[go: up one dir, main page]

WO2025042293A1 - Composés pour traiter le diabète et des états apparentés - Google Patents

Composés pour traiter le diabète et des états apparentés Download PDF

Info

Publication number
WO2025042293A1
WO2025042293A1 PCT/NZ2024/050094 NZ2024050094W WO2025042293A1 WO 2025042293 A1 WO2025042293 A1 WO 2025042293A1 NZ 2024050094 W NZ2024050094 W NZ 2024050094W WO 2025042293 A1 WO2025042293 A1 WO 2025042293A1
Authority
WO
WIPO (PCT)
Prior art keywords
amylin
compound
amyloid
compounds
preventing
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/NZ2024/050094
Other languages
English (en)
Inventor
Garth James Smith Cooper
Jacqueline F. Aitken
Shaoping Zhang
Hao Chen
Ke Ding
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jinan University
University of Jinan
Auckland Uniservices Ltd
Original Assignee
Jinan University
University of Jinan
Auckland Uniservices Ltd
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 Jinan University, University of Jinan, Auckland Uniservices Ltd filed Critical Jinan University
Publication of WO2025042293A1 publication Critical patent/WO2025042293A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to compounds useful for treating or preventing diabetes and related conditions, and for preventing, inhibiting or reversing amylin-amyloid fibril formation, preventing islets of Langerhans (Beta)-cell death, preventing or reversing the transition from soluble human amylin to insoluble human amylin, preventing and inhibiting or reversing cytotoxic amylin fibril formation.
  • the present invention also relates to pharmaceutical compositions comprising compounds of the invention, uses of the compounds for the above-mentioned purposes, and their use in the manufacture of medicaments for the above-mentioned purposes.
  • Misfolded protein aggregates known as amyloids have been reported to play a key role in the pathology of a number of diseases, such as rheumatoid arthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, Huntington’s disease, and diabetes.
  • Misfolded human amylin (hA) is the main component of islet amylin amyloid in diabetic patients and is thought to be at least partly responsible for the development and progression of type II diabetes mellitus (type II diabetes). Human amylin therefore represents a potential target for developing medicines that can prevent or slow the progression of type II diabetes.
  • Some molecules capable of altering hA-misfolding and aggregation are already known in the art, and include the broad-spectrum antibiotic, tetracycline. However, many of these molecules suffer from disadvantages, for example side-effect profiles or off-target activities, which make them unsuitable for long-term use.
  • the invention provides a compound of Formula (I): wherein: X is C 1 -C 5 alkyl, cyclopropyl, or C 2 -C 4 dialkyl ether; A is absent or is C 1 -C 6 alkyl optionally substituted with halide, C 1 -C 3 alkoxy, or C 1 - C 3 haloalkoxy, or A is phenyl; B is absent or is C 1 -C 6 alkyl; each R 1 is independently selected from OH, halide, C 1 -C 3 alkoxy, C 1 -C 3 deuteroalkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 deuterohaloalkoxy, CO 2 R 3 , OCO 2 R 4 , and O-glycosyl; R 3 is H or C 1 -C 3 alkyl; R 4 is C 1 -C 3 alkyl; and u is 1, 2 or 3; each R
  • X is CH 2 . In other embodiments, X is (CH 2 ) 2 , (CH 2 ) 3 , or (CH 2 ) 4 . In other embodiments, X is CH 2 -O-CH 2 . In further embodiments, X is cyclopropyl. In certain embodiments of the invention A is C 1 -C 5 alkyl substituted with OCH 3 , OCD 3 , OCH 2 F, or F. In certain embodiments of the invention R 1 is OH, F, CO 2 H, OCH 3 , OCD 3 , OCF 2 H, OCOEt, OCO 2 Pr or O-glucosyl.
  • R 2 is OH, F, OCH 3 or OCD 3 .
  • u is 2 and each R 1 is OH, O-glucosyl or OCO 2 Pr.
  • u is 2 and one R 1 is OH and the other R 1 is CO 2 H.
  • u is 2 and one R 1 is OH and the other R 1 is OCF 2 H.
  • u is 2 and one R 1 is OH and the other R 1 is F.
  • v is 1 and R 2 is OCH 3 or OCD 3 .
  • one R 2 is OCH 3 or OCD 3 and the other R 2 is F.
  • Compounds of the invention include, but are not limited to, the following:
  • the invention in another aspect relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable diluent, carrier or excipient.
