WO2019169011A1 - Mimétiques d'oligopeptides chimiothérapeutiques - Google Patents

Mimétiques d'oligopeptides chimiothérapeutiques Download PDF

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WO2019169011A1
WO2019169011A1 PCT/US2019/019868 US2019019868W WO2019169011A1 WO 2019169011 A1 WO2019169011 A1 WO 2019169011A1 US 2019019868 W US2019019868 W US 2019019868W WO 2019169011 A1 WO2019169011 A1 WO 2019169011A1
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substituted
alkyl
amino
group
optionally substituted
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Gerald F. SWISS
Mansour Bassiri
Richard D. Gless
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Bioxiness Pharmaceuticals Inc
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Bioxiness Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic

Definitions

  • This invention is directed to oligopeptides containing one or more amino acid mimetics.
  • the amino acid mimetics employed with said oligopeptides possess
  • chemotherapeutic properties against cancer cells as well as antibacterial properties for those cancer cells that harbor intracellular bacteria.
  • These mimetics are coupled to one or more optionally substituted amino acids preferably containting one or more amino acids selected from the group consisting of optionally substituted phenylglycine, histidine, tryptophan, phenylalanine or tyrosine. Accordingly, disclosed are compounds, compositions and methods for treating a cancer in a mammal as well as prodrugs for such compounds.
  • This invention is based, in part, on the discovery amino acid mimetics, particularly those incorporated into oligopeptides are absorbed preferentially by cancer cells through their amino acid transporters. Once internalized, these oligopeptides are converted to their corresponding single amino acid(s) and the amino acid mimetic by, for example, enzymatic processes. The mimetic then binds with high specificity to the tRNA AA synthesase thereby inhibiting the natural amino acid from being incorporated into the protein being synthesized by the cancer cell. Such inhibition leads to cell death. In addition, any bacterial population found within the cancer cells will likewise absorb such mimetics that will lead to bacterial death.
  • this invention provides for a method for treating cancer in a patient which method comprises administering one or more oligopeptide mimetics to said patient wherein each oligopeptide mimetic has from 1 to 8 optionally substituted amino acids and a C-terminal amino acid mimetic of formula I:
  • R is selected from hydrogen, optionally substituted aryl, or optionally substituted Ci-C 6 alkyl wherein said optional substitution is with from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, C 1 -C 4 alkylamino, di(Ci-C alkyl)amino, cyano, halo, Ci-C haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci-C 4 thioalkyl, amidino, amido, carboxyl, Ci-C 4 alkoxy, C 3 -C 7 cycloalkyl, oxo, and C 4 -C 4 alkyl-Ci-C 4 alkoxy;
  • R 1 is hydrogen or together with R forms an optionally substituted pyrrolidinyl ring wherein said optional substitution is with from 1 to 3 substituents selected from the group consisting of C 4 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci- C 4 alkylamino, di(Ci-C 4 alkyl)amino, cyano, halo, C 4 -C 4 haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci-C thioalkyl, amidino, amido, carboxyl, Ci-C alkoxy, C 3 -C 7 cycloalkyl, oxo, and Ci-C alkyl-Ci-C alkoxy; and
  • (L) indicates an L isomer at that stereochemical center
  • this invention provides for a method for treating cancer in a patient which method comprises administering one or more oligopeptide mimetics to said patient wherein each oligopeptide mimetic has from 1 to 9 optionally substituted amino acids and a C-terminal amino acid mimetic of formula II:
  • Ar is an optionally substituted phenyl, napthyl, imidazolyl or indolyl group
  • t is zero or one
  • said optional substitution on said phenyl, napthyl, imidazolyl, or indolyl groups is from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, C 1 -C 4 alkylamino, di(Ci-C alkyl)amino, cyano, halo, Ci-C haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, C 4 -C 4 thioalkyl, amidino, amido, carboxyl, C 4 -C 4 alkoxy, C 3 - C 7 cycloalkyl, oxo, and C 4 -C 4 alkyl-Ci-C 4 alkoxy; and
  • (L) indicates an L isomer at that stereochemical center
  • this invention provides for a method for treating cancer in a patient which method comprises administering one or more oligopeptide mimetics to said patient wherein each oligopeptide mimetic has from 1 to 9 optionally substituted amino acids and a C-terminal amino acid mimetic of formula III:
  • n and p are independently 0 or 1;
