US20170190735A1 - Derivatives of dolaproine-dolaisoleuine peptides - Google Patents

Derivatives of dolaproine-dolaisoleuine peptides Download PDF

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US20170190735A1
US20170190735A1 US15/313,906 US201515313906A US2017190735A1 US 20170190735 A1 US20170190735 A1 US 20170190735A1 US 201515313906 A US201515313906 A US 201515313906A US 2017190735 A1 US2017190735 A1 US 2017190735A1
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methoxy
methyl
pyrrolidin
mmol
methylbutanamido
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Brian Alan MENDELSOHN
Julien DUGAL-TERRIER
Stuart Daniel BARNSCHER
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Agensys Inc
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Agensys Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
    • 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
    • A61K38/07—Tetrapeptides
    • 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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • dolaproine-dolaisoleuine peptide analogs are provided herein, pharmaceutical compositions comprising such compounds, and methods of treating cancer with such compounds.
  • Cancer is the second leading cause of human death exceeded only by coronary disease. In the U.S., cancer accounts for nearly 1 in 4 deaths. Worldwide, millions of people die from cancer every year. In the United States alone, as reported by the American Cancer Society, cancer causes the death of well over a half-million people annually, with over 1.5 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise. In the early part of the next century, cancer is predicted to become the leading cause of death unless new medicines are found.
  • carcinomas of the lung, prostate, breast, colon, pancreas, ovary, and bladder represent the primary causes of cancer death. With very few exceptions, metastatic cancer is fatal. Moreover, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered. Many cancer patients experience strong anxieties driven by the awareness of the potential for recurrence or treatment failure. Many cancer patients experience physical debilitations following treatment. Furthermore, many cancer patients experience a recurrence.
  • Promising new cancer therapeutics include the dolastatins and synthetic dolastatin analogs such as auristatins (U.S. Pat. Nos. 5,635,483, 5,780,588, 6,323,315, and 6,884,869; Shnyder et al. (2007) Int. J. Oncol. 31:353-360; Otani, M. et al. Jpn. J. Cancer Res. 2000, 91, 837-844; PCT Intl. Publ. Nos. WO 01/18032 A3, WO 2005/039492, WO 2006/132670, and WO 2009/095447; Fennell, B. J. et al. J. Antimicrob. Chemther.
  • auristatins U.S. Pat. Nos. 5,635,483, 5,780,588, 6,323,315, and 6,884,869
  • auristatins have several properties which make them attractive for pharmaceutical development. First, these compounds are extremely potent. Second, their preparation is straight-forward because of the peptidic scaffold. Third, they possess good pharmacokinetic and metabolic profiles compared to peptides in general, or to other cancer drug classes in particular.
  • R 1 and R 2 are each independently —H or alkyl; X is —O—, —NR z —, —S—, or is absent;
  • R 15 and R 16 are each independently —H, —OH, —NH 2 , —SH, —N 3 , alkyl, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, or -alkyl-N 3 ;
  • R 4 is a group of the formula:
  • R 17 and R 18 are each independently —H, —OH, —NH 2 , —SH, —N 3 , —CO 2 H, alkyl, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, -alkyl-N 3 or -alkyl-CO 2 H
  • R 5 is sec-butyl or isobutyl
  • R 6 is —H or alkyl
  • R 7 and R 8 are each independently —H, alkyl, —CO 2 R a , CONR b R c , substituted or unsubstituted phenyl, or substituted or unsubstituted heterocyclic ring; wherein R a is —H or alkyl; R b and R c are each independently H or alkyl;
  • R 9 is —H or alkyl; or R 9 is taken together with R 4 and the atoms to which they are attached to
  • composition comprising an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Also provided herein is a method of treating a subject suffering from or diagnosed with cancer, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Also provided herein is use of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treatment of cancer in a subject in need of such treatment.
  • Also provided herein is use of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of cancer in a subject in need of such treatment.
  • kits containing at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need of such treatment, and instructions for use.
  • Also provided herein is an article of manufacture comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need of such treatment.
  • FIG. 1 shows in vitro tubulin polymerization data for tubulin treated with Example 2, Example 4, and Example 6. Untreated (buffer) tubulin shows the basal level of tubulin polymerization. A tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 2 shows in vitro tubulin polymerization data for tubulin treated with Example 1, Example 3, and Example 5.
  • Untreated (buffer) tubulin shows the basal level of tubulin polymerization.
  • a tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 3 shows in vitro tubulin polymerization data for tubulin treated with Example 8, Example 9, and Example 12. Untreated (buffer) tubulin shows the basal level of tubulin polymerization. A tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 4 shows in vitro tubulin polymerization data for tubulin treated with Example 7, Example 10, and Example 11. Untreated (Buffer) tubulin shows the basal level of tubulin polymerization. A tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 5 shows in vitro tubulin polymerization data for tubulin treated with Example 19, Example 20, and Example 21.