  • the invention in a further aspect relates to a method of treating or preventing diabetes, an amylin amyloid-associated disease, or islet of Langerhans beta-cell death comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention relates to a method of inhibiting, preventing, or reversing an amylin amyloidosis or the formation of amylin-amyloid fibrils or amylin amyloid plaques in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention in a further aspect relates to a method of inhibiting, preventing, or reversing an amylin amyloidosis, or the formation of one or more amylin-amyloid fibrils or amylin amyloid plaques, the method comprising contacting the amylin amyloidosis or one or more amylin-amyloid fibrils or amylin amyloid plaques with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the method is a method of inhibiting, preventing, or reversing the formation of islet amylin-amyloid fibrils.
  • the invention in another aspect relates to a method of treating or preventing diabetes in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention in another aspect relates to a method of treating or preventing islet of Langerhans beta-cell death in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention in a further aspect relates to a method of treating or preventing islet of Langerhans beta-cell death, the method comprising contacting one or more islet of Langerhans beta-cells with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition comprising one or more compounds of Formula (I), optionally together with a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to a compound of Formula (I) for use in one or more of treating or preventing an amylin amyloid-associated disease, inhibiting, preventing, or reversing an amylin amyloidosis or the formation of amylin-amyloid fibrils or amylin amyloid plaques, inhibiting, preventing, or reversing the formation of islet amylin-amyloid fibrils, treating or preventing diabetes, or treating or preventing islet of Langerhans beta-cell death, for example in a subject in need thereof.
  • a compound of Formula (I) for use in one or more of treating or preventing an amylin amyloid-associated disease, inhibiting, preventing, or reversing an amylin amyloidosis or the formation of amylin-amyloid fibrils or amylin amyloid plaques, inhibiting, preventing, or reversing the formation of islet amylin-amyloid fibrils, treating or
  • the invention additionally relates to the use of a compound of Formula (I) in the preparation of a medicament for one or more of treating or preventing an amylin amyloid- associated disease, inhibiting, preventing, or reversing an amylin amyloidosis or the formation of amylin-amyloid fibrils or amylin amyloid plaques, inhibiting, preventing, or reversing the formation of islet amylin-amyloid fibrils, treating or preventing diabetes, or treating or preventing islet of Langerhans beta-cell death, for example in a subject in need thereof.
  • the embodiments set out herein may relate to any of the above aspects.
  • Figure 2 is a graph showing thioflavin-T fluorescence following incubation of hA (25 ⁇ M) and thioflavin-T (10 ⁇ M) in the absence ( ⁇ ) or presence of 25 ⁇ M of either ZBBP92 ( ⁇ ), HC87610 , HC8762 or HC8768 ( ).
  • Figure 3 is a graph showing thioflavin-T fluorescence following incubation of hA (25 ⁇ M) and thioflavin-T (10 ⁇ M) in the absence ( ⁇ ) or presence of 25 ⁇ M of either ZBBP92 ( ⁇ ), HC8764 , HC8765 or HC8766 .
  • Figure 9 is a graph showing thioflavin-T fluorescence following incubation of hA (25 ⁇ M) and thioflavin-T (10 ⁇ M) in the absence ( ⁇ ) or presence of 25 ⁇ M of ZBBP92 ( ⁇ ), HC9534 or HC87682 . Results are means +/ ⁇ S.E.M.
  • Figure 10 shows the results of cell death assays for CN cells. Values are mean ⁇ SE of four independent experiments, each performed in duplicate. ***P ⁇ 0.001 versus control; # P ⁇ 0.05; ## P ⁇ 0.01; ### P ⁇ 0.001 versus hA-treated cells.
  • Figure 11 shows the results of cell death assays for RINm5F cells. Values are mean ⁇ SE of four independent experiments, each performed in duplicate. ***P ⁇ 0.001 versus control; # P ⁇ 0.05; ## P ⁇ 0.01; ### P ⁇ 0.001 versus hA-treated cells.
  • amyloid refers to protein aggregates resulting from the misfolding of proteins into forms that facilitate and/or promote aggregation, and/or that may lead to cytotoxicity.
  • amyloidosis refers to the deposition of amyloid in the body.
  • amylin amyloid refers to amylin amyloids comprising human amylin as the protein component in an insoluble state.
  • islet amylin amyloids refer to amylin amyloids comprising human amylin as the protein component in an insoluble state and typically found in the islets of Langerhans.
  • disruption refers to both priori disruption and posteriori disruption of amylin amyloidosis.
  • amylin monomer refers to 37-residue peptide hormone produced in and secreted by the Beta-cells of the islets of Langerhans.
