WO2008137599A2 - Analogues de 2-alcoxyestradiol et préparations pharmaceutiques - Google Patents

Analogues de 2-alcoxyestradiol et préparations pharmaceutiques Download PDF

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WO2008137599A2
WO2008137599A2 PCT/US2008/062294 US2008062294W WO2008137599A2 WO 2008137599 A2 WO2008137599 A2 WO 2008137599A2 US 2008062294 W US2008062294 W US 2008062294W WO 2008137599 A2 WO2008137599 A2 WO 2008137599A2
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alkyl
mmol
och
compound
reaction
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PCT/US2008/062294
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WO2008137599A3 (fr
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Pemmaraju N. Rao
James W. Cessac
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Evestra, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms

Definitions

  • 2-Methoxyestradiol is an endogenous mammalian metabolite formed by the sequential biochemical hydroxylation and methylation of the natural hormone Estradiol (Breuer, H. et al., Naturwissenschaften 12, pp. 280-281 (I960)).
  • Certain 2- alkoxyestradiols have been discovered to have antitumor activity (U.S. Pat. No. 6,136,992; U.S. Pat. No. 6,054,598; U.S. Pat. No. 6,051,726; U.S. Pat. No. 5,892,069; U.S. Pat. No. 5,661,143; U.S. Pat. No.
  • 2-Methoxyestradiol (2-ME2) is one such 2-alkoxyestradiol exhibiting antitumor activity (U.S. Pat. No. 5,892,069; U.S. Pat. No. 5,661,143; U.S. Pat. No. 5,504,074; WO 95/04535).
  • Microtubules facilitate and make possible, among other things, chromosome and organelle movement and segregation during cell mitosis (Stryer, L., Biochemistry (1988)). Preventing or interfering with microtubule formation and function leads to mitotic arrest and frequently to apoptosis.
  • many diseases are characterized by undesirable cell proliferation, and the value of compounds and methods that prevent such undesirable cell proliferation is of great importance to the treatment of such diseases.
  • Microtubule formation and function is also critical to cell maintenance, locomotion and the movement of specialized cell structures such as cilia and flagella (Stryer, L., Biochemistry (1988)).
  • cilia and flagella require proper tubulin polymerization (U.S. Pat. No. 6,162,930).
  • Certain 2-alkoxyestradiols are known to inhibit tubulin polymerization or to cause the formation of tubulin polymer with altered morphology and stability properties (U.S. Pat. No. 6,136,992). By interfering with normal microtubule dynamics, such compositions may be used to treat those diseases characterized by abnormal proliferation.
  • Certain 2-alkoxyestradiols including 2-ME2 have also been demonstrated to act as antiangiogenic agents (Fotsis et al., Nature 368, pp. 237-239 (1994); U.S. Publication No. 20050014737, U.S. Pat. No. 6,136,992; U.S. Pat. No. 6,054,598; U.S. Pat. No. 6,051,726; U.S. Pat. No. 5,892,069; U.S. Pat. No. 5,661,143; U.S. Pat. No. 5,504,074; WO 95/04535).
  • 2- alkoxyestradiols exhibiting antiangiogenic activity may be used to treat diseases in which angiogenesis plays an important role. Inducing mitotic arrest and preventing angiogenesis will cause tumors to shrink, and the combination of these methods will provide significant advantages over current anticancer therapies.
  • 2-alkoxyestradiols in murine models have been shown to be orally active, and to exhibit no appreciable toxicity at therapeutically effective doses (Fotsis et al., Nature 368, pp. 237-239 (1994)).
  • Compounds disclosed and tested include (i) 2-methoxyestra-l,3,5(10),15-tetraen-3,17 ⁇ -diol, (ii) 2-methoxyestra- l,3,5(10),14-tetraen-3,17 ⁇ -diol, (iii) 2-methoxyestra-l,3,5,(10),7tetraen-3,17 ⁇ -diol, and (iv) 2-methoxy-3,15 ⁇ ,16 ⁇ ,17 ⁇ -tetrahydroxyestra-l,3,5(10)-triene 15,16-acetonide.
  • R is O-alkyl (C 1- 6 );
  • R 2 is OH, SO 3 NHR 5 , with R 5 being hydrogen or alkyl (C 1-6 ), or CONHR 6 , with R 6 being hydrogen or alkyl (Ci -6 );
  • R 3 is alkyl (C 1-6 ); and
  • R 4 is H, OH, or OR 7 , with R 7 being alkyl (C 1-6 ).
