WO2023164777A1 - Produits radiopharmaceutiques ciblant gucy2c et leur utilisation - Google Patents

Produits radiopharmaceutiques ciblant gucy2c et leur utilisation Download PDF

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WO2023164777A1
WO2023164777A1 PCT/CA2023/050282 CA2023050282W WO2023164777A1 WO 2023164777 A1 WO2023164777 A1 WO 2023164777A1 CA 2023050282 W CA2023050282 W CA 2023050282W WO 2023164777 A1 WO2023164777 A1 WO 2023164777A1
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alkyl
acid
compound
aryl
integer
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William Leslie Turnbull
Saleemulla MAHAMMAD
Yun Cao
Zoë Louise O'GARA
Shekoufeh ALMASI
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Fusion Pharmaceuticals Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • Guanylate cyclase 2C (GUCY2C; also known as Guanylate cyclase C or GC-C) is a receptor expressed on brush border membranes of intestinal epithelial cells, as well as on transformed human colon cancer cell lines such as the T-84 cell line. Loss of expression of the natural peptide ligands guanylin and uroguanylin may lead to colorectal cancer. High expression of GUCY2C in both primary and metastatic colorectal tumors of >95% of colorectal cancer patients has provided interest for both in vivo imaging and radioligand therapies to diagnose and treat colorectal cancer using GUCY2C targeted agents.
  • colorectal cancer Current treatments of colorectal cancer include surgery, chemotherapy, external radiation therapy or a combination thereof. These therapies are non-specific and may come with severe side effects. Targeted therapies may be used to treat colorectal cancer with drugs such as Cetuximab (EGFR targeting) or Bevacizumab (VEGF-A targeting). However, no treatments targeting GUCY2C have been approved for treating colorectal cancer.
  • EGFR targeting Cetuximab
  • VEGF-A targeting Bevacizumab
  • GUCY2C no treatments targeting GUCY2C have been approved for treating colorectal cancer.
  • the present disclosure encompasses the insight that, as natural peptide ligands and peptides derived from Escherichia Coli enterotoxin bind with high specificity and selectivity for guanylate cyclase 2C (GUCY2C), this receptor is suitable for targeting with peptide receptor radioligand therapy (PRRT).
  • Radioactive decay can cause direct physical damage (such as single or double-stranded DNA breaks) or indirect damage (such as by-stander or crossfire effects) to the biomolecules that constitute a cell.
  • Drugs that deliver radionuclides to cancer cells, i.e., radiopharmaceuticals provide a mechanism to generate DNA damage with anti-cancer therapeutic effect.
  • the present disclosure provides certain radiopharmaceuticals, specifically, monocyclic peptide-based radiopharmaceuticals targeting GUCY2C positive tumors and using actinium-225, lutetium-177 or other suitable therapeutic radionuclides to target cancer cells to treat or ameliorate cancers such as colorectal cancer.
  • the present disclosure provides compounds of Formula I, or a pharmaceutically acceptable salt thereof:
  • A is a chelating moiety or a metal complex thereof
  • L 1 is a bond, optionally substituted Ci-6 alkylene, optionally substituted Ci-6 heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • W is -C(O)-, -C(O)NR -, -C(S)NR -, -OC(O)NR - -NR C(O)NR -, - CH2PhC(O)(NR )-, -CH2Ph-NH-C(S)NR -, -O-, or -NR -, in which each R independently is H or Ci -6 alkyl;
  • L 2 is optionally substituted Ci-50 alkylene or optionally substituted Ci-50 heteroalkylene
  • V is C1-6 alkylene, -C(O)-Ci-6 alkylene, -C(O)NR-CI-6 alkylene, -NR C(O)-Ci-6 alkylene, or arylene, in which the C1-6 alkylene or arylene is optionally substituted;
  • R at each occurrence, is independently H or optionally substituted C1-6 alkyl; n is an integer between 1-5 (inclusive); and
  • Ci-6 alkyl, Ci-6 heteroalkyl, aryl, and heteroaryl are each independently optionally substituted as described in the DETAILED DESCRIPTION below.
  • variable B is represented by Formula II:
  • R 1 , R 2 , and R 3 each independently are H, Ci-6 alkyl, Ci-6 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, C1-6 alkyl-aryl, heteroaryl, or C1-6 alkyl-heteroaryl;
  • R a and R b each independently are H or C1-6 alkyl
  • R x , R y , and R z each are H, or R x and R 1 , together with the nitrogen and carbon to which they bond respectively, form C3-8 heterocycloalkyl, or R y and R 2 , together with the nitrogen and carbon to which they bond respectively, form C3-8 heterocycloalkyl, or R z and R 3 , together with the nitrogen and carbon to which they bond respectively, form C3-8 heterocycloalkyl; each of C1-6 alkyl, C1-6 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, and heteroaryl is optionally substituted as described in the DETAILED DESCRIPTION below; and x is an integer between 1-20 (inclusive), y is an integer between 1-20 (inclusive), and z is an integer between 0-20 (inclusive).
  • R 1 , R 2 , and R 3 each independently are H, C1-6 alkyl, C1-6 heteroalkyl, C1-6 alkyl-aryl, or C1-6 alkyl-heteroaryl;
  • R a , R b , R x , R y , and R z each are H; and x is an integer of 1-5, y is an integer of 2-10, and z is an integer of 0-5.