  • Untreated (Buffer) tubulin shows the basal level of tubulin polymerization.
  • a tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 6 shows in vitro tubulin polymerization data for tubulin treated with Example 13, Example 16, and Example 22. Untreated (Buffer) tubulin shows the basal level of tubulin polymerization. A tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 7 shows in vitro tubulin polymerization data for tubulin treated with Example 14, Example 15, Example 18, Example 20, and Example 23. Untreated (Buffer) tubulin shows the basal level of tubulin polymerization. A tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 8 shows in vitro tubulin polymerization data for tubulin treated with Example 17, Example 19, Example 25, and Example 26.
  • Untreated (Buffer) tubulin shows the basal level of tubulin polymerization.
  • a tubulin stabilizer (Paclitaxel) and a tubulin de-stabilizer (Control) were used as controls. All compounds were used at a final concentration of 10 ⁇ M.
  • FIG. 9 shows the results for Examples 1, 2, 3 and Paclitaxel in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 10 shows the results for Examples 1, 2, 3 and Paclitaxel in an in vitro cytotoxicity experiment using HCT15 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 11 shows the results for Examples 1, 2, 3 and Paclitaxel in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 12 shows the results for Examples 4, 5, and 6 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 13 shows the results for Examples 4, 5, and 6 in an in vitro cytotoxicity experiment using HCT15 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 14 shows the results for Examples 4, 5, and 6 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 15 shows the results for Examples 7, 8, and 9 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 16 shows the results for Examples 7, 8, and 9 in an in vitro cytotoxicity experiment using HCT15 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 17 shows the results for Examples 7, 8, and 9 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 18 shows the results for Examples 10, 11, and 12 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 19 shows the results for Examples 10, 11, and 12 in an in vitro cytotoxicity experiment using HCT15 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 20 shows the results for Examples 10, 11, and 12 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 21 shows the results for Examples 13, 14, and 15 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 22 shows the results for Examples 13, 14, and 15 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 23 shows the results for Examples 16, 21, and 22 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 24 shows the results for Examples 16, 21, and 22 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 25 shows the results for Examples 17, 18, and 19 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 26 shows the results for Examples 17, 18, and 19 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 27 shows the results for Examples 20 and 23 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 28 shows the results for Examples 20 and 23 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 29 shows the results for Examples 25 and 26 in an in vitro cytotoxicity experiment using PC3 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • FIG. 30 shows the results for Examples 25 and 26 in an in vitro cytotoxicity experiment using HCC-1954 cells, as described in Example B1. Data is graphed as percent survival versus concentration of test compound, compared to untreated control wells.
  • alkyl refers to a saturated C 1 -C 12 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • Particular alkyl groups are those having 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • Examples of alkyl groups include, but are not limited to: methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), n-pentyl, isopentyl, tert-pentyl, and n-hexyl, isohexyl.
  • an alkyl group has normal, secondary, or tertiary carbon atoms and does not have cyclic carbon atoms.
  • alkenyl refers to a C 2 -C 12 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond.
  • Particular alkenyl groups are those having 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Examples include, but are not limited to: vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH 2 ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ).
  • an alkenyl group has normal, secondary, or tertiary carbon atoms and does not have cyclic carbon atoms.
  • alkynyl refers to a C 2 -C 12 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond.
  • Particular alkynyl groups are those having 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Examples include, but are not limited to: ethynyl (—C ⁇ CH) and 2-propynyl (—CH 2 C ⁇ CH).
  • an alkynyl group has normal, secondary, or tertiary carbon atoms and does not have cyclic carbon atoms.
  • alkoxy refers to an —O-alkyl group, where the O is the point of attachment to the rest of the molecule, and alkyl is as defined above.
  • heterocycloalkyl refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Particular heterocycloalkyl groups are those having from 3 to 8 ring atoms or from 5 to 7 ring atoms per ring structure.
  • the ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members.
  • Illustrative entities, in the form of properly bonded moieties include:
  • heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • Particular heteroaryl groups are those having from 3 to 8 ring atoms or from 5 to 7 ring atoms per ring structure.
  • Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:
  • heterocycle encompass both the “heterocycloalkyl” and “heteroaryl” moieties as defined above.
  • heterocyclyl, heteroaryl and heterocycloalkyl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents chloro, fluoro, bromo, or iodo.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
  • any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
  • the solvent is water and the solvates are hydrates.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds described herein and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • C i-j when applied herein to a class of substituents, is meant to refer to embodiments of any of the compositions, uses, or methods described herein for which each and every one of the number of carbon members, from i to j including i and j, is independently realized.