  • R is O-alkyl (Ci- 6 );
  • R 2 is OH, SO 3 NHR 5 , with R 5 being hydrogen or alkyl (C 1-6 ), or CONHR 6 , with R 6 being hydrogen or alkyl (Ci -6 );
  • R 3 is alkyl (Ci -6 );
  • R 4 is H, alkyl (Ci -6 ), C ⁇ R 7 with R 7 being H or alkyl (C 1-6 ), CN or COR 8 , with R 8 being H, alkyl (C )-6 ), OH, O-alkyl (C 1-6 ), NH 2 , or NH-alkyl (Ci -6 ).
  • Certain embodiments are compounds of formula III:
  • R 1 is O-alkyl (Ci- 6 );
  • R 2 is OH, SO 3 NHR 6 , with R 6 being hydrogen or alkyl (C 1 -6 ), or CONHR 7 , with R 7 being hydrogen or alkyl (Ci -6 );
  • R 3 is alkyl (Ci -6 );
  • R 4 (stereochemistry unspecified) is H, OH, O-alkyl (C 1-6 ), or SO 3 NHR 8 with R 8 being hydrogen or alkyl (C 1-6 ),
  • R 5 is H, OH, O- alkyl (Ci -6 ), SO 3 NHR 9 , with R 9 being hydrogen or alkyl (Ci -6 ).
  • Certain embodiments are compounds of formula IV:
  • R 1 is O-alkyl (C- 6 );
  • R 2 is OH, SO 3 NHR 6 , with R 6 being hydrogen or alkyl (C 1-6 ) or CONHR 7 , with R 7 being hydrogen or alkyl (Ci -6 );
  • R 3 is hydrogen, alkyl (Ci -6 ), OH, O-alkyl (Ci -6 ), SO 3 NHR 8 with R 8 being hydrogen or alkyl (Ci -6 ), or CONHR 9 , with R 9 being hydrogen or alkyl (C -6 );
  • R4 is hydrogen, alkyl (Ci -6 ), OH, O-alkyl (Ci -6 ), SO 3 NHR 10 with R 10 being hydrogen or alkyl (Ci -6 ), or CONHR 11 , with R 11 being hydrogen or alkyl (Ci -6 ); and
  • R 5 is hydrogen, alkyl (C 1 -6 ), OH, O-alkyl (C 1-6 );
  • R 1 is O-alkyl (C- 6 );
  • R 2 is OH, SO 3 NHR 4 , with R 4 being hydrogen or alkyl (C -6 ) or CONHR 5 , with R 5 being hydrogen or alkyl (Ci -6 ); and
  • R 3 is alkyl (C 1-6 ).
  • R 1 is O-alkyl (Ci- 6 );
  • R 2 is OH, SO 3 NHR 5 , with R 5 being hydrogen or alkyl (C 1-6 ) or CONHR 6 , with R 6 being hydrogen or alkyl (Ci -6 );
  • R 3 is alkyl (Ci -6 );
  • R 4 is OH, alkyl (Ci -6 ), or SO 2 NHR 7 , with R 7 being hydrogen or alkyl (Ci -6 ).
  • Certain embodiments are compounds of formula VII:
  • R 1 is O-alkyl (Ci- 6 );
  • R 2 is OH, SO 3 NHR 5 , with R 5 being hydrogen or alkyl (Ci -6 ) or CONHR 6 , with R 6 being hydrogen or alkyl (Ci -6 );
  • R 3 is alkyl (Ci -6 );
  • R 4 is OH, O-alkyl (C ]-6 ), or SO 3 NHR 7 , with R 7 being hydrogen or alkyl (Ci -6 ).
  • Certain embodiments are compounds of formula VIII:
  • R 1 is O-alkyl (Ci- 6 );
  • R 2 is OH, SO 3 NHR 4 , with R 4 being hydrogen or alkyl (Ci -6 ) or CONHR 5 , with R 5 being hydrogen or alkyl (C 1-6 ); and
  • R 3 is alkyl (Ci -6 ).
  • R 1 is O-alkyl (Ci- 6 );
  • R 2 is OH, SO 3 NHR 5 , with R 5 being hydrogen or alkyl (Ci -6 ) or CONHR 6 , with R 6 being hydrogen or alkyl (Ci -6 );
  • R 3 is alkyl (Ci -6 );
  • R 4 (stereochemistry unspecified) is OH, O-alkyl (Ci -6 ), COR 7 with R 7 being hydrogen, alkyl (Ci -6 ), OH, O-alkyl (Ci -6 ), NH 2 , or NH-alkyl (C, -6 ), or SO 3 NHR 8 , with R 8 being hydrogen or alkyl (Ci -6 ).
