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WO2025091117A1 - Composés modulant la fonction physiologique et l'homéostasie - Google Patents

Composés modulant la fonction physiologique et l'homéostasie Download PDF

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Publication number
WO2025091117A1
WO2025091117A1 PCT/CA2024/051430 CA2024051430W WO2025091117A1 WO 2025091117 A1 WO2025091117 A1 WO 2025091117A1 CA 2024051430 W CA2024051430 W CA 2024051430W WO 2025091117 A1 WO2025091117 A1 WO 2025091117A1
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salt
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formula
hydrate
anhydrous
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Carla Jehan Catherine SPINA
Katrina Helen VIZELY
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Noa Therapeutics Inc
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Noa Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/06—Zinc compounds

Definitions

  • the specification relates to compounds useful for modulating cellular physiological function and homeostasis and methods of use thereof.
  • AhR aryl hydrocarbon receptor
  • aryl hydrocarbon receptor Aryl hydrocarbon receptor: Its roles in physiology. Biochemical pharmacology. 2021 Mar 1 ; 185:114428; Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annual review of pharmacology and toxicology. 2003 Apr 1 ;43(1 ):309-34, incorporated herein by reference).
  • AhR heat shock protein 90
  • XRE xenobiotic responsive elements
  • CYP1A1 has therefore been used as a model system by which to define the mechanism by which AhR regulates gene expression (Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annual review of pharmacology and toxicology. 2003 Apr 1 ;43(1 ):309-34, incorporated herein by reference). Where binding of AhR to different intranuclear transcription factors may lead to non-canonical signaling pathways through binding of non-XRE deoxyribonucleic acid (DNA) elements.
  • DNA non-XRE deoxyribonucleic acid
  • AhR pathway Activation of the AhR pathway has been known to occur through a variety of ligands which are both synthetic in nature and those that are naturally occurring.
  • the majority of compounds which activate AhR include planar, hydrophobic halogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs) or related compounds thereof (Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annual review of pharmacology and toxicology. 2003 Apr 1 ;43(1 ):309-34, incorporated herein by reference).
  • Exogenous ligands are known to be inclusive of tea flavonoids (epigallocatechin gallate), bacterial metabolic byproducts including indirubin, and coal tar high molecular weight aromatic hydrocarbons (Palermo CM, Westlake CA, Gasiewicz TA.
  • tea flavonoids epigallocatechin gallate
  • bacterial metabolic byproducts including indirubin
  • coal tar high molecular weight aromatic hydrocarbons (Palermo CM, Westlake CA, Gasiewicz TA.
  • Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein. Biochemistry. 2005 Apr 5;44(13):5041-52; Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller CA, Kato T, Saeki K, Matsuda T.
  • Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. Journal of Biological Chemistry. 2001 Aug 24;276(34):31475-8; Furue M, Tsuji G, Mitoma C, Nakahara T, Chiba T, Morino-Koga S, Uchi H. Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor. Journal of dermatological science. 2015 Nov 1 ;80(2):83-8; Hahn ME. The aryl hydrocarbon receptor: a comparative perspective. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology. 1998 Nov 1 ; 121 (1 -3):23-53, all incorporated herein by reference).
  • Endogenous ligands are known to be inclusive of kyneurine, lumichrome, lipoxin A4, bilirubin, kynurenic acid, and 6-formylindolo[3,2-b] carbazole (FICZ) (Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. The Journal of Immunology. 2010 Sep 15;185(6):3190-8; Kou Z, Dai W. Aryl hydrocarbon receptor: Its roles in physiology. Biochemical pharmacology. 2021 Mar 1 ; 185:114428; Yale CJ, Bend JR.
  • AhR As a promiscuous receptor, a diverse population of ligands are able to activate the AhR pathway.
  • the range of AhR ligands is known to elicit differentiated downstream pathways through activation of the AhR. This variable activation along with co-activation of other AhR independent pathways can lead to the detrimental effects seen in ligands like 2,3,7,8-tetrachlorodibenzodioxin TCDD or the beneficial effects of ligands found in naturally occurring and pharmaceutically derived ligands (Larigot L, Juricek L, Dairou J, Coumoul X. AhR signaling pathways and regulatory functions. Biochimie open. 2018 Dec 1 ;7:1-9, incorporated herein by reference).
  • AhR AhR
  • pathway interactors results in a complex system with downstream impacts that are dependent upon the ligand structure
  • AhR ligands activate CYP1A1 pathways without activation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway and subsequent upregulation of the downstream heme oxygenase 1 gene (HMOX-1), glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H dehydrogenase [quinone] 1 (NQO1) to attenuate ROS production.
  • Constructive therapeutic pathways invoking AhR are also known to upregulate FLG and LOR through OVOL-1 pathways.
