EP1073633A2 - INHIBITEURS $g(b)-AMINO-ACIDE SUBSTITUES DE LA METHIONINE AMINOPEPTIDASE-2 - Google Patents

INHIBITEURS $g(b)-AMINO-ACIDE SUBSTITUES DE LA METHIONINE AMINOPEPTIDASE-2

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Publication number
EP1073633A2
EP1073633A2 EP99921611A EP99921611A EP1073633A2 EP 1073633 A2 EP1073633 A2 EP 1073633A2 EP 99921611 A EP99921611 A EP 99921611A EP 99921611 A EP99921611 A EP 99921611A EP 1073633 A2 EP1073633 A2 EP 1073633A2
Authority
EP
European Patent Office
Prior art keywords
amino
cyclohexyl
hydroxy
butanamide
hydroxybutanamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99921611A
Other languages
German (de)
English (en)
Inventor
Richard A. Craig
Jack Henkin
Megumi Kawai
Linda Lijewski Lynch
Jyoti Patel
George S. Sheppard
Jieyi Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority claimed from PCT/US1999/009641 external-priority patent/WO1999057098A2/fr
Publication of EP1073633A2 publication Critical patent/EP1073633A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C323/60—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 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to organic compounds having biological activity, to compositions containing the compounds, and to medical methods of treatment. More particularly, the present invention concerns a class of substituted beta-amino acids and their pharmaceutically acceptable salts, pharmaceutical compositions containing the compounds, and methods of treating pathological conditions arising from or dependent upon angiogenesis.
  • 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 microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period. (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267: 10931-10934 (1987), and Folkman, J. and Klagsbrun, M., Science, 235: 442-447 (1987)).
  • 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 exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness.
  • the present invention provides a compound having activity for inhibiting methionine aminopeptidase type 2 (MetAP2 or MetAP2-2) having the structural, formula I
  • n 1-3;
  • R 1 is selected from the group consisting of (1) hydrogen
  • alkanoyl where the alkanoyl can be optionally substituted with hydroxyl, and (5) -(CH 2 ) n CO 2 R , where n is 0-6, and R 4 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R ⁇ is selected from the group consisting of
  • R 3 is selected from the group consisting of (1) an aminoacyl group optionally capped with a carboxyl protecting group,
  • R 6 is defined above, and R 7 is selected from the group consisting of
  • alkyl where the alkyl can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
  • aryl where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
  • R 6 is defined above, and R ⁇ is selected from the group consisting of (i) hydrogen ( ⁇ ) alkyl, (iii) aryl, and
  • heterocycle (g) heterocycle, where the heterocycle can be optionally substituted with one, two, or three groups independently selected from the group consisting of
  • R 2 ⁇ and R 21 together with the nitrogen atom to which they are attached, are a 3- to 7-membered ring optionally containing therein 1 or 2 double bonds and optionally containing therein a moiety selected from the group consisting of (a) oxygen,
  • R 4 is defined above, 5') alkanoyloxy, 6') carboxaldehyde, 7') cycloalkyl, 8') cycloalkenyl, 9') halo, 10') nitro, 11') perfluoroalkyl, 12') perfluoroalkoxy,
  • X is hydroxyl or sulfhydryl
  • Y is hydrogen
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising adminstering to the mammal a pharmaceuticlly acceptable amount of a compound of formula I.
  • alkanoyl denotes an alkyl group attached to the parent molecular group through a carbonyl group.
  • the alkanoyl groups of this invention can be optionally substituted.
  • alkanoyloxy denotes an alkanoyl group attached to the parent molecular group through an oxygen atom.
  • the alkanoyloxy groups of this invention can be optionally substituted.
  • alkyl denotes a radical formed by the removal of one hydrogen atom from a straight or branched saturated hydrocarbon of one to twelve carbon atoms.
  • Representative hydrocarbon groups include methyl, ethyl, n-propyl, w ⁇ -propyl, n- butyl, sec-butyl, tert-butyl, and the like.
  • the alkyl groups of this invention can be optionally substituted.
  • alkoxy denotes a lower alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom and includes such groups as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, and the like.
  • the alkoxy groups of this invention can be optionally substituted.
  • aminoacyl group denotes a radical derived from naturally or unnaturally occuring amino acids.
  • Representative aminoacyl groups include glycyl, alanyl, valyl, leucyl, wo-leucyl, methionyl, seryl, threonyl, cysteinyl, phenylalanyl, homophenylalanyl, and O-methyltyrosinyl in the racemic, 6 or L configurations.
  • aryl denotes a mono- or bicyclic- carbocyclic ring system having one or two aromatic rings.
  • Aryl groups are exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, and indenyl.
  • Bicyclic aryl groups of this invention can be attached to the parent molecular group through a saturated or unsaturated part of the group.
  • the aryl groups of this invention can be optionally substituted.
  • arylalkoxy denotes an aryl group, as defined herein, attached to the parent molecular group through an alkoxy group.
  • the arylalkoxy groups of this invention can be optionally substituted.
  • arylalkyl denotes an aryl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the arylalkyl groups of this invention can be optionally substituted.
  • aryloxy denotes an aryl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • the aryloxy groups of this invention can be optionally substituted.
  • aryloyl denotes an aryl group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • the aryloyl groups of this invention can be optionally substituted.
  • aryloyloxy denotes an aryloyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • the aryloyloxy groups of this invention can be optionally substituted.