  • Any of the disclosed compounds as described above can be included in a pharmaceutical formulation or dosage form as described herein or as commonly known in the art. As such the compounds may be mixed with or dissolved in a pharmaceutically acceptable carrier
  • FIG. 1 is a schematic of the syntheses of compounds 2-11.
  • FIG. 2 is an alternate synthesis of 2-Methoxy-18a-homoestra-l,3,5,(10)-trien-
  • FIG. 3 is a schematic of the syntheses of ring D-unsaturated 2-Methoxy-18a- homoestra-l,3,5,(10)-trien-3-ol derivatives.
  • FIG. 4 is a schematic of the synthesis of 2-Methoxy-3-hydroxy-18a-homoestra- l,3,5,(10),16-tetraene.
  • FIG. 5 is the molecular structures of compounds 36, 37, and 38, which have been observed with 13 -ethyl gauche g + conformation.
  • FIG. 6 shows the observed conformations of 18a homosteroids including the trans (left) and gauche (right) conformations.
  • FIG. 7 is the MM3 energy profile for the rotation of the 13 -ethyl group of compounds 9 and 24.
  • FIG. 8 is the MM3 energy profile for the rotation of the 13 -ethyl group of compounds 9 and 28.
  • FIG. 9 is the molecular structures of the compounds compared in Table 3.
  • FIG. 10 is a schematic of the syntheses of compounds 2a - 12a.
  • FIG. 11 is a schematic of the syntheses of 2-methoxy-17-methyl and 2- methoxy-17-ethynyl steroids with unsaturated ring D.
  • FIG. 12 is a schematic of the synthesis of a Dimethylhexahydrochrysine analog.
  • FIG. 13 is a schematic of the synthesis of 2-methoxyestra-l,3,5(10),14,15- pentaen-3-ol.
  • FIG. 14 is a schematic of the synthesis of Dihydroxyhexahydrochrysine analog.
  • 17 ⁇ -hydroxysteroid dehydrogenases play a major role in oxidization of a 17 ⁇ -hydroxy function to an oxo group or the reduction of a 17-oxo group to a 17 ⁇ -hydroxy derivative. Since it has been observed that the 17-hydroxy derivatives of 2ME2 are more active than their corresponding 17-oxo derivatives, it is desirable to minimize the activity of 17 ⁇ -HSD on the oxidation of a 17 ⁇ -hydroxy steroid to a 17-oxo compound.
  • the present disclosure addresses this by incorporation of a sterically bulky substituent next to the 17 ⁇ -hydroxy function and also protecting the 17 ⁇ -hydroxy group as a methyl ether which cannot be readily hydrolyzed by the enzyme hydrolase.
  • 2ME2 has a methyl group at C- 13 position adjacent to the 17 ⁇ -hydroxyl group. Replacing the C- 13 methyl group with a sterically bulkier ethyl group, it is contemplated that the 17 ⁇ - hydroxyl function is protected from metabolic deactivation. Examples of 2ME2 derivatives with C- 13 ethyl substituents have been synthesized for evaluation of cytotoxic activity in multiple tumor cell lines.
  • the net effect of an increased population of the gauche g + conformations for compounds (24), (27), (28) and (31) would be a decrease in accessibility of the beta-face of the D-ring for interaction with tubulin. This could explain the decrease in biological activities observed for these compounds compared to (9) and (11). This is in agreement with the observation that for 16- substituted or 15,16-disubstituted 2ME2 analogs, the ⁇ -isomer is usually less active than the ⁇ -isomer.
  • the least active compound (15a) has a D-ring that projects above that of 2ME2, towards the ⁇ -side of the molecule.
  • substituents on the ⁇ -side of the D-ring decrease antiproliferative activity.
  • the ⁇ 13 ' 17 bond projects the entire D-ring towards the ⁇ face of the molecule which could explain its decreased antiproliferative activity.
  • the disclosed compounds can be used to treat diseases characterized by abnormal or undesired cell proliferation.
  • diseases include for example, but are not limited to: abnormal stimulation of endothelial cells (e.g., atherosclerosis), solid tumors and tumor metastasese, benign tumors (e.g., hemangiomas, acoustic neuromas, neurofibromas, trachomas and pyogenic granulomas), vascular malfunctions, abnormal wound healing, inflammatory and immune disorders, Bechet's disease, gout or gouty arthritis, abnormal angiogenesis accompanying for example, rheumatoid arthritis, psoriasis, diabetic retinopathy, and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplasia), macular degeneration, corneal graft rejection, neuroscular glaucoma and Oster Webber syndrome.