  • the compounds of this disclosure comprises a chelating moiety selected from the group consisting of DOTA (1,4, 7,10-tetraazacyclododecane- 1,4, 7, 10- tetraacetic acid), DOTMA (lR,4R,7R,10R)-a, a’, a”, a”’-tetramethyl-l,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid, DOTAM (l,4,7,10-tetrakis(carbamoylmethyl)- 1 ,4,7, 10-tetraazacyclododecane), DOTP A ( 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7, 10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-l,4,7,10-
  • the chelating moiety has the following structure: wherein Y 1 is -CH 2 OCH 2 -(W-L 2 -V) n -B, -C(O)-(W-L 2 -V) n -B, or -C(S)-(W-L 2 -V) n -B and Y 2 is -CH 2 CO 2 H; or wherein Y 1 is H and Y 2 is I -( W-L 2 -V) n -B.
  • L 1 has the following structure: wherein R is hydrogen or -CO 2 H.
  • the compounds of this disclosure comprises a metal complex comprising a metal selected from the group consisting of Bi, Pb, Y, Mn, Cr, Fe, Co, Zn, Ni, Tc, In, Ga, Cu, Re, a lanthanide, and an actinide; or the metal complex comprises a radionuclide selected from the group consisting of 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Ga, 67 Cu, 68 Ga, 69 Er, 77 As, 82 Rb, 89 Zr, 86 Y, 87 Y, 90 Y, 97 Ru, 99 Tc, " m Tc, 105 Rh, 109 Pd, m In, m Ag, 121 Sn, 127 Te,
  • W is -C(O)NR - and V is Ci-Ce alkylene, in which R is H.
  • n is 1.
  • the compound comprises one of the following: , .g., enantiomer) thereof.
  • A is a metal complex comprising a radionuclide.
  • the radionuclide is 64 Cu, n i In, 68 Ga, 177 Lu, or 225 Ac.
  • A is a metal complex comprising an alpha-emitting radionuclide.
  • the alpha-emitting radionuclide is 225 Ac.
  • the present disclosure also covers a pharmaceutical composition comprising one of the compounds set forth above and a pharmaceutically acceptable excipient.
  • a method of radiation treatment planning or radiation treatment comprising administering to a subject in need thereof one of the compounds set forth above or the above-described composition.
  • a method of treating cancer comprising administering to a subject in need thereof a first dose of one of the compounds or the composition described above in an amount effective for radiation treatment planning, followed by administering subsequent doses of one of the compounds or the composition described above in a therapeutically effective amount.
  • the compound or composition administered in the first dose and the compound or composition administered in the second dose are the same.
  • the compound or composition administered in the first dose and the compound or composition administered in the second dose are different.
  • the method of treatment can be used for treating gastrointestinal malignancies, e.g., colorectal cancer, gastric cancer, or esophageal cancer.
  • gastrointestinal malignancies e.g., colorectal cancer, gastric cancer, or esophageal cancer.
  • the present disclosure relates to compounds comprising a monocyclic peptide that comprises at least two cysteine residues with two sulfide units connected via a 3,5- dimethylenepyrazole moiety.
  • the monocyclic peptide specifically binds to guanylate cyclase 2C (GUCY2C).
  • GUCY2C is normally expressed at high levels within the lumen of the gut. With their expression maintained in transformed cells throughout the process of colorectal carcinogenesis, GUCY2C receptors are expressed on virtually all histologically confirmed primary and metastatic colorectal tumors examined in human patients, while normal tissues and other types of cancer express minimal or no GUCY2C receptors.
  • Radio-labelled targeting moieties also known as radiopharmaceuticals
  • Radiopharmaceuticals targeting GUCY2C provided in this disclosure can be used for treating gastrointestinal malignancies, including colorectal cancer, gastric cancer, and esophageal cancer.
  • alkyl is inclusive of both straight chain and branched chain saturated groups from 1 to 20 carbons (e.g., from 1 to 10 or from 1 to 6), unless otherwise specified.
  • Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of (1) Ci-6 alkoxy; (2) Ci-6 alkyl sulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2, where R N1 is as defined for amino); (4) Ce-io aryl-C
  • alkylene alkylidene
  • alk- alk-
  • alkylene alkylidene
  • alk- a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like.
  • C x -y alkyl C x -y alkylene
  • C x.y alkylidene C x.y alk-
  • Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., Ci-6, Cnio, C2-5, C2-8, C2-10, or C2-20 alkyl or alkylene).
  • the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for an alkyl group.
  • alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1- propenyl, 2-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyls include both cis and trans isomers.
  • Alkenyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • alkynyl represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like.
  • Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • amino represents -N(R N1 )2, wherein each R N1 is, independently, H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an ⁇ '-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionally substituted with an ( -protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an (9-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described here
  • Amino groups can be unsubstituted amino (i.e., -NH2) or substituted amino (i.e., -N(R N1 )2) groups.
  • amino is -NH2 or -NHR N1 , wherein R N1 is, independently, OH, NO2, NH2, NR N2 2, SO2OR N2 , SO2R N2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, and each R N2 can be H, Ci-20 alkyl (e.g., C1-6 alkyl), or Ce-io aryl.
  • amino acid refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of-CO2H or a sulfo group of-SOsH), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain).
  • the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group.
  • Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl.
  • Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.
  • Amino acid groups may be optionally substituted with one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2, where R N1 is as defined for amino); (4) Ce-io aryl-Ci-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (11) C1-7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CC>2R A , where R A is selected from the group consist
  • aryl represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2- dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, indenyl, and the like, and may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: (1) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-Ci-6 alkyl, C1-6 alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl, (carboxyaldehyde)-Ci
  • C1-7 acyl e.
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci- alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • arylalkyl represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alk-Ce-io aryl, Ci-10 alk-Ce-io aryl, or Ci-20 alk-Ce-io aryl).
  • the alkylene and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • Other groups preceded by the prefix “alk-” are defined in the same manner, where “alk” refers to a C1-6 alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.
