WO2008067451A1 - Chromanones 3-benzylidine et 3-benzyle substituées inédites - Google Patents

Chromanones 3-benzylidine et 3-benzyle substituées inédites Download PDF

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Publication number
WO2008067451A1
WO2008067451A1 PCT/US2007/085914 US2007085914W WO2008067451A1 WO 2008067451 A1 WO2008067451 A1 WO 2008067451A1 US 2007085914 W US2007085914 W US 2007085914W WO 2008067451 A1 WO2008067451 A1 WO 2008067451A1
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substituted
alkyl
amino
protected
group
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PCT/US2007/085914
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English (en)
Inventor
James E. Macdonald
Michelle K. Hysell
Qi Liu
Dehua Yu
Ning Ke
Guohong Liu
Henry Q. X. Li
Flossie Wong-Staal
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Itherx Pharmaceuticals, Inc.
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Publication of WO2008067451A1 publication Critical patent/WO2008067451A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4

Definitions

  • the present invention relates generally to the synthesis of novel derivative compounds. Such compounds can inhibit several different biological processes involved in disease, including proliferation, migration, inflammation and angiogenesis.
  • the invention provides novel 3-benzylidine and 3-benzyl substituted chromanone derivative compounds.
  • deoxysappanone b 7,3'-dimethyl ether examples include the 3-(4-methoxy-3hydroxybenzyl)chroman-4-one listed as deoxysappanone b 7,3'-dimethyl ether, derived from ex Caesalpinia Sappan, as well as the 3-(4-methoxy- 3-hydroxybenzylidine)chroman-4-one listed as dehydrodeoxysappanone b dimethyl ether and the 3-(3-acetoxy-4-methoxybenzylidine)chroman-4-one listed as deoxysappanone b 7,3'-dimethyl ether acetate.
  • the compound deoxysappanone b 7,3'-dimethyl ether is also listed for screening at the ICCB-Longwood Screening Facility, Harvard Medical school.
  • the present invention provides novel chromanone derivatives with the following formula:
  • Figure 1 shows that a compound of the invention, designated "IMS 1998" and described in Example ID, caused significant G2/M arrest as early as three days post- treatment.
  • FIG. 2 shows the inhibitory effect on tube formation of HUVEC cells (an angiogenesis process) of two different concentrations of IMS 1998.
  • Figure 3 shows that a compound of the invention, designated "IMS 1999" and described in Example IE, significantly decreased VEGF-induced blood vessel formation, with local delivery (s.c.) of the compound having an even stronger effect than systemic (i.p.) delivery.
  • Figure 4 shows that, in the first chamber slide experiment with HUVEC cells, IMS 1998 inhibited VEGF induced cell migration.
  • Figure 5 shows the results of the second chamber slide experiment with THP-I cells. Specifically, two compounds of the invention, “IMS2217” ( Figure 5A and described in Example 4) and “IMS2186” ( Figure 5B and described in Example 2) inhibit cell migration, with IMS2217 being even more potent that IMS2186.
  • FIG 6 shows the results of the wound healing experiment. Specifically, IMS2186 inhibited the migration of cells into the wound (scratch) - ( Figure 6A and Figure 6B). Control cells that were not exposed to IMS2186 migrated and covered the wound within 20 hours ( Figure 6C).
  • Figures 7A and Figure 7B each show that IMS2217 significantly decreased PGE2 production on both undifferentiated THP-I cells and differentiated THP-I cells in a dose dependent manner, with the levels of inhibition higher on differentiated THP-I cells.
  • Figure 8 shows that IMS 1998 inhibited iNOS mediated nitric oxide production in a dose dependent manner.
  • Figures 9, 10 and 11 show that IMS 1999 caused a significant reduction in all inflammatory indicators measured (TNF- ⁇ , IL-6 and PGE2, respectively), both in plasma and in the peritoneal fluid.
  • Figure 12 shows the results of mice inoculated with SKO V3 human ovarian cancer cells (ATCC) subcutaneously, with one group injected intraperitoneally (i.p.) with IMS2217 at 50mg/kg, and the other group injected with 5% dextrose (Sigma).
  • the results are shown in Figure 12A (tumor size) and Figure 12B (body weight).
  • IMS2186 was administered directly into the tumor (intratumoral injections) twice at weekly intervals. Tumor growth in the injected mice and mouse body weight was measured twice/week post injection. The results are shown in Figure 13A (tumor size) and Figure 13B (body weight).
  • the present invention provides novel chromanone derivatives with the following formula:
  • Ri is Ci to C 12 alkyl, C 2 to Ci 2 alkenyl, C 2 to Ci 2 alkynyl, Ci to Ci 2 substituted alkyl, C 2 to Ci 2 substituted alkenyl, C 2 to Ci 2 substituted alkynyl or the formula -OR, where R is Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, heterocycle or substituted heterocycle;
  • R 2 , R3, R 4 and R5 are, independently, hydrogen, halogen, cyano, Ci to Ci 2 alkyl, C 2 to Ci 2 alkenyl, C 2 to Ci 2 alkynyl, Ci to Ci 2 substituted alkyl, C 2 to Ci 2 substituted alkenyl, C 2 to Ci 2 substituted alkynyl or the formulas -OR, -NHC(O)R, -NHC(O)OR, -C(O)R, -C(O)OR or -SO 2 NRY, where R and Y are, independently, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, heterocycle or substituted heterocycle; and
  • R 6 is hydrogen, phosphate, sulfate, the formulas -C(O)X or -C(O)CH(R 7 )NH 2 , where X is Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, heterocycle or substituted heterocycle and where R 7 is hydrogen, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, heterocycle or substituted heterocycle.
  • R 2 is hydrogen
  • R 5 is hydrogen or both positions are hydrogen.
  • R 6 is -C(O)CH(Ry)NH 2 and, even more preferably, R 7 is hydrogen, methyl, -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 OH, -CH(OH)CH 3 , benzyl, 4-hydroxybenzyl, indol-3-ylmethyl, -CH 2 SH, - CH 2 CH 2 SCH 3 , -CH 2 C(O)NH 2 , -CH 2 CH 2 C(O)NH 2 , -CH 2 -C(O)OH, -CH 2 -C(O)O " , - CH 2 CH 2 -C(O)OH, -CH 2 CH 2 -C(O)O " , (CH 2 ) 4 NH 3 + , guaninidino-1 -butyl or imidazol- 4-ylmethyl.
  • R 6 is -C(O)X and, more preferably, X is 2- pyrrolidyl or 2-piperidinyl.
