WO2015057585A1 - Composés thérapeutiques - Google Patents

Composés thérapeutiques Download PDF

Info

Publication number
WO2015057585A1
WO2015057585A1 PCT/US2014/060308 US2014060308W WO2015057585A1 WO 2015057585 A1 WO2015057585 A1 WO 2015057585A1 US 2014060308 W US2014060308 W US 2014060308W WO 2015057585 A1 WO2015057585 A1 WO 2015057585A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
optionally substituted
aryl
halogen
Prior art date
Application number
PCT/US2014/060308
Other languages
English (en)
Inventor
Robert A. FECIK
Michael T. Peterson
Original Assignee
Regents Of The University Of Minnesota
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regents Of The University Of Minnesota filed Critical Regents Of The University Of Minnesota
Publication of WO2015057585A1 publication Critical patent/WO2015057585A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Tubulysins are naturally occurring antimitotic tetrapeptides with potent anticancer activity against multidrug-resistant (MDR) cancer cells, acting by inhibition of tubulin polymerization.
  • MDR multidrug-resistant
  • Their first report was in 2000, when they were identified through a screen of the culture broths from myxobacteria Archangium gephyra and Angiococcus disciformis against mammalian cell lines (Sasse, F.; et al., Tubulysins, New Cytostatic Peptides from Myxobacteria Acting on Microtubuli Production, Isolation, Physico-chemical and Biological Properties. J Antibiot. 2000, 53, 879-885.).
  • Tubulysins follow a standard tetrapeptide template with a few key modifications to the core structure ( Figure 1).
  • the four amino acid residues are N-methyl-D- pipecolinic acid (Mep), L-isoleucine (He), tubuvaline (Tuv), and tubuphenylalanine or tubutyrosine (Tup or Tut).
  • Mep N-methyl-D- pipecolinic acid
  • He L-isoleucine
  • Tuv tubuvaline
  • Tut tubuphenylalanine or tubutyrosine
  • Variations exist at the oxygen and nitrogen of tubuvaline, where substitution of a rare N, O-acetal is present in certain members (1-10), and at the phenyl ring of the C-terminus residue based on either a phenylalanine or tyrosine source for this residue.
  • Tubulysins bind to ⁇ -tubulin at the peptide site of the Vinca alkaloid domain and exert their anticancer activity through inhibition and destabilization of microtubule polymerization (Khalil, M. W.; et al., Mechanism of Action of Tubulysin, an Antimitotic Peptide from Myxobacteria. ChemBioChem, 2006, 7, 678-683).
  • Microtubules are long, polymeric cylinders made up of a- and ⁇ -tubulin heterodimers and are essential to normal cellular function. These functions include maintenance of the cellular structure and transportation of cellular components involved in cell signaling, mitosis and apoptosis.
  • Microtubule cellular tasks are achieved through its frequent lengthening and shortening via polymerization/depolymerization of the heterodimeric tubulin subunits, termed 'dynamic instability' (Jordan, M. A.; et al., Microtubules as a Target for
  • Anticancer Drugs Nat. Rev. Cancer 2004, 4, 253-265.
  • Agents that affect the dynamic instability of microtubules have found success as anticancer agents. These include the taxanes and epothilones (inducing and stabilizing tubulin polymerization), and the Vinca alkaloids (disrupting and inhibiting microtubule polymerization).
  • Mitosis is the multistage process of cell division, wherein a parent cell replicates into two genetically identical daughter cells. In contrast to the microtubule dynamics of interphase, the resting phase of the cell cycle, comparatively rapid dynamic instability is necessary for proper attachment and movement of the duplicated
  • chromosomes through each stage of mitosis (Jordan et al., 2004).
  • drugs targeting microtubules cause incomplete delivery of chromosomes to the metaphase plate, a process critical to cell division (Jordan and Wilson 2004).
  • Even one chromosome not aligned at the metaphase plate will stop forward mitotic progress, trapping the cell mid-mitosis and eventually causing programmed cell death, or apoptosis (Jordan et al., 2004).
  • These agents' effectiveness against malignant cells can be partially explained by the higher rate of mitosis cancer cells undergo compared to normal cells. An increased incidence of mitosis puts cancer cells in a position of vulnerability with drugs that arrest the mitotic cycle (Jordan et al., 2004).