  • aryloyloxy alkyl denotes an aryloyloxy group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the aryloyloxyalkyl groups of this invention can be optionally substituted.
  • aryloyloxyalkylcarbonyl denotes an aryloyloxy group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • the aryloyloxyalkylcarbonyl groups of this invention can be optionally substituted.
  • aryloyloxyalkylcarbonylalkyl denotes an aryloyloxyalkylcarbonyl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the aryloyloxyalkylcarbonylalkyl groups of this invention can be optionally substituted.
  • arylsulfonyl denotes an aryl group, as defined herein, attached to the parent molecular group through an -SO2- group.
  • the arylsulfonyl groups of this invention can be optionally substituted.
  • arylsulfonylalkyl denotes an arylsulfonyl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the arylsulfonylalkyl groups of this invention can be optionally substituted.
  • benzyl denotes a phenyl group, as defined herein, attached to the parent molecular group through a methyl group.
  • the benzyl groups of this invention can be optionally substituted.
  • Carboxaldehyde denotes -CHO.
  • carbonyl denotes -C(O)-.
  • carboxy denotes -CO 2 H.
  • cycloalkyl denotes a radical derived by the removal of a single hydrogen atom from a saturated cyclic or bicyclic hydrocarbon and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and the like.
  • the cycloalkyl groups of this invention can be optionally substituted.
  • (cycloalkyl)alkyl denotes a cycloalkyl group as just defined, attached to the parent molecular moiety through an alkyl group as defined above and includes such representative groups as cyclopropylmethyl, cyclopentylethyl, 2-methyl-3-cyclopentylbutyl, cyclohexylmethyl, and the like.
  • the (cycloalkyl)alkyl groups of this invention can be optionally substituted.
  • cycloalkenyl denotes a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbon atoms having at least one carbon-carbon double bond. The cycloalkenyl groups of this invention can be optionally substituted.
  • halo denotes -F, -Cl, -Br or -I.
  • heterocycle denotes any 5-, 6-or 7-membered saturated ring containing from one to three heteroatoms independently selected from the group consisting of 1, 2, or 3 nitrogens, one oxygen and one nitrogen, and one sulfur and one nitrogen; wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized.
  • heterocycle also includes and to 5-, 6-, or 7-membered aromatic rings having in the ring one, two, or three heteroatoms selected from N, O, and S, and also including benzo fused analogs of these 5-, 6-, or 7-membered heterocyclic aromatic rings.
  • heterocycles of this invention include, pyrrolidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl morpholinyl, piperazinyl, thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl, furyl, benzofuryl, thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, thienyl, triazolyl 1,3,4-thiadiazolyl, and tetrazolyl, and the like.
  • heterocycle also includes compounds of formula
  • Y* is selected from the group consisting of -C(O)- and
  • R is selected from the group consisting of hydrogen and alkyl.
  • heterocycle also includes bicyclic or tricyclic rings, wherein any of the aformentioned heteroaryl rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl ring.
  • heteroaryls include benzo[b]furanyl, benzo[b] thienyl, benzimidazolyl, cinnolinyl, imidazo[4,5-c]pyridinyl, quinazolinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3- b]pyridinyl,indolizinyl, and imidazo[l,2-a]pyridine and can be attached to the parent molecular group through either the heretoaryl group or the aryl, cycloalkyl, or cycloalkenyl group to which it is fused.
  • the heterocycle groups of this invention can be optionally substituted.
  • hydroxy denotes -OH.
  • nitro denotes -NO 2 .
  • nitrogen-protecting group denotes groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used nitrogen-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1991)).
  • Common N-protecting groups comprise (a) acyl groups such as formyl, acetyl, propionyl, pivaloyl, tert- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, and 4- nitrobenzoyl, (b) sulfonyl groups such as benzenesulfonyl, and p ⁇ r ⁇ -toluenesulfonyl, (c) carbamate forming groups such as benzyloxycarbonyl, /?
  • Preferred nitrogen-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl, tert- butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • perfluoroalkoxy denotes a perfluoroalkyl group attached to the parent molecular group through an oxygen atom.
  • perfluoroalkyl denotes an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
  • phenyl denotes a radical formed by the removal of one hydrogen atom from a benzene ring.
  • the phenyl groups of this invention can be optionally substituted.
  • prodrug denotes compounds that are rapidly transformed in vivo to yield the parent compounds of formula I, as for example, by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Prodrugs as Novel DeUvery Systems," Vol. 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups may be found on pages 14-21 of Bior ever sible Carriers in Drug Design: Theory and Application, edited by E.B. Roche, Pergamon Press (1987).
  • prodrug ester group denotes any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthahdyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters includes formates, acetates, propionates, butryates, acrylates and ethylsuccinates.
  • sulfhydryl denotes -SH.
  • thiocarbonyl denotes -C(S)-.
  • the compounds of the invention have at least one chiral center designated by the numeral "1."
  • Y is hydrogen
  • the compounds also possess at least one additional chiral center designated by the numeral "2" in the generic formula.
  • preferred compounds of the present invention are those in which the chirality at the site designated "1" is R and the chirality at the site designated "2" is S.
  • the "R” and “S” stereochemical designators follow the convention established by R. S. Cahn, et al, Angewandt Chemie. Int. Ed. Engl.. 5: 385-415 (1966).
  • Diastereomers having the preferred (Site 1)R and (Site 2)S stereochemistry can be synthesized by judicious choice of optically pure starting materials, asymmetric synthesis, or may be separated from mixtures of diastereomers by methods well known in the art as, for example, by reverse phase HPLC techniques.
