WO2000006556A1 - Antiproliferants a base d'oxazolines substituees - Google Patents
Antiproliferants a base d'oxazolines substituees Download PDFInfo
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- WO2000006556A1 WO2000006556A1 PCT/US1999/016782 US9916782W WO0006556A1 WO 2000006556 A1 WO2000006556 A1 WO 2000006556A1 US 9916782 W US9916782 W US 9916782W WO 0006556 A1 WO0006556 A1 WO 0006556A1
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- Prior art keywords
- oxazoline
- trimethoxyphenyl
- indolyl
- methyl
- methoxyphenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
Definitions
- the present invention relates to substituted oxadiazolines which are useful for treating pathological states which arise from or are exacerbated by cell proliferation, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting cell proliferation in a mammal.
- Neoplastic diseases are characterized by the proliferation of cells which are not subject to normal cell growth and are a major cause of death in humans and other mammals. Cancer chemotherapy has not only provided new and more effective drugs to treat these diseases but has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton are effective in inhibiting the proliferation of neoplastic cells.
- the microtubule system of eucaryotic cells is a major component of the cytoskelton and is a dynamic assembly and disassembly wherein heterodimers of tubulin are polymerized and form microtubule. Microtubules platy a key role in the regulation of cell architecture, metabolism, and division and in their dynamic state are critical to normal cell function.
- tubulin is polymerized into microtubules that form the mitotic spindle.
- the microtubules are then depolymerized when the mitotic spindle's use has been fulfilled.
- agents which disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis comprise some of the most effective cancer chemotherapeutic agents in clinical use.
- agents which have the ability to disrupt the microtubule system are useful for cancer treatment.
- R , R , and R are independently selected from the group consisting of
- R and R are independently selected from the group consisting of
- alkyl wherein the alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of (1 alkoxy, (20 cycloalkyl, and
- aryl wherein the aryl can be optionally substituted with one or two substituents independently selected from the group consisting of (aO alkanoyloxy, (bO hydroxy, and
- alkyl wherein the alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of
- alkyl wherein the alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of
- aryl wherein the aryl can be optionally substituted with one or two substituents independently selected from the group consisting of (aO -OC(O)R , wherein R is defined above,
- cycloalkenyl wherein (4) and (5) can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of (a) alkyl,
- Compounds of the invention include, but are not limited to, 2-(4-dimethylaminophenyl)- 5-(3,4,5-trimethoxyphenyl)- ⁇ 2,3-oxazoline, 2-(3-hydroxy-4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)- ⁇ 2,3-oxazoline,
- alkanoyl refers to an alkyl group attached to the parent molecular group through a carbonyl group.
- alkanoyloxy refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
- the alkanoyloxy groups of this invention can be optionally substituted.
- alkenyl refers to a monovalent straight or branched chain group of 2-6 carbon atoms containing at least one carbon-carbon double bond.
- alkoxy refers to an alkyl group attached to the parent molecular group through an oxygen atom.
- alkoxycarbonyl refers to an alkoxy group attached to the parent molecular group through a carbonyl group.
- alkyl refers to a saturated straight or branched chain group of 1-6 carbon atoms derived from an alkane by the removal of one hydrogen atom.
- the alkyl groups of this invention can be optionally substituted.
- alkynyl refers to a monovalent straight or branched chain group of 2-6 carbons containing at least one carbon-carbon triple bond.
- the alkynyl groups of this invention can be optionally substituted.
- aryl refers to a mono- or bicyclic carbocyclic ring system having 1 or 2 aromatic rings.
- the aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring.
- the aryl groups of this invention can be optionally substituted.
- azido refers to -N 3 .
- carboxydehyde refers to -CHO.
- carbonyl refers to -C(O)-.
- cyano refers to -CN.
- carboxydehyde refers to -CHO.
- cycloalkenyl refers to a monovalent group derived from a cyclic or bicyclic hydrocarbon of 3-12 carbons that has at least one carbon-carbon double bond.
- cycloalkyl refers to a monovalent group 3-12 carbons derived from a saturated cyclic or bicyclic hydrocarbon.
- halo refers to -F, -Cl, -Br, or -I.
- heterocycle represents a represents a 4-, 5-, 6- or 7- membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
- the 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds.
- heterocycle also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring.
- Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrid
- ⁇ eterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as
- heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl, and the like.
- the heterocycle groups of this invention can be optionally substituted.
- hydroxyl refers to -OH.
- nitro refers to -NO2.
- nitrogen protecting group refers to groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)). Preferred N- protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
- perfluoroalkyl refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
- prodrugs represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
- prodrug represents compounds which are rapidly transformed in vivo to parent compounds having formula I, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B.
- Particularly preferred prodrugs of the invention include compounds having formula I, wherein a nitrogen, hydroxy, or thiol group has attached thereto an aminoacyl, bisaminoacyl (2-mer), or trisaminoacyl (3-mer) group optionally capped with a carboxyl protecting group.
- aminoacyl refers to a group derived from naturally or unnaturally occuring amino acids.
- aminoacyl groups include those derived from glycine, alanine, ⁇ -alanine, valine, leucine, w ⁇ -leucine, methionine, serine, threonine, cysteine, phenylalanine, and tyrosine in the racemic, D or L configurations.
- bisaminoacyl and trisaminoacyl refer to di- and tri- aminoacyl groups, respectively.
- bisaminoacyl and trisaminoacyl groups include 2- mers and 3-mers derived from glycine, alanine, ⁇ -alanine, valine, leucine, wo-leucine, methionine, serine, threonine, cysteine, phenylalanine, and tyrosine in the racemic, D or L configurations.
- pharmaceutically acceptable salt refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M.
- Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
- the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
- lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
- dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
- long chain halides such as decyl
- Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
- a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
- Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
- Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
- a microtitre plate was charged sequentially with cultured cells and compounds of the invention (1.0 x 10" 4 to 1.0 x 10" 11 M in 10% DMSO prepared by dissolving compounds of the invention in DMSO and adding 11 ⁇ L of the DMSO solution to 100 ⁇ L of culture medium for a final DMSO concentration of 10%).
- Two of the following controls were also present in each microtitre plate: a solvent (DMSO) control without drug that yielded a 0% inhibition level and a trichloroacetic acid-treated well that yielded a 100% inhibition level.
- the cells were grown in culture (37 °C, 5% CO2 atmosphere) for 48 hours then fixed by the addition of trichloroacetic acid.
- the compounds of the invention are useful for the treatment of diseased caused or exascerbated by cell proliferation.
- these compounds are useful in the treatment of both primary and metastatic solid tumors and carcinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder, bile ducts, small intestine, urinary tract including kidney, bladder and urothelium, female genital tract including cervix, uterus, ovaries, choriocarcinoma, and gestational trophoblastic disease, male genital tract including prostate, seminal vesicles, testes, and germ cell tumors, endocrine glands including thyroid, adrenal, and pituitary, skin including hemangiomas, melanomas, sarcomas arising from bone or soft tissues including Ka
- the compounds of the present invention may also be useful for the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic treatments conventionally administered to patients for treating cancer.