  • Ri is -OR and, more preferably, R is Ci to Ci 2 alkyl, and even more preferably, R is methyl.
  • R 3 is -OR and, more preferably, R is Ci to Ci 2 alkyl and, even more preferably, R is methyl or ethyl.
  • R 6 is phosphate or hydrogen.
  • R 4 is halogen and, more preferably, is chloro or fluoro.
  • the compounds of the invention can be used against a variety of biological processes, including cell proliferation (see Example 16), cell cycle progression (see Example 17), angiogenesis (see Examples 18 and 19), cell migration (see Example 20) and inflammation (see Examples 21 and 22).
  • the compounds of the invention can be used to treat or assist in inhibiting a variety of diseases, including, but not limited to, cancer (see Example 23), keloids or hypertrophic scars and other conditions associated with fibroblast activity (see Example 24), inflammatory diseases and wet AMD (age-related macular degeneration, see Example 25).
  • the present invention provides a method for reduction of the growth or proliferation of mammalian cancer cells, comprising applying to the cancer cells a therapeutically effective amount of the novel compound of the invention.
  • the present invention provides a method for the treatment of mammalian cancer, comprising administering to the mammalian subject a pharmaceutical composition containing as an active ingredient a therapeutically effective amount of the novel compound of the invention.
  • the present invention provides similar methods for treating or preventing the biological processes or diseases described herein.
  • reduction of growth in relation to cancer cells, in the context of the present invention refers to a decrease in at least one of the following: number of cells (due to cell death which may be necrotic, apoptotic or any other type of cell death or combinations thereof) as compared to control; decrease in growth rates of cells, i.e.
  • the total number of cells may increase but at a lower level or at a lower rate than the increase in control; decrease in the invasiveness of cells (as determined for example by soft agar assay) as compared to control even if their total number has not changed; progression from a more differentiated cell type to a less differentiated cell type; a deceleration in the neoplastic progress; or alternatively the slowing of the progression of the cancer cells from one stage to the next.
  • Reduction of growth of cancer cells may be utilized for the treatment of cancer by the administration, to an individual in need of such treatment, of a therapeutically effective amount of the compound of the present invention, as described herein.
  • the present invention additionally discloses use of a composition of the invention, as described above, for preparing a medicament for the treatment of cancer in mammals.
  • treatment of cancer includes at least one of the following: a decrease in the rate of growth of the cancer (i.e. the cancer still grows but at a slower rate); cessation of growth of the cancerous growth, i.e., stasis of the tumor growth, and, in preferred cases, the tumor diminishes or is reduced in size.
  • the term also includes reduction in the number of metastasis, reduction in the number of new metastasis formed, slowing of the progression of cancer from one stage to the other and a decrease in the angiogenesis induced by the cancer. In most preferred cases, the tumor is totally eliminated. Additionally included in this term is lengthening of the survival period of the subject undergoing treatment.
  • cancer in the context of the present invention includes all types of neoplasm whether in the form of solid or non-solid tumors, from all origins, and includes both malignant and benign conditions as well as their metastasis.
  • this term refers to: carcinoma, sarcoma, adenoma, hepatocellular carcinoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphagiosarcoma, synovioama, Ewing's tumor, leimyosarcoma, rhabdotheliosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, hematoma, bile duct carcinoma, melanoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'
  • An inflammatory disease includes, but is not limited to, arthritis, including rheumatoid arthritis, inflammation associated with hypersensitivity, allergic reactions, asthma, systemic lupus erythematosus, collagen diseases and other autoimmune diseases, inflammation associated with atherosclerosis, arteriosclerosis, atherosclerotic heart disease, reperfusion injury, cardiac arrest, myocardial infarction, vascular inflammatory disorders, respiratory distress syndrome or other cardiopulmonary diseases, inflammation associated with peptic ulcer, ulcerative colitis and other diseases of the gastrointestinal tract, hepatic fibrosis, liver cirrhosis or other hepatic diseases, thyroiditis or other glandular diseases, glomerulonephritis or other renal and urologic diseases, otitis or other oto- rhino-laryngological diseases, dermatitis or other dermal diseases, periodontal diseases or other dental diseases, orchitis or epididimo-orchitis, infertility, orchidal trauma or other immune-related testicular
  • retinitis or cystoid macular oedema retinitis or cystoid macular oedema, sympathetic ophthalmia, scleritis, retinitis pigmentosa, immune and inflammatory components of degenerative fondus disease, inflammatory components of ocular trauma, ocular inflammation caused by infection, proliferative vitro-retinopathies, acute ischaemic optic neuropathy, excessive scarring, e.g.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease, substantially ameliorating clinical symptoms of a disease or substantially preventing the appearance of clinical symptoms of a disease.
  • preventing refers to a method for barring an organism from acquiring a disorder or disease in the first place.
  • organ refers to any living entity comprised of at least one cell.
  • a living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal, including a human being.
  • terapéuticaally effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • the medicament additionally comprises at least one active chemotherapeutic agent other than the compound of the invention.
  • the novel compound may be administered alongside with traditional chemotherapeutic drugs that are effective but have considerable side effects.
  • the combination of a compound of the invention and the traditional drug may allow administration of a lesser quantity of the traditional drug, and thus the side effects experienced by the subject may be significantly lower, while a sufficient chemotherapeutic effect is nevertheless achieved.
  • Preferred additional active chemotherapeutics include but are not limited to taxol or doxorubicin.
  • the compound is administered at a dosage selected from l ⁇ g-1000 mg/kg body weight.
  • compositions for the indications described herein comprising as the active ingredient a therapeutically effective amount of a compound of the invention, as described above.
  • compositions for the indications described herein comprising as the active ingredient a therapeutically effective amount of a compound of the invention, as described herein, and a pharmaceutically acceptable carrier.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, cyclodextrins and the like.
  • composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates.
  • Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides, microcrystalline cellulose, gum tragacanth or gelatin.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.
  • Such compositions will contain a therapeutically effective amount of a compound of the invention, preferably in a substantially purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • the carrier can be selected at times based on the desired form of the formulation.
  • the carrier may also at times have the effect of the improving the delivery or penetration of the active ingredient to the target tissue, for improving the stability of the drug, for slowing clearance rates, for imparting slow release properties, for reducing undesired side effects etc.
  • the carrier may also be a substance that stabilizes the formulation (e.g. a preservative), for providing the formulation with an edible flavor, etc.
  • the carriers may be any of those conventionally used and are limited only by chemical-physical considerations, such as solubility and lack of reactivity with the compound of the invention, and by the route of administration.