  • R is -SR where R is lower alkyl, most preferably, methyl or ethyl.
  • Another preferred sub-group of compounds of the invention are compounds of 2 formula I where R is cycloalkyl, preferably cyclohexyl.
  • Another preferred sub-group of compounds of the invention are compounds of
  • Another preferred sub-group of compounds of the present invention is defined by structural formula I above where X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl group, with carbonyl being particularly preferred.
  • a preferred sub-group of compounds of the invention are defined by structural 3 formula I where R is an aminoacyl group derived from a naturally occurring amino acid, where the nitrogen atom at the N-terminus of the aminoacyl group is attached to the immediately adjacent carbonyl group of the parent molecular moiety, and the C-terminus, or carboxyl functionality of the aminoacyl residue is optionally and preferably capped by a carboxyl blocking group.
  • Carboxyl blocking groups are well known to practitioners of the organic chemical arts, and are described in some detail in Chapter 5, pages 224-276 of "Protective Groups in
  • Such carboxyl protecting groups include esters such as substituted methyl esters, substituted ethyl esters, substituted benzyl esters, silyl esters, oxazoles, 2-alkyl-l,3- oxazolines, 4-alkyl-5-oxo- 1 ,3-oxazolidines, 5-alkyl-4-oxo- 1 ,3-dioxalanes, ortho esters, and amides such as N,N-dialkyl amides, pyrrolidinyl amides, piperidinyl amides, 5,6- dihydropiperidinyl amides, o-nitroanilides, and hydrazides such as N-phenylhydrazides and
  • N, N'-dialkylhydrazides N, N'-dialkylhydrazides .
  • Recombinant methionine aminopeptidase-2 (MetAP2) was expressed as a secreted protein with a baculovirus system and purified from the insect cell culture supernatant as previously described by R. L. Kendal, et al, J. Biol. Chem.. 267(29): 20667-20673 (1992) and Xuan Li, et al, Biochem. And Biophvs. Res. Comm.. 227: 152-159 (1996), the contents of which are incorporated herein by reference.
  • Assays for MetAP2 enzyme activity and MetAP2 inhibition were performed in 96- well microtiter plates. Compounds to be tested for MetAP2 inhibition were dissolved in dimethyl-sulfoxide at 10 mM and diluted ten-fold in assay buffer (50 nM ⁇ EPES, p ⁇ 7.4, 100 mM ⁇ aCl). Ten microliters of solution of each compound to be tested for inhibition were introduced into each cell of the plate, with each compound being tested in triphcate. Zero inhibition of enzyme activity was taken to be the result obtained in cells in which 10 mL of assay buffer was placed, and 100 percent inhibition of enzyme activity was taken to be the result obtained in cells in which 10 mM of fumagillin (Sigma Chemical Co., St. Louis, MO, USA, Catalog No. F-6771) in assay buffer was placed.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • 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.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, 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, dimethylformamide, 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 agents, sweetening, flavoring, and perfuming agents.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • 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 prior to use.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • 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.
  • 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 ambient 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 ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • 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, polyvinylpyrrolidinone, 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 glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • the dosage form may also comprise buffering agents.
  • Solid 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.
  • 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.
  • embedding compositions which can be used include polymeric substances and waxes. Solid 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 glycol
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. 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.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, 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.
  • 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.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluoro-hydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • disorders caused by undesirable angiogenesis are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the invention is meant a sufficient amount of the compound to inhibit angiogenesis, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • a well-known technique utilized by medical practitioners is to "dose titrate" the patient; that is, to start with dose lower than that required to obtain the desired effect, and to gradually increase the dose until the dseired therapeutic benefit is obtained.
  • the total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.11 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 1 mg to about 500 mg of the compound(s) of this invention per day in single or multiple doses.
  • 3-amino-2-hydroxy-carboxylic acids used as starting materials for the synthesis of compounds of the present invention are available from appropriately substituted alpha-aminoacids by conversion to the corresponding aminoaldehyde, formation of the corresponding cyanohydrin, and hydrolysis. Protection of the free amino group, for example with a tert-butyl carbamate group, followed by couphng with an appropriate amine, amino acid derivative, or alcohol and deprotection provides the target compounds.
  • the coupling partners may be purchased from commercial sources or prepared using known chemical transformations. Subsequent conversion of the 3-amino-2- hydroxy compounds to compounds of the present invention are by standard methods well known to practitioners of the organic chemical arts and are illustrated by the Examples which appear below.
  • Example 1A A solution of N-(tert-butoxycarbonyl)-L-methionine (12.47 g, 50 mmol) and RED-
  • Example IB A solution of the product of example 1 A (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, then treated sequentially with water (20 mL) and saturated aqueous KHSO4 (120 mL), and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO4 and brine, dried (MgSO4), and concentrated to give a colorless syrup (9.00 g).
  • Example ID A solution of the product of example IC (5.81 g, 32.4 mmol), BOC-ON (9.58 g,
  • Example IE A solution of example ID (2.79 g, 10 mmol), L-alanine ethylester hydrochloride
  • Example IF A solution of the product of example IE (0.40 g, 1.1 mmol), in hydrogen chloride saturated dioxane (8 mL) was stirred at ambient temperature for 1 hour, evaporated to dryness, suspended in ethyl ether then concentrated and vacuum dried to give the title compound (0.24 g).