  • Tubulysin A A Potential Anticancer and Antiangiogenic Natural Product. Biochem. J. 2006, 396, 235-242, Khalil et al., 2006). Additionally, cell angiogenesis was severely hindered upon treatment with tubulysin A, which may prove to be another venue in which these compounds exert their effects.
  • Competitive binding studies have shown non-competitive inhibition of vinblastine with tubulysin A, similarly to the peptide antimitotics dolastatin 10 and phomopsin A (Khalil et al., 2006). This, together with NMR conformation studies showing that tubulysin A and epothilone A share a common tubulin binding site (Kubicek, K.; et al., The Tubulin-Bound
  • Naturally derived tubulysins have shown potent in vitro growth inhibitory activity against a variety of different cancer cell lines, including breast (Ranganathan et al. 2009), cervix (Sasse et al. 2000, Steinmetz, H.; et al., Isolation, Crystal and Solution Structure Determination, and
  • tubulysin A in hollow fiber assays of 12 human cancer cell lines
  • tubulysins A and B show no therapeutic window
  • Tubulysins A and B show no therapeutic window
  • Tubulysin-Peptide Nanoparticles with Potent Antitumor Activity Clin. Cancer Res. 2009, 15, 181- 189, Reddy, J. A.; et al., In Vivo Structural Activity and Optimization Studies of Folate-Tubulysin Conjugates. Mol. Pharm. 2009, 6, 1518-1525).
  • Targeted delivery of tubulysins by conjugation to cancer-specific substrates has seen limited success in mouse studies. Over- expression of the folate receptor in cancer cells was taken advantage of by conjugation of tubulysins to folate, where the drug is released for its anticancer action follow cancer cell selective absorption of the complex (Vlahov, I.
  • anti-cancer agents as well as anti-cancer agents that are effective against drug-resistant cancers.
  • anti-cancer agents that disrupt microtubule dynamics (e.g., by inhibiting the polymerization of tubulin).
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers).
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers).
  • MDR drug resistant forms
  • R 1 is (d-Q alkyl
  • each R 2 is independently H or (C ! -C 6 )alkyl
  • R 3 is H or (C C 6 )alkyl
  • R 4 is (d-C 6 )alkyl
  • R 5 is H or (d-C 6 )alkyl
  • R 6 is (C]-C 6 )alkyl
  • R 7 is H or (C 1 -C 6 )alkyl
  • R 7 and R 8 together with the nitrogen to which they are attached form a 4-10 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from halogen, oxo, (C 1 -C 3 )alkyl, -OH and -0(C 1 -C 3 )alkyl;
  • R 12 when R 12 is NR 7 R 8 then R 9 is H or (C 1 -C 6 )alkyl, and R 10 is (C r C 6 )alkyl wherein the (d-
  • C 6 )alkyl of R 10 is substituted with one -C0 2 H group; or R 9 and R 10 together with the atoms to which they are attached form a 5, 6 or 7 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from (C 1 -C 6 )alkyl and oxo;
  • R 13 is R 13a
  • R 9 is H or (d-C 6 )alkyl
  • R 10 is (d-C 6 )alkyl wherein the (C ! -C 6 )alkyl of R 10 is substituted with one -C0 2 H group; or R 13 is R 13b , and R 9 and R 10 together with the atoms to which they are attached form a 5, 6 or 7 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from (d- C 6 )alkyl and oxo;
  • R 11 is aryl, wherein any aryl of R 11 is optionally substituted with one or more groups independently selected from halogen, (d-C 3 )alkyl, -OH or -0(C 1 -C 3 )alkyl;
  • R 12 is NR 7 R 8 or OR 13 ;
  • R a is (d-C 6 )alkyl
  • R b and R c are each independently selected from H and (C 1 -C 6 )alkyl; or R b and R c together with the nitrogen to which they are attached form a 4, 5, 6 or 7 heterocycle wherein the heterocycle is optionally substituted with one or more groups selected from (C 1 -C 6 )alkyl and oxo; and
  • n 1, 2, 3 or 4;
  • One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • One embodiment provides a method for treating cancer (e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers) in a mammal (e.g., a human), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, to the mammal.
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer
  • drug resistant forms e.g., MDR
  • One embodiment provides a method for inhibiting cancer (e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers) cell growth comprising contacting the cancer cell in vitro or in vivo with a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer
  • drug resistant forms e.g., MDR
  • One embodiment provides a method for inhibiting cancer (e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers) cell growth comprising contacting the cancer cell in vitro or in vivo with an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to provide an cancer inhibiting effect in the cell.
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer
  • drug resistant forms e.g., MDR
  • One embodiment provides a method for inhibiting tubulin polymerization in a mammal (e.g., a human), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • One embodiment provides a method for inhibiting tubulin polymerization in a mammal (e.g., a human) in need of such treatment, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, to the mammal to provide a inhibition of tubulin polymerization effect.
  • a mammal e.g., a human
  • One embodiment provides a method for inhibiting angiogenesis in a mammal (e.g., a human), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • One embodiment provides a method for inhibiting angiogenesis in a mammal (e.g., a human) in need of such treatment, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, to the mammal to provide an angiogenesis inhibition effect.
  • a mammal e.g., a human
  • One embodiment provides a method for inhibiting tubulin polymerization in a cell (e.g., a cancer cell (e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers), comprising contacting the cell in vitro or in vivo, with a compound of formula I or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • a cancer cell e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers
  • a compound of formula I or a salt e.g., a pharmaceutically acceptable salt
  • One embodiment provides a method for inhibiting tubulin polymerization in a cell (e.g., a cancer cell (e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers), comprising contacting the cell in vitro or in vivo, with a compound of formula I or a salt (e.g., a pharmaceutically acceptable salt) thereof effective to inhibit tubulin polymerization in the cell.
  • a cancer cell e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers
  • a compound of formula I or a salt e.g., a pharmaceutically acceptable salt
  • One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy.
  • One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of cancer (e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers).
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers).
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer
  • drug resistant forms e.g., MDR
  • One embodiment provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating cancer (e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer as well as drug resistant forms (e.g., MDR) of these cancers) in an mammal (e.g., a human).
  • cancer e.g., kidney cancer, cervical cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, ovarian cancer and prostate cancer
  • drug resistant forms e.g., MDR
  • One embodiment provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.
  • FIG 1 shows the structures of naturally occurring tubulysins.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2 or 3 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle).
  • Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system.
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring.
  • Typical aryl groups include, but are not limited to phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
  • heterocyclyl or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms. It is to be understood that the point of attachment for a heterocycle or heterocycle can be at any suitable atom of the heterocycle including a carbon atom and a heteroatom (e.g., a nitrogen).
  • heterocycle also includes a heterocycle as defined above that is fused to a phenyl to form a fused bi cyclic heterocycle.
  • the heterocycle is a 4-10 membered monocyclic or bicyclic heterocycle from about 1-9 carbon atoms and from about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,
  • the compounds disclosed herein can also exist as tautomeric isomers in certain cases.
  • this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( H or D).
  • a - CH 3 group may be substituted with -CD 3 .