  • the term C 1-3 refers independently to embodiments that have one carbon member (C 1 ), embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C 3 ).
  • C n-m alkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n ⁇ N ⁇ m, with m>n.
  • R 1 and R 2 are each independently —H or alkyl, for example C 1-6 alkyl In some embodiments, R 1 and R 2 are each independently —H or methyl. In some embodiments, R 1 and R 2 are each independently alkyl. In some embodiments, R 1 and R 2 are both methyl. In some embodiments, R 1 and R 2 are both —H.
  • X is absent. In other embodiments, X is —O—. In some embodiments, R 1 and R 2 are each independently alkyl, and X is absent. In some embodiments, R 1 and R 2 are both methyl, and X is absent. In other embodiments, R 1 and R 2 are both —H, and X is —O—. In some embodiments, X is —NR z —, wherein R z is —H or alkyl. In some embodiments, R z is —H. In some embodiments, X is R z is alkyl, for example C 1-6 alkyl or methyl.
  • R 3 is
  • R 15 and R 16 are each independently —H, —OH, —NH 2 , —SH, —N 3 , alkyl, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, or -alkyl-N 3 .
  • R 15 and R 16 are each independently —H, alkyl, —(CH 2 ) 0-6 C ⁇ CH, —(CH 2 ) 0-6 CH ⁇ CH 2 , —(CH 2 ) 0-6 OH, —(CH 2 ) 0-6 NH 2 , —(CH 2 ) 0-6 SH, or —(CH 2 ) 0-6 N 3 .
  • R 15 and R 16 are each independently —H, —OH, or alkyl.
  • R 15 and R 16 are each independently —H, —OH, or methyl.
  • R 15 is —OH and R 16 is hydrogen.
  • R 15 is —OH and R 16 is methyl.
  • R 3 is in the R stereochemical configuration relative to the remainder of the molecule. In other embodiments, R 3 is in the S stereochemical configuration relative to the remainder of the molecule. In certain embodiments, the R 3 group itself contains one or more chiral centers, and those stereocenters are each independently in the R or S configuration.
  • R 4 is
  • R 1 and R 8 are each independently —H, —OH, —NH 2 , —SH, —N 3 , —CO 2 H, alkyl, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, —alkyl-N 3 or -alkyl-CO 2 H.
  • R 4 is
  • R 17 is —H, —OH, —NH 2 , —SH, —N 3 , —CO 2 H, alkyl, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, -alkyl-N 3 or -alkyl-CO 2 H
  • R 18 is —H, —OH, —NH 2 , —SH, —N 3 , —CO 2 H, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, -alkyl-N 3 or -alkyl-CO 2 H.
  • R 17 and R 18 are each independently —H, alkyl, —(CH 2 ) 0-6 C ⁇ CH, —(CH 2 ) 0-6 CH ⁇ CH 2 , —(CH 2 ) 0-6 OH, —(CH 2 ) 0-6 NH 2 , —(CH 2 ) 0-6 SH, or —(CH 2 ) 0-6 N 3 .
  • R 17 and R 18 are each independently —H, —OH, —NH 2 , —SH, —N 3 , —CO 2 H, alkyl, -alkyl-NH 2 , or -alkyl-N 3 .
  • R 17 and R 18 are each independently —H, —OH, —NH 2 , —SH, —N 3 , —CO 2 H, methyl, —CH 2 NH 2 , or —CH 2 N 3 .
  • R 4 is taken together with R 9 and the atoms to which they are attached to form a substituted or unsubstituted heterocycloalkyl ring. In certain embodiments, R 4 is taken together with R 9 and the atoms to which they are attached to form a 5- to 7-member heterocycloalkyl ring, which may be unsubstituted or substituted with one or more groups selected from —OH, —NH 2 , —SH, and —N 3 . In certain embodiments, the heterocycloalkyl ring is a pyrrolidine ring, which may be unsubstituted or substituted with one or more groups selected from —OH, —NH 2 , —SH, and —N 3 .
  • R 4 is in the R stereochemical configuration relative to the remainder of the molecule. In other embodiments, R 4 is in the S stereochemical configuration relative to the remainder of the molecule. In certain embodiments, the R 4 group itself contains one or more chiral centers, and those stereocenters are each independently in the R or S configuration.
  • R 5 is sec-butyl. In other embodiments, R 5 is isobutyl. In certain embodiments, R 5 is in the R stereochemical configuration relative to the remainder of the molecule. In other embodiments, R 5 is in the S stereochemical configuration relative to the remainder of the molecule. In some embodiments, the chiral center within the R 5 group is in the R configuration, and in other embodiments, that center is in the S configuration.