  • Example 2 (2RS.3S.l'S)-N-(fl-Ethylcarboxamido)ethyl)-3-amino-2-hvdroxy-5- (methylthio)pentanamide hvdrochloride
  • the product of example ID and alanine ethylamide were processed as in examples
  • Example 3A N-(tert-butoxycarbonyl)-D-methionine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-(methylthio)pentanoic acid.
  • Example 3B The product of example 3 A and L-alanine ethylamide were processed as in example 2 to provide the title compound.
  • MS (ESI+Q1MS) m/e 278 (M+H) + , 300 (M+Na)+;
  • Example 12 A N-(tert-butoxycarbonyl)-D-ethionine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-(ethylthio)pentanoic acid.
  • Example 12B The product of example 12 A and L-alanine ethylester hydrochloride were processed as in example 2 to provide the title compound.
  • Example 16 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride
  • MS (ESI+Q1MS) m/e 307 (M+H) + 325 (M+Na) + ; *H NMR (300 MHz, DMSO-d 6 ) ⁇ 4.46 (d.
  • Example 17 (2RS.3R.1 'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hvdroxy-heptanamide hydrochloride
  • Example 17A N-(tert-butoxycarbonyl)-D-norleucine was processed as in examples .1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-heptanoic acid.
  • Example 18 (2RS,3R)-3-amino-2-hvdroxy-5-(methylthio)pentanoic acid N-(tert-butoxycarbonyl)-D-methionine was processed as in examples 1 A through IC to provide (2RS,3R) 3-amino-2-hydroxy-5-(methylthio)pentanoic acid.
  • MS (APCI) m e 180 (M+H) + ;
  • Example 20A N-(tert-Butoxycarbonyl)-D-phenylalanine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoic acid.
  • Example 20B The product of example 20A and ethyl 3-amino-propionate were processed as in example 2 to provide the title compound.
  • MS (ESI+Q1MS) m/e 295 (M+H) + , 317 (M+Na) + l H NMR (300 MHz, MeOH-d 4 ) ⁇ 1.19-1.26 (m, 3H), 2.49-2.58 (m, 2H), 2.80-3.10 (m, 2H), 3.41-3.53 (m, 2H), 3.78-3.85 (m, IH), 4.03 (d, 0.6H), 4.07-4.16 (m, 2H), 4.27 (d, 0.4H), 7.25-7.40 (m, 5H); 3.10-3.19 (m, IH), 4.02 (d, IH), 4.29 (m, IH), 7.10-7.27 (m, 5H).
  • Example 21 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hvdroxy-4-phenyl-butanamide hydrochloride
  • the product of example 20A and ethyl 4-amino-butyrate were processed as in example 2 to provide the title compound.
  • Example 22 (2RS.3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide hydrochloride
  • the product of example 20A and 4-phenylbutylamine were processed as in example
  • N-(tert-Butoxycarbonyl)-D-cyclohexylalanine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl- butanoic acid.
  • Example 25 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cvclohexyl-butanamide hydrochloride
  • the product of example 23 A and ethyl 4-amino-butyrate were processed as in example 2 to provide the title compound.
  • MS (ESI+Q1MS) m/e 335 (M+Na-H) + ; l U NMR (300 MHz, MeOH-d 4 ) ⁇ 0.82-1.88 (m, 18H, includes 1.25,t, 3H), 2.34-2.39 (m,
  • example 20A The product of example 20A and L-alanine ethyl ester hydrochloride were processed as in example IE to provide the title compound.
  • Example 27 (2RS.3R)-3-amino-2-hvdroxy-N-(4-methoxyphenethyl)-5-(methylsulfanyl)pentanamide hydrochloride
  • the product of example 23 A and l-amino-2-(4-methoxyphenyl)ethane were processed as in example 2 to provide the title compound.
  • Example 31 (2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride
  • the product of example 13 and methyl chloroformate were reacted in tetrahydrofuran in the presence of triethylamine and purified on silica gel column chromatography, eluting with 0.5-0.75 % methanol in chloroform to provide the title compound.
  • Example 32 (2RS.3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide
  • the product of example 3A and l-amino-2-(3-pyridyl)ethane were processed as in example 2 to provide the title compound.
  • Example 38 (2RS.3R)-N-((phenylbutyryl)-3-formylamino-2-hvdroxy-4-ethylthio)pentanamide
  • the product of example 13 and formic acid-acetic anhydride in methylene chloride in the presence of triethylamine were processed as in example IE, and purified by silica gel, eluting with 2% methanol in chloroform to provide the title compound.
  • MS (ESI+Q1MS) m e 353 (M+ H) + , 375 (M+ Na) + , 727 (2M+ Na) +
  • Example 39 (2RS.3RVN-Methyl-N-( ⁇ ethoxycarbonylmemyl)-3-amino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride
  • the product of example 12 A and sarcosine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • Example 42 (2RS.3R.rR)-N-((l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4-cvcIohexyl)butanamide hydrochloride
  • the product of example 23 A and D-alanine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 301 (M+ H) + , lH NMR (300 MHz, MeOH-d 4 ) ⁇ 4.54-4.42 (m, IH), 4.28-4.16 (m, 2H), 3.76-3.57 (m, 2H), 1.82-0.83 (m, 19H ).
  • Example 43 (2RS.3R)-N-((l-methyl-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cvclohexyDbutanamide hydrochloride
  • the product of example 23A and alpha aminoisobutyric acid ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • Example 44 (2RS.3R)-N-((Phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4- ethylthio)pentanamide hydrochloride
  • the product of example 13 and methyl bromoacetate were reacted in dimethylsulfoxide in the presence of sodium hydride and processed as in example IE to provide the title compound.