  • cyano represents an -CN group.
  • cycloalkyl represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycle heptyl, and the like.
  • the cycloalkyl group includes one carbon-carbon double bond or one carbon-carbon triple bond, the cycloalkyl group can be referred to as a “cycloalkenyl” or “cycloalkynyl” group respectively.
  • Exemplary cycloalkenyl and cycloalkynyl groups include cyclopentenyl, cyclohexenyl, cyclohexynyl, and the like.
  • Cycloalkyl groups can be optionally substituted with: (1) C1-7 acyl (e.g., carboxyaldehyde); (2) Ci-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-Ci-6 alkyl, C1-6 alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl,
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci- alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • stereomer means stereoisomers that are not mirror images of one another and are non-superimposable on one another.
  • enantiomer means each individual optically active form of a compound, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • halogen represents a halogen selected from bromine, chlorine, iodine, or fluorine.
  • heteroalkyl and “heteroalkylidene,” as used herein, each refer to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroalkenyl and heteroalkynyl refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • heteroalkenyl and heteroalkynyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroaryl represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4/?+2 pi electrons within the mono- or multicyclic ring system.
  • Exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.
  • the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups as defined for a heterocyclyl group.
  • heteroarylalkyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted heteroarylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as Ci-6 alk- Ci-12 heteroaryl, Cnio alk-Ci-12 heteroaryl, or Ci-20 alk-Ci-12 heteroaryl).
  • the alkylene and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.
  • Heteroarylalkyl groups are a subset of heterocyclylalkyl groups.
  • heterocycloalkyl or “heterocyclyl,” as used herein represents a 4-, 5-, 6- or 7- membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the 5- membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds.
  • Exemplary unsubstituted heterocyclyl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.
  • heterocyclyl also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group.
  • heterocyclyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
  • fused heterocyclyls include tropanes and l,2,3,5,8,8a-hexahydroindolizine.
  • Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinoly
  • Still other exemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-lH-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-lH-pyrazolyl (e.g., 2, 3,4,5- tetrahydro-2-phenyl-5-oxo-lH-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-lH-imidazolyl (e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-lH-imidazolyl); 2,3-dihydro-2-thioxo-l,3,4- oxadiazolyl (e.g., 2,3-dihydro-2-thioxo-5-phenyl-l,3,4-oxadiazolyl); 4,5-dihydro-5-ox
  • Additional heterocyclics include 3,3a,4,5,6,6a-hexahydro-pyrrolo[3,4-b]pyrrol-(2H)-yl, and 2,5- diazabicyclo[2.2.1]heptan-2-yl, homopiperazinyl (or diazepanyl), tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, and thiocanyl.
  • Heterocyclic groups also include groups of the formula
  • E' is selected from the group consisting of -N- and -CH-;
  • G' is selected from the group consisting of -CH- and -N-.
  • any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) C1-7 acyl (e.g., carboxyaldehyde ); (2) Ci-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-Ci-6 alkyl, C1-6 alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl, (carboxyaldehyde)-Ci-6 alkyl, halo- C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-Ci-6 alkyl, nitro-Ci-6 alkyl, or C1-6 thioalkoxy-Ci-6 alkyl); (3) Ci-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkyl sulfinyl; (5)
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci- alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • hydrocarbon represents a group consisting only of carbon and hydrogen atoms.
  • hydroxyl represents an -OH group.
  • the hydroxyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., ( -protecting groups) as defined herein for an alkyl.
  • isomer means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. It is recognized that the compounds can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • stereoisomers such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • stereomers depicted herein encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
  • Enantiomeric and stereoisomeric mixtures of compounds can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • W-protected amino refers to an amino group, as defined herein, to which is attached one or two Y-protecting groups, as defined herein.
  • -protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used Y-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • N- protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butyl acetyl, 2 -chloroacetyl, 2-bromoacetyl, trifluoroacetyl, tri chloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyl
  • Preferred Y-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butyl acetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • O-protecting group represents those groups intended to protect an oxygen containing (e.g., phenol, hydroxyl, or carbonyl) group against undesirable reactions during synthetic procedures. Commonly used ( -protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • Exemplary ( -protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butyl acetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, tri chloroacetyl, phthalyl, o-nitrophenoxyacetyl, a- chlorobutyryl, benzoyl, 4 -chlorobenzoyl, 4-bromobenzoyl, Ebutyldimethylsilyl, tri-/.w- propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4- isopropylpehenoxy acetyl, dimethylformamidino, and 4-nitrobenzoyl; alkylcarbonyl groups, such as acyl, acetyl, propionyl,
  • polyethylene glycol represents an alkoxy chain comprised of one or more monomer units, each monomer unit consisting of -OCH2CH2-.
  • Polyethyelene glycol (PEG) is also sometimes referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), and these terms may be considered interchangeable for the purpose of this disclosure.
  • a polyethylene glycol may have the structure, -(CH2)s2(OCH2CH2)si(CH2)s3O-, wherein si is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), and each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10).
  • Polyethylene glycol may also be considered to include an amino-polyethylene glycol of -NR N1 (CH2)S2(CH2CH 2 O)S1(CH2)S3NR N1 -, wherein si is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted Ci-6 alkyl.
  • si is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4)
  • each of s2 and s3, independently is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10)
  • each R N1 is, independently, hydrogen or optionally substituted Ci-6 alkyl.
  • stereoisomer refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds may exist in different tautomeric forms, all of the latter being included within the scope of the present disclosure.
  • sulfonyl represents an -S(O)2- group.
  • thiol as used herein represents an -SH group.