  • the atom to which the bond is attached includes all stereochemical possibilities.
  • a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted.
  • the compound may be at least 51% the absolute stereoisomer depicted.
  • the compound may be at least 60% the absolute stereoisomer depicted.
  • the compound may be at least 80% the absolute stereoisomer depicted.
  • the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.
  • (C 1 -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl or hexyl and (C 2 -C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl.
  • a specific compound of formula I is a compound of formula la:
  • R 1 is (C,-C 6 )alkyl
  • each R 2 is independently H or (C 1 -C )alkyl
  • R 3 is H or (d-C 6 )alkyl
  • R 4 is (C 1 -C 6 )alkyl
  • R 5 is H or (d-C 6 )alkyl
  • R 6 is (C ! -C 6 )alkyl
  • R 7 is H or (C r C 6 )alkyl
  • R 7 and R 8 together with the nitrogen to which they are attached form a 4-10 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from halogen, oxo, (C 1 -C3)alkyl, -OH and -0(C 1 -C3)alkyl;
  • R 9 is H or (d-C 6 )alkyl, and R 10 is (d-C 6 )alkyl wherein the (C C 6 )alkyl of R 10 is substituted with one -C0 2 H group; or R 9 and R 10 together with the atoms to which they are attached form a 5, 6 or 7 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from (d-C6)alkyl and oxo;
  • R 11 is aryl, wherein any aryl of R 11 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C3)alkyl, -OH or -0(d-C3)alkyl;
  • R a is (d-C 6 )alkyl
  • R b and R c are each independently selected from H and (C]-C6)alkyl; or R b and R c together with the nitrogen to which they are attached form a 4, 5, 6 or 7 heterocycle wherein the heterocycle is optionally substituted with one or more groups selected from (d-C 6 )alkyl and oxo; and
  • n 1 , 2, 3 or 4;
  • a specific group of compounds of formula I are compounds wherein R 9 is H or (d- C 6 )alkyl, and R 10 is (Ci-C 6 )alkyl wherein the (C C 6 )alkyl of R 10 is substituted with one -C0 2 H group.
  • a specific value for R 9 is H.
  • R 10 is (C 2 -C 4 )alkyl substituted with one -C0 2 H group.
  • R 10 A specific value for R 10 is:
  • a specific value for R 1 is methyl.
  • n 3
  • a specific value for R 2 is H.
  • a specific value for R is H.
  • R 4 is (C 3 -C 5 )alkyl.
  • R 4 is butyl
  • R 4 A specific value for R 4 is:
  • a specific value for R 5 is H.
  • R 6 is (C 2 -C4)alkyl.
  • R 6 is propyl
  • R 6 A specific value for R 6 is:
  • R 11 is phenyl, wherein any phenyl of R 11 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 3 )alkyl, -OH and -0(C 1 -C 3 )alkyl.
  • R 11 is phenyl
  • a R 8 is:
  • a specific compound of formula I is:
  • a specific compound of formula I is a compound of formula lb:
  • R 1 is (d-C 6 )alkyl
  • each R 2 is independently H or (C 1 -C 6 )alkyl
  • R 3 is H or (d-Q alkyl
  • R 5 is H or (C C 6 )alkyl
  • R 4 is (C]-C 6 )alkyl
  • R 6 is (C 1 -C 6 )alkyl
  • R 13 is R 13a , R 9 is H or (d-C 6 )alkyl, and R 10 is (d-C 6 )alkyl wherein the (d-C 6 )alkyl of R 10 is substituted with one -C0 2 H group; or R 13 is R 13b , and R 9 and R 10 together with the atoms to which they are attached form a 5, 6 or 7 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from (C 1 -C 6 )alkyl and oxo;
  • R 11 is aryl, wherein any aryl of R 9 is optionally substituted with one or more groups independently selected from halogen, (d-C 3 )alkyl, -OH or -0(C 1 -C 3 )alkyl; and
  • n 1, 2, 3 or 4;
  • a specific compound of formula I is a compound of formula lc:
  • R 9 is H or (d-C 6 )alkyl
  • R 10 is (C 1 -C 6 )alkyl, wherein the (CrC 6 )alkyl is substituted with one -C0 2 H group.
  • a specific value for R 9 is H.
  • R 10 is (C 2 -C 4 )alkyl substituted with one -C0 2 H group.
  • R 10 A specific value for R 10 is:
  • a specific com ound of formula I is a compound of formula Id:
  • R 9 and R 10 together with the atoms to which they are attached form a 5, 6 or 7 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from (d-C ⁇ alkyl and oxo.
  • R 9 and R 10 together with the atoms to which they are attached form a 5 membered heterocycle, wherein the heterocycle is optionally substituted with one or more groups independently selected from (C 1 -C 6 )alkyl and oxo.
  • R 9 and R 10 together with the atoms to which they are attached form a pyrrolidinyl, wherein the pyrrolidinyl is optionally substituted with one or more groups independently selected from or oxo.