  • Example 45A N-(tert-Butoxycarbonyl)-S-benzyl-D-cysteine was processed as in Example 1 A through IB to prepare N-(tert-butoxycarbonyl)-S-benzyl-D-cysteinal.
  • Example 45C The product of example 45B (3.40g) was dissolved in 50 mL of methanol in an ice bath and hydrogen chloride gas was bubbled through the reaction mixture until saturated. It was then stirred at 0 °C for 3 hours and at room temperature for one over night. Solvent was evaporated dryness and 20 mL of water was added to the residue. 10%-Sodium hydrogen carbonate was added to the mixture to adjust pH over 9, an oil was extracted with ethyl acetate (50 mLx2). The combined ethyl acetate layer was washed with 10%- sodium hydrogen carbonate (2X), brine (3X), quickly dried over sodium sulfate anhydrous. Ethyl acetate was removed by evaporation to yield 1.77g of dark brown oil.
  • Example 45D The product of example 45C was treated with lN-lithium hydroxide in methanol- water to provide its free carboxylic acid derivatives and coupled with L-alanine ethyl ester as in example IE and deprotection was carried out according to the method described in example IF to provide the title compound.
  • Example 46 (2RS.3R.rS)-N-((2-hvdroxy-l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4- cyclohexyDbutanamide hydrochloride
  • the product of example 23 A and L-serine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 317 (M+ H) + , 633 (2M+ H) + , *H NMR (300 MHz, MeOH-d 4 ) ⁇ 4.45-4.55 (m, IH), 4.26-4.18 (m, 3H), 4.00-3.87 (m,
  • N-(tert-Butoxycarbonyl)-L-alaninol (438 mg, 2.5mmol) was dissolved in 5 mL of methylene chloride in an ice bath and acetyl chloride (0.294 mL, 3.75 mmol), followed by triethylamine (0.7mL, 5 mmol) were added. It was then reacted at 0 °C for 1 hour and at room temperature for 2 days.
  • Example 47B The product of example 47 A (380 mg) was processed as in example IF to yield
  • Example 51 (2RS.3R.2'R)- ⁇ -((2-propionyloxypropyl)-3-amino-2-hvdroxy-4-cvcIohexyl)butanamide hydrochloride
  • N-(tert-butoxycarbonyl)-L- alaninol N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-D-alaninol.
  • Example 53 f2RS.3R.rS)-N-((l-benzyloxycarbonylethyl)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide hydrochloride
  • the product of example 23 A and L-alanine benzyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 363 (M+ H) + , 725 (2M+ H) + , !H NMR (300 MHz, MeOH-d 4 ) ⁇ 7.38-7.32 (m, 5H), 5.21-5.17 (m, 2H), 4.57-4.48 (m,
  • Example 54A N-(tert-Butoxycarbonyl)-L-alanine amide (3.76g, 20 mmol) was suspended in 70 mL of methylene chloride in an ice bath and triethyloxonium hexafluorophosphate (4.97g, 20 mmol) was added. It was stirred at 0 oC for 30 minutes and at room temperature for one over night. Methylene chloride layer was washed with water (2x), 10%-sodium hydrogen carbonate (2x), water (2x), dried over sodium sulfate anhydrous. It was then evaporated to dryness, dried under high vaccum to yiels 2.72 g of iminoether. MS (ESI+Q1MS) m/e 217 (M+ H) + , 433 (2M+ H) + , 455 (2M+ ⁇ a) +
  • Example 54B The product of example 54A (2.72g, 12.6 mmol) was dissolved in 40 mL of ethanol and L-cysteine ethyl ester hydrochloride (2.57g, 13.86 mmol) was added. It was stirred at room temperature for 2 days. Ethanol was removed by evaporation, and the residue was dsirectiy purified by silica gel column chromatography, eluting with 30% ethyl acetate in hexane to yield 2.91 g of pure thizoline analogue. MS (ESI+Q1MS) m e 303 (M+ H) + , 325 (M+ Na) + ,
  • Example 54C To the product of example 54B (604mg, 2 mmol) in a 50 mL of round bottle flask were addwd copper (I) bromide (316 mg, 1.1 mmol) and copper (II) acetate anhydrous (0.40g, 2.2 mmol). The flask was evacuated with argon repeatedly and 15 mL of benzene was added via syringe. While stirring at 60 °C, tert-butyl perbenzoate was carefully added in a period of 15 minutes, and gently refluxed for 4 hours.
  • the crude product was directly purified by silica gel column chromatography, eluting eith 30 % ethyl acetate in hexane to yield 390 mg of pure thiazole derivative.
  • the obtained product (320 mg ) was treated according to the method as in example IF and coupled with the product of example 23 A as in example IE to give N-(tert-butoxycarbonyl) derivative of the title compound (220 mg).
  • Example 54D The product of example 54C (60 mg) was processed as in example IF to yield the title compound.