- compounds of the present invention when used in the treatment of solid tumors, compounds of the present invention may be administered with chemotherapeutic agents such as alpha inteferon, COMP (cyclophosphamide, vincristine, methotrexate, and prednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone, and procarbazine), vincris
- the present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
- the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
- compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
- parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
- compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
- suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
- adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
- Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
- biodegradable polymers such as polylactide-polyglycolide.
- Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
- compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
- the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending
- Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
- the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
- the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed.,
- Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
- the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
- Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
- Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
- the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
- dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient.
- the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
- THF for tetrahydrofuran
- DMF for N,N-dimethylformamide
- EDC for l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- LDA lithium diisopropylamide
- TFA for trifluoroacetic acid
- DMSO for dimethylsulfoxide
- DMAP for 4-(N,N-dimethylamino)pyridine
- HBTU for
- the aldehyde (i) can be treated with trimethylsilylnitrile to provide silyloxynitrile intermediate (ii) which can be treated with reducing agents such as lithium aluminum hydride to provide amino alcohol (iii).
- Treatment of (iii) with carboxylic acids in the presence of a dehydrating agents such as trifluoromethane sulfonic anhydride and base provides compounds of Formula I.
- a dehydrating agents such as trifluoromethane sulfonic anhydride and base provides compounds of Formula I.
- the solvents used in these reactions is not particularly limited, a solvent which is little reactive with the starting materials and in which the starting materials are soluble is generally used.
- solvents examples include pyridine, diisopropylethylamine, triethylamine, THF, dioxane, benzene, toluene, diethyl ether, chloroform, dichloromethane, ethyl acetate, DMF, DMSO, or mixtures thereof.
- the reactions can be run at room temperature, or at lower or elevated temperatures, as needed.
- the reaction times are generally 30 minutes to 18 hours and can be arbitrarily selected depending on the types of starting materials and the reaction temperature.
- solvents examples include THF, dioxane, benzene, toluene, diethyl ether, chloroform, dichloromethane, ethyl acetate, or mixtures thereof.
- the reactions can be run at room temperature, or at lower or elevated temperatures, as needed.
- the reaction times are generally 30 minutes to 18 hours and can be arbitrarily selected depending on the types of starting materials and the reaction temperature.
- Example 1A l-(l-hydroxy-2-aminoethylV3.4.5-trimethoxy benzene
- a solution of 3,4,5-trimethoxybenzaldehyde (10 g, 51 mmol) and nitromethane (10 mL) in ethanol at 0 °C was treated with 10% sodium hydroxide (21.4 mL, 53.5 mmol), stirred for 45 sesonds, treated with 2% acetic acid (162 mL), stirred for 1 hour in the ice bath, and filtered. The solid was washed with water and dried under vacuum to provide 9.0 g of the desired product as an off-white solid.
- Example IB 2-amino-l-(3.4.5-trimethoxyphenyl)ethanol
- Example 1A was reduced with 10% Pd/C in acetic acid under 4 atmospheres for 3 hours to provide the desired product as the acetic acid salt, mp 103-104 °C;
- Example 1C l-((l-hvdroxy-2-r(4-dimethylamino)bezoylamino ethylV3.4.5-trimethoxy benzene
- a solution of Example IB (287 mg) and diisopropylethylamine (2 mL) in dichloromethane (15 mL) at 0 °C was treated slowly with a solution of 4-dimethylamino benzoylchloride (219 mg) in dichloromethane (10 mL), stirred for 18 hours warming to room temperature, and concentrated to near dryness.
- the concentrate was purified by column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 340 mg of the desired product as a white solid, mp 155-157 °C; MS (CDI/NH 3 ) m/z 375 (M+H) + ;
- Example 1C A solution of Example 1C (320 mg, 0.86 mmol) in chloroform (15 mL) at cooled to -20 °C was treated sequentially with pyridine (0.2 mL) and by triflic anhydride (0.2 mL), stirred for 30 minutes, washed with saturated NaHCO 3 and brine, dried (Na j SO ⁇ , filtered, and concentrated. The concentrate was purified by flash chromotography on silica gel with 1:1 hexanes/ethyl acetate to provide 220 mg of the desired product as an off-white solid.
- Example 20 was hydrolyzed to provide the desired product. MS (DCI/NH 3 ) m/z 360 (M+H) + ;
- Example 3 2-(4-methoxyphenylV5-(3.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline 3, 5-Dimethoxybenzoic acid was processed as described in Example 4 to provide the desired product.
- the concentrate was partitioned between ethyl acetate (400 mL) and water (200 mL), and the organic extract was washed sequentially with 10% HSO 4 (200 mL), water (100 mL), NaHCO 3 (200 mL), and water (100 mL), dried (MgSO 4 ), filtered, and concentrated to provide 1.56 g of the desired product as a white foamy semi-solid.
- Example 4B 2-(3.5-dimethoxyphenylV5-(3.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline
- Example 5 2-(3-acetylindol-5-yl)-5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- a solution of Example 11 (50 mg, 0.142 mmol) in dichloromethane at room temperature was treated sequentially with triethylamine (0.5 mL), DMAP (5 mg), and acetic anhydride (0.5 mL, excess), stirred at room temperature for 3 hour, and concentrated.
- the concentrate was purified by flash on silica gel with 1 : 1 hexanes/ethyl acetate to provide 25 mg of the desired product as an off-white solid.
- Example 7 2-(indol-3-yl)-5-G.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline 3-Indolecarboxylic acid was processed as described in Example 11 to provide the desired product.
- Example 8 2-(indol-2-yl)-5-G.4.5-trimethoxypheny - ⁇ 2.3-oxazoline 2-Indolecarboxylic acid was processed as described in Example 11 to provide the desired product. MS (DCI/NH 3 ) m/z 353 (M+H) + ;
- Example 11 2-(l-methoxymethylindol-5-ylV5-G.4.5-trimethoxypheny - ⁇ 2.3-oxazoline
- Example 11 was processed as described in Example 6 (substituting chloromethyl methyl ether for methyl iodide)to provide the desired product.
- Example 10A 2-( ' 4-amino-3-methoxypheny -5-( ' 3.4.5-trimethoxyphenyD- ⁇ 2.3-oxazoline
- a solution of Example 10A (90 mg, 0.23 mmol) in a mixture of 1 : 1 THF/H 2 O (2 mL) was treated with excess K ⁇ CO j and Na-S 2 O 4 , stirred at room temperature for 18 hours, treated with water, and extracted with ethyl acetate. The extract was washed with brine and dried (Na j SO , filtered, and concantrated. The concentrate was purified by prepative thin layer chromatography to provide 12 mg of the desired product.