  • endothelial cells e.g., atherosclerosis
  • Neoplasms which the disclosed compounds can be used to treat include, but are not limited to: mammary, small-cell lung, non-small-cell lung, colorectal, leukemia, lymphoma, melanoma, pancreatic, renal, liver, myeloma, multiple myeloma, mesothelioma, central nervous system including neuroblastoma, ovarian, prostate, sarcoma of soft tissue or bone, head and neck, esophageal, stomach, bladder, retinoblastoma, squamous cell, testicular, vaginal, and neuroendocrine-related, which includes thyroid, Hodgkin's disease and non-Hodgkin's disease neoplasms.
  • the disclosed compounds can be used in combination with other treatment modalities, e.g. surgery or radiation therapy, and in combination therapy with other known chemotherapeutic or antineoplastic agents (e.g., alkylating agents, antimetabolites, antitumor antibiotics, antimitotics (e.g., vinca alkaloids and taxanes), hormones (e.g., tamoxifen), Selective Estrogen Receptor Modulators (SERMs), antibodies (e.g., Herceptin), and platinum coordination complexes, etc.).
  • chemotherapeutic or antineoplastic agents e.g., alkylating agents, antimetabolites, antitumor antibiotics, antimitotics (e.g., vinca alkaloids and taxanes), hormones (e.g., tamoxifen), Selective Estrogen Receptor Modulators (SERMs), antibodies (e.g., Herceptin), and platinum coordination complexes, etc.
  • the compounds of the present invention can be used in combination therapy with a vinca alkaloid compound, such as vinblastine, vincristine, TaxolTM, etc.; an antibiotic, such as adriamycin (doxorubicin), dactinomycin (actinomycin D), daunorubicin (daunomycin, rubidomycin), bleomycin, plicamycin (mithramycin) and mitomycin (mitomycin C), etc.; an antimetabolite, such as methotrexate, cytarabine, azauridine, azaribine, fluorodeoxyuridine, deoxycoformycin, mercaptopurine, etc.; or a platinum coordination complex, such as cisplatin, carboplatin, etc.
  • a vinca alkaloid compound such as vinblastine, vincristine, TaxolTM, etc.
  • an antibiotic such as adriamycin (doxorubicin), dactinomycin (act
  • Certain embodiments relate to methods of treating diseases associated with undesired angiogenesis, the methods including administering to a subject an anti- angiogenic compound of any of Formulas I- VIII, or a pharmaceutically acceptable salt or ester thereof, prodrug or precursor thereof, in admixture with one or more pharmaceutically acceptable carriers, diluents, or excipients, in a therapeutically effective amount.
  • the methods can be used to treat a variety of diseases, including diseases associated with undesired angiogenesis.
  • diseases include those associated with corneal neovascularization including, but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasias, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis, mycobacterial infections, lipid degeneration, chemical bums, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren ulcer, Te ⁇ en's marginal degeneration, marginal keratolysis
  • Diseases associated with retinal/choroidal neovascularization that can be treated with the disclosed methods include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Pagets disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosus, retinopathy of prematurity, Eales disease, Bechets disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Bests disease, myopia, optic pits, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications.
  • Diseases associated with chronic inflammation can also be treated.
  • Diseases that can be treated with the disclosed methods include diseases with symptoms of chronic inflammation that include, but are not limited to, inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis and rheumatoid arthritis.
  • Unwanted angiogenesis is a key element that these chronic inflammatory diseases have in common. The chronic inflammation depends on continuous formation of capillary sprouts to maintain an influx of inflammatory cells.
  • Other diseases that can be treated include endometriosis, hemangiomas, Osler- Weber-Rendu disease, or hereditary hemorrhagic telagiectasia, solid or blood borne tumors and acquired immune deficiency syndrome (AIDS).
  • endometriosis hemangiomas
  • Osler- Weber-Rendu disease or hereditary hemorrhagic telagiectasia
  • solid or blood borne tumors and acquired immune deficiency syndrome (AIDS).
  • AIDS acquired immune deficiency syndrome
  • compositions and methods can also be used to treat diseases, other than cancer for example, in which normal tubulin polymerization and function plays a role.