  • the choice of carrier will be determined by the particular method used to administer the pharmaceutical composition.
  • the carrier may include additives, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • the carrier may be an adjuvant, which, by definition are substances affecting the action of the active ingredient in a predictable way.
  • Methods of introduction of a pharmaceutical composition comprising a compound of the invention include, but are not limited to, topical, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, ophthalmic, and oral routes.
  • the compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other therapeutically active agents. It is preferred that administration is localized, but it may be systemic.
  • intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.
  • composition of the invention may be administered locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material.
  • administration can be by direct injection e.g., via a syringe, at the site of a tumor or neoplastic or pre-neoplastic tissue.
  • compositions suitable for oral administration may consist of (a) liquid solutions, where an effective amount of the active substance is dissolved in diluents, such as water, saline, natural juices, alcohols, syrups, etc.; (b) solid dosage forms such as capsules (e.g.
  • the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers), tablets, lozenges (wherein the active substance is flavored, such as with sucrose and acacia or tragacanth, or the active substance is in an inert base, such as gelatin and glycerin), and troches, each containing a predetermined amount of the active ingredient as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; (e) suitable emulsions; (f) liposome formulation; and others.
  • the composition is prepared for topical administration, e.g. as an ointment, a gel a drop or a cream.
  • topical administration e.g. as an ointment, a gel a drop or a cream.
  • the compounds of the present invention can be prepared and applied in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • the present invention may be used topically or transdermally to treat cancer, for example, melanoma.
  • Adjuvants for topical or gel base forms may include, for example, sodium carboxymethylcellulose, polyacrylates, polyoxyethylene-polyoxypropylene-block polymers, polyethylene glycol and wood wax alcohols.
  • the pharmaceutical composition may be in the form of tablets or capsules, which can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; or a glidant such as colloidal silicon dioxide.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide.
  • dosage unit form can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which
  • a compound of the present invention can be delivered in a controlled release system.
  • an infusion pump may be used to administer a compound of the invention, such as one that is used for delivering insulin or chemotherapy to specific organs or tumors (see Buchwald et al, 1980, Surgery 88: 507; Saudek et al, 1989, N. Engl. J. Med. 321 : 574).
  • a compound of the invention is administered in combination with a biodegradable, biocompatible polymeric implant, which releases the compound over a controlled period of time at a selected site.
  • a controlled release system can be placed in proximity of the therapeutic target, thus requiring only a fraction of the systemic dose.
  • the active compound may be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as propane, butane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • the pharmaceutical compositions may be formulated for parenteral administration (subcutaneous, intravenous, intraarterial, or intramuscular injection) and may include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Oils such as petroleum, animal, vegetable, or synthetic oils and soaps such as fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents may also be used for parenteral administration.
  • compositions may also be used for direct intra-tumoral injection.
  • compositions may contain one or more nonionic surfactants.
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described and known in the art.
  • the amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition, including cancer, will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques.
  • in vitro assays may optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • a preferred dosage will be within the range of 0.01-1000 mg/kg of body weight, more preferably, 0.1 mg/kg to 100 mg/kg and even more preferably 1 mg/kg to 10mg/kg.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test bioassays or systems.
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
  • a “therapeutically effective amount” of a compound of the invention is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • the method of treatment according to the present invention includes both therapeutic and prophylactic utility.
  • a compound of the invention can be tested in vivo for the desired therapeutic or prophylactic activity as well as for determination of a therapeutically effective dosage.
  • such compounds can be tested in suitable animal model systems prior to testing in humans, including, but not limited to, rats, mice, chicken, cows, monkeys, rabbits, and the like.
  • suitable animal model systems prior to testing in humans, including, but not limited to, rats, mice, chicken, cows, monkeys, rabbits, and the like.
  • any animal model system known in the art may be used.
  • the stereochemistry of such chiral centers can independently be in the R or S configuration, or a mixture of the two.
  • the chiral centers can be further designated as R or S or R,S or d,D, 1,L or d,l, D,L.
  • the suffix "ene” added to any of the described terms means that two parts of the substituent are each connected to two other parts in the compound (unless the substituent contains only one carbon, in which case such carbon is connected to two other parts in the compound, for example, methylene).
  • Ci to C 12 alkyl denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • Preferred “Ci to C 12 alkyl” groups are methyl, ethyl, iso-butyl, sec-butyl and iso-propyl.
  • the term "Ci to C 12 alkylene” denotes radicals of 1 to 12 carbons connected to two other parts in the compound.
  • C 2 to Ci 2 alkenyl denotes such radicals as vinyl, allyl, 2-butenyl, 3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, (as well as octenyl, nonenyl, decenyl, undecenyl, dodecenyl radicals attached at any appropriate carbon position and the like) as well as dienes and trienes of straight and branched chains.
  • C 2 to Ci 2 alkynyl denotes such radicals as ethanol, propynyl, 2- butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-heptynyl, 3- heptynyl, 4- heptynyl, 5-heptynyl (as well as octynyl, nonynyl, decynyl, undecynyl, dodecynyl radicals attached at any appropriate carbon position and the like) as well as di- and tri-ynes of straight and branched chains.
  • Ci to Ci 2 substituted alkyl groups that are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C3 to C 7 cycloalkyl, phenyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Ci to Ci 2 alkoxy, Ci to Ci 2 acyl, Ci to
  • protected oxo denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety.
  • Ci to Ci 2 alkoxy denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred alkoxy is methoxy.
  • Ci to Ci 2 substituted alkoxy means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Ci to Ci 2 substituted alkyl. A preferred substitution is halo.
  • Ci to C 12 phenylalkoxy as used herein means "Ci to C 12 alkoxy" bonded to a phenyl radical.
  • Ci to C 12 acyloxy denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy and the like.
  • Ci to C 12 acyl encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl and the like.
  • Preferred acyl groups are acetyl and benzoyl.
  • Ci to C 12 substituted acyl denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Ci to C 12 alkoxy, Ci to C 12 acyl, Ci to C 12 acyloxy, nitro, Ci to C 12 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, N 5 N-CI
  • C 3 to C 7 cycloalkyl includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
  • a substituent that can be C 3 to C 7 cycloalkyl can also be "C 5 to C 7 cycloalkyl,” which includes the cyclopentyl, cyclohexyl or cycloheptyl rings.