  • the amino acid sequence for human preprotein also referred to as islet amyloid polypeptide preprotein, is present at RefSeq NP_000406.1, and at UniProtKB/SwissProt A0A024RAU1.
  • oligomer refers to a molecule with two or more monomer units. Amylin oligomers may comprise from about 2, 3, 4, 5, 6, 7, 8, 10, 15, 16, 20 or 25 monomer units to about 100 monomer units, or from about 100 to about 1000, 2000, 3000, or more monomer units.
  • the term "amylin oligomer” refers to oligomers in which the monomer units are human amylin.
  • aggregation refers to the disruption of the process of aggregation by a compound described herein, such that aggregation is slowed or prevented.
  • aggregation or “aggregate” refer to the accumulation of protein, such as human amylin or its precursor proIAPP, particularly in insoluble forms.
  • proIAPP proIAPP
  • mylin amyloid-associated disease refers to diseases including but not limited to diabetes, including type II diabetes (T2D), metabolic syndrome, syndrome X, dysregulation of blood glucose, insulin resistance, and the like.
  • prevent refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans beta- cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation that has not yet begun.
  • inhibitor is used in a similar manner to “prevent” but refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans Beta- cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation, that has already begun.
  • treat refers to inhibiting or arresting the development of an amylin amyloid-associated disease and/or causing the reduction, remission or regression of an amylin amyloid-associated disease or one or more side effects thereof.
  • treat refers to inhibiting or arresting the development of an amylin amyloid-associated disease and/or causing the reduction, remission or regression of an amylin amyloid-associated disease or one or more side effects thereof.
  • reverse refers to the return of an amylin amyloid-associated disease to a former or less developed state.
  • the terms "remission” and “regression” are to be interpreted in a similar manner.
  • administering refers to providing a therapeutically effective amount of a compound to a subject using one or more methods of administering compounds known in the art. These methods comprise administering compounds using oral, sublingual, intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like administration.
  • therapeutically effective amount refers to a dose of a compound sufficient to provide a concentration high enough to affect the desired result.
  • a therapeutically effect amount is a dose of a compound described herein sufficient to result in one or more of the following; the prevention, inhibition or reversal of amylin-amyloid fibril formation, islet of Langerhans beta- cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation.
  • pharmaceutically acceptable salt refers to the salt of a given compound, wherein the salt is suitable for administration as a pharmaceutical.
  • such salts may be formed by the reaction of an acid or a base with an amine or a carboxylic acid group respectively.
  • Acid/base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid/base forms.
  • the term "pro-drug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide.
  • ester derivatives include alkyl esters (for example acetates, lactates and glutamines), phosphate esters and those formed from amino acids (for example valine).
  • solvate is a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent.
  • composition is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers.
  • the terms “including” and “comprising” are used herein in their open, non-limiting sense.
  • the terms "(C 1 -C 6 )” and so forth refer to moieties having 1 to 6 carbon atoms and so forth, respectively.
  • (C 0 )- alkyl refers to a bond (i.e. in this case a directly bound hydroxy group), or in case of an unsubstituted “(C 0 )-alkyl” it refers to a hydrogen.
  • alkyl refers to saturated, monovalent hydrocarbon radicals.
  • alkenyl refers to monovalent hydrocarbon radicals, which contain at least one carbon-carbon double bond, wherein each double bond can have E- or Z-configuration.
  • alkynyl refers to monovalent hydrocarbon radicals, which contain at least one carbon-carbon triple bond.
  • the number of carbon atoms in an alkyl group can be 1-22, such as 1 to 12, such as 1, 2, 3, 4, 5 or 6, or 1, 2, 3, or 4.
  • alkyl examples include methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, pentyl including n-pentyl, 1- methylbutyl, isopentyl, neopentyl and tert-pentyl, hexyl including n-hexyl, 3,3- dimethylbutyl and isohexyl. Double bonds and triple bonds in alkenyl groups and alkynyl groups respectively can be present in any positions.
  • Substituted alkyl groups, alkenyl groups and alkynyl groups can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable for the desired purpose such as use as a therapeutic substance.
  • alkyloxy (also referred to as “alkoxy”), unless otherwise indicated, refers to a radical -ORa where Ra is an alkyl as defined above, e.g., methoxy, ethoxy, propoxy, butoxy and the like.
  • deuteroalkoxy refers to an alkoxy group where one or more of the hydrogen atoms have been replaced with a deuterium atom.
