WO2004013085A1 - Acides 3-amino-2-hrydroxyalkanoiques et leurs promedicaments - Google Patents

Acides 3-amino-2-hrydroxyalkanoiques et leurs promedicaments Download PDF

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WO2004013085A1
WO2004013085A1 PCT/US2003/024396 US0324396W WO2004013085A1 WO 2004013085 A1 WO2004013085 A1 WO 2004013085A1 US 0324396 W US0324396 W US 0324396W WO 2004013085 A1 WO2004013085 A1 WO 2004013085A1
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amino
compound
hydroxy
group
alkyl
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PCT/US2003/024396
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English (en)
Inventor
Nwe Y. Bamaung
Richard A. Craig
Jack Henkin
Megumi Kawai
Xenia B. Searle
George S. Sheppard
Jieyi Wang
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Abbott Laboratories
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Priority to EP03767171A priority Critical patent/EP1546087A1/fr
Priority to MXPA05001467A priority patent/MXPA05001467A/es
Priority to JP2004526421A priority patent/JP2005534702A/ja
Priority to CA002494632A priority patent/CA2494632A1/fr
Publication of WO2004013085A1 publication Critical patent/WO2004013085A1/fr

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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • 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
    • C07D263/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
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    • C07—ORGANIC CHEMISTRY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to novel compounds having methionine aminopeptidase- 2 inhibitory (MetAP2) activity useful for treating conditions which arise from or are exacerbated by angiogenesis, pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, methods of inhibiting angiogenesis, and methods of treating cancer.
  • MetalAP2 methionine aminopeptidase- 2 inhibitory
  • Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development, and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions these molecules appear to maintain the micro vasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods that may last for weeks, or in some cases, decades.
  • angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as “angiogenic diseases") are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. Thus, there is a continuing need for compounds which demonstrate antiangiogenic activity.
  • R is selected from the group consisting of alkyl, alkylsulfanylalkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocycle)alkyl, and hydroxyalkyl; and R is selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyloxyalkyl- alkylcarbonylalkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycle, and (heterocycle)alkyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (I).
  • the present invention provides a method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • alkenyl refers to a monovalent straight or branched chain group of one to ten carbon atoms containing at least one carbon-carbon double bond.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon of one to ten atoms.
  • alkylcarbonyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylcarbonyloxy refers to an alkylcarbonyl group attached to the parent molecular moiety through an oxygen atom.
  • alkylcarbonyloxyalkyl refers to an alkylcarbonyloxy group attached to the parent molecular moiety through an alkyl group.
  • alkylsulfanyl refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.
  • alkylsulfanylalkyl refers to an alkylsulfanyl group attached to the parent molecular moiety through an alkyl group.
  • amino refers to -NR a R b , wherein R a and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, cycloalkyl, (cycloaikyl)alkyl, and unsubstituted aryl.
  • aryl refers to a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group.
  • Bicyclic fused ring systems are exemplified by a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • the aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkyl, alkylcarbonyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, nitro, and oxo.
  • arylalkyl refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • the alkyl part of the arylalkyl can be optionally substituted with an amino group.
  • carbonyl refers to -C(O)-.
  • cyano refers to -CN.
  • cycloalkenyl refers to a non-aromatic cyclic or bicyclic ring system having three to ten carbon atoms and one to three rings, wherein each five- membered ring has one double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double bonds, and each nine-to ten- membered ring has one to four double bonds.
  • cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.
  • cycloalkyl refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl- and adamantyl.
  • (cycloalkyl)alkyl refers to a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
  • halo or halogen, as used herein, refers to F, Cl, Br, or I.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
  • heterocycle refers to a five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the five-membered ring has zero to two double bonds and the six- and seven-membered rings have zero to three double bonds.
  • heterocycle also includes bicyclic groups in which the heterocycle ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another monocyclic heterocycle group, as defined herein; and tricyclic groups in which a bicyclic system is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another monocyclic heterocycle group.
  • the heterocycle groups of the present invention can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom in the group.
  • heterocycles include, but are not limited to, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, thiazolyl, thienyl, and thiomorpholinyl.
  • heterocycle groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkyl, alkylcarbonyl, amino, carboxy, cyano, halo, haloalkoxj', haloalkyl, nitro, and oxo.
  • (heterocycle)alkyl refers to a heterocycle group attached to the parent molecular moiety through an alkyl group.
  • nitro refers to -NO 2 .
  • the compounds of the present invention can exist as therapeutically acceptable salts.
  • terapéuticaally acceptable salt represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are co mensurate with a reasonable benefit risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbon
  • amino groups in the compounds of the present invention can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a 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 metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethyl amine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N -dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • the present compounds can also exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood.
  • Prodrugs of the present invention are compounds of formula (I) where R is other than hydrogen (i.e., carboxylic esters).