  • C 3 to C 7 substituted cycloalkyl or "C 5 to C 7 substituted cycloalkyl” indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to C 10 substituted alkylthio, Ci to C 10 substituted alkylsulfoxide, Ci to Cio substituted alkylsulfonyl, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkyl, Ci to Ci 2 alkoxy, oxo, protected oxo, (monosubstituted)amino,
  • cycloalkylene means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups.
  • substituted cycloalkylene means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substituent.
  • C 5 to C 7 cycloalkenyl indicates a 1,2, or 3-cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring
  • substituted C5 to C 7 cycloalkenyl denotes the above C5 to C 7 cycloalkenyl rings substituted by a Ci to C 12 alkyl radical, halogen, hydroxy, protected hydroxy, Ci to C 12 alkoxy, trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, phenyl, substituted phenyl, amino, or protected amino.
  • C5 to C 7 cycloalkenylene is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups.
  • Examples of C 5 to C 7 cycloalkenylenes include 1,3-cyclopentylene and 1,2-cyclohexylene.
  • substituted C5 to C 7 cycloalkenylene means a cycloalkenylene further substituted by halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to C 10 substituted alkylthio, Ci to Ci 0 substituted alkylsulfoxide, Ci to Ci 0 substituted alkylsulfonyl, Ci to C 12 alkyl, Ci to C 12 alkoxy, Ci to C 12 substituted alkyl, Ci to C 12 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or
  • heterocycle or “heterocyclic ring” denotes optionally substituted five-membered to eight-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • heteroatoms such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • bicyclic heterocycle means two such rings fused to each other. These five-membered to eight-membered rings may be saturated, fully unsaturated or partially unsaturated, with fully saturated rings being preferred.
  • Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo, tetrahydrothiophen-yl, hexylmethyleneimino and heptylmethyleneimino.
  • substituted heterocycle or “substituted heterocyclic ring” and “substituted bicyclic heterocycle” mean the above-described heterocyclic or fused biheterocyclic rings are substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 12 alkyl, Ci to C 12 alkoxy, Ci to C 12 substituted alkoxy, Ci to C 12 acyl, Ci to C 12 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C12 al
  • heteroaryl means a heterocyclic aromatic derivative which is a f ⁇ ve- membered or six-membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, phthalimido, thiazolo and the like.
  • substituted heteroaryl means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to Ci 2 substituted acyl, Ci to Ci 2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected
  • C 7 to C 18 phenylalkyl denotes a Ci to Ci 2 alkyl group substituted at any position within the alkyl chain by a phenyl.
  • the definition includes groups of the formula: -phenyl-alkyl, -alkyl-phenyl and -alkyl-phenyl-alkyl.
  • groups of such a group include benzyl, 2-phenylethyl, 3-phenyl(n-propyl), 4-phenylhexyl, 3-phenyl(n- amyl), 3-phenyl(sec-butyl) and the like.
  • Preferred C 7 to C 18 phenylalkyl groups are any one of the preferred alkyl groups described herein combined with a phenyl group.
  • Ci to C 12 heterocycloalkyl denotes a Ci to C 12 alkyl group substituted at any position within the alkyl chain by a "heterocycle,” as defined herein.
  • the definition includes groups of the formula: -heterocyclic-alkyl, -alkyl- heterocyclic and -alkyl-heterocyclic-alkyl.
  • Preferred Ci to C 12 heterocycloalkyl groups are any one of the preferred alkyl groups described herein combined with any one of the preferred heterocycle groups described herein.
  • C 7 to C 18 substituted phenylalkyl and "Ci to C 12 substituted heterocycloalkyl” denote a C 7 to C 18 phenylalkyl group or Ci to C12 heterocycloalkyl substituted (on the alkyl or, where applicable, phenyl or heterocyclic portion) with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to Ci 2 substituted acyl, Ci to Ci 2 acyl
  • the substituted alkyl, phenyl or heterocyclic groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
  • C 7 to C 18 phenylalkylene specifies a C 7 to C 18 phenylalkyl, as defined above, where the phenylalkyl radical is bonded at two different positions connecting together two separate additional groups.
  • the definition includes groups of the formula: -phenyl-alkyl-, -alkyl-phenyl- and -alkyl-phenyl-alkyl-. Substitutions on the phenyl ring can be 1,2, 1,3 or 1,4.
  • C 7 to C 18 phenylalkylenes include, for example, 1,4-tolylene and 1,3-xylylene.
  • Ci to C12 heterocycloalkylene specifies a Ci to Ci 2 heterocycloalkyl, as defined above, where the heterocycloalkyl radical is bonded at two different positions connecting together two separate additional groups.
  • the definition includes groups of the formula: -heterocyclic-alkyl-, -alkyl-heterocyclic and -alkyl-heterocyclic-alkyl-.
  • C 7 to Ci 8 substituted phenylalkylene and "Ci to Ci 2 substituted heterocycloalkylene” means a C 7 to C 18 phenylalkylene or Ci to Ci 2 heterocycloalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to C 10 substituted alkylthio, Ci to C 10 substituted alkylsulfoxide, Ci to Cio substituted alkylsulfonyl, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkyl, Ci to Ci 2 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl,
  • substituted phenyl specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to Ci 2 substituted acyl, Ci to Ci 2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to Ci 2 alkyl)carboxamide, protected N-(Ci to Ci 2 alkyl)carboxamide, N, N-di(Ci to Ci 2 alkyl)carboxamide, N,
  • phenoxy denotes a phenyl bonded to an oxygen atom, wherein the binding to the rest of the molecule is through the oxygen atom.
  • substituted phenoxy specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 12 alkyl, Ci to C 12 alkoxy, Ci to C 12 substituted alkoxy, Ci to C 12 acyl, Ci to C 12 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, protected N-(
  • aryl refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl.
  • Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
  • aryloxy refers to an "aryl" group bonded to an oxygen atom, wherein the binding to the rest of the molecule is through the oxygen atom.
  • C 7 to C 18 substituted phenylalkoxy denotes a C 7 to C 18 phenylalkoxy group bonded to the rest of the molecule through the oxygen atom, wherein the phenylalkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, Ci to C 12 alkoxy, Ci to C 12 acyl, Ci to C 12 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to C 12 alkyl)carboxamide, N, N-(
  • the substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
  • phthalimide means a cyclic imide which is made from phthalic acid, also called 1,2-benzenedicarboxylic acid.