  • a specific value for R is methyl
  • n 3
  • a specific value for R 2 is H.
  • a specific value for R 3 is H.
  • R 4 is (C 3 -C )alkyl.
  • R 4 is butyl
  • a specific value for R 4 is:
  • a specific value for R 5 is (C 2 -C 4 )alkyl.
  • R 6 is propyl
  • R 6 A specific value for R 6 is:
  • a specific value for R 11 is phenyl, wherein any phenyl of R 11 is optionally substituted with more groups independently selected from halogen, (d-C 3 )alkyl, -OH and -0(C 1 -C 3 )alkyl.
  • a specific value for R 11 is phenyl.
  • a specific compound is:
  • a compound of formula I, or a salt thereof can be prepared by converting compound A, or a salt thereof to the compound of formula I, or a salt thereof:
  • a compound of formula A, or a salt thereof can be prepared by converting compound B, or a salt thereof to the compound of formula I, or a salt thereof:
  • compound A is prepared from compound B, by the reaction of
  • R 8 is (C!-C 6 )alkyl, (C 2 -C 6 )alkenyl, aryl, -OR a , or -NR b R c , wherein any (Q- C 6 )alkyl or (C 2 -C 6 )alkenyl of R 8 is optionally substituted with one or more groups selected from halogen and wherein any aryl of R 8 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 3 )alkyl, -OH, -0(d-C 3 )alkyl, -C0 2 H,
  • a compound of formula I, or a salt thereof can be prepared by converting compound A to the com ound of formula I:
  • R 13 is R 13a' or R 13b' , wherein; R 13a' is CH 2 C1, (C 2 -C 6 )alkyl, (C 2 -C 6 )alkenyl or aryl, wherein any (C 2 -C 6 )alkyl or (C 2 - C )alkenyl of R 13a is optionally substituted with one or more halogen and wherein any aryl of R 13a is optionally substituted with one or more groups independently selected from halogen, (C ⁇ - C 3 )alkyl, -OH and -0(C C 3 )alkyl; and
  • R 13b' is (Q-C f alkyl, -(C 2 -C 6 )alkenyl or aryl wherein any (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl of R 6b is optionally substituted with one or more halogen, and wherein any aryl of R 13b is optionally substituted with one or more groups independently selected from halogen, (Q-C ⁇ alkyl, -OH and -0(d-C 3 )alkyl.
  • a compound of formula I, or a salt thereof can also be prepared by converting compound A to the com ound of formula I:
  • R 13a is CH 2 C1, (C 2 -C 6 )alkyl, (C 2 -C 6 )alkenyl or aryl, wherein any (C 2 -C 6 )alkyl or (C 2 - C 6 )alkenyl of R 13a is optionally substituted with one or more halogen and wherein any aryl of R 13a is optionally substituted with one or more groups independently selected from halogen, (Q- C 3 )alkyl, -OH and -0(C C 3 )alkyl; and
  • R 13b' is d-C 6 )alkyl, (C 2 -C 6 )alkenyl or aryl wherein any (C C 6 )alkyl or (C 2 -C 6 )alkenyl of R 6b is optionally substituted with one or more halogen, and wherein any aryl of R 13 is optionally substituted with one or more groups independently selected from halogen, (Q-C ⁇ alkyl, -OH and -0(C 1 -C 3 )alkyl.
  • DMAP dimethyl aminopyridine
  • DCC dimethyl aminopyridine
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts include organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate,
  • Suitable inorganic acid addition salts may also be formed, which include a physiological acceptable anion, for example, chloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as
  • compositions or formulations in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other agents that are useful for the treatment of breast cancers, lung cancers, ovarian cancers, and Kaposi sarcoma.
  • agents include doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin, doxorubicin,
  • the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat breast cancers, lung cancers, ovarian cancers, and Kaposi sarcoma.
  • the ability of a compound of the invention to act as an anticancer agent may be determined using pharmacological models which are well known to the art, or using Test A below which describes cytotoxicity assays using various cancer cell lines.
  • Test A Cytotoxicity assay
  • Cytotoxity assays were performed against various cancer cell lines using methods known in the literature. Representative experimental descriptions of one such assay using a human ovarian carcinoma cell line can be found at Raghavan, B., et al., Cytotoxic Simplified Tubulsis Analogs, J. Med. Chem., 2008, 51, 1530-1533. Cytotoxicity assays using different known cancer cell lines were also carried out using assays similar to those described in Ragnaven and Sani. Experimental results from Test A for representative compounds described herein are shown in Tables 1 and 2. (