  • X, Y and Z are each independently an L-isomer of an optionally substituted amino acid provided that at least one of X, Y and Z is an optionally substituted aromatic amino acid selected from the group consisting of optionally substituted phenylglycine, optionally substituted phenylalanine, optionally substituted tyrosine, optionally substituted histidine, and optionally substituted tryptophan;
  • said optional substitution on said amino acids is from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci-C 4 alkylamino, di(Ci-C 4 alkyl)amino, cyano, halo, C 4 -C 4 haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci- C thioalkyl, amidino, amido, carboxyl, Ci-C alkoxy, C 3 -C 7 cycloalkyl, oxo, and Ci-C alkyl-Ci-C 4 alkoxy;
  • (L) indicates an L isomer at that stereochemical center
  • this invention provides for a method for treating cancer in a patient which method comprises administering one or more oligopeptide mimetics to said patient wherein each oligopeptide mimetic has from 1 to 9 optionally substituted amino acids and a C-terminal amino acid mimetic of formula IV:
  • R 10 , R 11 , and R 12 are independently an optionally substituted side chain of a non proline amino acid
  • any one of R 10 and R 1 , R 11 and R 2 and/or R 12 and R 3 forms an optionally substituted pyrrolidinyl group
  • Ar is optionally substituted phenyl, optionally substituted histidyl, or optionally substituted indolyl;
  • t is 0 or 1; and y and z are independently 0, 1, 2, 3, 4, 5, 6 or 7 provided that the total of plus z is no greater than 8;
  • said optional substitution on said amino acids is from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci-C 4 alkylamino, di(Ci-C 4 alkyl)amino, cyano, halo, C 4 -C 4 haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci- C thioalkyl, amidino, amido, carboxyl, Ci-C alkoxy, C 3 -C 7 cycloalkyl, oxo, and Ci-C alkyl-Ci-C 4 alkoxy;
  • R is selected from the group consisting of hydrogen, phenyl, (R 20 ) a -phenyl, Ci-C 6 alkyl, and (R 21 ) t ,-(Ci-C 6 alkyl) where R 20 is selected from the group consisting of hydroxyl, Ci-C alkyl, Ci-C alkoxy, halo, thiol, amino, nitro, cyano, and carboxy;
  • R 21 is selected from the group consisting of hydroxyl, C 4 -C 4 alkyl, C 4 -C 4 alkoxy, halo, thiol, amino, amido, nitro, cyano, carboxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, guanidino, substituted guanidino, and Ci-C alkylthiol; and
  • a and b are integers of from 1 to 3.
  • the cancer cells so treated by the methods of this invention also contain intracellular bacteria that are likewise killed by the compounds described herein.
  • Representative compounds for use in the methods of this invention include the following as provided in Table I below as well as their salts and/or solvates:
  • This invention provides for compounds and methods for killing prokaryotic cells and, in particular, pathogenic bacterial cells.
  • prokaryotic cells and, in particular, pathogenic bacterial cells.
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • Compounds comprising radioisotopes such as tritium, C 14 , P 32 and S 35 are thus within the scope of this invention. Procedures for inserting such labels into the compounds of this invention will be readily apparent to those skilled in the art based on the disclosure herein.
  • oligomeric refers to peptides having from 1-8 amino acids inclusive of the methionine mimetic of Formula I. In one embodiment, the oligomeric peptides are from 2 to 4 amino acids inclusive of the methionine mimetic of Formula I. In one preferred embodiment, the amino acids in the oligopeptide do not include methionine.
  • amino acid refers to L-amino acids inclusive of all natural amino acids including 4-hydroxyproline, 5-hydroxylysine, and phenyl glycine.
  • Aromatic amino acids include phenylglycine, tryptophan, tyrosine, phenylalanine and the like.
  • substituted amino acids preferably refers to L-amino acids having 1 to 3 substituents on the amino acid side chain which substituents are selected from the group consisting hydroxyl, oxo, nitro, acyl, acylamino, aryl, substituted aryl, amino, C 1 -C 4 alkylamino, di(Ci-C 4 alkyl)amino, cyano, halo, Ci-C haloalkyl, heteroaryl, substi-tuted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci-C thioalkyl, sulfonyl, amidino, amido, carboxyl, Ci-C alkoxy, C 3 -C 7 cycloalkyl, and Ci-C alkyl-Ci-C alkoxy.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 4 carbon atoms and preferably 1 to 2 carbon atoms. This term includes, by way of example, linear and branched alkyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), «-butyl (CH 3 CH 2 CH 2 CH 2 -), /.so -butyl
  • Substituted alkyl refers to an alkyl group substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci-C alkylamino, di(Ci-C alkyl)amino, cyano, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci-C thioalkyl, amidino, amido, carboxyl, Ci-C 4 alkoxy, oxo, and C 3 -C 7 cycloalkyl.