  • M is Zn, and n is 1 , 2 or 3;
  • X is a bidentate ligand, and each X independently is:
  • a 1 and A 2 each independently is CH, N, or SH;
  • R 6 is (_) (absent and is a negative charge), -H, or a C1-3 alkyl;
  • R 7 is -H, -Ci-Cs-substituent or aryl, wherein the -Ci-Cs-substituent or aryl optionally has one or more heteroatoms;
  • R 8 is -H, -OH, a Ci -3-alkyl substituent optionally having one or more heteroatoms, a -OCi-3-alkyl substituent optionally having one or more heteroatoms, or a halogen;
  • R 9 is - H, or a C1-3 alkyl substituent optionally having one or more heteroatoms;
  • a 11 and A 12 each independently is -CH or N;
  • R 11 and R 12 each independently is -H, a Ci-3-substituent optionally having one or more heteroatoms, a -O-Ci-3-substituent, or a halogen; [0030] - is a single or a double bond, and only one of > -> in > -> A 14 and z
  • a 13 is C-H or N
  • R 13 is -H, [0032] when - between A 13 and R 13 is a double bond, A 13 is C, and R 13 is
  • CH y wherein y is 1 or 2; and when y is 1 , the CH is coupled to a substituted or unsubstituted aryl or heteroaryl;
  • R 14 is -H, -COO (_) , or -
  • R 16 is CH Z optionally coupled to a substituted or unsubstituted aryl or heteroaryl, where z is 1 , 2 or 3;
  • R 14 when - of > -> R 14 is a double bond, R 14 is O or S; [0037] or
  • a 21 is N, and each of A 22 to A 27 independently is -CH or N; [0041] R 21 is -OR 24 or -SR 25 , wherein R 24 or R 25 is absent, -H, -Ci-Cs-alkyl or aryl; and
  • the specification relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), its hydrate form, anhydrous form, solvated form or salt thereof, disclosed herein, and a pharmaceutically acceptable excipient.
  • the specification relates to a use of the compound of formula (I), its hydrate form, anhydrous form, solvated form or salt thereof, as disclosed herein, for treatment of a disease associated with activation of aryl hydrocarbon receptor (AhR).
  • AhR aryl hydrocarbon receptor
  • the specification relates to a use of the compound of formula (I), its hydrate form, anhydrous form, solvated form or salt thereof, as disclosed herein, for modulating aryl hydrocarbon receptor (AhR) activity.
  • the specification relates to a process for preparation of the compound of formula (I), its hydrate form, anhydrous form, solvated form or salt thereof, the process comprising: [0050] reacting a zinc salt or zinc compound having a chelated ligand and one or more ligands in a solvent.
  • Figure 1 is a bar graph showing the fold change in AhR activation of stably transfected Human HT29 colon adenocarcinoma - AhR reporter cells (HT29- LuciaTM AhR Cells; InvivoGen; ht2l-ahr), following a 24-hour exposure of compound 1-5 at 6.25uM.
  • Adherent cells were plated at 56,000 cells/well into a 96 well plate. Fold change calculated at 24 hours, versus untreated media control.
  • the phrase “at least one of” is understood to be one or more.
  • the phrase “at least one of... and...” is understood to mean at least one of the elements listed or a combination thereof, if not explicitly listed.
  • “at least one of A, B, and C” is understood to mean A alone or B alone or C alone or a combination of A and B or a combination of A and C or a combination of B and C or a combination of A, B, and C.
  • the specification relates to a compound, its salt form, hydrate form or anhydrous form, which elicit activation of AhR pathways useful in treatment of a disease which may benefit from modulation of AhR pathways.
  • M is Zn, and n is 1 , 2 or 3;
  • X is a bidentate ligand, and each X independently is:
  • each R 4 independently is -H, or a C1-3 substituent optionally having one or more heteroatoms;
  • each R 5 independently is -H, a C1-3 alkyl
  • R 6 is (_) (absent and is a negative charge), -H, or a C1-3 alkyl;
  • R 7 is -H, -Ci-Cs-substituent or aryl, wherein the -Ci-Cs-substituent or aryl optionally has one or more heteroatoms;
  • R 8 is -H, -OH, a Ci -3-alkyl substituent optionally having one or more heteroatoms, a -OCi-3-alkyl substituent optionally having one or more heteroatoms, or a halogen;
  • R 9 is - H, or a C1-3 alkyl substituent optionally having one or more heteroatoms; [0080] (ii)
  • a 11 and A 12 each independently is -CH or N;
  • R 11 and R 12 each independently is -H, a Ci-3-substituent optionally having one or more heteroatoms, a -O-Ci-3-substituent, or a halogen;
  • - is a single or a double bond, and only one of - in - A 14 and z
  • R 14 is a double bond
  • a 13 is C-H or N
  • R 13 is -H
  • CH y wherein y is 1 or 2; and when y is 1 , the CH is coupled to a substituted or unsubstituted aryl or heteroaryl;
  • a 14 is N or CR 15 , wherein R 15 is
  • R 14 when - of - R 14 is a single bond, R 14 is -H, -COO (_) , or -
  • a 21 is N, and each of A 22 to A 27 independently is -CH or N;
  • R 21 is -OR 24 or -SR 25 , wherein R 24 or R 25 is absent, -H, -Ci-Cs-alkyl or aryl;
  • R 22 and R 23 each independently is -H, a Ci-3-substituent optionally having one or more heteroatoms, a halogen, or R 22 and R 23 together form a Cs- or Cs-membered aromatic ring, the Cs- or Cs-membered aromatic ring being optionally mono or di-substituted with C1-C3- alkyl, Ci-Cs-alkoxy, -NR 26 2, -C(O)R 27 , -COOR 28 , -CHO or halogen;
  • each of R 26 to R 28 is independently -H, -Ci-Cs-alkyl or aryl.