  • R 6 is —H. In other embodiments, R 6 is alkyl, for example C 1-8 alkyl, C 1-4 alkyl, methyl, or ethyl.
  • R 7 and R 8 are each independently is —H, alkyl, —CO 2 R a or —CONR b R c ; wherein R a is —H or alkyl, for example C 1-6 alkyl or methyl; and R b and R c are each independently —H or alkyl, for example C 1-6 alkyl or methyl.
  • R 7 and R 8 are each independently is substituted or unsubstituted phenyl or substituted or unsubstituted heterocyclic ring, wherein the phenyl or heterocyclic ring may be substituted with one or more groups selected from halo, oxo, hydroxy, amino, alkyl, and alkoxy.
  • R 7 is unsubstituted 3- to 8-member heterocyclic ring.
  • R 7 is substituted 3- to 8-member heterocyclic ring.
  • R 8 is phenyl which is optionally substituted with halo.
  • R 7 is in the R stereochemical configuration relative to the remainder of the molecule. In other embodiments, R 7 is in the S stereochemical configuration relative to the remainder of the molecule.
  • R is in the R stereochemical configuration relative to the remainder of the molecule.
  • R 8 is in the S stereochemical configuration relative to the remainder of the molecule.
  • R 7 is —CO 2 R a —CONR b R c ; tetrazolyl or thiazolyl, wherein R a is —H or alkyl, for example C 1-6 alkyl or methyl; and R b and R c are each independently —H or alkyl, for example C 1-6 alkyl or methyl; and R 8 is phenyl which is optionally subsutituted with halo.
  • R 9 is —H. In other embodiments, R 9 is alkyl, for example C 1-8 alkyl, C 1-4 alkyl, methyl, or ethyl. In some embodiments, R 9 is —H or methyl. In some embodiments, R 9 is methyl.
  • R 10 is —H. In other embodiments, R 10 is alkyl, for example C 1-8 alkyl, C 1-4 alkyl, methyl, or ethyl. In some embodiments, R 10 is —H or methyl. In some embodiments, R 10 is methyl.
  • R 11 is —H. In other embodiments, R 11 is alkyl, for example C 1-8 alkyl, C 1-4 alkyl, methyl, or ethyl. In some embodiments, R 11 is —H or methyl. In some embodiments, R 11 is methyl.
  • R 12 is —H. In other embodiments, R 12 is alkyl, for example C 1-8 alkyl, C 1-4 alkyl, methyl, or ethyl. In some embodiments, R 12 is —H or methyl. In some embodiments, R 12 is methyl.
  • R 13 is —H. In other embodiments, R 13 is alkyl, for example C 1-8 alkyl, C 1-4 alkyl, methyl, or ethyl. In some embodiments, R 13 is —H or methyl. In some embodiments, R 13 is methyl.
  • R 14 is —H. In some embodiments, R 14 is alkyl, for example C 1-6 alkyl, methyl, or ethyl. In some embodiments, R 14 is —OH.
  • R 14 is in the R stereochemical configuration relative to the remainder of the molecule. In other embodiments, R 14 is in the S stereochemical configuration relative to the remainder of the molecule.
  • R 7 is —CO 2 R a , wherein R a is —H or alkyl, for example C 1-6 alkyl or methyl; R 8 is phenyl; and R 14 is —H.
  • R 7 is —CONR b R c , wherein R b and R c are each independently —H or alkyl, for example C 1-6 alkyl or methyl; R 8 is phenyl; and R 14 is —H.
  • R 7 is alkyl, for example C 1-6 alkyl or methyl; R 8 is phenyl; and R 14 is —OH.
  • R 7 is methyl
  • R 8 is phenyl
  • R 14 is —OH.
  • R 7 and R 14 are both —H
  • R 8 is pyridinyl, piperidinyl, unsubstituted phenyl, or phenyl substituted with halo, for example fluoro, chloro, or bromo.
  • R 7 is —CO 2 R a , wherein R a is —H or alkyl, for example C 1-6 alkyl or methyl; R 8 is —H or alkyl, for example C 1-6 alkyl or methyl; and R 14 is alkyl, for example C 1-6 alkyl, methyl, or ethyl.
  • R is —CO 2 R a , wherein R a is —H or alkyl, for example C 1-6 alkyl or methyl; R 8 is —H or alkyl, for example C 1-6 alkyl or methyl; and R 14 is —OH.