  • the substituted alkyl is a Ci-C 4 haloalkyl having from 1 to 3 halo groups.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, t-butoxy, sec-butoxy and the like.
  • Substituted alkoxy refers to the group -O-substituted alkyl wherein substituted alkyl is defined herein.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)- aryl-C(O)-, substituted aiyl-C(O)-, heteroaiyl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-.
  • Acyl includes the“acetyl” group CHsCfO)-.
  • Acylamino refers to the groups -NR 10 C(O)alkyl, -NR 10 C(O)-substituted alkyl; -NR 10 C(O)aryl, -NR 10 C(O)substituted aryl, -NR 10 (CO)heteroaryl,
  • NR 10 C(O)substituted heteroaryl -NR 10 C(O)cycloalkyl, -NR 10 C(O)substituted cycloalkyl, -NR 10 C(O)heterocycloalkyl, and -NR 10 C(O)substituted heterocycloalkyl, where R 10 is hydrogen or alkyl.
  • Amino refers to the group -NH 2 .
  • “Amido” refers to the group -C(0)NR 1:L R 12 where R 11 and R 12 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aiyl, cycloalkyl, substituted cycloalkyl, heteroaiyl, substituted heteroaiyl, heterocyclic, and substituted heterocyclic and where R 11 and R 12 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
  • Aryl or“Ar” refers to a monovalent aromatic carbocyclic group of from
  • Preferred aryl groups include phenyl and naphthyl.
  • Substituted aiyl refers to aiyl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, amino, C 1 -C 4 alkylamino, di(Ci-C 4 alkyl)amino, cyano, halo, Ci-C 4 haloalkyl, heteroaiyl, substituted heteroaiyl, heterocyclic, substituted heterocyclic, thiol, Ci-C 4 thioalkyl, amidino, amido, carboxyl, Ci-C 4 alkoxy, C 3 -C 7 cycloalkyl, and C 1 -C 4 alkoxy-Ci-C 4 alkyl.
  • Carboxyl or“carboxy” refers to -COOH or salts thereof.
  • Cyano refers to the group -CN.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 and preferably 3 to 7 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • Halo or“halogen” refers to fluoro, chloro, bromo and iodo.
  • Heteroaiyl refers to a heteroaromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring ( e.g ., pyridinyl or furyl) or multiple condensed rings [e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group ln
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaiyl group are optionally oxidized to provide for the N-oxide (N®0), sulfinyl, or sulfonyl moieties.
  • N®0 N-oxide
  • sulfinyl or sulfonyl moieties.
  • Certain non-limiting examples include pyri
  • Substituted heteroaryl refers to heteroaiyl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • Heterocycle or“heterocyclic” or“heterocycloalkyl” or“heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
  • Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems ln fused ring systems, one or more the rings can be cycloalkyl, aiyl, or heteroaiyl provided that the point of attachment is through a non-aromatic ring ln one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties.
  • Substituted heterocyclic refers to heterocylic groups substituted with 1 to 3 and preferably 1 to 2 substituents selected from the group consisting of hydroxyl, nitro, acyl, acylamino, aiyl, substituted aryl, amino, C1-C4 alkylamino, di(Ci-C 4 alkyl)amino, cyano, halo, heteroaryl, substituted heteroaiyl, thiol, C 1 -C 4 thioalkyl, amidino, amido, carboxyl, C 1 -C 4 alkoxy, oxo, and C 3 -C 7 cycloalkyl.
  • heterocycle and heteroaiyls include, but are not limited to, azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide,
  • Niro refers to the group -NO2.
  • Thiol refers to the group -SH.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • lt is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aiyl having a substituted aryl group as a substituent which is itself substituted with a substituted aiyl group, etc.) are not intended for inclusion herein ln such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a limitation that, for example, substituted aiyl groups are limited to -substituted aiyl-(substituted aryl) -substituted aryl. [0048] lt is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups).
  • Subject refers to a mammal.
  • the mammal can be a human or non-human animal mammalian organism.
  • Treating” or“treatment” of a disease or disorder in a subject refers to 1) preventing the disease or disorder from occurring in a subject that is predisposed or does not yet display symptoms of the disease or disorder; 2) inhibiting the disease or disorder or arresting its development; or 3) ameliorating or causing regression of the disease or disorder.
  • “Pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical formulation administered to a subject without causing and significant undesirable biological effects or interfering in a deleterious manner with any of the other
  • “Pharmaceutically acceptable carrier” refers to materials such as solvents, stabilizers, pH-modifiers, tonicity modifiers, adjuvants, binders, diluents and other materials well known to the skilled artisan that are suitable for administration to a subject in combination with the compound or compounds of this invention.