  • substituted phthalimide specifies a phthalimide group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to Ci 2 alkyl, Ci to Ci 2 alkoxy, Ci to Ci 2 substituted alkoxy, Ci to Ci 2 acyl, Ci to Ci 2 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to Ci 2 alkyl)carboxamide, protected N- (Ci to C 12 alkyl)carboxamide, N, N-CIi(C 1 to Ci 2 alkyl)carboxamide, trifluoromethyl, N-((Ci to C i
  • substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 6 alkyl, Ci to C 7 alkoxy, Ci to C 7 acyl, Ci to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(Ci to C 12 alkyl)carboxamide, protected N-(Ci to Ci 2 alkyl)carboxamide, N, N- di(Ci to C 12 alkyl)carboxamide, trifluoromethyl, N-((Ci to Ci 2
  • naphthylene means a naphthyl radical bonded at two positions connecting together two separate additional groups.
  • substituted napthylene means a naphthylene group that is further substituted by halogen, hydroxy, protected hydroxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, Ci to C 10 substituted alkylthio, Ci to C 10 substituted alkylsulfoxide, Ci to Cio substituted alkylsulfonyl, Ci to C 12 alkyl, Ci to C 12 alkoxy, Ci to C 12 substituted alkyl, Ci to Ci 2 alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio,
  • halo and halogen refer to the fluoro, chloro, bromo or iodo atoms. There can be one or more halogens, which are the same or different.
  • (monosubstituted)amino refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, Ci to Ci 2 acyl, Ci to Ci 2 substituted acyl, C 2 to Ci 2 alkenyl, C 2 to Ci 2 substituted alkenyl, C 2 to Ci 2 alkynyl, C 2 to Ci 2 substituted alkynyl, C 7 to Ci8 phenylalkyl, C 7 to C 18 substituted phenylalkyl, heterocyclic ring, substituted heterocyclic ring, Ci to Ci 2 heterocycloalkyl and Ci to Ci 2 substituted heterocycloalkyl.
  • the (monosubstituted)amino
  • (disubstituted)amino refers to an amino group with two substituents chosen from the group consisting of phenyl, substituted phenyl, Ci to Ci 2 alkyl, Ci to Ci 2 substituted alkyl, Ci to Ci 2 acyl, C 2 to Ci 2 alkenyl, C 2 to Ci 2 alkynyl, C 7 to Ci 8 phenylalkyl, C 7 to Ci 8 substituted phenylalkyl, Ci to Ci 2 heterocycloalkyl and Ci to
  • Ci 2 substituted heterocycloalkyl The two substituents can be the same or different.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule.
  • protected amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule.
  • (monosubstituted)amino means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
  • protected carboxamide means there is an amino-protecting group on the carboxamide nitrogen.
  • protected N-(Ci to Ci 2 alkyl)carboxamide means there is an amino-protecting group on the carboxamide nitrogen.
  • amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the compounds.
  • Preferred amino-protecting groups are Boc, Cbz and Fmoc.
  • Further examples of amino-protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 7, M.
  • epimino means -NH-.
  • substituted epimino means - N(R)-, where R is a substitution group listed above under the definition of "(monosubstituted)amino.”
  • Ci to Cs alkylene epimino refers to a one to five carbon alkylene chain with an epimino at any point along the chain.
  • Ci to Cs substituted alkylene epimino refers to a Ci to Cs alkylene epimino group that is substituted a) at the epimino position (in the same way as “substituted epimino,” described above); and/or b) at one or more of the alkylene positions (in the same way as “substituted alkylene,” as described above).
  • thio refers to -SH or, if between two other groups, -S-.
  • Ci to Cio alkylene thio refers to a one to ten carbon alkylene chain with a thio at any point along the chain.
  • Ci to C 10 substituted alkylene thio refers to a Ci to Cio alkylene thio group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene,” as described above).
  • sulfonyl refers to -S(O) 2 -.
  • Ci to Ci 0 alkylene sulfonyl refers to a one to ten carbon alkylene chain with a sulfonyl at any point along the chain.
  • Ci to Cio substituted alkylene sulfonyl refers to a Ci to Cio alkylene sulfonyl group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene,” as described above).
  • sulfmyl refers to -S(O)-.
  • Ci to Ci 0 alkylene sulfmyl refers to a one to ten carbon alkylene chain with a sulfmyl at any point along the chain.
  • Ci to C 10 substituted alkylene sulfinyl refers to a Ci to C 10 alkylene sulfmyl group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene,” as described above).
  • oxy refers to -O-.
  • Ci to Ci 0 alkylene oxy refers to a one to ten carbon alkylene chain with, respectively, one, two or three -O- at any point along the chain, provided that no two oxygen atoms are consecutive, and provided that any two oxygen atoms are separated by at least two carbons.
  • Ci to C 10 substituted alkylene oxy refers, respectfully to "Ci to C 10 alkylene oxy,” “Ci to C 10 alkylene dioxy” and “Ci to Cio alkylene trioxy” that are substituted at one or more of the alkylene positions (in the same way as “substituted alkylene,” as described above).
  • thiocarbonyl refers to -C(S)H or, if between two other groups, - C(S)-.
  • thioester refers to -C(O)SH or, if between two other groups, - C(O)S-.
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry,” J. GW. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T. W. Greene and PGM. Wuts, "Protective Groups in Organic Synthesis,” 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 5, each of which is incorporated herein by reference.
  • a related term is "protected carboxy,” which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
  • hydroxy-protecting group refers to readily cleavable groups bonded to hydroxyl groups.
  • the species of hydroxy-protecting groups is not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Examples of hydroxy-protecting groups are described by CB. Reese and E. Haslam, "Protective Groups in Organic Chemistry,” J. GW McOmie, Ed., Plenum Press, New York, NY, 1973, Chapters 3 and 4, respectively, and T. W Greene and PGM.
  • Ci to C 10 alkylthio refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.
  • the term "Ci to C 10 alkylsulfoxide” indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n- butylsulfoxide, sec-butylsulfoxide and the like.
  • Ci to C 10 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like, it should also be understood that the above thio, sulfoxide or sulfonyl groups can be at any point on the alkyl chain (e.g., 2-methylmercaptoethyl).
  • Ci to Ci 0 substituted alkylthio Ci to Ci 0 substituted alkylthio
  • Ci to Ci 0 substituted alkylsulfoxide Ci to Ci 0 substituted alkylsulfoxide
  • Ci to C 10 substituted alkylsulfonyl denote the Ci to C 10 alkyl portion of these groups may be substituted as described above in relation to “substituted alkyl.”
  • phenylthio phenylsulfoxide
  • phenylsulfonyl specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group.