  • a dose of about 100 kBq/kg indicates a dose range of 100 ⁇ 10% kBq/kg, i.e., from 90 kBq/kg to 110 kBq/kg, inclusive.
  • the term “administered in combination,” “combined administration,” or “co-administered” means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient.
  • two or more agents that are administered in combination need not be administered together.
  • they are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day(s)), within 28 days (e.g., with 14, 7, 6, 5, 4, 3, 2, or 1 day(s), within 24 hours (e.g., 12, 6, 5, 4, 3, 2, or 1 hour(s), or within about 60, 30, 15, 10, 5, or 1 minute of one another.
  • the administrations of the agents are spaced sufficiently closely together such that a combinatorial effect is achieved.
  • administering includes contacting cells of said subject with the agent.
  • cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
  • a “solid tumor cancer” is a cancer comprising an abnormal mass of tissue, e.g., sarcomas, carcinomas, and lymphomas.
  • a “hematological cancer” or “liquid cancer,” as used interchangeably herein, is a cancer present in a body fluid, e.g., lymphomas and leukemias.
  • chelate as used herein, refers to an organic compound or portion thereof that can be bonded to a central metal or radiometal atom at two or more points.
  • conjugate refers to a molecule that contains a chelating group or metal complex thereof, a linker group, and which optionally contains a therapeutic moiety or a targeting moiety.
  • the term “compound,” is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.
  • the compounds described herein can be asymmetric e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4- triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual sub-combination of the members of such groups and ranges.
  • the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.
  • a phrase of the form “optionally substituted X” e.g., optionally substituted alkyl
  • X optionally substituted alkyl
  • alkyl wherein said alkyl is optionally substituted
  • the terms “decrease,” “decreased,” “increase,” “increased,” or “reduction,” “reduced,” have meanings relative to a reference level.
  • the reference level is a level as determined by the use of said method with a control in an experimental animal model or clinical trial.
  • the reference level is a level in the same subject before or at the beginning of treatment.
  • the reference level is the average level in a population not being treated by said method of treatment.
  • an “effective amount” of an agent is that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied.
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • a “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radioprotectants, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid,
  • salts of the compounds described here that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • Compounds may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of compounds, be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for forming basic salts. Methods for preparation of the appropriate salts are well- established in the art.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemi sulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • radiopharmaceutical refers to any compound or conjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.
  • the term “radionuclide,” refers to an atom capable of undergoing radioactive decay (e.g., 3 H, 14 C, 15 N, 18 F, 35 S, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 75 Br, 76 Br , 77 Br , 89 Zr, 86 Y, 87 Y, 90 Y, 97 RU, 99 TC, " m Tc, 105 Rh, 109 Pd, m In, 123 I, 124 I, 125 I, 131 I, 149 Pm, 149 Tb, 153 Sm, 166 HO, 177 LU, 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 At, 212 Pb , 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 229Th , 66 Ga, 67 Ga, 68 Ga, 82 Rb, 117m Sn
  • radioactive nuclide may also be used to describe a radionuclide.
  • Radionuclides may be used as detection agents.
  • the radionuclide is an alpha-emitting radionuclide.
  • Exemplary radionuclides used in the method of this invention include, but are not limited to, 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Th.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • “ameliorating” may include, for example, reducing incidence of metastases, reducing tumor volume, reducing tumor vascularization and/or reducing the rate of tumor growth. “Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • the compounds of Formula I comprise chelating moieties or chelators.
  • the chelating moiety is selected from the group consisting of DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid), DOTMA (lR,4R,7R,10R)-a, a’, a”, a’”-tetramethyl-l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid, DOTAM ( 1 ,4,7, 10-tetrakis(carbamoylmethyl)- 1 ,4,7, 10-tetraazacyclododecane), DOTP A (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetra propionic acid), DO3 AM-acetic acid (2-(4,7,10-tris(2- amino-2-oxoethyl)-l,4,7,10-tetraazacyclo
  • the chelating moiety is selected from DOTA, NOTA, DTPA, TETA, EDTA, NOD AGA, NODASA, TRITA, CDTA, BAT, DFO and HYNIC, which are defined as below:
  • DOTA stands for l,4,7,10-tetrazacyclododecane-l,4,7,10-tetraacetic acid
  • NOTA stands for 1,4,7-triazacyclononanetriacetic acid
  • DTPA stands for diethylenetriaminepentaacetic acid
  • TETA stands for 1,4,8, 11 -tetraazacyclododecane- 1,4, 8,11 -tetraacetic acid
  • EDTA stands for ethylenediamine-N,N' -tetraacetic acid
  • NODAGA stands for 1,4,7-triazacyclononane-N-glutaric acid-N',N" -diacetic acid
  • NODASA stands for 1,4,7- triazacyclononane -1 -succinic acid-4, 7-diacetic acid
  • TRITA stands for 1,4,7,10 tetraazacyclotridecane-l,4,7,10-tetraacetic acid
  • CDTA stands for trans-
  • BAT stands for the Bisamino-bisthiol group of chelators, the chemical name of the non limiting example is l-[2-(2-mercapto-2-methyl-propylamino)-ethylamino]-2-methyl-propane-2- thiol,
  • HYNIC 6-Hydrazino-nicotinic acid, and with the chemical structures thereof being as follows: Radiopharmaceuticals
  • Radiopharmaceuticals in accordance with the present disclosure refer to compounds of Formula I comprising a radionuclide, each variable as defined in the SUMMARY section above:
  • compounds of Formula I comprise monocyclic peptide B having Formula II with * indicating the attachment point, wherein R 1 , R 2 , R 3 , R a , R b , R x , R y , R z , x, y, and z are as defined in the SUMMARY section above:
  • the compound of Formula I is capable of binding to GUCY2C with detectable affinity.