- N-( " hydroxyG.4.5-trimethoxyphenyl)methyl)-lH-indole-5-carboxamide A solution of 5-indolecarboxylic acid (2.0 g, 12.4 mmol) in DMF (25 mL) at room temperature was treated portionwise with 1, l'-carbonyldiimidazole (2.1g, 13.0 mmol). In a separate reaction, a suspension of ⁇ -hydroxyamine acetic acid salt (3.92g, 13.7 mmol) in DMF (20 mL) was treated with diisopropylethylamine (5.0 mL, 28.7 mmol) and DMAP (30.3 mg, 0.25 mmol).
- the imidazolide solution was transferred dropwise to the ⁇ -hydroxyamine solution.
- the pink solution was stirred at room temperature for 3 hours, treated with water (100 mL), and adjusted to pH 5.5 with 3N HCl to cause precipitation of white solid.
- the solid was filtered, washed with cold water and dried in a vacuum oven to provide 3.7 g of the desired product as a white solid.
- Example 11B ( " 5R1 2-(indol-5-yl)-5-GA5-trimethoxyphenylV ⁇ 2.3-oxazoline A solution of Example 11 A (200 mg, 0.54 mmol) in THF (10 mL) was treated with Burgess Reagent (142 mg, 0.60 mmol), refluxed 1 hour, cooled ,and partitioned between ethyl acetate and brine. The organic layer was dried (Na j SO ⁇ , filtered, and concentrated. The concentrate was purified by flash column chromotography on silica gel with 1:1 hexanes/ethyl acetate to provide 120 mg of the desired product as a light yellow solid.
- Examples 13-15 were prepared.
- Example 13 2-(3-hydroxy-4-methoxyphenyl)-4-dimethyl-5-(3.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline MS (DCI/NH 3 ) m z 372 (M+H) + ; H NMR (CDC1 3 ) ⁇ 7.91-7.88 (m, 2H), 6.71-6.67 (m, 2H), 6.52 (s, 2H), 5.16 (s, IH), 3.85 (s, 3H), 3.84 (s, 6H), 3.03 (s, 6H), 1.53 (s, 3H), 0.88 (s, 3 H).
- Example 16B 2-r4-ethoxyphenyl)-5-(3.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline
- a solution of Example 16A in THF was treated with treated with (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess Reagent, 1.1 equivalents) in THF, heated at 70 °C for three days, cooled, and concentrated. The residue was purified by preparative reverse phase HPLC to provide the desired product. HPLC retention time: 6.57 minutes using the HPLC gradient system described in Example 16A. MS (APCI(+)) m/z 358 (M+H) + .
- Example 17B 2-(3.4-dimethxoyphenyl)-5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 17 A was processed as described in Example 16 to provide the desired product.
- Example 18A was processed as described in Example 16 to provide the desired product.
- HPLC retention time 7.07 minutes using conditions as described in described in Example 16A.
- Example 4 to provide the desired product.
- HPLC retention time 4.5 minutes using the conditions described in Example 16A.
- Example 19B 2-( " 2.3-dihydro-5-bromo-7-benzofuranylV5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 19A was processed as described in Example 16 to provide the desired product.
- Example 20A 5-rr(2-hydroxy-2-(3.4.5-trimethoxyphenyl')ethyl)amino'))carbonv -2-methoxyphenyl
- 3-acetoxy-4-methoxybenzoic acid 392 mg, 1.86 mmol
- dichloromethane 10 mL
- DMF 1 drop
- oxalyl chloride 0.33 mL
- the concentrate was dissolved in toluene and concentrated to provide a yellow solid.
- This concentrate was dissolved in pyridine (5 mL), cooled to 0 °C and treated with 2-amino-l- (3,4,5-trimethoxyphenyl)ethanol, acetic acid salt (536 mg, 1.86 mmol), stirred for 18 hours while warming to room temperature, diluted with ethyl acetate, and washed sequentially with 1M sodium bisulfate (2x), water (lx), 10% NaHCO 3 , and brine, dried (MgSO4), filtered, and concentrated to provide 297 mg of the desired product.
- Example 20A A solution of Example 20A (290 mg, 0.69 mmol) in chloroform (10 mL) at 0 °C was treated with thionyl chloride (0.1 mL, 1.38 mmol), stirred for 40 minutes, warmed to room temperature, stirred for 1 hour, poured into 10% NaHCO 3 , and extracted with dichloromethane (2 ⁇ ). The extracts were dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash chromotography on silica gel with 1:1 hexanes/ethyl acetate to provide 137 mg of the desired product as an off-white solid.
- Example 21 A l-methyl-2. 3-dihydro-indole-5-carboxylic acid (N-r2-hydroxy-2-G.4.5- trimethoxyphenyl) ethyll) amide
- Example 2 IB 2-(l-methyl-2.3-dihydro-indol-5-yl)-5-G.4.5-trimethoxypheny - ⁇ 2.3-oxazoline
- a solution of Example 21A (151 mg, 0.39 mmol) in THF (5 mL) was treated with Burgess' Reagent (102 mg, 0.43 mmol), heated to reflux for 1.5 hours, cooled, poured into 10% NaHCO 3 and extracted twice with dichloromethane. The extracts were dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1 : 1 ethyl acetate/hexanes to provide 25 mg of the desired product. MS (DCI/NH 3 ) m/z 369 (M+H) + ;
- Example 23C ( ' lS ) -2-r4-methylbenzenesulfonyloxyVl-G.4.5-trimethoxyphenyl ethanol
- the extract was washed with water (2 ⁇ ) and brine (lx), dried (MgSO 4 ), filtered, and concentrated to provide 470 mg (61%) of the desired product as a colorless oil which was used in the next step without further purification.
- Example 23F f5SV2-fl-methylindol-5-ylV5-(3.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- a suspension of Example 23E (3.41 g, 15.0 mmol), N-methyl-5-cyanoindole (3.75 g, 24.0 mmol) K J CO J (320 mg, 2.3 mmol) in mixture of ethylene glycol (4.8 mL) and glycerol (2.6 mL) was heated to 140 °C under nitrogen for 40 hours, cooled to room temperature, treated with dichloromethane, washed sequentially with water and brine, dried (MgSO 4 ), filtered, and concentrated.
- Example 24 (5S)-2-(l-methylindol-5-yl ' )-5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline hydrochloride
- a solution of of Example 23 (3.73 g, 10.2 mmol) in dichloromethane (67 mL) and diethyl ether (67 mL) was treated with 4M HCl in dioxane (2.8 mL), stirred for 30 minutes, treated with diethyl ether (200 mL), and cooled in a refrigerator for 20 minutes. The resulting precipitate was filtered, washed with ether, and dried under vacuum to provide 3.8 g (93%) of the desired compound as a white solid.