  • Example 55 (2RS.3R) N-(monodansylcadaveno)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide dihydrochloride
  • the product of example 23A and monodansyl cadaverive were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 519 (M+ H) + ; !H NMR (300 MHz, MeOH-d 4 ) ⁇ 8.90 (d, IH), 8.58 (d, IH), 8.36 (d, IH), 8.06 (d, IH),
  • Example 57 (2RS.3R) N-(5-nitropyridyl-2-aminoethyl) 3-amino-2-hydroxy-4-cvclohexy butanamide dihydrochloride
  • the product of example 23A and 2-(2-aminoethylamino)-5-nitro-pyridine were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 366 (M+ H) + , 731 (2M+ H) + ;
  • Example 61 A The product of example 23 A and L-alanine benzyl ester hydrochloride were processed as in example IE to yield N-(tert-butoxycarbonyl) drivative (3.80 g), which was hydrogenated in 50 mL of ethanol in the presence of 0.3g of 10% palladium on charcoal as a catalyst for 3.5 hours. The mixture was passed through celite 545 and evaporated to dryness to yield (2RS,3R) N-[(3-tert-butoxycarbonylamino-2-hydroxy-4- cyclohexyl)butanoyl-L-alanine (3.16g)
  • Example 6 IB The product of example 61 A and l-(2-aminoethyl)-2-methyl-5-nitro imidazole were processed as in examples IE and IF to yield the title compound.
  • MS (ESI+Q1MS) m/e 425 (M+ H) + , 849 (2M+ H) + , !H ⁇ MR (300 MHz, MeOH-d 4 ) ⁇ 8.58, 8.56 (both s, total IH), 4.73-4.57 (m, 2H), 4.26-
  • Example 62 ((2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- nitropyridylaminoethvDamide dihydrochloride
  • the product of example 61 A and 2-(2-aminoethylamino)-5-nitro-pyridine were processed as in examples IE and IF to yield the title compound.
  • MS (ESI+Q1MS) m/e 437 (M+ H) + , 873 (2M+ H) + , 1H ⁇ MR (300 MHz, MeOH-d 4 ) ⁇ 8.94-8.37 (br. m, IH), 7.92-7.75 (m, IH), 7.62-7.50
  • Example 65 ((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(5- methoxytrvptamine)amide hydrochloride
  • the product of example 61 A and 5-methoxy tryptamine were processed as in examples IE and IF to yield the title compound.
  • Example 66 (Y2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(3-O- methoxydopamine)amide hydrochloride
  • the product of example 61 A and 3-O-methoxydopamine hydrochloride were processed as in examples IE and IF to yield the title compound.
  • Example 67 (( " 2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(2- benzimidazolemethvDamide hydrochloride
  • the product of example 61 A and 2-(aminomethyl)benzimidazole dihydrochloride monohydrate were processed as in examples IE and IF to yield the title compound.
  • Example 72 f(2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoylL-alanyl-(l-ethylpyrazole)amide hydrochloride
  • the product of example 61 A and 5-amino-l-ethylpyrazole were processed as in examples IE and IF to yield the title compound.
  • Example 73 ((2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide hydrochloride
  • the product of example 23 A and ethyl isonipecotate were processed as in examples IE and IF to yield the title compound.
  • MS (ESI+Q1MS) m/e 341 (M+ H) + , l H NMR (300 MHz, MeOH-d 4 ) ⁇ 4.14 (q, 2H), 3.73-3.48 (m, 2H), 0.83-1.93 (m, 20H).
  • Example 75 (2RS.3R)- 3-amino-2-hvdroxy-4-cyclohexyl)hutanoyl-(4-carboxyl-2-( 1 'amino)ethyl thizole hydrochloride
  • the product of example 54C (0.2g, 0.414 mmol) was treated with lN-lithium hydroxide (0.5 mL, 0.5 mmol) in methanol for 3 hours. 8 mL of water was added to the mixture, and methanol was removed by evaporation. The aqueous layer was washed with ethyl acetate, and acidified by an addition of 10 % potassium hydrogen sulfate.
  • Example 79 (2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)but ⁇ noyl-monodansylcadaverine amide dihydrochloride
  • the product of example 12 A and monodansyl cadaverine were processed as in examples IE and IF to yield the title compound.
  • Example 80A Following example 77, the product of example 23 A and N-benzyloxycarbonyl-1,4- diaminobutane hydrochloride were coupled as in examples IE to yield the both protected compound.
  • the product (260 mg) was hydrogenated in 10 mL of ethanol in the presence of 30 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same method described in Example 61A to yield 200 mg.
  • Example 80B The product of example 80A (92.8 mg, 0.25 mmol) was dissolved in 5 mL of methylene chloride in an ice bath, and diisopropylethylamine (0.048 mL, 0.275 mmol) and p-toluenesulfonyl chloride (47.7 mg, 0.25 mmol) were added. It was reacted at 0 °C for 3 hours and at room temperature for over night. Methylene chloride was removed and the residue was purified by silica gel column chromatography, eluting with 15-30% acetone in hexane. The obtained product was processed as in example IF to yield the title compound
  • Example 81 A Following example 77, the product of example 23 A and benzyl N-(2- aminoethyl)carbamate hydrochloride were coupled as in example IE to yield the protected compound. The product (220 mg) was hydrogenated in 10 mL of ethanol in the presence of 20 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same method described in example 61 A to yield 130 mg. MS (ESI+Q1MS) m/e 344 (M+ H) +
  • Example 8 IB The product of example 81 A (42.8 mg, 0.125 mmol) and p-toluenesulfonyl chloride (23.8 mg, 0.125 mmol) were processed as in example 80B to yield the title compound (20 mg). MS (ESI+Q1MS) m/e 426 (M+ H) ⁇ 448 (M+Na) + , 533 (M+ Na) + ;
  • Example 83 (2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-(2-aminoethyl)amide dihydrochloride
  • the product of example 81 A (60 mg) was processed as in example IF to yield the title compound (45 mg).