  • detectable affinity it is generally meant that the binding ability between a targeting moiety and its target, reported by a KD, EC50, or IC50 value, is at most about 10 5 M or lower.
  • the compound of Formula I is capable of binding to GUCY2C with a KD of 100 nM or less (e.g., 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, about 9 nM, about 8 nM, about 7 nM, about 6 nM, about 5 nM, about 4 nM, about 3 nM, about 2 nM, about 1 nM).
  • a KD 100 nM or less (e.g., 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, about 9 nM, about 8 nM, about 7 nM, about 6 nM
  • the compound of Formula I is capable of binding to GUCY2C with a KD of 1000 nM or less (e.g., 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less).
  • a KD 1000 nM or less (e.g., 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less).
  • chelating moieties include, but are not limited to, DOTA (1,4,7,10- tetrazacyclododecane-l,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclononanetriacetic acid), DTPA (diethylenetriaminepentaacetic acid), TETA (1,4,8, 11-tetraazacy clododecane-1, 4,8,11- tetraacetic acid), EDTA (ethyl enediamine-N,N' -tetraacetic acid), NODAGA (1,4,7- triazacyclononane-N-glutaric acid-N',N"-diacetic acid), NODASA (1,4,7- triazacyclononane -1- succinic acid-4, 7-diacetic acid), TRITA (1,4,7,10 tetraazacyclotridecane-l,4,7,10-tetraacetic acid), CD
  • the chelating moiety is DOTA (1,4,7, 10-tetraazacyclododecane- 1,4,7, 10-tetraacetic acid).
  • radiopharmaceuticals each comprising a radionuclide.
  • suitable radionuclides include, but are not limited to, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Ga, 67 Cu, 68 Ga, 69 Er, 77 As, 82 Rb, 89 Zr, 86 Y, 87 Y, 90 Y, 97 Ru, "Tc, " m Tc, 105 Rh, 109 Pd,
  • the radionuclide is selected from the group consisting of 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Th.
  • the radionuclide is an alpha emitter, e.g., Astatine-211 ( 211 At), Bismuth-212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium-227 ( 227 Th), or Terbium-149 ( 149 Tb).
  • alpha emitter e.g., Astatine-211 ( 211 At), Bismuth-212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium-227 ( 227 Th), or Terbium-149 ( 149 Tb).
  • the compounds of the present disclosure comprise the linker as shown within the structure of Formula I that comprises -L ⁇ W-L ⁇ V)]!-, each variable as defined in the SUMMARY section above.
  • L 1 typically is Ci-6 alkyl (e.g., C2 alkyl, C3 alkyl, C4 alkyl, or C5 alkyl).
  • An exemplary Li is can b e optionally substituted with a substituent described herein (e.g., substituted with oxo).
  • W is -C(O)-, -C(O)NR -, -O-, or -NR -, in which each R independently is H or Ci-Ce alkyl.
  • An exemplary W is -C(O)NR - wherein R is H.
  • L2 typically is Ci-50 heteroalkyl (e.g., Ci-40 heteroalkyl, Ci-30 heteroalkyl, Ci-20 heteroalkyl, Ci-15 heteroalkyl, Ci-10 heteroalkyl, C1-9 heteroalkyl, C1-8 heteroalkyl, C1-7 heteroalkyl, C1-6 heteroalkyl, or C1-5 heteroalkyl) comprising at least one heteroatom of O or N.
  • Exemplary L2 includes, but is not limited to, the following: an be optionally substituted with a substituent described herein (e.g., substituted with oxo).
  • V is Ci-6 alkyl (e.g., Ci alkyl, C2 alkyl, C3 alkyl, or C4 alkyl).
  • An exemplary V substituent described herein e.g., substituted with oxo).
  • the compounds of the present disclosure comprise a monocyclic peptide that is capable of binding to GUCY2C.
  • the monocyclic peptide comprises at least two cysteine residues with two sulfide units connected via a 3,5-dimethylenepyrazole moiety.
  • the monocyclic peptide is capable of binding to GUCY2C with an affinity reported by a KD of 1000 nM or less (e.g., 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less).
  • a KD 1000 nM or less (e.g., 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less).
  • the monocyclic peptide is capable of binding to GUCY2C with a KD of 100 nM or less (e.g., 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, about 9 nM, about 8 nM, about 7 nM, about 6 nM, about 5 nM, about 4 nM, about 3 nM, about 2 nM, about 1 nM).
  • a KD 100 nM or less (e.g., 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, about 9 nM, about 8 nM, about 7 nM, about 6
  • compounds of Formula I each comprise a monocyclic peptide, or variable B, having Formula II with * indicating the attachment point: (II), wherein
  • R 1 , R 2 , and R 3 each independently are H, Ci-6 alkyl, Ci-6 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, C1-6 alkyl-aryl, heteroaryl, or C1-6 alkyl-heteroaryl;
  • R a and R b each independently are H or C1-6 alkyl
  • R x , R y , and R z each are H, or R x and R 1 , together with the nitrogen and carbon to which they bond respectively, form C3-8 heterocycloalkyl, or R y and R 2 , together with the nitrogen and carbon to which they bond respectively, form C3-8 heterocycloalkyl, or R z and R 3 , together with the nitrogen and carbon to which they bond respectively, form C3-8 heterocycloalkyl; each of C1-6 alkyl, C1-6 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, and heteroaryl is optionally substituted as described in the DETAILED DESCRIPTION below; and x is an integer of 1-20, y is an integer of 1-20, and z is an integer of 0-20.