  • prodrugs include, but are not limited to, methyl (3R)-3- amino-2-hydroxy-5-(methylsulfanyl)pentanoate; methyl (2i?S,3i?)-3-amino-4-cyclohexyl-2- hydroxybutanoate; (lS,2i?)-2-amino-2,3-dihydro-lH-inden-l-yl (2i?S,3i?)-3-amino-4- cyclohexyl-2-hydroxybutanoate; benzyl (2S,3R)-3-arnino-3-cyclopentyl-2- hydroxypropanoate; benzyl (2S,3i?)-3-arnino-3-cycloheptyl-2-hydroxypropanoate; (2S)-2- (methyIamino)-2-(l-naphthyl)ethyl (2S,3R)-3-amino-5-(ethylsulfanyl)-2-hydroxypentan
  • the compounds can be administered alone or in combination with other anticancer agents.
  • the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
  • the compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • Parenterally administered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the antiangiogenic effect of parenterally administered compounds can be prolonged by slowing their absorption.
  • injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.
  • Transdermal patches can also provide controlled delivery of the compounds.
  • the rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • Capsules, tablets, and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefore.
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
  • Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • MetAP2 plays a critical role in the proliferation of endothelial cells and may serve as a promising target for the development of new anti-angiogenic drugs.
  • Assays for the inhibition of catalytic activity of MetAP2 were performed in 96-well microtiter plates.
  • the absorbence at 450 nanometers was measured every 20 seconds over a period of twenty minutes using an automatic plate reader (Molecular Devices, CA, USA).
  • the Vmax in mOD/min, calculated for each well, was used to represent MetAP2 activity.
  • the IC 50 for each inhibitor was obtained by plotting the remaining activity versus inhibitor concentrations.
  • Representative compounds of the present invention had IC 50 's between about 0.030 ⁇ M and about 1.80 ⁇ M.
  • Preferred compounds of the present invention had ICso's between about 0.030 and about 0.05 ⁇ M.
  • angiogenesis inhibitors such compounds are useful in the treatment of both primary and metastatic solid tumors, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including kidney, bladder, and urothelium), female genital tract (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes, and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes, and meninges (including
  • Such compounds may also be useful in treating solid tumors arising from hematopoietic malignancies such as leukemias (i.e., chloromas, plasmacytomas and the plaques and tumors of mycosis fungosides and cutaneous T-cell lymphoma/leukemia) as well as in the treatment of lymphomas (both Hodgkin's and non- Hodgkin's lymphomas).
  • leukemias i.e., chloromas, plasmacytomas and the plaques and tumors of mycosis fungosides and cutaneous T-cell lymphoma/leukemia
  • lymphomas both Hodgkin's and non- Hodgkin's lymphomas
  • these compounds may be useful in the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic agents.
  • the compounds of the invention can also be useful in the treatment of the aforementioned conditions by mechanisms other than the inhibition of angiogenesis.
  • autoimmune diseases such as rheumatoid, immune and degenerative arthritis
  • various ocular diseases such as diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration, hypoxia, angiogenesis in the eye associated with infection or surgical intervention, and other abnormal neovascularization conditions of the eye
  • skin diseases such as psoriasis
  • blood vessel diseases such as hemagiomas, and capillary proliferation within atherosclerotic plaques
  • Osier- Webber Syndrome myocardial angiogenesis
  • plaque neovascularization telangiectasia
  • hemophiliac joints angiofibroma
  • wound granulation such as rheumatoid, immune and degenerative arthritis
  • various ocular diseases such as diabetic retinopathy, retinopathy of prematurity
  • Other uses include the treatment of diseases characterized by excessive or abnormal stimulation of endothelial cells, including not limited to intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, and hypertrophic scars, i.e., keloids.
  • Another use is as a birth control agent, by inhibiting ovulation and establishment of the placenta.
  • the compounds of the invention are also useful in the treatment of diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele minutesalia quintosa) and ulcers (Helicobacter pylori).
  • the compounds of the invention are also useful to reduce bleeding by administration prior to surgery, especially for the treatment of resectabie tumors. Synthetic Methods
  • BOC for tert-butoxycarbonyl
  • PCC for pyridinium chlorochromate
  • EDC for l-(3-dimethylaminopropyl)-3-ethyIcarbodiimide hydrochloride
  • HO AT for 1- hydroxy-7-azabenzot ⁇ azole
  • DCC for 1,3-dicyclohexylca ⁇ -bodiimide
  • HOBT for 1- hydroxybenzotriazole
  • DMSO for dimethylsulfoxide
  • BOC-ON for [2-(tert- butoxyca ⁇ onyloxyimino)-2-phenylacetomtrile
  • THF for tetrahydrofuran.
  • This invention is intended to encompass compounds having formula (I) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • compounds of formula (2) can be converted to compounds of formula (3) by treatment with a reducing agent.
  • reducing agents include sodium bis(2-methoxye oxy)aluminum hydride (Red-Al ), lithium aluminum hydride, and borane.
  • Oxidation of compounds of formula (3) can be accomplished by treatment with an oxidizing agent such as sulfur trioxide pyridine complex, PCC, or the Dess-Martin periodinane to provide compounds of formula (4).