  • hydrate as used herein is not particularly limited and should be known or understood to a person of skill in the art.
  • a hydrate is a substance that contains water or its constituent elements. Hydrates can be considered as inorganic salts containing water molecules combined in a definite ratio as an integral part of the crystal that are either bound to a metal center or that have crystallized with the metal complex. Such hydrates are also said to contain water of crystallization or water of hydration.
  • anhydrous form as disclosed herein is not particularly limited and should be known or understood by a person of skill in the art.
  • An anhydrous form of a substance refers to a compound that contains no water or substantially no water. In practice, it is very difficult to achieve perfect dryness as anhydrous compounds gradually absorb water from the atmosphere, requiring careful storage. In one embodiment, an anhydrous compound is where water is generally absent from the crystal lattice of the compound.
  • salt as disclosed herein is not particularly limited and should be known or understood by a person of skill in the art.
  • the term includes acid or base addition salts, where an acid or a base is present or added to the compound to form its acid or base addition salt.
  • the compound of formula (I) is formed as a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt form of the compound of formula (I) may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.
  • Pharmaceutically acceptable salt of the compound of formula (I) refer to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Non-limiting examples of such salts can include, without limitation, acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid
  • the counter-ion can be, for example and without limitation, HCOs', BF4; CO3 2 -, NO3-, CIO4; SO4 2 ; F’, Br, C3H3O 2 -, NH 3 , MnO 4 -, NO 2 ’, BrOs; IO3-, Cr 2 O7 2 -, OH; CIO 3 ; HCO 2 -, and the like.
  • the metal (M) present in the compound of formula (I) is zinc (Zn).
  • Zinc has an electron configuration of [Ar]3d 10 4s 2 and is a member of the group 12 of the periodic table.
  • the oxidation state of zinc is +2, and is present as Zn +2 , having an electronic configuration of [Ar]3d 10 .
  • the geometry of the complexes can exist as square planar, distorted square planar, octahedral or distorted octahedra.
  • ligand is not particularly limited and should be known or understood by a person of skill in the art.
  • a ligand is an ion or molecule (having a functional group) that binds to a central metal atom to form a coordination complex. This is typically achieved by the ligand donating a pair of electron (forming a dative bond) to the electronegative central M element.
  • the bonding with the metal generally involves formal donation of one or more of the ligand's electron pairs, often through Lewis bases.
  • the nature of metal-ligand bonding can range from covalent to ionic.
  • the metal-ligand bond order typically can range from one to three, with higher bond orders also known to exist.
  • Ligands are viewed as Lewis bases, although some cases are known to involve Lewis acidic "ligands”.
  • the ligands as disclosed herein chelate with zinc to form a zinc complex.
  • the zinc complex can have 1 , 2 or 3 ligands that bind to zinc.
  • the ligands can be the same or different.
  • the zinc complex formed can be present as a salt form.
  • the zinc complex can be in an anhydrous form or hydrate form.
  • the zinc complex can also be present in a salt form of the hydrate or anhydrous form.
  • water can bind to the zinc metal in forming the complex.
  • each of the one or more ligand is a bidentate ligand.
  • bidentate ligand is not particularly limited and should be known or understood by a person of skill in the art.
  • a bidentate ligand is a Lewis base that can donate two pairs (“bi”) of electrons to a metal atom.
  • Bidentate ligands are often referred to as chelating ligands (“chelate” is derived from the Greek word for “claw”) because they can “grab” a metal atom in two places. It should be noted that the ligands disclosed herein can bind to zinc from more than two sites.
  • the ligand can bind from three (tridentate ligand) or four (tetradentate) sites.
  • the ligands disclosed herein are at least a bidentate ligand.
  • the ligands contemplated herein can also be tridentate or tetradentate, and thereby have three or four atoms that bond to zinc.
  • the position of the atom donating the lone pair of electrons to bind to the zinc is not particularly limited.
  • the binding can take place from a pair of electrons being donated from an atom present on the aromatic ring of the ligand, or from a moiety that is coupled to the aromatic ring, as disclosed herein.
  • the bidentate ligands, as disclosed herein can have the core structure of:
  • one or more of the ligands present in the compound of formula (1) is ligand (i) (or ligand type (i)), as shown below:
  • a 1 and A 2 each independently is CH, N, or SH;
  • each R 4 independently is -H, or a C1-3 substituent optionally having one or more heteroatoms;
  • R 6 is (_) (absent and is a negative charge), -H, or a C1-3 alkyl;
  • R 7 is -H, -Ci-Cs-substituent or aryl, wherein the -Ci-Cs-substituent or aryl optionally has one or more heteroatoms;
  • R 8 is -H, -OH, a Ci-3-alkyl substituent optionally having one or more heteroatoms, a -OCi-3-alkyl substituent optionally having one or more heteroatoms, or a halogen;
  • R 9 is - H, or a C1-3 alkyl substituent optionally having one or more heteroatoms.