  • Chagas' disease for example, is caused by Trypanosoma cruzi, a flagellate protozoa which has a substantial protein composition containing tubulin both as a component of the subpellicular microtubule system and the flagellum.
  • Chagas 1 disease is characterized by lesions in the heart, alimentary tract and nervous system. The disease is the leading cause of myocarditis in the Americas. Inhibition of tubulin polymerization, crucial to the parasite's mobility, would provide an effective treatment.
  • the benzimidazoles are very effective antihelmenthic drugs, and the dinitroanilines have shown promise against Leishmania, a parasite closely related to Trypanosoma (U.S. Pat. No. 6,162,930).
  • the disclosed compositions are contemplated to be used to contact such parasites or sites of parasitic infection and thereby treat the associated disease.
  • Certain embodiments relate to a method of treating fungal diseases, the method comprising administering a therapeutically effective amount of a compound of any of Formulas I- VIII, or a pharmaceutically acceptable salt or ester, prodrug or precursor thereof, in admixture with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the progression of fungal diseases has proven particularly susceptible to treatment by drugs that act by disruption of microtubule organization, as for example by cryptophycin (U.S. Pat. No. 6,180,679).
  • the methods of the present invention may be used in controlling mycotic infections or in controlling a yeast infection, where controlling refers to slowing, stopping or interrupting the spread of the given infection and not necessarily to a complete and total elimination of the mycotic infection or yeast infection.
  • Administration refers to slowing, stopping or interrupting the spread of the given infection and not necessarily to a complete and total elimination of the mycotic infection or yeast infection.
  • compositions can be provided in therapeutically effective amounts as physiologically acceptable formulations using known techniques, and these formulations can be administered by standard routes.
  • the compositions can be administered alone or in combination, and by topical, oral, rectal, intravenous, subcutaneous or intramuscular route.
  • the compounds can be incorporated into biodegradable polymers allowing for sustained release, the polymers being implanted in the vicinity of where delivery is desired, for example, at the site of a tumor.
  • Biodegradable polymers and their use are described in detail in Brem et al., J. Neurosurg. 74, 441-446 (1991), and are familiar to those skilled in the art.
  • the dosage of the compositions will depend on the condition being treated, the particular compound used, the type and severity of the disease or malady, and other clinical factors such as weight, sex, age and condition of the patient, the patient's tolerance to drugs and/or treatment, and the route of administration. Those skilled in the art will be able to determine the appropriate dosages depending on these and other factors.
  • a therapeutically effective amount of a compound can range from about 1 mg per day to about 1000 mg per day for an adult human individual.
  • a dosage of 0.01 to 100 mg/kg/day, preferably 0.01-1 mg/kg/day is generally a therapeutically effective amount.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intraocular, intratracheal and epidural) administration.
  • the formulations can conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques may include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or excipient(s).
  • Pharmaceutical carriers or excipients can contain inert ingredients which do not interact with the compound, or ingredients that do interact with the compound but not in a fashion so as to interfere with the desired effect.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, et cetera.
  • the oral formulations can be designed for immediate release in a gastric fluid environment or they can be designed for delayed or sustained release.
  • the use of hydrophobic and hydrophilic polymers for coatings or drug matrices is known in the art and is contemplated for use in the described pharmaceutical formulations.
  • Oral dosage forms can be prepared in which release is pH sensitive, to be released only at low or high pH, pH insensitive, released over a period of time of from 30 minutes to 1 to 4 hours, or even 10, 20, 30 or more hours, for example.
  • release of the compositions can be targeted to a particular portion of the digestive tract such as the gastric, ileal or colonic areas to provide for optimal absorption or stability of the active ingredient.
  • sustained release also allows the use of less frequent administrations, resulting in a more convenient protocol.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may optionally be coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein as described above.
  • Oral dosage forms can also include capsules such as gel capsules that contain particles of therapeutic compositions in which either the particles or capsule can include coating layers.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, usually sucrose and gum acacia or gum tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and gum acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutically acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for nasal administration include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nose.
  • Suitable formulations for administration wherein the carrier is a liquid are nasal sprays or nasal drops including aqueous or oily solutions of the active ingredient.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known by those skilled in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injection, immediately prior to use.
  • sterile liquid carrier for example, water for injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described herein.
  • compositions of the present disclosure may be administered in a formulation including liposomes in order to improve availability and to regulate dosage.
  • the liposome may or may not form part of a targeted drug delivery system, for example in a liposome coated with a tumor-specific antibody.