  • substituted phenylthio substituted phenylsulfoxide
  • substituted phenylsulfonyl means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl.”
  • Ci to Ci 2 alkylaminocarbonyl means a Ci to Ci 2 alkyl attached to a nitrogen of the aminocarbonyl group.
  • Examples of Ci to Ci 2 alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and butylaminocarbonyl.
  • Ci to Ci 2 substituted alkylaminocarbonyl denotes a substituted alkyl bonded to a nitrogen of the aminocarbonyl group, which alkyl may be substituted as described above in relation to Ci to Ci 2 substituted alkyl.
  • Ci to Ci 2 alkoxycarbonyl means a “Ci to Ci 2 alkoxy” group attached to a carbonyl group.
  • Ci to Ci 2 substituted alkoxycarbonyl denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to "Ci to Ci 2 substituted alkyl.”
  • phenylaminocarbonyl means a phenyl attached to a nitrogen of the aminocarbonyl group.
  • substituted phenylaminocarbonyl denotes a substituted phenyl bonded to a nitrogen of the aminocarbonyl group, which phenyl may be substituted as described above in relation to substituted phenyl.
  • Ci to C 12 alkylaminothiocarbonyl means a Ci to C 12 alkyl attached to an aminothiocarbonyl group, wherein the alkyl has the same meaning as defined above.
  • Ci to C 12 substituted alkylaminothiocarbonyl denotes a substituted alkyl bonded to an aminothiocarbonyl group, wherein the alkyl may be substituted as described above in relation to Ci to C12 substituted alkyl.
  • phenylaminothiocarbonyl means a phenyl attached to an aminothiocarbonyl group, wherein the phenyl has the same meaning as defined above.
  • substituted phenylaminothiocarbonyl denotes a substituted phenyl bonded to an aminothiocarbonyl group, wherein phenyl may be substituted as described above in relation to substituted phenyl.
  • phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups.
  • substituted phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, wherein the phenyl is substituted as described above in relation to "substituted phenyl.”
  • substituted Ci to Ci 2 alkylene means a Ci to Ci 2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent.
  • cyclic C 2 to C 7 alkylene defines such a cyclic group bonded (“fused") to the phenyl radical resulting in a bicyclic ring system.
  • the cyclic group may be saturated or contain one or two double bonds.
  • the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms that are the cyclic C 2 to C 7 heteroalkylene.
  • the cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents which, if appropriate, can be connected to another part of the compound (e.g., alkylene) selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, Ci to C 4 acyloxy, formyl, Ci to Ci 2 acyl, Ci to Ci 2 alkyl, Ci to C 7 alkoxy, Ci to C 10 alkylthio, Ci to C 10 alkylsulfoxide, Ci to C 10 alkylsulfonyl, halo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, hydroxymethyl or a protected hydroxymethyl.
  • the cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members.
  • saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro-indanyl and a tetralin ring.
  • unsaturated examples occur when the resultant bicyclic ring system is a naphthyl ring or indolyl.
  • fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl, dihydropyrrolo, or dihydropyridinyl ring.
  • fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring.
  • fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring.
  • cyclic groups that contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring.
  • Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring.
  • Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl.
  • the term "carbamoyl” means an -NC(O)- group where the radical is bonded at two positions connecting two separate additional groups.
  • organic or inorganic cation refers to counter-ions for the carboxylate anion of a carboxylate salt.
  • the counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.
  • the compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent.
  • the solvates and hydrates of such compounds are included within the scope of this invention.
  • One or more compounds of the invention can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester- form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non-esterified forms of the compounds.
  • Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the -(Ci to C12) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl and the like; the 2-oxo-l,3-diooxlen-4- ylmethyl groups, such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl, 5-phenyl-2-oxo- l,3-dioxolen-4-ylmethyl and the like; the Ci to C 10 alkylthio
  • amino acid includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids.
  • amino acid also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally-occurring amino acids.
  • non-naturally-occurring amino acids include, for example, norleucine ("NIe"), norvaline (“Nva”), L- or D- naphthalanine, ornithine (“Orn”), homoarginine (homoArg) and others well known in the peptide art, such as those described in M.
  • any position of the claimed invention has up to three serial “substitutions.”
  • a "substituted alkyl” that is substituted with a "substituted phenyl” that is, in turn, substituted with a “substituted alkyl” can, in turn, be substituted by one more group and no longer further substituted.
  • the invention contemplates, if appropriate, more than three parallel substitutions.
  • more than three hydrogens on an alkyl moiety may be substituted with any one or more of a variety of groups, including halo and hydroxy.
  • Example 1 Synthesis of Phosphoric acid mono- ⁇ 2-methoxy-5-[7-methoxy-4-oxo- chroman-(3E)-ylidenemethyl] -phenyl ⁇ ester disodium salt.
  • Resorcinol (10.0 g, 90.9 mmol, Spectrum chemicals,) and 3-chloropropionic acid (10.0 g, 92.0 mmol, Aldrich,) were charged into a 250 ml round-bottomed flask with magnetic stirring bar. Trifluoromethanesulfonic acid (50.0 g, Aldrich,) was added to the flask in one portion. The solution was heated at 85°C for 30 min, cooled to room temperature, and poured into chloroform (200 ml). The solution was slowly poured into H 2 O (200 ml) and the layers were separated. The aqueous layer was further extracted with chloroform (2 x 100 ml). The combined organic layers were dried over Magnesium sulfate and filtered.
  • a 20 X 200 mm test tube was loaded with 6-methylchroman-4-one, 4.7 g, then 2-methoxyethanol, 6 ml, then 3-hydroxy-4-methoxybenzaldehyde.
  • the mixture was treated with concentrated hydrochloric acid, 0.1 ml, and warmed to 80° C. After 4 days the solid orange mass was washed into a 500 ml Erlenmeyer flask and suspended in 95% ethanol, 200 ml. The mix was warmed to reflux for 2 hours, dissolving all the solids.
  • the hot solution was treated slowly with water, and at 60 ml a precipitate began to form. The suspension was vigorously stirred and allowed to cool to room temperature for two hours.
  • a 20 X 200 mm test tube was loaded with 6-chlorochroman-4-one, 1.00 g, and 3-hydroxy-4-methoxybenzaldehyde, 0.9 g, and a magnetic stirring bar. Then 4 ml of butanol was added, followed by 4 drops of concentrated hydrochloric acid. The mixture was warmed to 100 0 C for 24 hours, the tube full of solids was cooled to 22 0 C. After standing three days at RT, 12 ml of ethano 1 was added, and the tube was warmed to 85 0 C to dissolve the solids. The mix was then treated slowly with 4 ml of water, and cooled to 3O 0 C with stirring.