  • Example 84 (2RS.3R)-3-amino-4-cvclohexyI-2-hvdroxy-N-(4-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide hydrochloride
  • the product of example 81 A and m-(trifluoromethyl)benzenesulfonyl chloride were processed as in example 80B to yield the title compound.
  • Example 86 (2RS.3R)-N-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4-cvclohexyl-2- hydroxybutanamide hydrochloride
  • the product of example 81 A and 4-acetamidobenzenesulfonyl chloride were processed as in example 80B to yield the title compound.
  • MS (APCI) m/e 469 (M+ H) + ; !H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.72 (m, 4H), 7.41 (m, IH), 5.93 (d, IH), 3.79 (m,
  • Example 87 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-(T2- naphthylsulfonyl amino)butyl)butanamide hydrochloride
  • the product of example 81 A and 2-naphthylsulfonyl chloride were processed as in example 80B to yield the title compound.
  • Example 89 (2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine benzyl ester hydrochloride
  • the product of example 23A and amino isobutyric acid benzyl ester were processed as in examples IE and IF to yield the title compound.
  • Example 90A N-(tert-Butoxycarbonyl)-L-alanine (0.945g, 5 mmol) was dissolved in 10 mL of methanol and 2 mL of water was added, and pH was then adjusted to 7.0 by an addition of 20% cesium carbonate. The mixture was eveporated to dryness, re-evaporated twice from 5 mL of N,N-dimethylformamide, and suspended into 10 mL of N,N-dimethylformamide. Cyclohexyl bromide (0.677 mL, 5.5 mmol) was added and stirred at room temperature for over night.
  • Example 90B The product of example 23A and the product of example 90A were processed as in examples IE and IF to yield the title compound.
  • Example 97 (2RS.3R)-3-amino-4-cvclohexyl-N-(2,4-dichlorobenzyl)-2-hvdroxybutanamide hydrochloride
  • the product of example 23A and 2,4-dichlorobenzylamine were processed as in example 101 to provide the title compound.
  • Example 101 f2RS.3R.rRSV3-amino-4-cvclohexyl-2-hvdroxy-N-(l-( , l-naphthyl)ethyl)hutanamide hydrochloride
  • the product of example 23 A (2.4g, 8.64mmol) was dissolved in N,N- dimethylacetamide to give 48ml (solution A).
  • l-Hydroxy-7-azabenzotriazole (HOAT- 1.92g, 13.2mmol), O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU-4.8g, 13.4mmol), and disopropylethylamine (2.4ml, 13.4mmol) were dissolved in N,N-dimethylacetamide to make 48ml (solution B).
  • Solution A was distributed equally into 48 individual reactors.
  • Solution B was then added to these same reactors in equal portions. The reactors were shaken lOmin at room temperature.
  • Example 102 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-(2-oxo-l-pyrrolidinyl)propyl)butanamide hydrochloride
  • the product of example 23A and l-(3-aminopropyl)-2-pyrrolidone were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 326 (M+ H) + , 651 (2M+ H) + ; *H NMR (300 MHz, MeOH-d 4 ) ⁇ 4.24 (d, 0.4H), 4.15 (d, 0.6H), 3.54-3.41 (m, 2H),
  • Example 103 (2RS .3R)-3-amino-4-cyclohexyl-N-( 1.2-dimethylpropyl)-2-hydroxybutanamide hydrochloride
  • the product of example 23 A and 1,2-dimethylpropylamine were processed as in example 101 to provide the title compound.
  • MS (ESI+Q1MS) m/e 271 (M+H) + , 293 (M+Na) +
  • Example 106 A The product of example 20A and L-alanine benzyl ester were processed as in examples IE to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4- cyclohexyl)butanoyl-L-alanine benzyl ester.
  • 0.5g of the above product was hydrogenated in 20 mL of isopropyl alcohol in the presence of 20 mg of 10%-palladium on charcoal to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine (0.4g).
  • Example 109 (2RS,3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(3-phenylpropyl)butanamide hydrochloride
  • the product of example 23 A and 3-phenyl-l-propylamine were processed as in example 101 to provide the title compound.
  • Example 111 2.81 (m, 2H), 2.05 (m, IH), 0.90-1.90 (m, 16H).
  • Example 114 butyl (2RS.3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)acetate hydrochloride
  • the product of example 23A and glycine n-butyl ester were processed as in example 101 to provide the title compound.
  • MS (APCI) m e 315 (M+H) + 1H NMR (300MHz, MeOH-d 4 ) ⁇ 4.16 (m, 2H), 4.02 (m, IH), 3.50 (m, IH), 0.90-1.85 (m,
  • Example 116 (2RS.3R)-3-amino-4-cvcIohexyl-N-(2.4-dimethoxyphenyl)-2-hydroxybutanamide hydrochloride
  • the product of example 23A and 2, 4-dimethoxy aniline were processed as in example 101 to provide the title compound.
  • Example 120 (2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hvdroxybutanamide hydrochloride
  • the product of example 23 A and 2-fluorobenzylamine were processed as in example 101 to provide the title compound.
  • MS (APCI) m/e 309 (M+H) + , 616 (2M+H) + 1H NMR (300MHz, MeOH-d 4 ) ⁇ 7.32 (m, 2H), 7.11 (m, 2H), 4.5 (q, 2H), 4.14 (d, IH),
  • Example 121 (2RS.3R)-3-amino-4-cvclohexyl-N-( , 4-fluoro-3-(trifluoromethyl)benzyl)-2- hydroxybutanamide hydrochloride
  • the product of example 23A and 3-(trifluoromethyl)-4-fluorobenzylamine were processed as in example 101 to provide the title compound.