  • Conversion of compounds of formula (2) to compounds of formula (4) may also be achieved by conversion to the N-methoxy-N-methylamide using NO-dimethylhydroxylamine and an activating agent such as DCC or EDCI, followed by treatment with a reducing agent such as lithium aluminum hydride.
  • Reacting compounds of formula (4) with trimethylsilylcyanide or sodium bisulfite and potassium cyanide provides the cyanohydrin which can be treated in situ with a strong acid such as HCl to simultaneously hydrolyze the cyano group and remove the protecting group, providing compounds of foraiula
  • (8) to compounds of formula (9) can be accomplished by treatment with tert-butylcarbamate, tert-butylhypochlorite, and NaOH, followed by treatment with potassium osmate and either hydroquinine 1,4-phthalazinediyl di ether or 1,4-phthalazinediyl diether (depending on which enantiomer is desired).
  • Hydrolysis of the ester can be accomplished by methods known to those of ordinary skill in the art (for example, lithium hydroxide and hydrogen peroxide) to provide compounds of formula (10), which can be deprotected using conditions known to those of ordinary skill in the art (such as HCl) to provide compounds of formula (la).
  • Compounds of formula (lb) can also be prepared by the procedures described in Scheme 5.
  • Compounds of formula (11) can be treated with 2,2-dimethoxypropane in the presence of an acid such as methylbenzenesulfonic acid or p-toluenesulfonic acid to provide compounds of formula (12).
  • Hydrolysis of the ester using conditions known to those of ordinary skill in the art provides compounds of formula (13).
  • Esterif ⁇ cation of compounds of formula (13) can be accomplished by treatment with an appropriately substituted alcohol (R OH) and a coupling agent such as EDC and HO AT or DCC and HOBT.
  • Compounds of formula (14) can be treated with a strong acid such as HCl in the presence of water to provide compounds of formula (lb).
  • Example 1A tert-butyl (lR)-l-(hvdiOXvmethyl)-3-(methylsulfanyl propylcarbamate
  • N-(tert-butoxycarbonyl)-D-methionine (12.47 g, 50 mmol) and sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al ) (50 mmol) in dry toluene (125 mL) was stirred at 0 °C for 30 minutes- then at ambient temperature for 1 hour.
  • the mixture was treated with aqueous Rochelle salt and extracted with diethyl ether.
  • the extract was washed sequentially with brine and aqueous ⁇ aHC ⁇ 3 , dried (MgSO ), filtered, and concentrated to provide the desired product (9.05 g).
  • Example 1A A solution of Example 1A (9.05 g, 38.5 mmol), sulfur trioxide pyridine complex (30.64 g, 192.5 mmol), and triethylamine (26.8 mL, 192.5 mmol) in DMSO (30 mL) was stirred at ambient temperature for 30 minutes, cooled to 0 °C, treated sequentially with water (20 mL) and saturated aqueous KHSO 4 (120 mL), and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO 4 and brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product (9.00 g).
  • Example 1C (2RS i?)-3-arr ⁇ ino-2-hvdroxy-5-(methylsulfanyl)pentanoic acid
  • a solution of Example IB (9.00 g, 38.5 mmol) and sodium bisulfite (3.80 g, 36.6 mmol) in water (200 mL) was stirred at 5 °C for 72 hours, warmed to ambient temperature, treated with a mixture of potassium cyanide (2.51 g, 38.6 mmol) in ethyl acetate (250 mL), and stirred for 4 hours.
  • the separated ethyl acetate layer was washed sequentially with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • Example 2B (2RS,3RV3-amino-5-(ethylsulfanyl)-2-hvdroxypentanoic acid
  • the desired product was prepared by substituting Example 2A for Example 3C in Example 3D.
  • MS (ESI) m/e 194 (M+H) + ;
  • H NMR 300 MHz, DMSO-d 6 ) ⁇ 8.14 (br s, 0.6H), 7.95 (br s, 1.4H), 4.35 (d, 0.3H), 4.16 (d, 0.7H), 3.70 (m, 0.3H), 3.46 (m, 0.7H), 2.63 (m, 2H), 2.49 (m, 2H), 1.84 (m, 2H), 1.18 (m, 3H).
  • Example 3 A A solution of Example 3 A (25.8 g,100 mmol), sulfur trioxide pyridine complex (79.6 g, 500 mmol), and iriethylamine (69.7 mL, 500 mmol) in DMSO (70 mL) at room temperature was stirred for 30 minutes, cooled to 0 °C, treated with water and saturated aqueous KHSO 4 , and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO 4 and brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product.
  • the combined extracts were washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated.
  • the concentrate was dissolved in dioxane (150 mL), treated with 12M HCl (150 mL), heated to reflux, stirred for 21 hours, and cooled to room temperature.
  • the mixture was concentrated, dissolved in a mixture of water (30 mL) and acetone (200 mL), adjusted to pH 5.5 with 1M NaOH, treated with acetone (3.5 L), and cooled to 0 °C for 4 hours. The resulting precipitate was collected by filtration.