  • R 15 and R 16 are each independently —H, —OH, or C 1-6 alkyl
  • R 17 is —OH, —NH 2 , —SH, —N 3 , —CO 2 H, —C 1-6 alkyl-NH 2 , alkynyl, alkenyl, or —C 1-6 alkyl-N 3 ; and R 18 is —H or C 1-6 alkyl;
  • R 15 and R 16 are each independently —H, —OH, or methyl
  • R 17 is —OH, —NH 2 , —SH, —N 3 , —CO 2 H, aminomethyl, alkynyl, alkenyl, or azidomethyl; and R 18 is —H or methyl;
  • R 15 and R 16 are each independently —H, —OH, or C 1-6 alkyl
  • R 17 is —N 3 , and R 18 is —H or methyl
  • R 15 and R 16 are each independently —H, —OH, or C 1-6 alkyl
  • R 17 is —N 3 , and R 18 is —H or methyl
  • variable group definition provided herein can be used in combination with any other variable group definition provided herein, such that all possible combinations and permutations of variable groups provided herein, where chemically feasible, are contemplated.
  • compounds of Formula (I) are selected from the group consisting of:
  • compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include acid addition salts such as sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsul
  • compositions comprising compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate formulation and administration of a compound described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, emulsifiers, or taste-modifying agents.
  • pharmaceutical compositions are sterile compositions.
  • compositions described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • the compounds described herein are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the pharmaceutical compositions and compounds described herein may be administered in the inventive methods by a suitable route of delivery, e.g., oral, nasal, parenteral, rectal, topical, ocular, or by inhalation.
  • treat or “treating” as used herein is intended to refer to administration of a compound described herein to a subject for the purpose of creating a therapeutic benefit. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, or lessening the severity of, a disease, disorder, or condition, or one or more symptoms of cancer.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • an effective amount means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds described herein may be ascertained by routine methods, such as modeling, dose escalation or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about 1 ug to 2 mg of active compound per kilogram of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/day.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the compounds described herein may be used in pharmaceutical compositions or methods in combination with additional active ingredients in the treatment of cancer.
  • the additional active ingredients may be administered separately from a compound described herein or may be included with a compound described herein in a pharmaceutical composition provided herein.
  • additional active ingredients are those that are known or discovered to be effective in treating cancer, including those active against another target associated with cancer, such as but not limited to, Velcade, Rituximab, Methotrexate, Herceptin, Vincristine, Prednisone, Irinotecan, or the like, or a combination thereof.
  • Such a combination may serve to increase efficacy, decrease one or more side effects, or decrease the required dose of a disclosed compound.
  • the compounds described herein may be used in pharmaceutical compositions or methods in combination with additional active ingredients in the treatment of cancer.
  • the additional active ingredients may be administered separately from a compound described herein or may be included with a compound described herein in a pharmaceutical composition provided herein.
  • additional active ingredients are those that are known or discovered to be effective in treating cancer, including those active against another target associated with cancer, such as but not limited to, Velcade, Rituximab, Methotrexate, Herceptin, Vincristine, Prednisone, Irinotecan, or the like, or a combination thereof.
  • Such a combination may serve to increase efficacy, decrease one or more side effects, or decrease the required dose of a disclosed compound.
  • reactions are run in the presence of diethyl cyanophosphonate (DEPC), PyBrOP, PyBOP, BOP, diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), HBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), and the like, or a combination thereof.
  • DEPC diethyl cyanophosphonate
  • PyBrOP PyBrOP
  • PyBOP PyBOP
  • Reactions are typically run in the presence of a tertiary amine base, such as diisopropylethylamine.
  • Suitable solvents include dichloromethane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate and the like.
  • the amino protecting group on resultant dipeptide (C) is removed by deprotection under suitable conditions. For example, where PG is a Boc group, compound (C) is treated with trifluoroacetic acid to form free amine (D). Where PG is an Fmoc group, compound (C) is treated with piperidine or diethylamine to yield compound (D). Compound (D) is then coupled to amino acid derivative (E), in protected form if necessary, under peptide coupling conditions as described above, to generate tripeptide (F). Treatment with acid removes the carboxy protecting group to provide free acid (G).
  • Dov (dolavaline); Abu (2-aminobutyric acid); Dil (dolaisoleuine); Dpr (2,3-diaminopropionic acid); Su (succinimidinyl); Dab (2,4-diaminobutyric acid); Dap (dolaproine); Bzl (benzyl); and Tr (trityl).
  • Method A isocratic 80 water/10 acetonitrile/10 1% formic acid in water; 0.50-3.50 min: linear gradient 80 water/10 acetonitrile/10 1% formic acid in water to 0 water/90 acetonitrile/10 1% formic acid in water; 3.50-3.99 min isocratic 0 water/90 acetonitrile/10 1% formic acid in water; 3.99-4.00 min linear gradient 0 water/90 acetonitrile/10 1% formic acid in water to 80 water/10 acetonitrile/10 1% formic acid in water.