  • Example 123 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(tetrahvdro-2-furanylmethyl)butanamide hydrochloride
  • the product of example 23 A and tetrahydrofurfurylamine were processed as in example 101 to provide the title compound.
  • Example 126 tert-butyl (2RS,3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)acetate hydrochloride
  • the product of example 23A and glycine tert-butyl ester were processed as in example 101 to provide the title compound.
  • Example 130 methyl (2RS.3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-3-methylbutanoate hydrochloride
  • the product of example 23A and L-valine methyl ester were processed as in example 101 to provide the title compound.
  • the product of example 23 A and (S)-l -amino- l-(2-naphthyl)ethane were processed as in example 24 to provide the title compound.
  • Example 132 (2RS.3R)-3-amino-4-cvclohexyI-2-hvdroxy-N-(Y 1 R)- 1 -(2-naphthyl)ethyl)butanamide hydrochloride
  • the product of example 23A and (R)-l-amino-l-(2-na ⁇ hthyl)ethane were processed as in example 24 to provide the title compound.
  • Example 133 (2RS.3R -3-amino-4-cvclohexyl-2-hvdroxy-N-f(lS)-l-(l-naphthvDethyl)butanamide hydrochloride
  • the product of example 23A and (S)-l-amino-l-(l-naphthyl)ethane were processed as in example 24 to provide the title compound.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Indole Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Furan Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrrole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une catégorie de β-amino-acides substitués, lesquels constituent des inhibiteurs puissants de la méthionine aminopeptidase de type 2 (MetAP2) et sont donc utiles pour inhiber l'angiogénie et des pathologies qui dépendent de l'angiogénie pour leur développement, comme la rétinopathie diabétique, la croissance tumorale et des états inflammatoires. L'invention concerne également des préparations pharmaceutiques contenant ces composés, ainsi que des procédés d'inhibition de la méthionine aminopeptidase-2 et de l'angiogénie.
EP99921611A 1998-05-01 1999-04-30 INHIBITEURS $g(b)-AMINO-ACIDE SUBSTITUES DE LA METHIONINE AMINOPEPTIDASE-2 Withdrawn EP1073633A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7171498A 1998-05-01 1998-05-01
US71714 1998-05-01
PCT/US1999/009641 WO1999057098A2 (fr) 1998-05-01 1999-04-30 INHIBITEURS β-AMINO-ACIDE SUBSTITUES DE LA METHIONINE AMINOPEPTIDASE-2

Publications (1)

Publication Number Publication Date
EP1073633A2 true EP1073633A2 (fr) 2001-02-07

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Application Number Title Priority Date Filing Date
EP99921611A Withdrawn EP1073633A2 (fr) 1998-05-01 1999-04-30 INHIBITEURS $g(b)-AMINO-ACIDE SUBSTITUES DE LA METHIONINE AMINOPEPTIDASE-2

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Country Link
EP (1) EP1073633A2 (fr)
JP (1) JP2002513781A (fr)
KR (1) KR20010043198A (fr)
CN (1) CN1308608A (fr)
AU (1) AU3877899A (fr)
CA (1) CA2329704A1 (fr)
CO (1) CO5021134A1 (fr)
IL (1) IL139139A0 (fr)
PL (1) PL346444A1 (fr)

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CN100357283C (zh) * 2002-04-02 2007-12-26 中国科学院上海药物研究所 一类甲硫氨酰氨肽酶抑制剂
EP1551815A1 (fr) * 2002-10-09 2005-07-13 Pfizer Products Inc. Composes thiazole utiles pour le traitement des maladies neurodegeneratives
JP2006516573A (ja) * 2003-01-31 2006-07-06 メルク　エンド　カムパニー　インコーポレーテッド 糖尿病の治療および予防のためのジペプチジルペプチダーゼ阻害薬としての３−アミノ−４−フェニルブタン酸誘導体
FR2858617A1 (fr) * 2003-08-06 2005-02-11 Inst Nat Sante Rech Med Derives de 4',4'-dithiobis-(3-aminobutane-1-sulfonate-1- sulfonates) nouveaux et compositions les contenant
CN102241678B (zh) * 2011-04-26 2014-10-29 辽宁利锋科技开发有限公司 含有脂环结构化合物的抗肿瘤作用与应用
CN104230935A (zh) * 2011-04-26 2014-12-24 辽宁利锋科技开发有限公司 含有脂环结构化合物的抗肿瘤作用与应用
CA3239447A1 (fr) * 2016-01-11 2017-07-20 Syndevrx, Inc. Traitement de tumeurs induites par un dysfonctionnement metabolique
CN115124449B (zh) * 2022-05-24 2024-02-02 上海英诺富成生物科技有限公司 一种吲哚化合物及制备方法与应用

Non-Patent Citations (1)

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Title
See references of WO9957098A2 *

Also Published As

Publication number Publication date
JP2002513781A (ja) 2002-05-14
IL139139A0 (en) 2001-11-25
PL346444A1 (en) 2002-02-11
KR20010043198A (ko) 2001-05-25
CA2329704A1 (fr) 1999-11-11
CO5021134A1 (es) 2001-03-27
AU3877899A (en) 1999-11-23
CN1308608A (zh) 2001-08-15

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