  • the filter cake was dried, dissolved in 1:1 water/dioxane, treated with BOC-ON (1.2 eq.), and triethylamine (2 eq.), heated to 45 °C, stirred for 15 hours, treated with 10% aqueous KHSO 4 , and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried (MgSO ), filtered, and concentrated to provide the desired product.
  • Example 3D (2 ?S,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoic acid
  • a solution of Example 3C (75 mg, 0.25 mmol) in 4M HCl in dioxane (2 mL) at room temperature was stirred for 1 hour, concentrated, then purified by reverse phase HPLC with acetonitrile/water to provide the desired product.
  • Example 6A (2RS,3i?)-3-r(tert-butoxycarbonyl)amino1-2-hydroxy-5-phenylpentanoic acid
  • the desired product was prepared by substituting (2R)-2-((tert- butoxycarbonyl)amino)-4-(phenyl)butanoic acid for (2R)-2-((tert-butoxycarbonyl)amino)-3- cyclohexylpropanoic acid in Examples 3A-3C.
  • MS (ESI) m/e 310 (M+H) + .
  • Example 6B (2RS,3R)-3-amino-2-hvdroxy-5-phenylpentanoic acid
  • the desired compound was obtained by substituting Example 6A for Example 3C in
  • MMSS ((EESSII((++)))) mm//ee 221100 ((MM++HH)) ++ ;
  • HH NNMMRR ((3300(0MHz, DMSO-d 6 ) ⁇ 7.34-7.16 (m, 5H), 4.19 (br d, IH), 2.76-2.65 (m, 2H), 1.97-1.68 (m, 2H).
  • Example 7B (2RS,37 ⁇ )-3-r(tgrt-butoxycarbonyl)aminol-2-hvdroxy-5-(isopropylsulfanyl)pentanoic acid
  • the desired product was prepared by substituting Example 7A for (2R)-2-((tert- butoxycarbonyl)amino)-3-cyclohexylpropanoic acid in Examples 3A-3C.
  • Example 7C (2RS,3R)-3-amino-2-hvdroxy-5-(isopropylsulfanyl pentanoic acid
  • the desired product was prepared by substituting Example 7B for Example 3C in Example 3D.
  • MS (ESI) m/e 208 (M+H) + ;
  • H NMR 300 MHz, DMSO-d 6 ) ⁇ 7.34 (br s,
  • Example 8 f2S.3 ?,4S)-3-amino-2-hvdOxy-4-(3-hvdiOxypiOpyl)-7-methyloctanoic acid
  • Example 8A 5-methylhexanoyl chloride A mixture of 5-methylhexanoic acid (25 mL, 175 mmol) and thionyl chloride (50 mL, 0.69 mol) was stirred at reflux for 90 minutes. The mixture was concentrated, then distilled at reduced pressure to give the desired product (22.35 g).
  • Example 8B (4i?)-4-benzyl-3-(5-methylhexanoyl)-l,3-oxazolidin-2-one
  • a -78 °C solution of 4(i?)-benzyl-2-oxazolidinone (21.28 g, 0.12 mol) in THF (360 mL) was added .z-butyllithium (48 mL, 2.5M in hexane, 120 mmol). After 10 minutes Example 8A (19.76 g, 0.134 mol) was added. After 30 minutes the mixture was warmed to 0 °C, and quenched with saturated ammonium chloride. The supernatant was decanted and concentrated.
  • Example 8C (4J? -4-benzyl-3-r(2S)-2-(3-methylburyl)-4-pent&novn- 3-oxazolidin-2-one
  • THF 160 mL
  • sodium bis(trimethylsilyl)amide 55 mL, IM in THF
  • the reaction mixture was stirred for 45 minutes and allyl bromide (5.3 mL, 60.9 mmol) was added.
  • the reaction mixture was stirred for 90 minutes, warmed to 0 °C, and stirred an additional 90 minutes.
  • Example 8D (2S)-2-(3-memylbutyl;-4-pentenoic acid
  • THF 200 mL
  • water 25 rriL
  • 30% hydrogen peroxide 25 mL, 220 mmol
  • a solution of lithium hydroxide monohydrate (4.38 g, 104 mmol) in water (100 mL) was added and the resulting solution was stirred for 12 hours, i e mixture was quenched with aqueous NaHSO 3 then concentrated and made basic with 5M NaOH.
  • Example 8E (2S)-N-methoxy-N-methyl-2-(3-methylbutyl)-4-pentenamide
  • a solution of Example 8D (4.54 g, 26.7 mmol), N,O-dimethyl hydroxylamine hydrochloride (5.6 g, 57 mmol), l-(3-dime ylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.19 g, 27 mmol), 1-hydroxybenzotriazole (4.12 g, 30.5 mmol), andN- methylmorpholine (7.0 mL, 64 mmol) in dichloromethane (270 mL) at room temperature was stirred for 4 hours, diluted with dichloromethane, washed sequentially with aqueous ⁇ aHC ⁇ 3 , brine, 10% KHSO 4 , and brine, dried (MgSO 4 ), filtered, and concentrated. Flash column chromatography (silica gel, 10% ethyl acetate
  • Example 8F (2S)-2-(3-hvdroxy ⁇ ropyl)-N-methoxy-N,5-dimethylhexanamide A solution of Example 8E (2.31 g, 10.8 mmol), and THF-borane complex (12.0 mL,
  • Example 8F A solution of Example 8F (2.58 g, 11.1 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (2.8 mL, 12 mmol), and 2,6-lutidine (1.5 mL, 13 mmol) in dichloromethane (100 mL) at 0 °C was stirred for 2 hours; diluted with dichloromethane, washed sequentially with 10% KHSO 4 , aqueous ⁇ aHC ⁇ 3 , and brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product.