- Example 25 f5R)-2-f l-methylindol-5-yl -5-GA5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 23A and AD-mix- ⁇ were processed as described in Example 23B to provide the desired product as white solid.
- Example 6 Example 11, or Example 23, to prepare the following compounds:
- Example 39B N-G-f9-fluorenylmethoxycarbonyl amino-4-methoxybenzoyD-l-GA5- trimethoxyphenylV2-aminoethanol
- a suspension of Example 39A (765 mg, 1.96 mmol) and ethanoamine (446 mg, 1.96 mmol) in THF (20 mL) and DMF (1.5 mL) at room temperature was treated sequentially with HATU (747 mg, 1.96 mmol) and N-methylmorpholine (0.22 mL), stirred at room temperature for 18 hours, and concentrated. The concentrate was dissolved in dichloromethane, washed with water, dried (MgSO 4 ), filtered, and concentrated to provide 981 mg (84%) of the desired product.
- Example 39B (980 mg, 1.63 mmol) was processed as described in Example 1C to provide 920 mg of the desired product.
- Example 39D 2-G-amino-4-methoxyphenyl)-5-G.4.5-trimethoxypheny - ⁇ 2.3-oxazoline
- a solution of Example 39C (500 mg, 0.86 mmol) in acetonitrile (5 mL) was treated with diethylamine, stirred at room temperature for 20 minutes, and concentrated.
- the concentrate was purified by flash column chromatography on silica gel with 95:6:0.5 dichloromethane/methanol/ammonium hydroxide to provide 227 mg (74%) of the desired product.
- Example 40 2-G-amino-4-methyphenv -5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline 3-Amino-4-methylbenzoic acid (910 mg, 6.0 mmol) was processed as described in Example 39 to provide 438 mg of the desired product. MS (ESI(+)) m/z 343 (M+H) + ;
- Example 41 A suspension of compound of Example 39 (492 mg, 1.37 mmol) and Fmoc-Ala-
- Example 41B 2-G- Ala-Ala-amino-4-methoxyphenyl)-5-(3.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- a solution of Example 41 A (500 mg, 6.9 mmol) in acetonitrile (30 mL) was treated with diethylamine (6.0 mL), stirred for 20 minutes, and concentrated.
- the concentrate was purified by flash column chromatography with with 93:7:1 dichloromethane/methanol ammonium hydroxide to provide 200 mg of the desired product.
- Example 43 2-G-rr3-aminopropionov amino-4-methoxyphenylV5-(3.4.5-trimethoxyphenyl)- ⁇ 2.3- oxazoline
- Example 39 (302 mg, 0.842 mmol) and Fmoc-/?-Ala-OH (250 mg, 0.803 mmol) were processed as described in in Examples 41 to provide 176 mg of the desired product.
- Example 44 2-(3-(Ser-amino-4-memoxyphenyl -5-(3.4.5-trimethoxyphenyl - ⁇ 2.3-oxazoline
- Example 39 (287 mg, 0.800 mmol) and Fmoc-Ser-OH (250 mg, 0.763 mmol) were processed as described in in Example 41 to provide 133 mg of the desired product.
- Example 45 2-(3-(Gly-amino-4-methoxyphenyl)-5-(3.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 39 and Fmoc-Gly-OH were processed as described in in Example 41 to provide the desired product.
- Example 46B 2-( 1 -methyl- 1 H-pyridin-2-on-4-yl)-5-G A5-trimethoxyphenylV ⁇ 2.3-oxazoline
- Example 46A (363 mg, 2.37 mmol) was processed as described in Example 4 to provide 493 mg of the desired product.
- Example 47 2-r2-( ' 2-hvdroxyethyloxy)-4-pyridinyl)-5-G.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline
- 2-(2-Hydroxyethoxy)isonicotinonitrile 350 mg, 2.6 mmol was processed as described in Example 23F to provide 250 mg (28%) of the desired product.
- Example 48A methyl imidazori.2- 1pyridin-6-carboxylate
- a solution of bromoacetaldehyde diethyl acetal (3.2 mL, 21.3 mmol) in 12M HCl (0.5 mL) and water (23 mL) was heated at 90 °C for 1 hour, cooled to room temperature, treated sequentially with NaHCO 3 , (1.67 g, 20 mmol) and methyl 6-aminonicotinate (1.10 g, 7.0 mmol), heated at 60 °C for 30 minutes, cooled to room temperature, adjusted to pH 9, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4 ), filtered, and concentrated.
- Example 48B imidazor 2- ⁇ 1pyridin-6-carboxylic acid
- a mixture of Example 48A (100 mg, 0.56 mmol) and IM lithium hydroxide (0.62 mL) in THF (2 mL) was stirred at room temperature for 30 minutes, treated with IM HCl (0.62 mL), and concentrated.
- the concentrate was purified by a flash column chromatography with 85:10:5 dichloromethane/methanol/ammonium hydroxide to provide 68.4 mg (74%) of the tiltle compound.
- Example 48C 2-rimidazori.2- ⁇ lpyridin-6-yl)-5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 48B 550 mg, 0.34 mmol was processed as described in Example 4 to provide 261 mg of the desired product.
- Example 49A ethyl 6-hydroxymethylnicotinate A slurry of dry calcium chloride (22.7 g, 0.205 mol) in ethanol (300 mL) and THF
- Example 49 A solution/slurry of Example 49 (5.00 g, 27.9 mmol) and manganese dioxide (24.3 g, 279 mmol) in dioxane (100 mL) was heated at 90 °C for 30 minutes and filtered while hot. The filtrate was concentrated to provide 2.95 g (60%) of the desired product, which was used in the next step without further purification.
- Example 49C ethyl 6-formylnicotinate oxime A mixture of sodium acetate (8.68 g, 106 mmol), and hydroxyamine hydrochloride (7.35 g, 106 mmol) in methanol (70 mL) was stirred at room temperature for 30 minutes. The precipitate which formed was removed by filtration, and the filtrate was poured into a solution of Example 49B (6.33 g, 35.3 mmol) in methanol (20 mL), stirred at room temperature for 18 hours, and concentrated.
- the concentrate was dissolved in 3:1 dichloromethane/isopropanol, and this solution was washed sequentially with IM K J CO J and water, dried (MgSO 4 ), filtered, and concentrated to provide 6.38 g (93%) of the desired product.
- Example 49D ethyl 6-aminomethylnicotinate A solution of Example 49C (3.40 g, 17.5 mmol) in water (40 mL) and acetic acid
- Example 49E ethyl 6-(formylamino')methylnicotinate
- a solution of Example 49D (6.49 g, 36.0 mmol) in formic acid (75 mL) was refluxed for 18 hours and concentrated.
- the concentrate was dissolved in dichloromethane, and this solution was washed sequentially with 10% NaHCO 3 and water, dried (MgSO 4 ), filtered, and concentrated.