  • the binding of the bidentate ligands to the zinc metal can take place from a number of different atoms on the ligand. For instance, when ligand (i) is present in the zinc complex, the lone pair of electrons from the ligand can be donated by A 1 , A 2 , D 1 , D 2 , R 1 , R 2 or R 3 , or the structure represented by A 1 , A 2 , D 1 , D 2 , R 1 , R 2 or R 3 .
  • the two pairs of electrons donated to zinc can come from any one or a combination of any two of A 1 , A 2 , D 1 , D 2 , R 1 , R 2 or R 3 .
  • the two pairs of electrons can be donated by a single functional group, such as -COO (_) , that can represent any one of A 1 , A 2 , D 1 , D 2 , R 1 , R 2 or R 3 .
  • the position of the atoms donating the lone pairs of electrons in the ligand is also not particularly limited, so long as the ligand can chelate to zinc.
  • the two lone pairs of electrons from the bidentate ligand can be donated by any one or two A 11 , A 12 , A 13 , A 14 , R 11 , R 12 , R 13 , or R 14 .
  • the two lone pairs of electrons from the bidentate ligand can be donated by any one or two A 21 , A 22 , A 23 , A 24 , A 25 , A 26 , A 27 , R 21 , R 22 , or R 23 .
  • the bidentate ligand present in the zinc complex of formula (I) can be any one or combination of ligand (i), (ii) or (iii).
  • the zinc complex of formula (I) can have only type of ligand, such ligand (i), (ii) or (iii).
  • the zinc complex of formula (I) can have any two types of the bidentate ligands, such as, ligands (i) and (ii), ligands (i) and (iii), or ligands (ii) and (iii).
  • the zinc complex of formula (I) can have all types of ligands (i), (ii) and (iii), depending on the compound of formula (I) being formed.
  • C1-9 substituent, and the like, as used herein is not particularly limited and should be known or understood by a person of skill in the art.
  • the term relates to an organic substituent having from one to nine carbon atoms.
  • the number of carbon atoms present in the substituent are noted in the subscript with C (denoting the carbon atom).
  • a C1-3 substituent refers to an organic substituent having from one to three carbon atoms
  • a C1-5 substituent refers to an organic substituent having from one to five carbon atoms.
  • An organic substituent, as used herein, is any chemical moiety containing carbon.
  • the C1-9 substituent can be, for example and without limitation, an alkyl, an alkenyl, an alkynyl, a cyclic structure, such as, for example and without limitation, a carbocyclic moiety, an aromatic moiety, a polycyclic moiety, or a combination thereof.
  • Non-limiting examples of a C1-9 substituent can include methyl, ethyl, ethylenyl, ethynyl, propyl, propylenyl, propynyl, isopropyl, butyl, butenyl, butynyl, phenyl, benzyl, cyclohexanyl, ethyl-cyclohexyl, coumarin moiety, and others.
  • the C1-9 substituent can be optionally substituted having one or more heteroatoms, -OR 4 , -SR 4 , -N(R 4 )2, or a halogen.
  • the presence of the non-carbon atom changes the class of organic compounds, but are considered to be included in the specification, so long as the total number of carbon atoms range from one to nine.
  • heteroatom refers to any atom other than carbon and hydrogen.
  • the heteroatom is one or more of nitrogen, oxygen, sulphur or a halogen.
  • halogen as used herein is not particularly limited and should be known or understood by a person of skill in the art.
  • the halogens are elements that form group 17 of the periodic table.
  • Halogen include fluorine, chlorine, bromine, or iodine.
  • the R 1 and R 2 can together form a Cs- or Cs-membered ring, optionally substituted, as disclosed herein.
  • the Cs- or Cs-membered ring are bonded to the aromatic core structure of ligand (i), and form a polycyclic ring structure.
  • the Cs- or Cs-membered ring can be an aromatic ring, or saturated or unsaturated ring.
  • structures, such as like, are contemplated to be within the scope of the specification.
  • the Cs- or Cs-membered ring optionally being mono or di-substituted with C1-3- alkyl, C1- 3-alkoxy, phenyl, -N(R 4 )2, -C(O)R 4 , -COOR 4 , or a halogen.
  • R 3 when both A 1 and A 2 are other than CH, R 3 is absent. As such, R 1 , R 2 and R 3 can only be present when one or both A 1 and A 2 are CH. When both, A 1 and A 2 are, for example, N and/or SH, then R 3 is not present in the ligand (i).
  • both D 1 and D 2 cannot be -H in ligand (i). If one of D 1 is -H, then the other D 2 is a substituent other than -H. Furthermore, both D 1 and D 2 can be other than -H in ligand (i) disclosed herein.
  • alkyl as used herein is not particularly limited and should be known or understood by a person of skill in the art.
  • an alkyl group is an alkane missing one hydrogen.
  • the term alkyl is intentionally unspecific to include many possible substitutions.
  • An acyclic alkyl has the general formula of -CnH2n+i.
  • a cycloalkyl group is derived from a cycloalkane by removal of a hydrogen atom from a ring and has the general formula -CnH2n-i.
  • an alkyl is a part of a larger molecule.
  • the smallest alkyl group is methyl, with the formula -CH3.