  • MS (ESI) m/e 346 (M+H) + .
  • Example 8F A solution of Example 8F (3.16 g, 9.16 mmol) and lithium aluminum hydride (0.34 g, 9.2 mmol) in diethyl ether (100 mL) at room temperature was stirred 30 minutes, treated with IM NaHSO 4 , diluted with diethyl ether, washed sequentially with 10% NaHSO 4 , and brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product.
  • MS (ESI) m/e 287 (M+H) + .
  • Example 81 benzyl (2E.4S)-4-(3-(rtert-butyl(dimethyl silynoxy]propyl)-7-methyl-2-octenoate
  • Example 8J benzyl (2S.3J?.4S)-3-r(tert-buto ⁇ ycarbonyl)amino1-4-(3- ⁇ Ttert- butyl(dimethyl)siIylloxy)propyl -2-hydroxy-7-methyloctanoate
  • the desired product was prepared by substituting Example 81 for Example 9B in Example 9C. Flash column chromatography (silica gel, 10% ethyl acetate/hexanes) provided the purified product. MS (ESI) m e 552 (M+H) + .
  • Example 8K (2-?3J?.4S)-3-amino-2-hvdroxy-4-(3-hydro ⁇ ypropyl)-7-methyloctanoic acid
  • a mixture of Example 8J (15 mg, 0.027 mmol) and 10% Pd/C in THF (5 mL) under a hydrogen atmosphere at room temperature was stirred for 3.5 hours and filtered.
  • the filtrate was treated with tetrabutylammonium fluoride (0.25 mL, l.OM in THF) for 18 hours, diluted with diethyl ether, washed twice with IM HCl, dried (Na 2 SO 4 ), filtered, and concentrated.
  • Example 9B ethyl (2E)-6-phenyl-2-hexenoate
  • a solution of Example 9A (1.17 g, 7.9 mmol), triethyl phosphonoacetate (1.05 mL, 7.9 mmol), lithium bromide (0.70 g, 8.1 mmol), and triethylamine (1.1 mL, 7.8 mmol) in THF (80 mL) at room temperature was stirred for 16 hours, quenched with water, stirred for 15 minutes, diluted with ethyl acetate, washed sequentially with pH 7 buffer and brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with l:l/dichloromethane:hexanes to provide the desired product. MS (ESI) m/e 218 (M+H) + .
  • Example 9C ethyl (2S-3R)-3-r(te7 -butoxycarbonyl)aminol-2-hydroxy-6-phenylhexanoate
  • tert-butylcarbamate (1.00 g, 8.55 mmol
  • tert-butylhypochlorite (0.96 mL, 8.5 mmol)
  • 0.5M NaOH 17.3 mL, 8.5 mmol
  • Example 9B (0.614 g, 2.82 mmol), potassium osmate dihydrate (0.030 g, 0.08 mmol) and hydroquinine 1,4-phthalazinediyl diether (0.109 g, 0.14 mmol) were added, and the mixture was stirred at 0 °C for 2 hours, diluted with ethyl acetate, washed sequentially with water, IM HCl, aqueous NaHCO 3 , and brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with l:4/ethyl acetate:hexanes to provide the desired product. MS (ESI) m/e 352 (M+H) + .
  • Example 9C A solution of Example 9C (0.316 g, 0.90 mmol), 30% hydrogen peroxide (0.40 mL, 3.5 mmol), and lithium hydroxide monohydrate (0.076 g, 1.8 mmol) in 3:1 tetrahydrofuran/water (8 mL) was stirred at 0 °C for 3 hours and concentrated. The concentrate was dissolved in water and the pH adjusted to 10 with IM NaOH. The solution was washed twice with diethyl ether, adjusted to pH 2 with IM HCl, and extracted twice with ethyl acetate. The combined extracts were dried (MgSO 4 ), filtered, and concentrated to provide the desired product. MS (ESI) m/e 324 (M+H) + .
  • Example 9E (2S.3R)-3-amino-2-hydroxy-6-phenvIhexanoic acid
  • a solution of Example 9D (25.7 mg, 0.08 mmol) in 4M HCl in dioxane (2 mL) was stirred at room temperature for 1 hour and concentrated to provide the desired product.
  • MS (ESI) m/e 224 (M+H) + ; ! H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.29 (m, 2H), 7.18 (m, 3H). 4.11 (d, IH), 3.69 (m, IH), 2.57 (m, 2H), 1.73-1.49 (m, 4H).