  • Such liposomes will be targeted to and taken up selectively by the site of interest (e.g., a tumor cell)
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers. Further, long- circulating, or stealth, liposomes may be employed (U.S. Pat. No. 5,013,556) (incorporated herein by reference).
  • such liposomes or other drug delivery systems typically have a targeting moiety, i.e., ligand, conjugated thereto that is specific for the target site of interest (e.g., tumor cell).
  • a targeting moiety i.e., ligand
  • Tumor vasculature which is composed primarily of endothelial cells, is inherently different than normal differentiated vasculature.
  • the architecture of tumor vasculature is known to be leaky, and blood flow through them is mostly intermittent, with periods of perfusion and periods of occlusion and subsequent hypoxia.
  • This aberrant microenvironment may be caused by and, in turn, leads to, additional differential gene expression in tumor vasculature relative to normal vasculature.
  • This abnormal architecture and function, at the molecular level, is characterized by differences in surface markers in tumor microvessels relative to normal vessels and such differences can be exploited to target the liposome or other drug delivery system to the site of interest. Liposomes offer the added advantage of shielding the drug from most normal tissues.
  • liposomes When coated with polyethylene glycol (PEG) (i.e., stealth liposomes) to minimize uptake by phagocytes and with a tumor vasculature-specific targeting moiety, liposomes offer longer plasma half-lives, lower non-target tissue toxicity and delivery, and increased efficacy over non-targeted drug.
  • PEG polyethylene glycol
  • ADEPT antibody- directed enzyme prodrug therapy
  • GDEPT gene-directed EPT
  • VDEPT virus- directed EPT
  • ADEPT antibody- directed enzyme prodrug therapy
  • GDEPT gene-directed EPT
  • VDEPT virus- directed EPT
  • ADEPT the targeting of an inactive prodrug to a tumor mass is effected by an antibody against a tumor-associated marker.
  • the enzyme milieu in or about the tumor transforms the prodrug into an active toxic agent that then acts on the tumor tissue.
  • differential gene expression or viral targeting at the tumor site is used to activate a prodrug into its active, toxic form in GDEPT and VDEPT, respectively.
  • Other strategies include targeting differentially expressed genes, enzymes or surface markers that appear on, for example, tumor-associated vasculature to effect control of tumor progression or to other sites of interest (e.g., endothelial cells, TNF-. alpha., TNF- . alpha, receptor, etc.).
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
  • formulations can include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring and other agents.
  • the 3 -hydroxy- 17-ketone derivative (1) was prepared from Norgestrel according to Rao et al., Steroids 1994;59:621-627.
  • the syntheses of compounds (2-11) are outlined in Fig. 1 and were based on the procedures previously developed for the 13 -methyl analogs (Rao and Cessac, Steroids 2002;67: 1065- 1070).
  • Reduction of the ketone via sodium borohydride in ethanol/THF at room temperature overnight gave the diol compound (2) in 98% yield.
  • Simple acetylation of this material with acetic anhydride in pyridine at room temperature for 48 hours gave the 3,17 ⁇ -diacetate compound (3) in 80% yield.
  • the 3,17 ⁇ -diol derivative (9) was then selectively acetylated in isopropanol with acetic anhydride in the presence of 2M KOH to give the 3-acetate derivative (15) in 91% yield.
  • Oxidation of this material with Jones's reagent in acetone at 0 °C gave the 17-ketone compound (16) in 95% yield.
  • the 17-ketone (27a) was converted to the 17- thioketal (28a) in 71 % yield by reaction with ethanedithiol and boron trifluoride diethyl etherate in acetic acid at room temperature for ninety minutes. This material was then refluxed with deactivated Raney nickel in acetone to give the ⁇ 14 ' 16 derivative (29a) in 9.3 % yield. Simple base hydrolysis of (29a) with potassium carbonate in methanol/water gave the 3-hydroxy compound (30a) in quantitative yield.
  • Robinson annulation of diketone (32a) was accomplished by refluxing in methanol with 10% KOH to give compound (33a) in quantitative yield.
  • Compound (33a) was converted to the 3- acetate derivative (34a) in 51% yield by reaction with acetic anhydride in pyridine.
  • Aromatization of compound (34a) to give the chrysene derivative (35a) was carried out in 70% yield following the procedure of Rao et al (Steroids 1994;59:621-627) using copper II bromide in acetonitrile.
  • Hydrolysis of compound (35a) in methanol/water with potassium carbonate gave the 2,8-diol derivative (36a) in 88% yield.