- the concentrate was purified by a flash column chromatography on silica gel with 96:4 dichloromethane/methanol to provide 2.83 g (38%) of the desired product.
- Example 49F methyl imidazori.5- ⁇ 1pyridine-6-carboxylate
- dichloromethane 30 mL
- POCl 3 2.8 mL, 30.0 mmol
- the concentrate was treated with IM Na 2 CO 3 and extracted with dichloromethane. The extract was washed with water, dried (MgSO 4 ), filtered, and concentrated.
- the concentrate was purified by flash column chromatography with 98:2 dichloromethane/methanol to provide 2.64 g (93%) of the desired product.
- Example 49G imidazori.5- ⁇ lpyridine-6-carboxylic acid
- IM LiOH 41 mL
- THF 50 mL
- the extract washed with water, dried (MgSO 4 ), filtered, and concentrated to provide 1.92 g (86%) of the desired compound, which was used in the next step without further purification.
- MS (DCI/NH 3 ) m/z 163 (M+H) + ; ! H NMR (DMSO-d *v,) ⁇ 13.28 (br s, IH), 9.08 (s, IH), 8.65 (br s, IH), 7.57 (d, J 9.0 Hz,
- Example 49H 2-(imidazori.5- 1pyridin-6-yl)-5-G.4.5-trimethoxyphenyD- ⁇ 2.3-oxazoline
- Example 49G (1.92 g, 11.9 mmol) was processed as described in Example 4 to provide 337 mg (8%) of the desired product.
- Example 50B methyl 2-methyl-indolizine-6-carboxylate
- a mixture of Example 50A (570 mg, 2.32 mmol) and sodium carbonate (400 mg, 5.0 mmol) in ethanol (10 mL) was refluxed for 3 hours and concentrated.
- the concentrate was dissolved in dichloromethane, and this solution was washed with water, dried (MgSO 4 ), filtered, and concentrated.
- the concentrate was purified by flash column chromatography on silica gel with 2: 1 hexanes/dichloromethane to provide 407 mg (93%) of the desired product.
- Example 50D 2-r2-methyl-6-indolizinvD-5-f3.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline
- Example 50C (210 mg, 0.99 mmol) was processed as described in Example 4 to provide 75.2 mg (21%) of the desired product.
- Example 5 2-G-fluoro-4-methoxyphenyl>5-GA5-trimethoxyphenyl> ⁇ 2.3-oxazoline
- Example 51A 530 mg, 1.4 mmol was processed as described in Example 4 to provide 415 mg of the desired product.
- Example 52A 1 - ftgrt-butoxycarbonyl 1 H-indole-2-carboxylic acid (S)-(-)-Indoline-2-carboxylic acid (1.88 g, 11.5 mmol) was processed as described in Example 4 to provide 2.89 g of the desired product.
- Example 52B tert-butyl 2-(Tf2-hydroxy-2-(3.4.5-trimethoxyphenyl)ethy amino)carbony - lH-indole- 1- carboxylate
- Example 52A (1.02 g, 3.88 mmol) was processed as described in Example 4 to provide 1.08 g of the desired product as a 1:1 mixture of diastereomers.
- Example 52C tert-butyl 2-(5-G A5-trimethoxyphenyl)-4,5-dihydro- 1 ,3-oxazol-2-yD- lH-indole- 1- carboxylate
- a solution of Example 52C (146 mg, 0.31 mmol) in chloroform (3 mL) and pyridine (0.125 mL) at 0 °C was treated with thionyl chloride (70 mL, 0.93 mmol), stirred for 20 minutes, treated with dichloromethane, washed with 10% Na ⁇ CO 3 , dried
- Example 53A 2-chloro-N-(2-hvdroxy-2-GA5-tiimethoxyphenyDethylV4-nitrobenzamide 2-Chloro-4-nitrobenzoic acid (765 mg, 3.79 mmol) was processed as described in Example 4 to provide 735 mg of the desired product.
- Example 53 A (706 mg, 1.72 mmol) was processed as described in Example 4 to provide 570 mg of the desired product.
- Example 54B 2-(2-fluoro-4-nitrophenylV5-GA5-trimefhoxyphenyD- ⁇ 2.3-oxazoline
- Example 54A (760 mg, 1.93 mmol) was processed as described in Example 4 to provide 640 mg (88%) of the desired product.
- MS (ESI(+)) m/z 377 (M+H) + ;
- Example 11 A solution of Example 11 (179 mg, 0.51 mmol) in THF (4 mL) at 0 °C was treated with sodium hydride (15 mg, 0.61 mmol), stirred for ten minutes, treated with carbon disulfide (61 mL, 1.02 mmol), stirred for 18 hours while warming to room temperature, cooled to 0 °C, treated with methyl iodide (0.1 mL, 1.53 mmol, stirred for thirty minutes at room temperature, poured into water, and extracted with ethyl acetate The extract was dried (MgSO 4 ), filtered, and concentrated.
- sodium hydride 15 mg, 0.61 mmol
- carbon disulfide 61 mL, 1.02 mmol
- methyl iodide 0.1 mL, 1.53 mmol
- Example 57A N-(2-hvdroxy-2-f3.4.5-trimethoxypheny ethy -1.2-dimethyl-lH-indole-5-carboxamide l,3-Dimethylindole-5-carboxylic acid (400 mg, 2.12 mmol) was processed as described in Example 4 to provide the desired product, which was used in the next step without further purification. MS (ESI(+)) m/z 399 (M+H) + ; Example 57B
- Example 57A was processed as described in Example 4 to provide 490 mg of the desired product.
- Example 58A methyl 4- amino-2-chloro-5-iodo-benzoate
- dichloromethane (30 mL) and methanol (15 mL) was treated sequentially with calcium carbonate (1.85 g, 18.5 mmol) and benzyl trimethylammonium dichloroiodate (3.22 g, 9.24 mmol), stirred for 18 hours, treated with additional benzyl trimethylammonium dichloroiodate (2 g, 5.75 mmol), stirred for 3 days, filtered into a separatory funnel, washed with saturated NaHSO 3 , dried (MgSO 4 ), filtered, and concentrated.
- the concentrate was recrystallized from ethyl acetate to provide the majority of the desired product.
- the filtrate was concentrated, and the concentrate was purified on silica gel with a gradient of from 10% to 20% ethyl acetate/hexanes to provide a total of 1.3 g of the desired product.