  • Example 10A (2R)-2-r(tgrt-butoxycarbonyl)arr ⁇ ino1-4-(tgrt-butylsuIfanyl)butanoic acid
  • D-homocystine 3.0 g, 11 mmol
  • sodium 1.3 g, 56 mmol
  • the ammonia was allowed to evaporate under a stream of nitrogen, and the residue was dissolved in IM HCl (10 mL).
  • the pH was adjusted to 0 with concentrated HCl, treated with tert-butanol (5 mL, 53 mmol), heated to reflux for 16 hours, and concentrated.
  • the concentrate was dissolved in 1:1 2-propanol water (80 mL), treated with di-tert-butyl dicarbonate (20.2 g, 92.7 mmol), stirred at room temperature for 16 hours, and concentrated.
  • the concentrate was dissolved in water adjusted to pH 10 with 50% NaOH.
  • the solution was washed twice with diethyl ether, adjusted to pH 2 with HCl, and extracted twice with ethyl acetate.
  • the combined extracts were dried (MgSO 4 ), filtered, then concentrated to provide the desired product.
  • MS (ESI) m/e 292 (M+H) + .
  • Example IIA (3R)-3-r(tgrt-butoxycarbonyl)amino "
  • a solution of Example 1C (2.68 g, 12.5 mmol), triethylamine (3.47 ml, 75.0 mmol), and 2-(tert-butyoxycarbonyloxyimino)-2-phenylacetonitrile (3.22 g, 13.0 mmol) in 30% aqueous dioxane was heated to 50 °C for 6 hours, cooled to ambient temperature, and concentrated. The residue was diluted with aqueous sodium hydroxide (0.25M, 50 mL) and extracted twice with ethyl acetate.
  • Example 1 IB (3R)-3-r(tgrt-butoxycarbonyl)aminol-5-fmethylsulfanyl)-2-(tetrahydro-2H-pyran-2- yloxy)pentanoic acid
  • the concentrate was diluted with aqueous sodium hydroxide (0.25M, 15 mL) and extracted twice with ethyl acetate.
  • the aqueous layer was adjusted to p ⁇ 3 with aqueous ⁇ 3 PO 4 (l.OM) and extracted three times with ethyl acetate. These three extracts were combined, washed sequentially with water (20 mL) and brine (20 mL), dried (MgSO 4 ), filtered, and concentrated to provide the desired product (0.61 g).
  • MS (APCI(+)) m/e 364 (M+H) + MS (APCI(+)) m/e 364 (M+H) + .
  • Example 11C methyl (3R)-3-((tgrt-butoxyc--rbonyI)arnino)-2-hvdroxy-5-(methylthio)pentanoate
  • a solution of Example 11B (0.25g, 0.68 mmol) and trimethylsilyldiazomethane (2.0M in hexanes, 15 mL) in THF at room temperature was stirred for 4 hours, treated with acetic acid (1 mL), and concentrated. The residue was dissolved in methanol, treated with p- toluenesulfonic acid (10 mg), and heated to 55 °C for 16 hours. The mixture was concentrated and purified by flash column chromatography on silica gel with 25% ethyl acetate hexanes to provide the desired product. MS (APCI(+)) m/e 294 (M+H) + .
  • Example IIP methyl (3R)-3-amino-2-hydroxy-5-(methylsulfanyl)pentanoate A solution of Example 11C in 4M HCl in dioxane (10 mL) at room temperature was stirred for 4 hours and concentrated to provide the desired product.
  • Example 12A memyl (2RS,3R)-3-(tgrt-butoxyc--rbonyl amino-4-cvclohexyl-2-hvdroxybutanoate
  • MS (ESI) m e 316 (M+H) + .
  • Example 12B methyl (2i ⁇ S,3J? -3-amino-4-cyclohexyl-2-hvdro ⁇ ybutanoate
  • the desired product was prepared by substituting Example 12 A for Example 3C in
  • Example 14A benzyl (2E)-3-cyclopentylacrylate
  • cyclopentanecaboxaldehyde 0.069 g, 0.70 mmol
  • benzyl (diethylethyl phosphono)acetate 0.100 g, 0.35 mmol
  • lithium bromide 0.030 g, 0.35 mmol
  • triethylamine 0.049 L, 0.35 mmol
  • THF triethylamine
  • Example 14B benzyl (2S,3R)-3-r(tert-butoxycarbonyl)aminol-3-cvclopentyl-2-hvdroxypropanoate
  • the desired product was prepared by substituting Example 14A for Example 9B in Example 9C.
  • MS (ESI) m/e 364 (M+H) + .
  • Example 14C benzyl (2S,3J?)-3-amino-3-cyclo ⁇ entyl-2-hydroxypropanoate
  • the desired product was prepared by substituting Example 14B for Example 3C in Example 3D.