  • Ketone 9 (200 mg, 0.353 mmol, 1 equiv) was added as a solution in THF (6 mL, with 3 mL wash) dropwise. The reaction was stirred at 0 °C for 30 min and was then warmed to room temperature. After 3.5 h, TLC (20% EtOAc:hexanes) showed remaining starting material. The reaction was re-cooled to 0 °C and additional BH 3 » SMe 2 (2.0 M in THF, 0.21 mL, 0.42 mmol, 1.2 equiv) was added. The reaction was slowly warmed to room temperature overnight. After 24 h total, TLC showed complete consumption of starting material.
  • Compound 23 is also a compound of the invention.
  • the reaction was concentrated under reduced pressure and purification by HPLC (C 18 , 250 x 10 mm, 0-20% MeCN/0.04% aqueous HCl over 2 min, 20% MeCN/0.04% aqueous HCl for 2 min, 20-90% MeCN/0.04% aqueous HCl over 35 min, 90% MeCN/0.04% aqueous HCl for 5 min, 90-10% MeCN/0.04% aqueous HCl over 5 min, 3 mL/min) afforded the benzyl ester intermediate as a white solid (1.3 mg, 42 % yield) as confirmed by HRMS. The intermediate was brought forward without further characterization.
  • Compound 27 was obtained using compound 20 (5.2 mg, 6.8 ⁇ , 1 equiv), pyridine (14 ⁇ , 0.17 mmol, 25 equiv) and trimethylacetyl chloride (21 ⁇ , 0.17 mmol, 25 equiv) following the standard procedure outlined in Example 12 and after purification by HPLC (C 18 , 150 x 10 mm, 30- 35% MeCN/25 mM aqueous N3 ⁇ 4OAc, pH 4.78 over 3 min, 35% MeCN/25 mM aqueous N3 ⁇ 4OAc, pH 4.78 for 7 min, 90% MeCN/25 mM aqueous N3 ⁇ 4OAc, pH 4.78 for 5 min, 5 niL/min).
  • Compound 28 was obtained using compound 20 (2.2 mg, 2.9 ⁇ , 1 equiv), pyridine (11 L, 0.14 mmol, 50 equiv), and TFAA (4 ⁇ , 0.03 mmol, 10 equiv) following the standard procedure outlined in Example 12 and after purification by HPLC (C 18 , 150 x 10 mm, 10-50% MeCN/25 mM aqueous NFLtOAc, pH 4.78 over 10 min, 90% MeCN/25 mM aqueous N3 ⁇ 4OAc, pH 4.78 for 5 min, 5 mL/min).
  • the aqueous layer (pH 8) was extracted with CH 2 C1 2 (4 x 10 mL), and the combined organic layers were dried (Na 2 S04), filtered, and concentrated under reduced pressure.
  • the resulting orange/white solid (1.363 g) was a 1 :1 mixture of 32:imidazole by 1H NMR.
  • a portion of this crude intermediate was purified by partitioning between CH 2 C1 2 (15 mL) and saturated aqueous NH4CI (15 mL), and the layers were separated.
  • the aqueous layer was extracted with CH 2 C1 2 (3 x 10 mL), and the combined organic layers were dried (Na 2 S0 4 ), filtered, and concentrated under reduced pressure.
  • the resulting white solid was exclusively 32 by !
  • the aqueous layer (pH 11) was extracted with CH 2 C1 2 (4 x 10 mL), and the combined organic layers were dried (Na 2 S0 4 ), filtered, and concentrated under reduced pressure.
  • the resulting yellow liquid (2.63 g) was a 2: 1 mixture of 34: imidazole by 1H NMR.
  • a portion of this crude intermediate was purified by partitioning between CH 2 C1 2 (15 mL) and saturated aqueous N3 ⁇ 4C1 (15 mL), and the layers were separated.
  • the aqueous layer was extracted with CH 2 C1 2 (3 x 10 mL), and the combined organic layers were dried (Na 2 S0 4 ), filtered, and concentrated under reduced pressure.
  • Example 20 Pre aration of compound 102.
  • Example 22 Standard procedure for compound 104 acylation using anhydrides in pyridine.
  • Example 23 Standard procedure for compound 104 acylation using DCC activated acids.
  • Example 31 Preparation of compound 112 and compound 113.
  • Example 32 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) : ou des sels de ceux-ci. L'invention porte également sur des compositions pharmaceutiques comprenant un composé de formule (I), des procédés de préparation de composés de formule (I), des intermédiaires utiles pour la préparation de composés de formule (I) et des méthodes thérapeutiques pour le traitement du cancer.
PCT/US2014/060308 2013-10-14 2014-10-13 Composés thérapeutiques WO2015057585A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201361890754P 2013-10-14 2013-10-14
US201361890789P 2013-10-14 2013-10-14
US61/890,754 2013-10-14
US61/890,789 2013-10-14