  • the diol (36a) was converted to the dimethoxymethyl ether (37a) in 88% yield by reaction with chloromethyl methyl ether and N,N-diisopropylethylamine in THF at 65 0 C.
  • Metallation of compound (37a) by reaction with sec-BuLi in THF at -65 0 C followed by the addition of trimethyl borate and sodium perborate gave the 8-hydroxy compound (38a) in 84% yield.
  • O-Methylation of compound (38a) with methyl iodide in DMF in the presence of potassium carbonate and tetra-n-butyl ammonium iodide afforded the 3,9- dimethoxychrysine derivative (39a) in 73% yield.
  • Suitable cell lines for testing biological activity include human umbilical vein endothelial cells (HUVEC), human breast carcinoma cells (MDA-MB-231) and human gliomablastoma cells (U87-MG).
  • HEVEC human umbilical vein endothelial cells
  • MDA-MB-231 human breast carcinoma cells
  • U87-MG human gliomablastoma cells
  • Human umbilical vein endothelial cells can be obtained from Clonetics
  • HUVEC cultures are maintained for up to 5 passages in EGM
  • Proliferation assays are performed by evaluating detection of DNA synthesis by the use of the 5-bromo-2'-deoxyuridine (BrdU) cell proliferation colorimetric ELISA kit from
  • the cells are seeded at 1,000 cells/well (MDA-MB-231 and U87-MG cells, anti-tumor activity) or 3,000 cells/well (HUVEC, anti-angiogenic activity) in a 96 well plate, allowed to attach overnight and then exposed to the compound to be tested for 48 hours.
  • the 3 -hydroxy- 17 ketone derivative (1) was prepared from Norgestrel according to Rao et al., Steroids 1994;59:621-627. Under nitrogen, the 3-phenol (1, 9.4 g, 33 mmol) was dissolved in 50 ml of 1 :1 EtOHZH 2 O. Sodium borohydride, (2.5 g, 66 mmol) was dissolved in 450 ml of 1 :1 EtOH/H 2 O. The sodium borohydride solution was added to the steroid solution dropwise over 2 hours and stirred overnight. Analysis by TLC confirmed complete reaction (5% acetone/CH 2 Cl 2 ).
  • Trimethyl borate (68 ml, 0.61 mol) was then added maintaining the temperature below -65 0 C and the reaction stirred for 15 minutes at -78 °C and then warmed to 0 °C.
  • the reaction was quenched with 1 L of 20% NH 4 Cl solution, then allowed to come to room temperature and stirred for 1 hour.
  • Sodium perborate tetrahydrate (93 g, 0.6 mol) was then added at such a rate that the temperature did not exceed 35 0 C and the reaction carried out at room temperature overnight.
  • the reaction mixture was concentrated in vacuo and extracted with EtOAc (3x). The organic fractions were washed with water and brine, combined, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the 17-hydroxy compound (15, 20 g, 55.8 mmol) was dissolved in 400 ml of acetone and chilled to 0 0 C. Jones's Reagent was slowly added with stirring until the yellow-orange color persisted ( ⁇ 40 ml). The reaction was stirred an additional five minutes then slowly quenched with isopropanol. The solution was concentrated in vacuo, diluted with water, and extracted with EtOAc (3x). The organic fractions were washed with water and brine, combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the 17-ketone (16, 19 g, 95.5 %).
  • the 17-ketal (17, 20 g, 50 mmol) was dissolved in 400 ml of THF and chilled to -5 0 C.
  • Benyltrimethylammonium tribromide (97%, 22.5 g, 56 mmol) was added in 5 g portions over 1/2 hour. Once the addition was complete, the reaction mixture was stirred at -5 0 C overnight.
  • the reaction was quenched with cold, saturated NaHCO 3 and extracted with EtOAc (3x). The organic fractions were washed with saturated NaHCO 3 solution (2x), 10% sodium thiosulfate solution, cold water (2x), and brine, combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the reaction mixture was evaporated to 1/3 volume and extracted with CH 2 Cl 2 (3x). The organic fractions were washed with water and brine, combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by flash chromatography (2.5 % acetone/CH 2 Cl 2 ) to give a mixture of the ⁇ 14 and ⁇ 15 isomers (21 and 22, 2.7 g) as well as the pure ⁇ 15 derivative (22, 0.46 g, 45 %).
  • the reaction mixture was diluted with water and extracted with EtOAc (3x). The organic fractions were washed with water and brine, combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the hydrazone (32, 1.65 g) as a green/brown solid. The material was used in the subsequent reaction without further purification.