  • Ci-3-alkyl as used herein refers to an alkyl group having from one to three carbon atoms. Examples of a Ci-3-alkyl include, methyl, ethyl, propyl or isopropyl.
  • alkoxy is not particularly limited and should be known or understood by a person of skill in the art. Describe Ci-3-alkoxy [00130]
  • An alkoxy group is an alkyl group which is singularly bonded to oxygen, and can be denoted by the structure R-O, where R is an organic substituent.
  • a C1-3- alkoxy refers to an alkoxy group having from one to three carbon atoms. Examples of a Ci-3-alkoxy include methoxy (CH3O-), ethoxy (CH3CH2O-), propyloxy (CH3CH2CH2O-), or iso-propyloxy ((CH 3 ) 2 CHO-).
  • aryl as used herein is not particularly limited and should be known or understood by a person of skill in the art.
  • An aryl is any compound, functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon.
  • An example of an aryl group is phenyl (CeHs-), having the structure denotes the point of bonding of the phenyl group to the remaining chemical structure.
  • the carboxylic acid or phenolic group when a carboxylic acid or a phenolic group is present on the ligand, the carboxylic acid or phenolic group can be in the protonated form (-COOH or -OH) or it can be in the deprotonated form (-COO (_) or- O (_) ).
  • carboxylic acid or a phenolic structure when the term carboxylic acid or a phenolic structure is noted, both the protonated and deprotonated forms are contemplated within the context of the specification. Further, where a protonated form of carboxylic acid or phenolic group is denoted, the deprotonated form is also considered to be encompassed within it.
  • the form the carboxylic acid or phenol group is present in depends upon the pH of the solution, and the protonated form can convert to the deprotonated form at lower pH’s, and vice versa.
  • the amine group present on the chelate can be in a protonated form (-N (+) H) or the deprotonated form (-N:).
  • a protonated form -N (+) H
  • a deprotonated form -N:
  • a ligand binds to the zinc and forms a five or six membered ring, with an absence of adjacent bulky or sterically hindered moieties, is more likely to occur than when the chelation atoms are further apart in the ligand or adjacent to bulky or sterically hindered structures.
  • a particular ligand can chelate with the zinc from more than two locations, as noted herein.
  • the ligand can chelate with zinc from two different positions, as shown below, with chelation from the N and the O of the carboxylic acid moiety being more likely to occur.
  • the other possible chelation of the ligand is from the two oxygen atoms of the carboxylic acid group, and which is less likely to occur.
  • Complexes formed from types of chelation are contemplated and considered encompassed within the specification. (chelation through N and O is more likely than) (chelation through the two oxygen atoms of carboxylic acid is possible, however, less likely to occur).
  • the chelation of the ligand can also occur from more than two atoms, thereby being, for example and without limitation, a tridentate ligand or a tetradentate ligand.
  • the ligand is a tetradentate ligand, with binding of the ligand taking place from four different atoms in the ligand, as shown below, with the — (the arrow) representing the point of chelation of the ligand to the metal.
  • one or more of the ligands present in the compound of formula (1) is ligand (ii) (or ligand type (ii)), as shown below: [00139] wherein
  • a 11 and A 12 each independently is -CH or N;
  • R 11 and R 12 each independently is -H, a Ci-3-substituent optionally having one or more heteroatoms, a -O-Ci-3-substituent, or a halogen;
  • - is a single or a double bond, and only one of > -> in > -> A 14 and - R 14 is a double bond;
  • a 13 is C-H or N
  • R 13 is -H, [00144] when - between A 13 and R 13 is a double bond, A 13 is C, and R 13 is
  • CH y wherein y is 1 or 2; and when y is 1 , the CH is coupled to a substituted or unsubstituted aryl or heteroaryl;
  • a 14 is NH or CH2
  • a 14 is N or CR 15 , wherein R 15 is
  • R 14 is -H, -COO (_) , or-
  • R 16 is CH Z optionally coupled to a substituted or unsubstituted aryl or heteroaryl, where z is 1 , 2 or 3;
  • R 14 is O or S
  • the feature “ - ” in the structure of ligand (ii) can be a single or a double bond.
  • the feature “ - ” is present, one between A 13 and R 13 (denoted as A 13 -> R 13 ), a second instance can occur where ligand (ii) has the structural feature A 14 - C
  • C is the carbon of the five membered ring of ligand (ii)). It should be recognized by a person of skill in the art that the C bonded to A 13 , A 14 and R 14 can only form a double bond between one of A 14 and R 14 , and not both, as it would result in a carbon atom having five bonds. Consequently, in ligand (ii), only one of “ - ” in > -> A 14 and
  • CHy can be -CH2 or-CH-, which is bonded to substituted or unsubstituted heteroaryl. Consequently, when y is 1 , the CH is coupled to a substituted or unsubstituted aryl or heteroaryl.
  • the heteroaryl is not particularly limited and can have from four to nine carbon atoms (i.e. C4-9-heteroaryl).
  • the heteroaryl can be substituted with one or more Ci-3-substituent having one or more heteroatoms.
  • R 14 is a single bond
  • R 16 is CH Z optionally coupled to a substituted or unsubstituted aryl or heteroaryl, where z is 1 , 2 or 3.