- Example 58B methyl 6-chloro-5-indolecarboxylate A 50% solution of ethyl ethynyl ether in hexanes (2.1 mL, 10.8 mmol) at 0 °C was slowly treated with IM catechol borane in THF (9.7 mL, 9.7 mmol), warmed to room temperature, stirred for 2 hours, heated at 70 °C for 2 hours, cooled to room temperature, treated sequentially with Example 58A (1.77 g, 5.69 mmol) in THF (30 mL), tetrakis(triphenylphosphine)-palladium(0) (329 mg, 0.28 mmol), and powdered sodium hydroxide (683 mg, 17.1 mmol), heated to reflux, stined for 18 hours, cooled to room temperature, treated with 2M HCl (30 mL), stined for 18 hours, treated with ethyl acetate, washed sequentially with water, 2M Na
- Example 58B A solution of Example 58B (1.17 g, approximately 5.6 mmol) in THF (50 mL) was treated with IM LiOH (56 mL, 56 mmol), heated at 50 °C, stined for 18 hours, treated with IM NaOH, washed with diethyl ether, acidified with HCl, and extracted with ethyl acetate. The extract was dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified on silica gel with 50% ethyl acetate/hexanes to provide of 660 mg of the desired product. l H NMR (DMSO-d 6 ) ⁇ 12.73 (br s, IH), 11.45 (s, IH), 8.13 (s, IH), 7.49 (m, 2H), 6.57 (m, IH).
- Example 58C 6-chloro-N-( " 2-hydroxy-2-G.4.5-trimethoxyphenv ethyl -lH-indole-5-carboxamide
- Example 58C (660 mg, 3.38 mmol) was processed as described in Example 4A to provide 128 mg of the desired product.
- Example 58E 2-(6-chloroindol-5-ylV5-GA5-trimethoxyphenylV ⁇ 23-oxazoline
- Example 58D (63 mg, 0.156 mmol) was processed as described in Example 4B to provide 36 mg of the desired product.
- Example 59 A benzyl 1 -methyl-oxindole-5-carboxylate A solution of 5-bromo-l -methyl oxindole (3.75 g, 16.6 mmol) and triethylamine
- Example 59B 1 -methyl-oxindole-5-carboxylic acid
- ethyl acetate 30 mL
- methanol 20 mL
- Pd/C 200 mg
- stined under hydrogen balloon
- filtered through diatomaceous earth Celite®
- 9:1 dichloromethane/methanol solution rinses and concentrated to provide 460 mg of the desired product.
- Example 59C N-(2-hydroxy-2-G.4,5-trimethoxypheny ethv -l-methyl-2-oxo-5-indolinecarboxamide
- Example 59B (430 mg, 2.25 mmol) was processed as described in Example 4A to provide 340 mg of the desired product.
- Example 59D 2-( " l-methyloxindol-5-yl)-5-(3.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline
- Example 59C (110 mg, 0.275 mmol) was processed as described in Example 4B to provide 50 mg of the desired product.
- Example 60 2-(6-Chloro-l-methylindol-5-yl)-5-( " 3.4.5-trimethoxypheny - ⁇ 2.3-oxazoline
- Example 61 2-( 1 -difluoromethylindol-5-y - 5-G .4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- a solution of Example 11 (427 mg, 1.21 mmol) in THF (5 mL) at 0 °C was treated with sodium hydride (35 mg, 1.46 mmol), stined for 15 minutes, cooled to -78 °C, treated with excess difluorochloromethane, stined for 18 hours warming slowly to room temperature, poured into 5.5M NH 4 C1 and extracted with ethyl acetate. The extract was dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified on silica gel with s gradient of from 50% to 60% ethyl acetate/hexanes to provide 16.9 mg of the desired product.
- Example 62B 3-chloro-5-indolecarboxylic acid
- a solution of Example 62A (361 mg, 1.62 mmol) in THF (7 mL) and IM LiOH (3.3 mL) was heated at 50 °C for 5 hours, treated with ethyl acetate and extracted with 10% NaHCO 3 (3 ⁇ ). The extract was treated with 6M HCl and extracted with ethyl acetate (2x40 mL). The organic layer was dried (MgSO 4 ), filtered, and concentrated to provide 253.2 mg of the desired compound.
- MS (ESI(+)) m/z 211 (M+H) + ;
- the extract was washed with brine, dried (MgSO 4 ), filtered, and concentrated.
- the concentrate was purified by flash chromatography on silica gel with 15:85 ethyl acetate/hexanes to provide 0.315 g of the desired product.
- Example 63C methyl-7-fluoro-5-indole-carboxylate A mixture of Example 63B (1.188 g, 4.2 mmol), PdCl 2 (dppf) 2 , and triethylamine (1.08 mL, 8.4 mmol) in methanol (40 mL) at 120 °C under carbon monoxide (450 psi) was stined, for 15 hours, cooled to room temperature, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash chromatography on silica gel with 15:85 ethyl acetate/hexanes to provide 0.63 g of the desired product.
- Example 63D 7-fluoro- lH-indole-5-carboxylic acid A mixture of Example 63C (0.22 g, 1.13 mmol) and LiOH (0.136g, 5.7 mmol) in 1:1 methanol/water (20 ml) was heated at reflux for 2 hours, poured into water (1 mL), and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product which was used in the next step without further purification.
- a solution of Example 63D in DMF (10 mL) was treated sequentially with 2- amino-l-(3,4,5-trimethoxyphenyl)ethanol hydrochloric acid salt (0.343 g, 1.30 mmol), EDC (0.325 g, 1.7 mmol), triethylamine, DMAP (catalytic), heated at 50°C for 15 hours, cooled to room temperature, poured into water (100 ml), and extracted with ethyl acetate.
- Example 63F 2-(7-fluoro-5-indolyl)-5-GA5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- a mixture of Example 63E (0.24g, 0.62 mmol) and Burgess's agent (0.176g, 0.74 mmol) in of anhydrous THF (10 mL) was heated at reflux for 1 hour, cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate. The extract was washed with brine, and , dried (MgSO 4 ), filtered, and concentrated. The solution was concentrated under vacuum. The concentrate was purified by flash column chromatography on silica gel to provide 0.15 g of the desired product.
- Example 64 2- i-methyl-7-fluoro-5-indolyl)-5-( , 3.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 63 (0.100 g, 0.27 mmol) in DMF (3 mL) was treated with 60% NaH (92 mg, 2.31 mmol) at 0°C, stined for 15 minutes, treated with methyl iodide (76 mg, 0.54 mmol) in DMF (1 mL), stirred for 1 hour, treated with water, and extracted with ethyl acetate. The extract was dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel to provide 101 mg of the desired product.
- Example 65A l-acetyl-5-bromo-7-chloro-indoline A mixture of l-acetyl-5-bromo-indoline (1.20 g, 5 mmol) and N-chlorosucinimide
- Example 65B 5-bromo-7-chloro-indoline
- Example 65A was hydrolyzed with excess LiOH in methanol/water to provide the desired product.
- Example 65C 5-bromo-7-chloro-indole
- a mixture of Example 65B (0.120 g, 0.55 mmol) and salcomine (0.022 g, 0.06 mmol) in methanol (30 mL) was treated with oxygen over 18 hours and concentrated.
- the concentrate was purified by flash column chromatography on silica gel to provide 0.112 g of the desired product.