  • R 1 , R 2 , and R 3 each independently are H, C1-6 alkyl, C1-6 heteroalkyl, C1-6 alkyl-aryl, or C1-6 alkyl-heteroaryl;
  • R a , R b , R x , R y , and R z each are H; and x is an integer of 1-5, y is an integer of 2-10, and z is an integer of 0-5.
  • each of the amino acid residues comprising R 1 , R 2 , or R 3 in Formula II is formed from one of the following natural amino acids:
  • Monocyclic peptides of Formula II can be prepared from a non-cyclic peptide of Formula III by following the protocols provided in J. Am. Chem. Soc. 2021, 143, 5497-5507. A skilled artisan would appreciate that any non-cyclic peptide of Formula III can be synthesized using standard peptide synthesis known in the field.
  • An exemplary non-cyclic peptide of Formula III is a disulfide-reduced form (i.e., a disulfide bond is reduced to be two free thiols via a disulfide reducing agent such as P- mercaptoethanol or dithiothreitol) of one of the following:
  • the non-cyclic peptide of Formula III comprises an amino acid sequence according to: a. S-X-C-X-X-X-X-X-X-C, or b. S-X-C-X-X-X-X-X-X-C wherein each X, independently, is any natural amino acid, and each X can be the same as or different from any other X.
  • the non-cyclic peptide of Formula III has an amino acid sequence according to: a. S-X-C-X-X-X-X-X-X-X-C, or b. S-X-C-X-X-X-X-X-X-X-X-C
  • each X independently, is any natural amino acid, and each X can be the same as or different from any other X.
  • the non-cyclic peptide of Formula III comprises an amino acid sequence according to: c. S-Q-C-E-X-X-P-X-X-C (SEQ ID NO: 34), d. S-X-C-K-I-Q-X-X-X-N-C (SEQ ID NO: 35), or e. S-Q-C-E-X-X-N-P-I-C (SEQ ID NO: 36) wherein each X, independently, is any natural amino acid, and each X can be the same as or different from any other X.
  • the non-cyclic peptide of Formula III has an amino acid sequence according to: c. S-Q-C-E-X-X-P-X-X-C (SEQ ID NO: 34), d. S-X-C-K-I-Q-X-X-X-N-C (SEQ ID NO: 35), or e. S-Q-C-E-X-X-N-P-I-C (SEQ ID NO: 36) wherein each X, independently, is any natural amino acid, and each X can be the same as or different from any other X.
  • the non-cyclic peptide of Formula III comprises an amino acid sequence of Y-V. In some embodiments, the non-cyclic peptide of Formula III comprises an amino acid sequence of S-Y-V. In some embodiments, the non-cyclic peptide of Formula III comprises an amino acid sequence of V-Y. In some embodiments, the non-cyclic peptide of Formula III comprises an amino acid sequence of I-N.
  • the non-cyclic peptide of Formula III comprises an amino acid sequence described in Table 1. In some embodiments, the non-cyclic peptide of Formula III comprises an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90 identical to the amino acid sequence of the heavy chain variable domain of an antibody described in Table 1. [0109] In some embodiments, the non-cyclic peptide of Formula III has an amino acid sequence described in Table 1. In some embodiments, the non-cyclic peptide of Formula III has an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90 identical to the amino acid sequence of the heavy chain variable domain of an antibody described in Table 1.
  • a therapy (e.g., comprising a therapeutic agent) is administered to a subject.
  • the subject is a mammal, e.g., a human.
  • the subject has cancer or is at risk of developing cancer.
  • the subject may have been diagnosed with cancer.
  • the cancer may be a primary cancer or a metastatic cancer.
  • Subjects may have any stage of cancer, e.g., stage I, stage II, stage III, or stage IV with or without lymph node involvement and with or without metastases.
  • Provided compositions may prevent or reduce further growth of the cancer and/or otherwise ameliorate the cancer (e.g., prevent or reduce metastases).
  • the subject does not have cancer but has been determined to be at risk of developing cancer, e.g., because of the presence of one or more risk factors such as environmental exposure, presence of one or more genetic mutations or variants, family history, etc. In some embodiments, the subject has not been diagnosed with cancer.
  • the cancer is a colorectal cancer, gastric cancer, or esophageal cancer.
  • the present disclosure provides methods of using a compound of Formula I for treating clinical indications expressing GUCY2C, with the compound administered to a subject (e.g., a human) in an amount therapeutically effective for such treatment.
  • a subject e.g., a human
  • This disclosure also covers combination therapies in which the amounts of each therapeutic may or may not be, on their own, therapeutically effective.
  • a first therapy e.g., a compound of Formula I
  • a second therapy e.g., an anti -cancer agent provided in Table 1 below
  • at least one of the first and second therapies is administered to the subject in a lower effective dose.
  • both the first and the second therapies are administered in lower effective doses.
  • therapeutic combinations as disclosed herein are administered to a subject in a manner (e.g., dosing amount and timing) sufficient to cure or at least partially arrest the symptoms of the disorder and its complications.
  • a dose e.g., a single therapy (a “monotherapy”)
  • an amount adequate to accomplish this purpose is defined as a “therapeutically effective amount,” an amount of a compound sufficient to substantially improve at least one symptom associated with the disease or a medical condition.
  • the “therapeutically effective amount” typically varies depending on the therapeutic. For known therapeutic agents, the relevant therapeutically effective amounts may be known to or readily determined by those of skill in the art.
  • an agent or compound that decreases, prevents, delays, suppresses, or arrests any symptom of the disease or condition would be therapeutically effective.
  • a therapeutically effective amount of an agent or compound is not required to cure a disease or condition but will provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered, or prevented, or the disease or condition symptoms are ameliorated, or the term of the disease or condition is changed or, for example, is less severe or recovery is accelerated in an individual.