  • a 20 X 200 mm test tube was loaded with 6-chlorochroman-4-one, 3.64 g, and 3-hydroxy-4-methoxybenzaldehyde, 3.04 g, and a magnetic stirring bar. Then 4 ml of methoxyethanol, followed by 0.1 ml of concentrated hydrochloric acid. The tube was then placed in a 100 0 C heat block, and heated with stirring for 18 hours. The mix was then cooled, and the resulting solids transferred to a 500 ml Erlenmeyer flask. The solids were suspended wit 150 ml of ethanol, and warmed to reflux. Once all the solids had dissolved, 50 ml of water was slowly added, at which point solids began to separate from the hot solution.
  • the residue was dissolved in 5 ml of dichloromethane, and flash chromatographed on silica, 1 X 4 inch column, with 100 ml each of dicloromethane, 2% acetone in dichloromethane, and 4 % acetone in dichloromethane.
  • the major peak elutes with the dichloromethane and early 2% acetone in DCM.
  • the factions containing pure major spot were combined and evaporated in vacuum.
  • the residue was sisolved hot with 10 ml of 95% ethanol, and the solution cooled to -20 C for one hour.
  • This example shows that compounds of the invention can be micronized to give an injectable suspension.
  • IMS2186 was micronized using a MC One fluid jet mill reducing the particle size from 850 microns to less than 10 microns.
  • the powder particles are fed into the flat cylindrical milling chamber tangentially through a venturi system by pressurized air or nitrogen.
  • the particles are accelerated in a spiral movement inside the milling chamber by a number of nozzles placed around the periphery of the chamber.
  • the micronizing effect takes place by the collision between the incoming particles and those already accelerated into the spiral path. Whilst centrifugal force retains the larger particles at the periphery of the milling chamber, the smaller particles exit with the exhaust air from the centre of the chamber.
  • the particle size distribution is controlled by adjusting a number of parameters, two of the main ones being pressure and feed rate.
  • the micronized IMS2186 with a particle size of less than 10 microns was suspended at 50 mg/ml in PBS containing 0.5% carboxymethylcellulose. The suspension could then pass through a 30 gage needle. A similar suspension of IMS2186 that had not been micronized plugged a 25 gage needle.
  • This example shows the anti-pro liferative activity of compounds of the subject invention.
  • the compounds of the invention have a marked anti-pro liferative effect with little cell type selectivity.
  • the compounds have an IC50 of less than 10 mM (most between 1-3 mM) in cell lines as diverse as HCTl 16 (colon cancer), MCF-7 (breast cancer), NIH-H460, HOP62 (NSCL cancer), ARPE- 19 (retinal pigmented epithelial cells), and HUVEC (human umbilical vein endothelial cells).
  • HCTl 16 colon cancer
  • MCF-7 breast cancer
  • NIH-H460 n-H460
  • HOP62 NSCL cancer
  • ARPE- 19 retina pigmented epithelial cells
  • HUVEC human umbilical vein endothelial cells
  • This example shows that a compound of the subject invention can block cell cycle progression at the G2/M phase.
  • Human umbilical vein endothelial cells (HUVEC) were seeded on Matrigel- coated 96-well plates and incubated with different concentrations of compounds of the subject invention. 10ng/ml VEGF was added to the culture medium to stimulate angiogenesis. 20 hours later, tube formation was observed and quantified manually by counting branch points under the microscope. Paclitaxol, a commercially marketed anti-tumor compound with known anti- angiogenesis activity, served as a positive control.
  • the cells were allowed to grow for three days in culture and then stained with alamarBlueTM (as described above).
  • 0.5ml Matrigel (Matrigel plugs) with or without lOOng vascular endothelial growth factor (VEGF) were subcutaneously (s.c.) injected into nude mice.
  • the compounds of the subject invention were either systemically delivered by intraperitoneal (i.p.) injection or locally administrated by subcutaneous injection (together with the Matrigel plug).
  • i.p. intraperitoneal
  • subcutaneous injection together with the Matrigel plug.
  • the Matrigel plugs in the mice were harvested and the hemoglobin measured using the Drabkin method and Drabkin reagent kit 525 (Sigma) for the quantification of blood vessel formation.
  • Paclitaxol and capsaicin were used as positive controls for the i.p. and s.c. delivery routes, respectively. See Min et al., Cancer Research, 64:644-651 (2004).
  • THP-I monocyte cells were seeded on the upper chamber together with different concentrations of "IMS2217" (described in Example 4) and "IMS2186" (described in Example 2).
  • Anti-MCP-1 antibody (Fab) was used as a positive control and isotype control IgG was used as a negative control.
  • the results of the first chamber slide experiment with HUVEC cells show that IMS1998 inhibits VEGF induced cell migration (see Figure 4).
  • the results of the second chamber slide experiment with THP-I cells show that both IMS2217 (Figure 5A) and IMS2186 (Figure 5B) inhibit cell migration, with IMS2217 being more potent.
  • the results of the wound healing experiment show that IMS2186 inhibited the migration of cells into the wound (scratch) - ( Figure 6 A and Figure 6B). Control cells which were not exposed to IMS2186 migrated and covered the wound within 20 hours ( Figure 6C).
  • Example 21 This example shows that compounds of the subject invention have antiinflammatory activity in vitro.
  • Murine macrophage RAW cells were seeded and differentiated as described above. After treatment with LPS and different concentrations of IMS 1998, the medium was collected and transferred to a 96-well plate for the nitric oxide assay according to the manufacturer's instructions.
  • IMS2217 significantly decreased PGE2 production on both undifferentiated THP-I cells and differentiated THP-I cells, in a dose dependent manner, with the levels of inhibition higher on differentiated THP-I cells. Little cytotoxicity was observed. Furthermore, as can be seen from Figure 8, IMS 1998 inhibited iNOS mediated nitric oxide production in a dose dependent manner.
  • Example 22 This example shows that compounds of the subject invention have antiinflammatory activity in vivo.
  • the anti-inflammatory effects of the compounds of the present invention were shown in vivo using a peritonitis model of inflammation in athymic nude mice induced by the injection of LPS, with TNF- ⁇ and IL-6 (both pro-inflammatory cytokines) and PGE2 as the measured indicators.