  • CH Z can be -CH3, -CH2-, or-CH ⁇ , where the CH2 is bonded to another moiety and the CH is bonded to two other chemical moieties.
  • CHz is CH2 or CH, it is coupled to a substituted or unsubstituted aryl or heteroaryl.
  • the heteroaryl is not particularly limited and can have from four to nine carbon atoms (i.e. C4-9-heteroaryl).
  • the heteroaryl can be substituted with one or more Ci-3-substituents having one or more heteroatoms.
  • Non-limiting examples of ligand (ii) include
  • one or more of the ligands present in the compound of formula (1) is ligand (iii) (or ligand type (iii)), as shown below:
  • a 21 is N, and each of A 22 to A 27 independently is -CH or N.
  • R 21 is -OR 24 or -SR 25 , wherein R 24 or R 25 is absent, -H, -Ci- Cs-alkyl or aryl.
  • R 24 or R 25 is absent, there is a negative charge (anion formed) on O or S (represented as, O (_) or S (_) ).
  • R 22 and R 23 each independently is -H, a Ci-3-substituent optionally having one or more heteroatoms, a halogen, or R 22 and R 23 together form a Cs- or Cs-membered aromatic ring, the Cs- or Cs-membered aromatic ring being optionally mono or di-substituted with C1-C3- alkyl, Ci-Cs-alkoxy, -NR 26 2, -C(O)R 27 , -COOR 28 , -CHO or halogen, wherein each of R 26 to R 28 is independently -H, -C1- Cs-alkyl or aryl.
  • a non-limiting example of ligand (iii) includes
  • the compounds, their hydrate form, anhydrous form, or salt thereof in a first embodiment, for example and without limitation, can have a minimum solubility in aqueous media of 0.1 nM at 25 °C and 1 bar at neutral pH.
  • the compounds, their hydrate form, anhydrous form, or salt thereof in a second embodiment, for example and without limitation, can have a minimum solubility in aqueous media of 0.1 pM at 25 °C.
  • the compounds, their hydrate form, anhydrous form, or salt thereof in a first embodiment, for example and without limitation, can have a minimum solubility in non-aqueous media, including, for example and without limitation, in DMSO, of 0.1 pM at 25 °C and 1 bar at neutral pH.
  • the compounds, their hydrate form, anhydrous form, or salt thereof in a second embodiment, for example and without limitation, can have a minimum solubility in non-aqueous media, including, for example and without limitation, in DMSO, of 1 .0 pM at 25 °C.
  • the structures disclosed herein above permit secondary interactions encountered by the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, with atoms derived from solvents encountered by the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, during synthetic procedures, isolation procedures, formulation, and or therapeutic uses. These interactions may afford structures that include atoms and ligands derived encountered by the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, during synthesis, isolation, formulation and therapeutic uses.
  • Such secondary interactions may result in a ligand displacement, thereby affording an opening or exchange, wherein the atoms and ligands encountered in the secondary interaction may insinuate themselves into the compounds, its hydrate form, anhydrous form, solvated form or salt thereof.
  • Such structures are expressly contemplated in the present specification.
  • the specification also provides embodiments of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, disclosed herein as pharmaceutical formulations.
  • compositions of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, described herein may be manufactured in a manner that is known including, but not limited to dissolution, granulation, emulsification, mixing, encapsulation, lyophilizing or combinations thereof.
  • compositions may include appropriate solutions including but not limited to physiologically compatible buffers.
  • compositions may be formulated with the intention of delivery as a bolus injection or continuous infusion and may include excipients known in the art to enable suspension, stabilization, delivery, or dispersion.
  • the specification also provides embodiments of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, that may be formulated with appropriate penetrants, known in the art, to afford transmucosal or transcutaneous administration.
  • Such formulations may be inclusive of carriers including, but not limited to, liquids, gels, hydrogels, solids, slurries and may include suitable excipients known in the art to afford control over rheological and release properties.
  • the specification also provides embodiments of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, that may be formulated into an aerosolized, spray, or nebulized format, with or without the use of a suitable propellant known in the art.
  • Such formulations may be prepared in a solid, liquid or gel format through the inclusion of appropriate excipients known in the art.
  • Such formulations may be utilized for delivery of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, and formulations described herein to dermal, hair, mucosal membranes, or inhaled.
  • the specification also provides embodiments of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, that may be formulated into a reservoir such that the release or delivery of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, may proceed over the course of an extended period for long-acting formulations.
  • the specification also provides embodiments of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, that may be formulated in combination with excipients or pharmaceutical compounds which may direct or target delivery to a discrete location within a biological system.
  • Such formulations may employ use of liposomes, emulsions, self-assembled structures, polymeric compounds, sustained release materials, or combinations thereof.
  • the specification also provides embodiments of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, that may be formulated in combination with non-aqueous formulations.
  • Such formulations may employ use of silica, silicones, cross-linked silicones and suitable excipients known in the art to contribute to rheological and delivery properties.