  • a treatment may be therapeutically effective if it causes a cancer to regress or to slow the cancer’s growth.
  • the dosage regimen (e.g., amounts of each therapeutic, relative timing of therapies, etc.) that is effective for these uses may depend on the severity of the disease or condition and the weight and general state of the subject.
  • the therapeutically effective amount of a particular composition comprising a therapeutic agent applied to mammals can be determined by the person of ordinary skill in the art with consideration of individual differences in age, weight, and the condition of the mammal.
  • the dosage of these compounds can be lower than (e.g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of) the equivalent dose of required for a therapeutic effect of the unconjugated agent.
  • Therapeutically effective and/or optimal amounts can also be determined empirically by those of skill in the art. Thus, lower effective doses can also be determined by those of skill in the art.
  • a radiopharmaceutical or a composition e.g., a pharmaceutical composition comprising a therapeutic agent or a radiopharmaceutical
  • dose levels and pattern being selected by the treating physician.
  • the dose and administration schedule can be determined and adjusted based on the severity of the disease or condition in the subject, which may be monitored throughout the course of treatment according to the methods commonly practiced by clinicians or those described herein.
  • the first and second therapies may be administered sequentially or concurrently to a subject.
  • a first composition comprising a first therapeutic agent and a second composition comprising a second therapeutic agent may be administered sequentially or concurrently to a subject.
  • a composition comprising a combination of a first therapeutic agent and a second therapeutic agent may be administered to the subject.
  • the radiopharmaceutical is administered in a single dose. In some embodiments, the radiopharmaceutical is administered more than once, i.e., multiple doses. When the radiopharmaceutical is administered more than once, the dose of each administration may be the same or different.
  • compositions are administered for radiation treatment planning or diagnostic purposes.
  • compositions may be administered to a subject in a diagnostically effective dose and/or an amount effective to determine the therapeutically effective dose.
  • a first dose of disclosed conjugate or a composition (e.g., pharmaceutical composition) thereof is administered in an amount effective for radiation treatment planning, followed administration of a combination therapy including a conjugate as disclosed herein and another therapeutic.
  • compositions comprising one or more agents (e.g., radiopharmaceuticals) can be formulated for use in accordance with disclosed methods and systems in a variety of drug delivery systems.
  • agents e.g., radiopharmaceuticals
  • One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Examples of suitable formulations are found in Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
  • suitable formulations are found in Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
  • Langer Science 249: 1527- 1533, 1990.
  • compositions may be formulated for parenteral, intranasal, topical, oral, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment.
  • Pharmaceutical compositions can be administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application or intraarticular injection at areas affected by the vascular or cancer condition.
  • parenterally e.g., by intravenous, intramuscular, or subcutaneous injection
  • additional routes of administration include intravascular, intra-arterial, intratumor, intraperitoneal, intraventricular, intraepidural, as well as nasal, ophthalmic, intrascleral, intraorbital, rectal, topical, or aerosol inhalation administration.
  • compositions comprising include agents (e.g., compounds as disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
  • an acceptable carrier preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
  • Compositions may contain pharmaceutically acceptable auxiliary substances to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, or detergents, among others.
  • compositions are formulated for oral delivery; for example, compositions may contain inert ingredients such as binders or fillers for the formulation of a unit dosage form, such as a tablet or a capsule.
  • compositions are formulated for local administration; for example, compositions may contain inert ingredients such as solvents or emulsifiers for the formulation of a cream, an ointment, a gel, a paste, or an eye drop.
  • compositions may be sterilized, e.g., by conventional sterilization techniques, or sterile filtered.
  • Aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the preparations typically will be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 6 and 7, such as 6 to 6.5.
  • compositions in solid form are packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents, such as in a sealed package of tablets or capsules.
  • compositions in solid form are packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment.
  • Other agents such as in a squeezable tube designed for a topically applicable cream or ointment.
  • disclosed methods of treatment further include administering an antiproliferative agent, radiation sensitizer, or an immunoregulatory or immunomodulatory agent.
  • antiproliferative or “antiproliferative agent,” as used interchangeably herein, is meant any anticancer agent, including those antiproliferative agents listed in Table 2, any of which can be used in combination with a radiopharmaceutical to treat a condition or disorder.
  • Antiproliferative agents also include organo-platinum derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and anthroquinone derivatives thereof.
  • immuno-modulatory agent or “immunomodulatory agent,” as used interchangeably herein, is meant any immuno-modulator, including those listed in Table 2, any of which can be used in combination with a radiopharmaceutical provided herein.
  • Radiation sensitizer includes any agent that increases the sensitivity of cancer cells to radiation therapy.
  • Radiation sensitizers may include, but are not limited to, 5- fluorouracil, analogs of platinum (e.g., cisplatin, carboplatin, oxaliplatin), gemcitabine, EGFR antagonists (e.g., cetuximab, gefitinib), farnesyltransferase inhibitors, COX-2 inhibitors, bFGF antagonists, and VEGF antagonists.
  • Compounds of Formula I comprise monocyclic peptide-based conjugates targeting GUCY2C, which can be radiolabeled with a radionuclide such as Indium- 111 ( H 1 In), Lutetium- 177 ( 177 LU) or Actinium-225 ( 225 Ac) to form radionuclide-chelated radiopharmaceuticals.
  • a radionuclide such as Indium- 111 ( H 1 In), Lutetium- 177 ( 177 LU) or Actinium-225 ( 225 Ac) to form radionuclide-chelated radiopharmaceuticals.
  • the synthesis of compounds of Formula I, or their radionuclide-chelated radiopharmaceuticals can be referred to J. Am. Chem. Soc. 2021, 143, 5497-5507; and US Patent No. 11,191,854.