  • Method B isocratic 85 water/5 acetonitrile/10 1% formic acid in water; 0.50-1.60 min: linear gradient 85 water/5 acetonitrile/10 1% formic acid in water to 0 water/98 acetonitrile/2 1% formic acid in water; 1.60-1.80 min isocratic 0 water/98 acetonitrile/2 1% formic acid in water; 1.80-1.90 min linear gradient 0 water/98 acetonitrile/2 1% formic acid in water to 85 water/5 acetonitrile/10 1% formic acid in water; 1.90-2.00 min isocratic 85 water/5 acetonitrile/10 1% formic acid in water.
  • Boc-Dap-Phe-OMe was isolated by flash chromatography on silica gel (silica gel 40 ⁇ m, 60 ⁇ , 3.0 ⁇ 17.0 cm) using 2% to 10% MeOH in CH 2 Cl 2 as the eluent. A total of 7.45 g of Boc-Dap-Phe-OMe (16.61 mmol, 97% yield) was obtained.
  • CMPI 2-Chloro-1-methylpyridinium iodide
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.882 g Dov-Ser(Bzl)-Dil-OtBu (1.30 mmol, 48%) was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 1.09 g Dov-Ser(Bzl)-Dil-OtBu (1.58 mmol, 29%) was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10j Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.290 g Dov-Thr(Bzl)-Dil-Dap-Phe-OMe (0.300 mmol, 63%) was obtained as the TFA salt.
  • Boc-Dap-2-(2-pyridyl)ethylamine was isolated by flash chromatography on silica gel (silica gel 40 ⁇ m, 60 ⁇ , 3.0 ⁇ 17.0 cm) using 2% to 10% MeOH/1% NEt 3 in CH 2 Cl 2 as the eluent. A total of 7.42 g of Boc-Dap-2-(2-pyridyl)ethylamine (19.0 mmol, 89% yield) was obtained.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.598 g Dov-Dpr(Boc)-Dil-OtBu (0.871 mmol, 46%) was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.150 g of Dov-Dpr(Fmoc)-Dil-Dap-2-(2-pyridyl)ethylamine was obtained as the TFA salt (0.146 mmol, 20%).
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.410 g of Dov-Dab(Boc)-Dil-OtBu (0.583 mmol, 34%) was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.2% aqueous formic acid as the eluent.
  • a total of 449 mg of enriched Dov-Dab(Fmoc)-Dil-Dap-Phe-OMe was obtained as the formic acid salt.
  • the resulting viscous oil was purified by flash chromatography on silica gel (silica gel 40 ⁇ m, 60 ⁇ , 23 ⁇ 123 mm) using 5% to 10% MeOH in CH 2 Cl 2 as the eluent. A total of 0.888 g of Fmoc-Val-Dil-Dap-2-(2-pyridyl)ethylamine (1.11 mmol, 73% yield) was obtained.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.168 g of N,N-dimethylSer(Bzl)-OH (0.498 mmol, 19%) was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.220 g of N,N-dimethylSer(Bzl)-Val-Dil-OtBu (0.325 mmol, 14%) was obtained as the TFA salt.
  • N,N-dimethylSer(Bzl)-Val-Dil-OtBu TFA salt 0.220 g, 0.325 mmol
  • CH 2 Cl 2 5 mL
  • TFA 2 mL
  • analysis by LCMS showed the reaction was complete.
  • Volatile organics were evaporated in vacuo to yield crude N,N-dimethylSer(Bzl)-Val-Dil-OH TFA salt that was used without further purification.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent. A total of 1.54 g of N,N-dimethylThr(Bzl)-OH (4.38 mmol, 19%) was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.161 g of N,N-dimethylThr(Bzl)-Val-Dil-OtBu (0.234 mmol, 7%) was obtained as the TFA salt.
  • N,N-dimethylThr(Bzl)-Val-Dil-OtBu TFA salt (0.220 g, 0.325 mmol) in CH 2 Cl 2 (5 mL) was added TFA (2 mL). After 10 h, analysis by LCMS showed the reaction was complete. Volatile organics were evaporated in vacuo to yield crude N,N-dimethylThr(Bzl)-Val-Dil-OH TFA salt that was used without further purification.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • CMPI (2.76 g, 10.8 mmol) was added to the reaction mixture and the reaction mixture was allowed to reach room temperature. After 12 h, analysis by LCMS showed the reaction was complete. The crude reaction was washed with 0.1 M HCl (100 mL ⁇ 2), followed by brine (20 mL ⁇ 2). The organic fraction was dried over a pad of magnesium sulfate, filtered and concentrated in vacuo. Fmoc-Cys(Trt)-Dil-OtBu was isolated by flash chromatography on silica gel (silica gel 40 ⁇ m, 60 ⁇ , 3.0 ⁇ 17.0 cm) using 18% to 90% EtOAc in hexanes as the eluent. A total of 4.73 g of Fmoc-Cys(Trt)-Dil-OtBu (5.72 mmol, 85% yield) was obtained.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 1.40 g Dov-Cys(Trt)-Dil-OtBu (1.66 mmol, 52%) was obtained as the TFA salt.