  • ELISA enzyme linked immuno-sorbent as
  • IL-6 and TNF- ⁇ assay For the IL-6 and TNF- ⁇ assay (eBioscience, Inc., San Diego), 96 well ELISA plates were coated with 100 ⁇ l/well of captured antibody overnight at 4°C and then washed 5 times with wash buffer. The plates were blocked with 200 ⁇ l/well of IX assay diluent at room temperature for one hour and washed five times with wash buffer. The samples were added to the appropriate wells and the plates were incubated at room temperature for two hours. After washing five times, avidin-HRP was added and the plates incubated at room temperature for 30 minutes. The plates were washed a total of seven times and the substrate solution was added to each well and then incubated at room temperature for another 15 minutes. The reaction was stopped by adding 50 ⁇ l/well of stop solution and the plates were read with a spectrum densitometer at 450 nm. The concentrations of IL-6 and TNF- ⁇ were calculated by comparing with the standard controls.
  • the plasma and peritoneal fluid samples were diluted 50 times with PBS.
  • the diluted samples were applied together with a PGE2 monoclonal antibody to a 96-well ELISA plate. After 2 hours of incubation, the plates were washed and substrates were added. The reaction was stopped after 45 minutes, and the yellow color generated were read on a microplate reader at 405nm. The intensity of the bound yellow color is inversely proportional to the concentration of PGE2 in the samples.
  • the concentration of PGE2 was calculated by comparing with the Standard controls
  • IMS 1999 caused a significant reduction in all inflammatory indicators measured (TNF- ⁇ , IL-6 and PGE2, respectively), both in plasma and in the peritoneal fluid. IMS2217 also showed reduction.
  • This example shows that a compound of the subject invention inhibited the growth of ovarian cancer using a xenograft mouse model.
  • ATCC SKO V3 human ovarian cancer cells
  • This example shows that compounds of the invention are useful for the treatment of wet AMD, by reducing proliferation and mobilization of cells, including endothelial cells, in the choroid of the eye, as demonstrated by an in vivo CNV (choroidal neovascularization) model.
  • CNV choroidal neovascularization
  • 35 Brown Norway rats were randomly divided into three groups of nine rats each and one group of eight rats.
  • An 810 Diode laser was used to place five to seven burns around the disc of one eye of each of the rats, between 2-3 disc diameters away from the optic nerve.
  • Laser parameters were: power - 33OmW, spot size - 75 ⁇ m, exposure - 10OmS. Only burns with cavitation air bubble formation (indicating broken Bruch's membrane) were accounted as valid burns.
  • the eyes of each group were injected intravitreally with 2 ⁇ l of the following compounds: Group 1 - IMS 2217; Group 2 - IMS 2186; Group 3 - Kenalog (positive control); and Group 4 - PBS (negative control).
  • the dosages were: lOO ⁇ g/eye for IMS 2217 and 2186 (2 ⁇ l of the solution of 50mg/ml), 80 ⁇ g/eye for Kenalog, and 50 ⁇ l of PBS containing 0.5% carboxymethylcellulose. All compounds were delivered through a 30 gauge needle connected to a quantitative Hamilton syringe dispenser. Two weeks after the laser burns and intravitreal drug injection, all rats had fluorescein angiogram (FA) exams. Two days after FA, the rats were sacrificed and the globes prepared for immunohistochemical processing for FITC-isolectin and Dapi staining.
  • FA fluorescein angiogram
  • the globes were rinsed with PBS 2 times xlO' and permeabilized in 1% Triton X-IOO for 2 hours. Following 2 times PBS rinse xlO', the anterior segment and neural retina were removed and the eyecups were incubated in 1 :150 fluorescein-labeled isolectin B4 (Vector Laboratories) at 4°C (wrapped with foil paper) overnight. After rinsing again twice with PBS, the eye cups were submerged completely in the ImM DAPI staining solution and covered with foil and left to incubate in 4°C for 1 hour. After further rinsing with PBS, the cups were cut radially (4 to 5 radial cuts), mounted and cover slipped.
  • the laser burns were graded by two ophthalmologists (who were masked to the study design) into four levels (0, 1, 2, and 3) according to the intensity of the fluorescein (a measure of leakage). Average grades were used for the statistical analysis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés inédits de chromanone, utilisables pour le traitement des affections inflammatoires, du cancer et de la dégénérescence maculaire liée à l'âge.
PCT/US2007/085914 2006-11-30 2007-11-29 Chromanones 3-benzylidine et 3-benzyle substituées inédites WO2008067451A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2010027189A2 (fr) * 2008-09-02 2010-03-11 가톨릭대학교 산학협력단 Nouvelle utilisation d'homo-isoflavanone ou d'un sel associe
KR101066465B1 (ko) 2008-09-02 2011-09-23 가톨릭대학교 산학협력단 호모아이소플라베논 또는 이의 염을 유효성분으로 포함하는염증성 질환 또는 알레르기 질환 예방 및 치료용 약학적 조성물
KR101083790B1 (ko) * 2008-09-02 2011-11-18 신동헌 호모아이소플라베논 또는 이의 염을 유효성분으로 포함하는염증 또는 알레르기 예방 및 개선용 화장료 조성물
WO2015051447A1 (fr) * 2013-10-09 2015-04-16 University Health Network Méthodes et compositions pour le traitement du cancer
CN111939148A (zh) * 2019-05-15 2020-11-17 上海交通大学医学院附属第九人民医院 Deox B 7,4在制备血管生成抑制剂中的用途

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010027189A2 (fr) * 2008-09-02 2010-03-11 가톨릭대학교 산학협력단 Nouvelle utilisation d'homo-isoflavanone ou d'un sel associe
WO2010027189A3 (fr) * 2008-09-02 2010-07-08 가톨릭대학교 산학협력단 Nouvelle utilisation d'homo-isoflavanone ou d'un sel associe
KR101066465B1 (ko) 2008-09-02 2011-09-23 가톨릭대학교 산학협력단 호모아이소플라베논 또는 이의 염을 유효성분으로 포함하는염증성 질환 또는 알레르기 질환 예방 및 치료용 약학적 조성물
KR101083790B1 (ko) * 2008-09-02 2011-11-18 신동헌 호모아이소플라베논 또는 이의 염을 유효성분으로 포함하는염증 또는 알레르기 예방 및 개선용 화장료 조성물
WO2015051447A1 (fr) * 2013-10-09 2015-04-16 University Health Network Méthodes et compositions pour le traitement du cancer
CN111939148A (zh) * 2019-05-15 2020-11-17 上海交通大学医学院附属第九人民医院 Deox B 7,4在制备血管生成抑制剂中的用途

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