  • the specific carrier selected is predicated in part on the intended route of administration such as rectal, oral, intravenous, parenteral, topical, inhalation, and the like. Such is well within purview of the skilled artisan.
  • an“effective amount” refers to that amount that results in a desired pharmacological or physiological effect for a specific condition such as an infection ln some cases, an effective amount is that amount sufficient to treat the symptoms of the disease or condition ln some cases, an effective amount is that amount sufficient to partially or completely cure the subject of the disease or condition ln reference to bacterial infections, an effective amount is preferably that amount that reduces the number of bacterial cells, inhibit bacterial growth, and/or kill existing bacteria ln some cases, an effective amount is that amount that is provided to a subject to prevent a bacterial infection when the subject is at risk of such an infection.
  • the compounds used in the methods of this invention utilize oligopeptide mimetics having from 1 to 8 optionally substituted amino acids and a C-terminal amino acid mimetic of formula I:
  • R is selected from hydrogen, optionally substituted aryl, or optionally substituted Ci-C 6 alkyl wherein said optional substitution is with from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci-C 4 alkylamino, di(Ci-C 4 alkyl)amino, cyano, halo, C 4 -C 4 haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci-C 4 thioalkyl, amidino, amido, carboxyl, Ci-C alkoxy, C 3 -C 7 cycloalkyl, oxo, and Ci-C alkyl-Ci-C alkoxy;
  • R 1 is hydrogen or together with R forms an optionally substituted pyrrolidinyl ring wherein said optional substitution is with from 1 to 3 substituents selected from the group consisting of C 4 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci- C alkylamino, di(Ci-C alkyl)amino, cyano, halo, Ci-C haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci-C thioalkyl, amidino, amido, carboxyl, C 4 -C 4 alkoxy, C 3 -C 7 cycloalkyl, oxo, and Ci-C 4 alkyl-Ci-C 4 alkoxy;
  • the methods of this invention utilize oligopeptide mimetic having from 1 to 8 optionally substituted amino acids and a C-terminal amino acid mimetic of formula II:
  • R is selected from hydrogen, optionally substituted optionally substituted aryl, or Ci-C 6 alkyl optionally substituted with from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci- C 4 alkylamino, di(Ci-C alkyl)amino, cyano, halo, Ci-C haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, C 4 -C 4 thioalkyl, amidino, amido, carboxyl, C 4 -C 4 alkoxy, C 3 -C 7 cycloalkyl, oxo, and C 4 -C 4 alkyl-Ci-C 4 alkoxy;
  • (L) indicates an L isomer at that stereochemical center
  • the methods of this invention utilize an oligopeptide of formula III:
  • R and R 1 are as defined above;
  • n and n are independently 0 or 1 ;
  • X, Y and Z are each independently an L-isomer of an optionally substituted amino acid provided that at least one of R, X, Y and Z is an optionally substituted aromatic amino acid selected from the group consisting of optionally substituted phenylglycine, phenylalanine, optionally substituted histidine, optionally substituted tyrosine, and optionally substituted tryptophan;
  • aromatic amino acids is from 1 to 3 substituents selected from the group consisting of C 4 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, Ci-C alkylamino, di(Ci-C alkyl)amino, cyano, halo, Ci-C haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted
  • (L) indicates an L isomer at that stereochemical center
  • the methods of this invention utilize a compound of formula IV:
  • R 10 , R 11 , and R 12 are independently an optionally substituted side chain of a non proline amino acid
  • any one of R 10 and R 1 , R 11 and R 2 and/or R 12 and R 3 forms an optionally substituted pyrrolidinyl group
  • Ar is optionally substituted phenyl, optionally substituted histidyl, or optionally substituted indolyl;
  • t is 0 or 1
  • y and z are independently 0, 1, 2, 3, 4, 5, or 6 provided that the total of plus z is no greater than 7
  • said optional substitution on said amino acids is from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, nitro, acyl, acylamino, aryl, substituted aryl, amino, C 1 -C 4 alkylamino, di(Ci-C alkyl)amino, cyano, halo, Ci-C haloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, thiol, Ci- C 4 thioalkyl, amidino, amido, carboxyl, C1-C4 alkoxy, C 3 -C 7 cycloalkyl, oxo, and C1-C4 alkyl-Ci-C4alkoxy;
  • the amino acids in the oligopeptides described herein do not include methionine as such would be compete with the methionine mimetics described herein with the tRNA Met synthesase.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis , Third Edition, Wiley, New York, 1999, and references cited therein.