  • MS (ESI) m/e 264 (M+H) + ; H NMR (300 MHz, CD 3 OD) ⁇ 7.39 (m, 5H), 5.29 (dd, 2H), 4.04 (d, IH), 3.88 (dd, IH), 3.66 (s, IH), 1.96 (m, IH), 1.86 (m, IH), 1.68 (m, 2H), 1.58 (m, 2H), 1.43 (m, IH), 1.23 (m, IH).
  • Example 15 benzyl (2S,3R)-3-amino-3 -cvcIoheptyI-2-hydroxypropanoate
  • the desired product was prepared by substituting cycloheptanecarboxaldehyde for cyclopentanecarboxaldehyde in Examples 14A-C.
  • MS (ESI) m e 292 (M+H) + ; !
  • the concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired products MS(ESI(+)) m/e 302 (M+H) + and 316 (M+H) + .
  • Example 16B (2R)-2-(memylamino)-2-(l-naphthyl)e yl (2S.3R)-3-amino-5-(ethylsulfanyl)-2- hydroxypentanoate
  • the desired product was prepared by substituting tgrt-butyl (lR)-2-hydroxy-l-(l- naphthyl)ethyl(methyl)carbamate from Example 16A and Example 2A for (lS,2 ⁇ )-l-amino- 2-hydroxyindane and Example 3C, respectively, in Example 13.
  • the crude product was purified by reverse phase HPLC with acetonitrile/water to provide the desired product.
  • the desired compound was obtained by substituting methyl (2S)-[(tert- butoxycarbonyl)amino](l-na ⁇ hthyl)acetate for methyl (2R)-[(t g 7t-butoxycarbonyl)amino](l- naphthyl)acetate in Examples 16A-B.
  • Example 19 (2i?)-2-rmethylamino)-2-(l-naphthyl)ethv ⁇ 2S.3i?)-3-amino-4-cyclohexyl-2- hydroxybutanoate
  • the desired product was prepared by substituting te??-butyl (l/?)-2-hydroxy-l-(l- naphthyl)ethyl(methyl)carbamate from Example 16A for (lS,2 ⁇ )-l---mino-2-hydroxyindane in Example 13.
  • the crude product was purified by reverse phase HPLC with acetonitrile/water to provide the desired product.
  • MS (ESI) m/e 385 (M+H) + ; !
  • Example 20 (2ig)-2-(memyl-m ⁇ ino -2-(l-naphthyl)e yl (2S,3/ ⁇ )-3-ar ⁇ ino-2-hydroxy-5-phenylpentanoate
  • the desired compound was obtained by substituting tert-butyl (lR)-2-hydroxy-l-(l- naphthyl)ethyl(methyl)carbamate from Example 16A and Example 6A for (lS,2i?)-l-arnino- 2-hydroxyindane and Example 3C, respectively, in Example 13.
  • the crude product was purified by reverse phase HPLC to provide the desired product.
  • MS (ESI) m/e 393 (M+H) + ; !
  • Example 21A methyl (2/?S-3R)-3-r(tert-butoxycarbonyl aminol-5-(ethylsulfanyl -2-hvdroxypentanoate
  • the desired product was prepared by substituting Example 7B and diazomethane for
  • Example 3C and trimethylsilyldiazomethane, respectively, in Example 12A were prepared.
  • Example 2 IB methyl (2RS.3R)-3-amino-5-(ethylsulfanyl)-2-hydroxypentanoate
  • the desired product was prepared by substituting Example 21 A for Example 3C in
  • Example 21 A A mixture of Example 21 A (1.12 g, 3.65 mmol) and catalytic 4- methylbenzenesulfonic acid (15 mg) in 2,2-dimethoxypropane (35 mL) at ambient temperature was stirred for 36 hours, diluted with ethyl acetate, washed sequentially with aqueous NaHCO 3 and pH 7 buffer, dried (MgSO 4 ), filtered, and concentrated. Flash column chromatography (silica gel, 10% acetone/hexanes) provided the desired product. MS (ESI) m e 348 (M+H) + .
  • Example 22A A 0 °C solution of Example 22A (0.65 g, 1.87 mmol) in THF (6 mL) was treated with a solution of lithium hydroxide monohydrate (0.088 g, 2.1 mol) in water (2 mL), stirred for 2 hours, concentrated, and diluted with water. The aqueous phase was washed with diethyl ether, adjusted to pH 4 with 0.5M citric acid, and extracted twice with ethyl acetate. The combined extracts were dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product. MS (ESI) m/e 334 (M+H) + .
  • Example 22C benzyl (2flS,3.R -3-amino-5-(ethylsulfanyl -2-hydroxypentanoate
  • a solution of Example 22B (0.11 g, 0.33 mmol), benzyl alcohol (0.07 mL, 0.7 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.080 g, 0.41 mmol), HOAT (0.045 g, 0.33 mmol), and N-methylmorpholine (0.055 mL , 0.50 mmol) in 3: 1 dichloromethane/DMF (4 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous ⁇ aHC ⁇ 3 , brine, 0.5M citric acid, and brine, dried (MgSO 4 ), filtered, and concentrated.