  • compositions of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, described in the present specification may be formulated and administered through a variety of means. Such administration may include systemic, localized, or topical including but not limited to oral, rectal, transmucosal, transcutaneous, intestinal, parenteral, intramuscular, subcutaneous, intramedullary, intrathecal, intravenous, intraventricular, intraperitoneal, intranasal, and intraocular. Therein the mode of administration may be tailored to the desired site and delivery scheme.
  • compositions of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, described in the present specification may be suitable wherein the active ingredients are contained and delivered in an effective amount to achieve a desired outcome and intended purpose.
  • a therapeutically effective quantity can include an amount of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, described in the present specification which may treat, prevent, or ameliorate a disease or disorder in a subject.
  • the terms “treating,” “preventing,” and “ameliorating” refer to interventions performed with the intention of alleviating the symptoms associated with, preventing the development of, or altering the pathology of a disease, disorder or condition.
  • the terms may include the prevention (prophylaxis), moderation, reduction, or curing of a disease, disorder or condition at various stages.
  • those in need of therapy/treatment may include those already having the disease, disorder or condition and/or those prone to, or at risk of developing, the disease, disorder or condition and/or those in whom the disease, disorder or condition is to be prevented.
  • compositions of the compounds, their hydrate form, anhydrous form, solvated form or salt thereof, described in the present specification may be suitable for medical, dental, pharmaceutical, cosmeceutical, personal care, veterinary, agricultural, materials engineering, and over-the-counter fields. Such compositions may be used in the treatment and or therapy of subject inclusive of humans or other vertebrate wherein the composition provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • the therapeutically effective does for any of the compounds, , their hydrate form, anhydrous form, solvated form or salt thereof, described in the present specification may initially be estimated by in-vitro cell culture assays as disclosed herein.
  • the specific dose required for higher organisms including animals and humans may be determined more accurately through in-vivo studies including determination of lethal dose (LDso) concentrations and effective dose concentrations (EDso) and the effective ratios thereof. It is also understood to those skilled in the art that the dosing regimen can more accurately through dose-finding studies in a clinical setting. It is also understood that the specific dose for any particular patient may be dependent upon a variety of factors including but not limited to age, sex, weight, height, health, time of administration, route of administration, drug pharmacokinetics and pharmacodynamics, drug interactions, the severity of the disease, and the recommendations and judgement of the prescribing physician.
  • compounds, their hydrate form, anhydrous form, solvated form or salt thereof, disclosed herein can have certain pharmacological properties including low toxicity, low carcinogenicity, desirable in-vitro and in-vivo half lives and reasonable efficacy.
  • the specification relates to a process for preparation of the compound of formula (I), its hydrate form, anhydrous form, solvated form or salt thereof, the process comprising:
  • the compound is prepared via an initial dissolution of the central M metal into an aqueous media following by the addition of a suitable oxidizing or reducing agent and acid or base to affect the desired orbital geometry prior to addition of the desired chelate to form the compound of formula (I), its hydrate form, anhydrous form, solvated form or salt thereof .
  • Conjugate acid and base or desired salts of the compounds may be prepared through appropriate adjudgment of the pH of the complex or ion exchange to obtain the desired salt.
  • the process involves reaction of a salt or chelate form of the central metal with a secondary chelate or mixed chelate system to form a desired chelate complex exhibiting various physiochemical properties, particularly stability and yield, rendering them suitable for industrial and commercial applications.
  • the process involves dissolution of the central metal into a suitable solvent, pH, and temperature to support dissolution.
  • the solvent may be selected from aqueous or organic media; inclusive but not limited to water, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, toluene, or hexanes.
  • the pH of the media may be adjusted by appropriate strong or weak acid or base to a pH of 2 to 14. In a more preferred embodiment, the pH of the media may be adjusted by a strong acid or base to a pH of 4 to 10.
  • the dissolution of the metal is conducted at a temperature ranging from about 0° C to about 100° C for about 0 minutes to about 90 minutes.
  • the dissolution of the metal is conducted at a temperature ranging from about 20° C to about 50° C for about 0 minutes to 10 minutes.
  • the concentration of the metal ranges from about 0.01 mM to about 2.0 M.
  • the process can involve dissolution of the ligand chelate or ligand chelates into a suitable solvent, pH, and temperature to support dissolution.
  • the solvent may be selected from aqueous or organic media; inclusive but not limited to water, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, toluene, or hexanes.
  • the pH of the media may be adjusted by appropriate strong or weak acid or base to a pH of 2 to 14. In a more preferred embodiment, the pH of the media may be adjusted by a strong acid or base to a pH of 4 to 10.
  • the dissolution of the metal is conducted at a temperature ranging from about 0° C to about 100° C for about 0 minutes to about 90 minutes. In another further embodiment, for example and without limitation, the dissolution of the metal is conducted at a temperature ranging from about 20° C to about 50° C for about 0 minutes to 10 minutes. In a still embodiment, for example and without limitation, the concentration of the ligand chelate or ligand chelates ranges from about 0.01 mM to about 4.0 M.
  • the ligand chelate solutions are added in series to the metal solution.
  • the mixed ligand chelate solution is added simultaneously to the metal solution.
  • the ligand chelate, or ligand chelate systems are added directly to the metal solution.
  • the metal is added directly to the ligand chelate solution or mixed ligand chelate solution.