  • the compounds of this invention contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Sigma-Aldrich (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka- Chemce or others).
  • Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic
  • the compounds comprise a methionine mimetic coupled to one to seven optionally substituted amino acids wherein at least one of the amino acids is an aromatic amino acid.
  • the methionine mimetics employed in the oligopeptides of formula 1 are readily prepared from the N-protected methyl ester of methionine as shown below:
  • the N-Boc protected methyl ester of amino acid (1) is treated with hydroxylamine in a solvent mixture of dioxane and water so as to provide for compound (2).
  • That compound can be isolated or purified by conventional conditions such as chromatography, precipitation, crystallization and the like or, alternatively, used in the next step without isolation and/or purification.
  • the Boc protecting group is removed by conventional conditions such as the addition of an acid such as HC1 so as to provide for compound (3).
  • that compound can be isolated or purified by conventional conditions such as chromatography, precipitation, crystallization and the like.
  • protection of functional groups such as amino or carboxyl groups will be necessary.
  • side chain carboxyl group protection such protection should be orthogonal to that of the methyl carboxylate. Suitable orthogonal protecting groups are well known in the art.
  • Compound (3) is then coupled to an amino acid chain of from 1 to 7 amino acids using conventional amino acid coupling conditions well known in the art as shown in the following reaction scheme:
  • m, n, R, X, Y and Z are as defined above and Pg is an amino protecting group such as a Cbz group.
  • Pg is an amino protecting group such as a Cbz group.
  • the compounds and compositions of this invention are useful in killing cancer cells.
  • these compounds and compositions are capable of treating cancer in subjects when administered thereto in an effective amount.
  • Exemplary cancers that are treatable in the claimed methods include breast, prostate, ovarian, cervical, colorectal, renal, pancreatic, non-small cell lung, epithelial, brain, liver, skin (including melanoma), and the like.
  • the compounds and compositions of this invention are also capable of inhibiting bacterial growth and, accordingly, are useful as bactericidal, antibacterial, and anti -infective agents and are particularly useful in treating cancers wherein bacteria populate the intracellular domain of the cancer cells such as in certain phenotypes of pancreatic cancer.
  • the compounds and compositions of this invention are capable of inhibiting intracellular protein synthesis in cancer cells by at least 20%, or by at least 50%, or by at least 75%, or by at least 90%, or by at least 95% or 100% when compared to intracellular protein synthesis in the absence of the compounds and compositions described herein.
  • the compounds and compositions of this invention are capable of intracellular inhibition of methionyl-tRNA synthetase by at least 20%, or by at least 50%, or by at least 75%, or by at least 90%, or by at least 95% or 100% when compared to the enzymatic activity in the absence of the compounds and compositions described herein.
  • the compounds of this invention are effective when administered to a subject in a therapeutically effective amount.
  • such amounts range from about 0.1 pg/kg to about 300 mg/kg when administered orally, intravenously, intra-arterially, intraperitoneally, intramuscularly, subcutaneously, intraocularly, rectally, transdermally, intrapulmonarily, and the like.
  • the amounts so administered more preferably range from about 1 pg/kg to about 40 mg/kg.
  • the compounds and compositions are administered topically such as cream, ointment, lotion, and the like, particularly when treating skin cancer.
  • the amount of compound employed in such topical formulations ranges from 0.1 mg/mL to about 100 mg/mL.
  • the amount of compound administered to the subject depends upon the weight, age, sex, severity of the condition to be treated and other factors well known to the skilled clinician.
  • the compounds of this invention can be administered at least once a day, preferably once or twice a day, and in some cases, three or more times a day.
  • Veegum K (Vanderbilt Co.) 1.0 g
  • a suppository of total weight 2.5 g is prepared by mixing the compound of this invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches- Nelson, Inc., New York), and has the following composition:
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • all language such as“up to,”“at least,”“greater than,”“less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.
  • a range includes each individual member.

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Abstract

L'invention concerne des mimétiques d'acides aminés qui possèdent des propriétés chimiothérapeutiques contre les cellules cancéreuses. Ces mimétiques sont couplés à un ou plusieurs acides aminés éventuellement substitués, à condition qu'au moins l'un des acides aminés soit un acide aminé éventuellement substitué choisi dans le groupe constitué par la phénylglycine, le tryptophane, la phénylalanine, l'histidine et la tyrosine.
PCT/US2019/019868 2018-02-28 2019-02-27 Mimétiques d'oligopeptides chimiothérapeutiques Ceased WO2019169011A1 (fr)

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