  • Example 23 bu l (2J?S.3/? -3-amino-5-(ethylsulfanyl)-2-hvdroxypentanoate
  • the desired product was prepared by substituting 1-butanol for benzyl alcohol in Example 22C.
  • MS (ESI) m/e 250 (M+H) + ; !
  • Example 24 isopropyl (2S i?)-3-arnino-2-hydroxy-5-(isopropylsulfanyl)pentanoate
  • the desired product was prepared by substituting 2-propanol and Example 7B for
  • Example 25 isopropyl (2J?S,3R)-3-armno-5-(ethylsulfanyl)-2-hydro ⁇ ypentanoate
  • the desired product was prepared by substituting 2-propanol for benzyl alcohol in Example 22C.
  • MS (ESI) m/e 236 (M+H) + ;
  • H NMR 300 MHz, DMSO-d 6 ) ⁇ 7.73 (br s,
  • Example 22B -3-amino-5-(ethylsulfanvI -2- hydroxypentanoate
  • DMF dimethyl sulfoxide
  • Example 22B a solution of Example 22B (0.102 g, 0.31 mmol), cesium carbonate (0.111 g, 0.34 mmol), and chloromethyl pivalate (0.055 mL, 0.38 mmol) in DMF (3 mL) at room temperature was stirred for 24 hours, diluted with ethyl acetate, washed sequentially with water, aqueous NaHCO 3 , pH 7 buffer, and brine, dried (MgSO 4 ), filtered, and concentrated.
  • Example 27 sec-butyl (2J?S,3j?)-3-amino-5-(ethylsulfanyl)-2-hydroxypentanoate
  • the desired product was prepared by substituting 2-butanol for benzyl alcohol in Example 22C.
  • Example 30 r(2,2-dimethylpropanoyl)oxy1methyl (2S,3R)-3-amino-2-hydroxy-5- (isopropylsulfanyl)pentanoate
  • The. desired product was prepared by substituting Example 29 A for Example 22B in
  • Example 26 The crude product was purified by reverse phase HPLC with acetonitrile/water to provide the desired product.
  • MS (ESI) m/e 322 (M+H) + ; ! H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.97-7.83 (br m, 2H), 6.73 (d, IH), 5.78 (dd, 2H), 4.33 (t, IH), 4.16 (m, IH), 3.73-3.63 (m, IH), 3.53-3.38 (m, IH), 2.98-2.85 (m, IH), 2.70-2.55 (m, IH), 1.87-1.78 (m, IH), 1.20 (d, 6H), 1.12 (s, 9H).
  • Example 29 A for chloromethyl pivalate and Example 22B, respectively, in Example 26 The crude product was purified by reverse phase ⁇ PLC with acetonitrile/water to provide the desired product.
  • the desired product was prepared by substituting 3-bromophthalide and Example 29A for chloromethyl pivalate and Example 22B, respectively, in Example 26.
  • the crude product was purified by reverse phase HPLC with acetonitrile/water to provide the desired product.
  • MS (ESI) m/e 340 (M+H) + ; J H NMR (300 MHz, DMSO-d 6 ) ⁇ 8.03-7.92 (m, 3H), 7.83-7.78 (m, 2H), 7.66 (d, IH), 6.63 (s, IH), 4.28 (m, IH), 4.18 (d, IH), 3.73-3.63 (m, IH), 3.53-3.38 (m, IH), 2.98-2.85 (m, IH), 2.70-2.55 (m, IH), 1.87-1.78 (m, IH), 1.20 (d, 6H).

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Abstract

Les composés représentés par cette formule sont utiles pour le traitement d'états provoqués ou exacerbés par l'angiogenèse. L'invention concerne également des compositions pharmaceutiques renfermant lesdits composés, des méthodes de traitement au moyen de ces composés, des méthodes permettant d'inhiber une angiogenèse et des méthodes de traitement du cancer.
PCT/US2003/024396 2002-08-06 2003-08-05 Acides 3-amino-2-hrydroxyalkanoiques et leurs promedicaments WO2004013085A1 (fr)

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MXPA05001467A MXPA05001467A (es) 2002-08-06 2003-08-05 Acidos 3-amino-2-hidroxialcanoicos y sus profarmacos.
JP2004526421A JP2005534702A (ja) 2002-08-06 2003-08-05 ３−アミノ−２−ヒドロキシアルカン酸及びそのプロドラッグ
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CN112047964A (zh) * 2020-09-07 2020-12-08 宋喂 格氏试剂制备方法与应用

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WO1999057098A2 (fr) * 1998-05-01 1999-11-11 Abbott Laboratories INHIBITEURS β-AMINO-ACIDE SUBSTITUES DE LA METHIONINE AMINOPEPTIDASE-2
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WO1999057098A2 (fr) * 1998-05-01 1999-11-11 Abbott Laboratories INHIBITEURS β-AMINO-ACIDE SUBSTITUES DE LA METHIONINE AMINOPEPTIDASE-2
WO2001079157A1 (fr) * 2000-04-14 2001-10-25 Abbott Laboratories Inhibiteurs d'angiogenese a base d'hydrazide et d'alcoxyamide

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