  • the pH of the reaction solution forming the metal chelate complex may be adjusted by appropriate strong or weak acid or base to a pH of 2 to 14.
  • the pH of the media may be adjusted by a strong acid or base to a pH of 4 to 10.
  • the formation of the metal chelate complex may be conducted at a temperature ranging from about 0° C to about 100° C for about 0 minutes to about 48 hours.
  • the formation of the metal chelate complex is conducted at a temperature ranging from about 20° C to about 90° C for about 0 minutes to 90 minutes.
  • the metal chelate complex may be isolated by filtration and optionally further purified.
  • the metal chelate complex may be isolated by the reaction solution by formation of a conjugate acid or base and filtration and optionally further purified.
  • the metal chelate complex may be isolated from the reaction solution by the addition of a pharmaceutically suitable counterion to form a desired salt complex and isolated by filtration and optionally further purified.
  • further purification may proceed via recrystallization, sublimation, extraction, adsorption chromatography, column chromatography, high pressure liquid chromatography, or other methods known in the art.
  • the present specification describes compounds which induce the genetic expression of cyplal via Human HT29 colon adenocarcinoma or AhR reporter cells.
  • Figure 1 the chelates described herein have demonstrated significant induction of the expression of cyplal, a gene which is exclusively downstream of AhR promoter region and transcribed upon activation of AhR, within Human HT29 colon cells.
  • Example 1 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1 -benzopyran- 4-one (0.5mmol, 10ml milli-Q water) was solubilized at room temperature with stirring following the addition of KOH (0.5mmol, 10Oul). In a separate flask, 2-aminophenol (1 mmol, 10ml milli-Q water) was solubilized by heating between 40-50 °C with KOH (1 mmol, 200ul).
  • Example 2 ZnC (1 mmol, 1 mL H2O) was added slowly to 5-bromo-3- methyl picolinic acid (1 mmol, 4ml 50% EtOH) while stirring at room temperature. 2- aminophenol (0.227g, 2mmol, 5mL H2O) was solubilized with KOH (2mmol, 10Oul), stirring between 40-50 °C, and then titrated slowly into the previous solution. The reaction mixture was quickly transferred to a round bottom and was set to reflux under stirring (70-80 °C) for 3 hours resulting in the formation of a brown precipitate and dark brown solution.
  • Example 3 2-Aminophenol (0.114g, 2mmol) was solubilized in 5mL H2O with KOH (2mmol, 100uL) by stirring at 40-50 °C.
  • a reaction mixture was made by first adding previously solubilized ZnCl2 (0.146g, 1 mmol, 1ml H2O) at room temperature, to indoline-2-carboxylic acid (0.169g, 1 mmol, 6.7ml EtOH) stirring at 50 °C resulting in a colourless turbid solution.
  • the heated 2-aminophenol was added to the reaction mixture stirred at 50 °C for 30min.
  • a pale green byproduct was separated from a red-brown solution by centrifugation (1000xg, 5min).
  • Example 4 lndoline-2-carboxylic acid (0.162g, 1mmol, 12mL EtOH) was dissolved at 45 °C, before room temperature dissolved Picolinic acid (0.097g, 0.76mmol, 2.3ml H2O) was added and the reaction mixture continued to stir at 45 °C. Room temperature dissolved ZnCh (0.136g, 0.5mmol, 0.5mL H2O) was added slowly and then refluxed while stirring for 2 hours between 50-72 °C. The red-brown reaction solution was cooled to room temperature and left overnight wherein a fine white precipitate formed.
  • Example 5 Separately, indoline-2-carboxylic acid (0.836g, 0.5mmol, 3mL H2O) and isoquinoline-1 -carboxylic acid (0.085g, 0.5mmol, 2.5mL H2O) were dissolved in H2O and solubilized with 1 M equivalent of KOH (100uL, 5M). Both reactants were warmed to 40-50 °C to solubilize and was kept warm to maintain solubility.
  • HT29- LuciaTM AhR Cells were used to determine the EC50 of the described compounds.
  • HT29-LuciaTM AhR Cells are engineering to express Lucia luciferase reporter gene with human Cyp1a1 gene transcription upon AhR activation. Briefly, cells were expanded using DMEM supplemented with 5% heat inactivated FBS, 1 % Penicillin-Streptomycin, 2mM L-Glutamine, and 100
  • a working stock of QUANTI-LucTM 4 Reagent was prepared by adding 23.75m L of sterile H2O to the concentrated stock. 45pL of QUANTI-LucTM 4 Reagent was added to each well containing cell supernatant. The luminescence of each compound evaluated at 6.25 uM was immediately and reported fold change was determined where statistically significant from baseline induction as shown in Figure 1.

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Abstract

L'invention concerne un composé de formule (I), son hydrate, sa forme anhydre ou saline, M, X et n étant tels que décrits dans la description. Les composés peuvent être utilisés pour moduler l'activité du récepteur d'hydrocarbure aryle (AhR), et pour le traitement de maladies associées à la modulation de l'activité AhR. L'invention concerne également des compositions pharmaceutiques contenant le composé de formule (I), son hydrate, sa forme anhydre ou saline. (Formule I)
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