- Example 65E 2-(7-chloro-5-indolv -5-(3.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 65D was processed as described in Examples 63D and 63E to provide the desired product.
- Example 66 2- i-methyl-7-chloro-5-indolv -5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 65 was processed as described in Example 60 to provide the desired product.
- Example 67 A methyl-3-fluoro-5-indole-carboxylate
- methanol 100 mL
- the concentrate was purified by flash column chromatography on silica gel to provide 200 mg of the desired product.
- Example 67B was processed as described in Example 63E to provide the desired product.
- Example 68 f2-(l-methyl-3-fluoro-5-indolyl)-5-(3.4.5-trimethoxyphenylV ⁇ 2.3-oxazoline
- Example 67 was processed as described in Example 60 to provide the desired product.
- Example 11 A mixture of Example 11 (0.716 g, 0.500 mmol) in ethanol (3 mL) was treated sequentially with 37% aqueous formaldehyde (2.5 mL) and IM NaOH (10 drops), stirred for 3.5 hours to form a thick, white precipitate, treated with water (60 mL) and brine (20 mL), and extracted sequentially with 1:1 dichloromethane/ethyl acetate (80 mL) and dichloromethane (20 mL). The combined extracts were washed with brine (25 mL), dried (MgSO 4 ), filtered, and concentrated to provide 146 mg of the desired product.
- the combined extracts were, dried (MgSO 4 ), filtered through a short plug of silica gel with ethyl acetate rinses, and concentrated.
- the concentrate was purified by radial chromatography with 98:2 dichloromethane/ methanol to provid the 82.4 mg of the desired product.
- Example 71 A ethyl 2-methyl-3-thiomethoxy-5-indolecarboxylate A solution of ethyl 4-aminobenzoate (2.53 g, 15.0 mmol) in dichloromethane (75 mL) at -70 °C was treated dropwise with trimethylacetyl chloride (1.62 g, 14.9 mmol) in dichloromethane (7.5 mL), stirred forl hour, treated dropwise with a a solution of (methylthio)acetone (1.59 g, 15.0 mmol) in dichloromethane (7.5 mL), stined for 1.25 hours, treated with triethylamine (1.52 g, 15.0 mmol), stined for 10 minutes, warmed to room temperature, stined for 16 hours, washed with water (15 mL), dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography with 1 :4 hexane/
- Example 7 IB ethyl 2-methyl-5-indolecarboxylate A solution of ethyl 2-methyl-3-thiomethoxy-5-indolecarboxylate (1.90 g, 7.62 mmol) in ethanol (60 mL) at room temperature was treated with Raney Ni (approximately 3 teaspoons), stirred for 17 hours, filtered, and concentrated to provide 1.51 g of the desired product.
- Example 71 C ethyl L2-dimethyl-5-indolecarboxylate A 60% oil dispersion of NaH (1.51 g, 7.43 mmol) was rinsed with THF (2x10 mL), slurried in DMF (35 mL), and cooled to 0 °C.
- This slurry was treated dropwise with ethyl l,2-dimethyl-5-indolecarboxylate (1.51 g, 7.43 mmol) in DMF (5 mL), stined for 5 minutes, treated with methyl iodide (1.11 g, 7.80 mmol), warmed to room temperature, stined for 4 hours, treated with ethyl acetate (25 mL), cooled to 0 °C, treated with ethanol (approximately 5 mL), treated with ethyl acetate (125 mL), washed sequentially with 2: 1:1 water/saturated a2CO3/brine (100 mL then 2x50 L) and brine (50 mL), dried (MgSO 4 ), filtered, through silica gel with ethyl acetate rinses, and concentrated to provide 1.61 g of the desired product.
- Example 7 ID 2-( 1.2-dimethyl-5-indolyl)-4.5-trimethoxyphenylV ⁇ 2.3-oxazoline Ethyl l,2-dimethyl-5-indolecarboxylate was processed as described in Examples
- Example 72A 3 -methyl-4-nitrophenyl trifluoromethanesulfonate
- a solution of 3-methyl-4-nitrophenol, Example 72A, (5.00 g, 32.6 mmol) and triethylamine (9.90 g, 97.8 mmol) in dichloromethane (100 mL) at 0 °C was treated dropwise over 30 minutes with trifluoromethanesulfonic anhydride (18.4 g, 65.2 mmol), warmed to room temperature, stined for 22 hours, and transfened to 10%o NaHCO3 (200 mL).
- the organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL).
- Example 72B 7-methyl-5-indolyl trifluoromethanesulfonate
- a solution of 3-methyl-4-nitrophenyl trifluoromethanesulfonate (8.96 g, 31.4 mmol) in THF (200 mL) at 0 °C was treated dropwise with IM allylmagnesium bromide in THF (110 mL 110 mmol), stined for 2 hours, transfened into saturated NH4CI (200 mL), and extracted with ethyl acetate (200 mL). The extract was dried (MgSO 4 ), filtered, and concentrated.
- Example 72C 7-methyl-5-indolecarboxilic acid
- Example 72D 2-(7-methyl-5-indolyl)-5-GA5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 72C was processed as described in Example 63E to provide the desired product.
- Example 73 2-(1.7-dimethyl-5-indolylV5-G.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 72 (141 mg, 0.385 mmol) was processed as described Example 64 to provide 113 mg of the desired product.
- 0 °C was treated with 2M methylamine in methanol (350 mL 700 mmol) warmed to room temperature, stined for 64 hours, and concentrated.
- the concentrate was slurried in methanol (100 mL), treated with 10%> Pd/C (10 g, 9.4 mmol), stined under hydrogen (1 atm) for 22 hours, diluted with ethyl acetate (1 L), filtered through silica gel, and concentrated to provide 27.0 g of the desired product.
- Example 75B methyl 3-acetylamino-4-methylaminobenzoate
- a solution of Example 75A (1.80 g, 10.0 mmol) in dichloromethane (100 mL) was treated sequentially with acetic anhydride (3.06 g, 30.0 mmol) and 10% NaHCO3 (100 mL) and stined for 30 minutes.
- the organic layer was separated, washed with brine (30 mL), dried (MgSO 4 ), filtered, concentrated until solid precipitated, treated with diethyl ether, and filtered to provide 1.66 g of desired product.
- Example 75C was processed as described in Examples 63D and 63E to provide the desired product.
- Example 76 2-G-trifluoroacetyl-5-indolylV5-GA5-trimethoxyphenylV ⁇ 23-oxazoline
- Example 76A methyl 3-trifluoroacetyl-5-indolecarboxylate
- methyl 5-indolecarboxylate 0.876 g, 5.0 mmol
- Example 76A was processed as described in Examples 63D and 63E to provide 279 mg of the desired product.
- Methyl l-methyl-5-indolecarboxylate was processed as described in Example 76A to provide 325 mg of the desired product.