  • the crude reaction mixture was diluted with saturated sodium bicarbonate (10 mL) and extracted with EtOAc (50 mL ⁇ 3). The combined organic fractions were washed with brine, dried over a pad of magnesium sulfate, filtered, and concentrated in vacuo and used without further purification.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.509 g of enriched Dov-Cys(Trt)-Dil-Dap-Phe-OtBu was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • a total of 0.378 g Dov-Ser(Bzl)-Dil-Dap-Phe-OtBu (0.380 mmol, 98%) was obtained as the TFA salt.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • the title compound may be prepared using methods analogous to those described in the Examples and general synthetic schemes.
  • the crude reaction mixture was purified by preparatory RP-HPLC with a Phenomenex Synergi 10 ⁇ Max-RP 80 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.05% aqueous TFA as the eluent.
  • the crude reaction mixture was purified by preparatory RP-HPLC with a Phenomenex Gemini-NX 10 ⁇ C-18 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous ammonium hydroxide as the eluent. A total of 13.4 mg of the title compound was obtained (0.017 mmol, 33%).
  • LCMS RT 1.05 min (Method B); ESI-MS m/z 772.61 [M+H] + ; HRMS m/z 772.5078 [C 39 H 65 N 9 O 7 +H] + .
  • the crude reaction mixture was purified by preparatory RP-HPLC with a Phenomenex Gemini-NX 10 ⁇ C-18 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous ammonium hydroxide as the eluent. A total of 15.4 mg of the title compound was obtained (0.017 mmol, 59%).
  • LCMS RT 1.27 min (Method B); ESI-MS m/z 828.8 [M+H] + ; HRMS m/z 828.5671 [C 39 H 66 N 6 O 8 +H] + .
  • CMPI (2.03 g, 7.93 mmol) was added to the reaction mixture which was allowed to slowly warm to room temperature and stirred for 10 h.
  • the crude reaction was washed with 1 M HCl (30 mL ⁇ 2), followed by brine (25 mL ⁇ 2).
  • the organic fraction was dried over a pad of magnesium sulfate, filtered, and concentrated in vacuo.
  • the crude product was used without further purification.
  • a total of 3.13 g of cis-Fmoc-Pro(4-N 3 )-Dil-OtBu was obtained as a yellow oil (5.05 mmol, 76%).
  • LCMS RT 1.73 min (Method B); ESI-MS m/z 621.46 [M+H] + .
  • the combined organic fractions were washed with brine, dried over a pad of magnesium sulfate, filtered, and concentrated in vacuo.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 5% to 90% MeCN in 0.1% aqueous NH 4 OH as the eluent. A total of 37.0 mg of the title compound was obtained as a yellow solid (0.046 mmol, 18%) was obtained as a yellow solid.
  • CMPI (5.93 g, 23.2 mmol) was added to the reaction mixture which was allowed to slowly warm to room temperature and stirred for 10 h.
  • the crude reaction was washed with 1 M HCl (30 mL ⁇ 2), followed by brine (25 mL ⁇ 2).
  • the organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
  • the crude product was used without further purification.
  • a total of 7.85 g of Boc-Asp(OBzl)-Dil-OtBu was obtained as a brown oil (13.9 mmol, 90%).
  • LCMS RT 1.72 min (Method B); ESI-MS m/z 565.3 [M+H] + .
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous NH 4 OH as the eluent.
  • a total of 2.00 g of Dov-Asp(OBzl)-Dil-OH was obtained as a white solid (3.74 mmol, 28%).
  • LCMS RT 1.10 min (Method B); ESI-MS m/z 536.5 [M+H] + .
  • the crude reaction mixture was purified by preparatory RP-HPLC with a Phenomenex Gemini-NX 10 ⁇ C-18 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous ammonium hydroxide as the eluent. A total of 2.7 mg of the title compound was obtained (0.003 mmol, 18%).
  • LCMS RT 0.85 min (Method B); ESI-MS m/z 746.6 [M+H]+; HRMS m/z 802.5799 [C 43 H 75 N 7 O 7 +H] + .
  • the crude reaction mixture was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous formic acid as the eluent.