  • the 17a-ketone (8a, 1.0 g, 2.79 mmol) was dissolved in 20 ml of THF and cooled to 0 °C.
  • Lithium tri-tert-butoxyaluminum hydride solution (IM in THF, 5.6 ml, 5.6 mmol) was added dropwise and the solution stirred at room temperature for 2.5 hours.
  • the reaction was quenched with ethyl acetate, concentrated in vacuo, diluted with water, acidified with IM HCl, and extracted with ethyl acetate (3x).
  • the 3-methoxymethoxy ether (21a, 0.8 g, 2.48 mmol) was dissolved in 20 ml of dry THF and chilled to -78 °C. To this was added sec-BuLi (1.4 M/cyclohexane, 3.5 ml, 4.9 mmol) at such a rate that the temperature did not exceed -65 °C. The reaction mixture was stirred at -78 °C for 3 hours. Trimethyl borate (1.1 ml, 9.9 mmol) was then added at such a rate that the temperature did not exceed -65 0 C and the mixture stirred for one hour at -78 0 C.
  • reaction mixture was quenched with 15 ml of 20 % NH 4 Cl solution, allowed to come to room temperature, and stirred for 1 hour.
  • Sodium perborate tetrahydrate (1.5 g, 9.7 mmol) was then added at such a rate that the temperature did not exceed 35 °C and the reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was quenched with water and extracted with ethyl acetate (3x). The organic fractions were washed with water and brine, combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the 3-methoxymethoxy ether (23a, 0.46 g, 1.3 mmol) was hydrolyzed with 6M .
  • HCl (15 ml) in THF (20 ml) at room temperature over the weekend.
  • the reaction mixture was quenched with water and extracted with ethyl aceate (3x). The organic fractions were washed with water and brine, combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the diketone compound (32a, 3 g, 8.4 mmol) was cyclized in methanol (100 ml) with 10% KOH solution (40 ml) at reflux for 2.5 hours. Analysis by TLC (5%acetone/CH 2 Cl 2 ) indicated a complete reaction. The reaction mixture was quenched with water, acidified with 10% HCl, concentrated in vacuo, and extracted with EtOAc (3x).
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Abstract

L'invention concerne de nouveaux analogues de 2-alcoxyestradiol, des compositions pharmaceutiques et des procédés de traitement d'affections prolifératives et associées à l'angiogenèse.
PCT/US2008/062294 2007-05-01 2008-05-01 Analogues de 2-alcoxyestradiol et préparations pharmaceutiques WO2008137599A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110078604A (zh) * 2019-05-08 2019-08-02 台州学院 一种茚并茚酮衍生物的制备方法
CN110183298A (zh) * 2019-05-10 2019-08-30 台州学院 一种二苯并戊烯衍生物的制备方法
CN111410677A (zh) * 2020-03-02 2020-07-14 周亚耀 2-甲氧基雌莫司汀及其衍生物、制备方法和应用

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Publication number Priority date Publication date Assignee Title
US5892069A (en) * 1993-08-06 1999-04-06 The Children's Medical Center Corporation Estrogenic compounds as anti-mitotic agents
US6054598A (en) * 1997-03-13 2000-04-25 Pharm-Eco Laboratories, Inc. Synthesis of 2-alkoxyestradiols
US6852710B2 (en) * 2001-06-11 2005-02-08 Southwest Foundation For Biomedical Research 2-alkoxyestradiol analogs with antiproliferative and antimitotic activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5892069A (en) * 1993-08-06 1999-04-06 The Children's Medical Center Corporation Estrogenic compounds as anti-mitotic agents
US6054598A (en) * 1997-03-13 2000-04-25 Pharm-Eco Laboratories, Inc. Synthesis of 2-alkoxyestradiols
US6852710B2 (en) * 2001-06-11 2005-02-08 Southwest Foundation For Biomedical Research 2-alkoxyestradiol analogs with antiproliferative and antimitotic activity

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110078604A (zh) * 2019-05-08 2019-08-02 台州学院 一种茚并茚酮衍生物的制备方法
CN110183298A (zh) * 2019-05-10 2019-08-30 台州学院 一种二苯并戊烯衍生物的制备方法
CN110183298B (zh) * 2019-05-10 2021-09-17 台州学院 一种二苯并戊烯衍生物的制备方法
CN111410677A (zh) * 2020-03-02 2020-07-14 周亚耀 2-甲氧基雌莫司汀及其衍生物、制备方法和应用

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