astex Therapeutics Ltd | Combinations |
JOP20200201A1 (en) | 2015-02-10 | 2017-06-16 | Astex Therapeutics Ltd | Pharmaceutical compositions comprising n-(3,5-dimethoxyphenyl)-n'-(1-methylethyl)-n-[3-(1-methyl-1h-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine |
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- 2005-06-03 KR KR1020077000158A patent/KR20070047276A/en not_active Application Discontinuation
- 2005-06-03 WO PCT/US2005/019591 patent/WO2005117894A1/en active Application Filing
- 2005-06-03 EP EP05758823A patent/EP1765354A4/en not_active Withdrawn
- 2005-06-03 AU AU2005249555A patent/AU2005249555A1/en not_active Abandoned
- 2005-06-03 JP JP2007515625A patent/JP2008501710A/en active Pending
- 2005-06-03 CA CA002568341A patent/CA2568341A1/en not_active Abandoned
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- 2005-06-03 BR BRPI0511066-1A patent/BRPI0511066A/en not_active IP Right Cessation
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Also Published As
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US7446196B2 (en) | 2008-11-04 |
EP1765354A4 (en) | 2009-04-15 |
MXPA06014045A (en) | 2007-02-28 |
IL179772A0 (en) | 2007-05-15 |
JP2008501710A (en) | 2008-01-24 |
US20050272727A1 (en) | 2005-12-08 |
BRPI0511066A (en) | 2007-12-26 |
US7655808B2 (en) | 2010-02-02 |
AU2005249555A1 (en) | 2005-12-15 |
EP1765354A1 (en) | 2007-03-28 |
US20090042837A1 (en) | 2009-02-12 |
CA2568341A1 (en) | 2005-12-15 |
KR20070047276A (en) | 2007-05-04 |
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