  • a total of 3.16 g of Fmoc-MeVal-Abu(3-N3)-Dil-OtBu (4.12 mmol, 65%) was obtained as the formic acid salt.
  • LCMS RT 2.08 min (Method A); ESI-MS m/z 722.7 [M+H] + .
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous TFA as the eluent. A total of 354 mg of the title compound was obtained as the TFA salt (0.406 mmol, 79%).
  • LCMS RT 1.15 min (Method B); ESI-MS m/z 758.24 [M+H] + ; HRMS m/z 758.4915 [C 38 H 63 N 9 O 7 +H] + .
  • the crude reaction mixture was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.1% aqueous formic acid as the eluent. A total of 26.0 mg of the title compound was obtained as a white formic acid salt (0.030 mmol, 5%).
  • LCMS RT 1.41 min (Method B); ESI-MS m/z 815.33 [M+H] + ; HRMS m/z 815.5383 [C 42 H 70 N 8 O 8 +H] + .
  • the crude reaction mixture was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.1% aqueous formic acid as the eluent.
  • a total of 648 mg of Fmoc-MeVal-Abu(3-N 3 )-Dil-Dap-Phe-OtBu was obtained as a white formic acid salt (0.598 mmol, 97%).
  • LCMS RT 1.41 min (Method B); ESI-MS m/z 1037.41 [M+H] + .
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous TFA as the eluent. A total of 360 mg of the enriched title compound was obtained as the TFA salt.
  • LCMS RT 1.19 min (Method B); ESI-MS m/z 759.13 [M+H] + ; HRMS m/z 759.4755 [C 38 H 62 N 8 O 8 +H] + .
  • the crude reaction was diluted with saturated sodium bicarbonate (10 mL) and extracted with EtOAc (20 mL ⁇ 3). The combined organic fractions were washed with brine, dried over a pad of magnesium sulfate, filtered, and concentrated in vacuo.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 10% to 90% MeCN in 0.1% aqueous formic acid as the eluent.
  • the crude oil was purified by preparatory RP-HPLC with a Phenomenex Gemini NX-C18 10 ⁇ 110 ⁇ column (150 ⁇ 30 mm) using 5% to 95% MeCN in 0.1% aqueous TFA as the eluent. A total of 20.0 mg of the title compound was obtained as the TFA salt (0.022 mmol, 5%).
  • LCMS RT 1.37 min (Method B); ESI-MS m/z 783.42 [M+H] + ; HRMS m/z 783.4979 [C 38 H 62 N 12 O 6 +H] + .
  • the in vitro efficacy of the compounds was measured by evaluating their cytotoxic activity on various cancer cell lines. This assay was conducted in clear tissue-culture treated 96-well plates.
  • the cell lines used were PC3 (human prostate carcinoma), HCC-1954 (human mammary ductal carcinoma), and HCT15 (human colorectal adenocarcinoma, Pgp-expressing). Cells were seeded at approximately 1,000-1,500 cells per well in 50 ⁇ L of growth media (RPMI-1640+10% heat-inactivated fetal bovine serum) and incubated overnight at 37° C. with 5% CO 2 to allow them to attach.
  • growth media RPMI-1640+10% heat-inactivated fetal bovine serum
  • tubulin polymerization was evaluated on bovine brain tubulin.
  • tubulin was seeded at approximately 400 ⁇ g per well in 100 ⁇ L of general tubulin buffer, and then treated with 10 ⁇ M final concentration of compound in duplicate at the initiation of the assay.
  • Tubulin polymerization assays were usually carried out at 37° C. for 60 min after the addition of test compounds.
  • Tubulin polymerization was determined by absorbance spectroscopy using the optical density value at 340 nm. To assess the amount of polymerized tubulin, the optical density value at 340 nm was obtained each minute after the addition of test compounds.
  • tubulin inhibition studies were performed using HTS-Tubulin Polymerization Assay Kit (Cytoskeleton Inc.; Catalog #BK004P), using the following sample protocol:
  • FIGS. 1-8 Data for compounds tested in this assay are presented in FIGS. 1-8 .
  • test compounds are diluted with 20 mM Histidine, 5% Sucrose, pH 6 with 15% DMSO.
  • Male ICR SCID mice (Taconic Farm, Hudson, N.Y.) are housed in standard rodent micro isolator cages. Environment controls for the animal rooms are set to maintain a temperature between 20-24° C., a relative humidity between 30% to 70%, and an approximate 12 h light/12 h dark cycle. Food and water are provided ad libitum.

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WO2024036329A3 (en) * 2022-08-12 2024-04-11 Seagen Inc. Cytotoxic compounds and conjugates thereof

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JP2017519740A (ja) 2017-07-20
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