Publications (1)

Publication Number Publication Date
WO2015057585A1 true WO2015057585A1 (fr) 2015-04-23

Family

ID=52828585

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/060308 WO2015057585A1 (fr) 2013-10-14 2014-10-13 Composés thérapeutiques

Country Status (1)

Country Link
WO (1) WO2015057585A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11229708B2 (en) 2015-12-04 2022-01-25 Seagen Inc. Conjugates of quaternized tubulysin compounds
WO2023102627A1 (fr) * 2021-12-06 2023-06-15 Cristália Produtos Químicos Farmacêuticos Ltda Procédé de préparation de témozolomide
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100047841A1 (en) * 2007-02-27 2010-02-25 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Synthesis of desacetoxytubulysin h and analogs thereof
US20110027274A1 (en) * 2009-08-03 2011-02-03 Medarex, Inc. Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof
US20110245295A1 (en) * 2008-09-25 2011-10-06 Universitat Des Saarlandes Bioactive pre-tubulysins and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100047841A1 (en) * 2007-02-27 2010-02-25 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Synthesis of desacetoxytubulysin h and analogs thereof
US20110245295A1 (en) * 2008-09-25 2011-10-06 Universitat Des Saarlandes Bioactive pre-tubulysins and use thereof
US20110027274A1 (en) * 2009-08-03 2011-02-03 Medarex, Inc. Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11229708B2 (en) 2015-12-04 2022-01-25 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds
WO2023102627A1 (fr) * 2021-12-06 2023-06-15 Cristália Produtos Químicos Farmacêuticos Ltda Procédé de préparation de témozolomide

Similar Documents

Publication Publication Date Title
AU2016248366B2 (en) Heterocycles useful as IDO and TDO inhibitors
CA3118354A1 (fr) Derives de pyridazine en tant qu'agents de degradation de smarca2/4
EP3388427B1 (fr) Dérivés de la dolastatine 10 et auristatines
KR101831005B1 (ko) 테트라히드로카르볼린 유도체
WO2018089355A1 (fr) Composés mono et spirocycliques contenant du cyclobutane et de l'azétidine en tant qu'inhibiteurs de l'intégrine alpha v
EA025845B1 (ru) Модуляторы фармакокинетических свойств лекарственных средств
EA019749B1 (ru) Противовирусные соединения
AU2011221037A1 (en) 1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine derivative and use of same as HIV integrase inhibitor
CN107108660A (zh) 硼酸衍生物
CA3179526A1 (fr) Derives de diamine macrocyclique servant d'inhibiteurs d'ent pour le traitement de cancers, et leur combinaison avec des antagonistes du recepteur de l'adenosine
JP2021531310A (ja) ボロン酸誘導体
WO2015057585A1 (fr) Composés thérapeutiques
JP2020531510A (ja) ボロン酸誘導体
JPWO2003064422A1 (ja) イミダゾ［１，２−ａ］ピリジン誘導体
KR20220005554A (ko) 전구약물 화합물
GB2583606A (en) Indoleamine 2,3-Dioxygenase inhibitors and use of same in medicine
US9782392B2 (en) Azaindole derivative
CA3141747A1 (fr) Nouveaux antagonistes de 5-ht2tricycliques
KR20080077414A (ko) 스트렙토그라민 유도체, 이의 제조방법 및 이를 함유하는 조성물
JP2020019732A (ja) γ−チューブリン阻害剤
JP2009013176A (ja) 抗腫瘍剤
OA17575A (en) Derivatives of dolastatin 10 and auristatins.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14853324

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14853324

Country of ref document: EP

Kind code of ref document: A1