  • Analytical HPLC-MS was performed using a Waters Acquity HPLC-MS system comprised of a Waters Acquity Binary Solvent Manager, a Waters Acquity Sample Manager (samples cooled to 10 °C), a Waters Acquity Column Manager (column temperature 30 °C), a Waters Acquity Photodiode Array Detector (monitoring at 254 nm and 214 nm), a Waters Acquity TQD with electrospray ionization and a Waters Acquity BEH C18, 2.1x50 mm (1.7 pm) column.
  • a Waters Acquity HPLC-MS system comprised of a Waters Acquity Binary Solvent Manager, a Waters Acquity Sample Manager (samples cooled to 10 °C), a Waters Acquity Column Manager (column temperature 30 °C), a Waters Acquity Photodiode Array Detector (monitoring at 254 nm and
  • Ethyl hydrazinoacetate hydrochloride (1.00 g, 6.47 mmol, 1 eq) was dissolved in deionized water (20 mL) followed by the addition of sodium carbonate (2.74 g, 25.9 mmol, 4 eq). The mixture was cooled in an ice bath and di-/c/7-butyl dicarbonate (3.53 g, 16.2 mmol, 2.5 eq) were added as a solution in THF (20 mL). The mixture was warmed to room temperature and stirred for 24 hours. The mixture was acidified to pH 4-5 by the addition of 1 M citric acid and then extracted with ethyl acetate (50 mL).
  • the linear peptide was dissolved in an 8: 1 mixture of water/acetonitrile at a concentration of 2 mM. Tris-2-carboxyethylphosphine was added as a 125 mM solution in water (1.2 eq based on linear peptide) and the solution stirred for 5 minutes at room temperature. A bicarbonate buffer (1 M, pH 8.5) was added to give a final buffer concentration of 0.1 M. A 50 mM solution of l,5-dichoro-2,4-pentanedione (1.6 eq based on linear peptide) in acetonitrile was added and the mixture stirred for 30 minutes. The resulting cyclized peptide was purified by preparative HPLC or automated reversed-phase flash chromatography to give the diketone-linker (DKL) modified peptide.
  • DKL diketone-linker
  • the DKL modified peptide (1 eq) was dissolved in a 5: 1 mixture of water/acetonitrile at a concentration of 2 mM. Ammonium acetate buffer (1 M, pH 4.5-5) was added to give a final buffer concentration of 0.1 M. L-NHNH2 or L11-L-NHNH2 dissolved in water (25 mM, 1.2 eq) was added and the mixture stirred for 24 hours. The crude peptide was purified by preparative HPLC to give the DOTAGA modified peptide.
  • Peptide binding was determined using biolayer interferometry, where streptavidin-coated probes were coated with a 1 pM concentration of biotinylated peptide, followed by blocking with Biotin at a concentration of 2 pM. After washing with buffer (IX PBS), probes were incubated with recombinant, Fc-tagged GUCY2C protein (extracellular domain, amino acids 24-430) at a concentration of 300 nM, followed by rinsing with IX PBS buffer. Binding affinities were determined for 32 peptides as well as a reference compound. Binding affinity (Kd) results are summarized in Table 3, where 0 nM ⁇ A ⁇ 30 nM, and B > 30 nM.
  • GUCY2C targeting peptide-radioligand competes with nonradioconjugated GUCY2C targeting peptide for available receptor sites. Data from competition is analysed to produce an IC50 value, which can be used to rank the relative receptor binding affinities of a series of ligands.
  • mice bearing colorectal tumour xenografts expressing GUCY2C are given compounds of Formula I, and then the radioactivity in various mouse organs, including tumour tissue, are measured to determine the biodistribution pattern of the GUCY2C targeting peptide-radioligand.
  • xenograft tumor bearing mice are either pre-administered or co-administered with nonradioconjugated GUCY2C targeting peptide along with the compounds of Formula I, to improve tumour uptake and the radiopharmaceutical's pharmacokinetic profile.
  • Pre-administration or co-administration of non-radioconjugated GUCY2C targeting peptide with the compounds of Formula I and the effect on tumour regression and overall survival of GUCY2C expressing colorectal xenograft tumour bearing mice are also be assessed.

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Abstract

L'invention concerne des composés comprenant un peptide monocyclique qui se lie spécifiquement à la guanylate cyclase 2C (GUCY2C) et comprend au moins deux résidus de cystéine avec deux unités de sulfure reliées par l'intermédiaire d'une fraction de 3,5-diméthylenepyrazole. L'invention concerne également des compositions pharmaceutiques et des méthodes de traitement du cancer avec celles-ci.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11191854B2 (en) * 2017-05-05 2021-12-07 Centre For Probe Development And Commercialization Pharmacokinetic enhancements of bifunctional chelates and uses thereof
WO2022115799A1 (fr) * 2020-11-30 2022-06-02 Rayzebio, Inc. Conjugués radiopharmaceutiques ciblant la guanylyle cyclase c, et compositions et utilisations de ceux-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11191854B2 (en) * 2017-05-05 2021-12-07 Centre For Probe Development And Commercialization Pharmacokinetic enhancements of bifunctional chelates and uses thereof
WO2022115799A1 (fr) * 2020-11-30 2022-06-02 Rayzebio, Inc. Conjugués radiopharmaceutiques ciblant la guanylyle cyclase c, et compositions et utilisations de ceux-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BLOMAIN ERIK S: "Translating colorectal cancer prevention through the guanylyl cyclase C signaling axis", EXPERT REV CLIN PHARMACOL, vol. 6, no. 5, pages 557 - 64, XP055918361, DOI: 10.1586/17512433.2013.827406 *

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