- Example 78A 5-benzyloxy- 1 -trifluoroacetylindole
- a solution of trifluoroacetic anhydride (12.7 g, 60.0 mmol) in dichloroethane (80 mL) at 0 °C was treated dropwise with a solution of 5-benzyloxyindole (3.34 g, 15.0 mmol) in dichloroethane (40 mL), stined for 18 hours, diluted with ethyl acetate (200 mL), washed sequentially with 10% NaHCO3 (300 mL), 2:1:1 water/ 10% NaHC ⁇ 3/brine (2x100 mL), and brine (50 mL), dried (MgSO4), filtered, and concentrated to provide 2.33 g of the desired product.
- Example 78B 5-benzyloxy-l-(2,2.2-trifluoroethyDindole A solution of Example 78A (1.98 g, 6.20 mmol) in THF (20 mL) at 0 °C was treated dropwise with IM BH3 THF in THF (11.2 mL, 11.2 mmol), heated at reflux for 16 hours, cooled to 0 °C, treated 6M HCl (approximately 1 mL), diluted with ethyl acetate (60 mL), washed with 10% NaHCO3 (30 mL) and brine (30 mL), dried (MgSO 4 ), filtered, and concentrated to provide 1.56 g of the desired compound.
- Example 78D l-(2.2.2-trifluoroethyl)-5-indolyl trifluoromethanesulfonate 5-Hydroxy-l-(2,2,2-trifluoroethyl)indole (114 mg, 0.53 mmol) was processed as described in Example 76A to provide 84.3 mg of the desired product.
- Example 79B 1 -cyclopropyl- 5 -cyanoindole A solution of 40% by weight ethyl ethynyl ether (5.00 g, 28.5 mmol) in hexanes at 0 °C was treated dropwise with IM catecholborane in THF (27.4 mL, 27.4 mmol), warmed to room temperature for 2 hours, heated at 70 °C for 2 hours, treated sequentially with a solution of 79 A (1.35 g, 5.70 mmol) in THF (25 mL), l,l'-bis(diphenylphosphino)fenocene palladium (II) chloride (0.233 g, 0.285 mmol), and CsF (3.04 g, 20.0 mmol), stined for 22 hours, treated with double the amount of catalyst and base, stined for 20 hours, cooled to room temperature, treated with diethyl ether to double the reaction volume, filtered
- the concentrate was dissolved in THF (10 mL), treated with 2M HCl (10 mL), stined for 2 days, transfened to 10% N ⁇ 1HCO3 (100 mL), and extracted with ethyl acetate (100 mL then 3x30 mL). The combined extracts were washed with brine (50 mL), dried (MgSO 4 ), filtered through silica gel with ethyl acetate rinses, and concentrated. The concentrate was purified by radial chromatography with 9: 1 hexane/ethyl acetate to provide 291 mg of the desired product.
- Example 79C 2-fl-cvclopropyl-5-indolyl)-5-( ' 3.4.5-trimethoxyphenyl)- ⁇ 2.3-oxazoline
- Example 79B (291 mg, 1.60 mmol) was processed as described in Example 23F to provide 23 mg of the desired product.
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WO2003014133A1 (fr) * | 2001-08-09 | 2003-02-20 | Ciba Specialty Chemicals Holding Inc. | Derives d'isoxazoline sous forme de p, n ligands |
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US6849656B1 (en) | 1999-09-17 | 2005-02-01 | Baylor University | Indole-containing and combretastatin-related anti-mitotic and anti-tubulin polymerization agents |
WO2006103057A1 (fr) * | 2005-03-31 | 2006-10-05 | Ucb Pharma, S.A. | Compounds comprising an oxazoline or thiazoline moiety, processes for making them, and their uses |
US7157486B2 (en) | 2001-07-25 | 2007-01-02 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
US7229987B2 (en) | 2002-05-13 | 2007-06-12 | Eli Lilly And Company | Multicyclic compounds for use as melanin concentrating hormone antagonists in the treatment of obesity and diabetes |
WO2009067706A1 (fr) | 2007-11-21 | 2009-05-28 | Oxigene, Inc. | Procédé pour traiter des néoplasmes hématopoïétiques |
US7700641B2 (en) | 2005-04-11 | 2010-04-20 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their uses as therapeutic agents |
US7799798B2 (en) | 2005-04-11 | 2010-09-21 | Xenon Pharmaceuticals Inc. | Spiroheterocyclic compounds and their uses as therapeutic agents |
US20110152312A1 (en) * | 2009-12-17 | 2011-06-23 | Le Hir De Fallois Loic Patrick | Antiparisitic dihydroazole compounds and compositions comprising same |
US8101647B2 (en) | 2008-10-17 | 2012-01-24 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their use as therapeutic agents |
US8263606B2 (en) | 2008-10-17 | 2012-09-11 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their use as therapeutic agents |
US8445696B2 (en) | 2009-10-14 | 2013-05-21 | Xenon Pharmaceuticals Inc. | Synthetic methods for spiro-oxindole compounds |
US8450358B2 (en) | 2009-06-29 | 2013-05-28 | Xenon Pharmaceuticals Inc. | Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents |
US8466188B2 (en) | 2006-10-12 | 2013-06-18 | Xenon Pharmaceuticals Inc. | Use of spiro-oxindole compounds as therapeutic agents |
US9504671B2 (en) | 2010-02-26 | 2016-11-29 | Xenon Pharmaceuticals Inc. | Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents |
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US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
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CN114656417A (zh) * | 2022-04-08 | 2022-06-24 | 合肥工业大学智能制造技术研究院 | 一种手性噁唑啉的合成方法及用途 |
US11419934B2 (en) | 2015-08-18 | 2022-08-23 | Oncotelic Therapeutics, Inc. | Use of VDAS to enhance immunomodulating therapies against tumors |
US11932650B2 (en) | 2017-05-11 | 2024-03-19 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
US12030888B2 (en) | 2021-02-24 | 2024-07-09 | Massachusetts Institute Of Technology | Himastatin derivatives, and processes of preparation thereof, and uses thereof |
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US6849656B1 (en) | 1999-09-17 | 2005-02-01 | Baylor University | Indole-containing and combretastatin-related anti-mitotic and anti-tubulin polymerization agents |
US7157486B2 (en) | 2001-07-25 | 2007-01-02 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
US7081536B2 (en) | 2001-08-09 | 2006-07-25 | Ciba Specialty Chemicals Corporation | Isoxazoline derivatives as P N ligands |
WO2003014133A1 (fr) * | 2001-08-09 | 2003-02-20 | Ciba Specialty Chemicals Holding Inc. | Derives d'isoxazoline sous forme de p, n ligands |
WO2003027096A1 (fr) * | 2001-09-26 | 2003-04-03 | Bayer Pharmaceuticals Corporation | 3-pyridyl imidazoles substitues en tant qu'inhibiteurs de la lyase c17,20 |
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