  • halo refers to fluoro, chloro, bromo, or iodo, preferably fluoro and chloro. In some embodiments halo is F. It will be understood that in certain circumstances a fluorine atom may function as an isostere for hydrogen, and accordingly the skilled person may in certain embodiments substitute one or more hydrogen atoms in an alkyl, alkenyl, aryl and/or cycloalkyl group, for example, for fluorine atoms.
  • haloalkyl refers to alkyl substituted with one or more, preferably one, two or three, same or different halo atoms, e.g., -CH 2 Cl, -CF 3 , - CH 2 CF 3 , -CH 2 CCl 3 , and the like.
  • haloalkoxy refers to a radical -OR b where R b is a haloalkyl as defined above, e.g., trifluoromethoxy, trichloroethoxy, 2,2-dichloropropoxy, and the like.
  • deuterohaloalkoxy refers to a haloalkoxy group where one or more of the hydrogen atoms have been replaced with a deuterium atom. Examples include mono-, di-, and tri-deuterohaloalkoxy groups, such as OCDF 2 , OCD 2 F and OCD 3 .
  • and/or means "and” or "or”, or both.
  • the invention provides various compounds suitable for use in the treatment of amylin amyloidoses, including, for example, diabetes.
  • the compounds have advantageous physicochemical and/or therapeutic properties rendering them particularly suitable for use in the treatment of amylin amyloid-associated diseases, such as diabetes.
  • the invention provides compounds of Formula (I): wherein: X is C 1 -C 5 alkyl, cyclopropyl, or C 2 -C 4 dialkyl ether; A is absent or is C 1 -C 6 alkyl optionally substituted with halide, C 1 -C 3 alkoxy, or C 1 - C 3 haloalkoxy, or A is phenyl; B is absent or is C 1 -C 6 alkyl; each R 1 is independently selected from OH, halide, C 1 -C 3 alkoxy, C 1 -C 3 deuteroalkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 deuterohaloalkoxy, CO 2 R 3 , OCO 2 R 4 , and O-glycosyl; R 3 is H or C 1 -C 3 alkyl; R 4 is C 1 -C 3 alkyl; and u is 1, 2 or 3; each R 2 is independently selected from OH, halide, C
  • Solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric centre. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • this invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free from other stereoisomers on a molar basis) as well as a mixture of such isomers.
  • Particular optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereomeric salts, by treatment with an optically active acid or base.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulphonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another method involves synthesis of covalent diastereomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesised diastereomers can be separated by conventional means such as chromatography, distillation, crystallisation or sublimation, and then hydrolysed to deliver the enantiomerically pure compound.
  • Optically active compounds of the invention can be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • the compounds of the invention require purification, chromatographic techniques such as high-performance liquid chromatography (HPLC) and reversed-phase HPLC may be used.
  • HPLC high-performance liquid chromatography
  • the compounds may be characterised by mass spectrometry and/or other appropriate methods.
  • the compound comprises one or more functional groups that may be protonated or deprotonated (for example at physiological pH) the compound may be prepared and/or isolated as a pharmaceutically acceptable salt. It will be appreciated that the compound may be zwitterionic at a given pH.
  • pharmaceutically acceptable salts of one or more compounds described herein are administered in a therapeutically effective amount to a subject.
  • Such salts may be prepared by methods known in the art that involve reacting the compound with a suitable organic or inorganic acid or base.
  • Organic salts include methanesulphonate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulphonate (tosylate), citrate, malate, maleate, fumarate, succinate, tartrate, napsylate, methanesulphonate, 2- naphthalenesulphonate, nicotinate, benzenesulphonate, butyrate, camphorate, camphorsulphonate, cyclopentanepropionate, digluconate, dodecylsulphate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, undecanoate, 2- hydroxyethanesulphonate, ethanesulphonate, and the like.
  • Representative inorganic salts can be formed from inorganic acids such as sulphate, bisulphate, hemisulphate, hydrochloride, chlorate, perchlorate, hydrobromide, hydroiodide, and the like.
  • a base salt include ammonium salts; alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like.
  • Such salts can readily be prepared employing methods well known in the art.
  • one or more compounds described herein is administered to a subject as a pro-drug.
  • Pro-drugs are well known in the art and are compounds which are administered in a form that is then metabolised into a pharmacologically active drug. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention.
  • Conventional procedures for the preparation of suitable prodrugs according to the invention are described in text books, such as "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985 - the entire contents of which is incorporated herein by reference.
  • Compound synthesis Certain compounds of the invention were synthesised according to the following reaction schemes, which are provided by way of example only.
  • the aniline intermediates were synthesised from 4-nitrobenzene-1,2-diol (2-1), applying an alkylation reaction to protect the phenol group followed by the reduction of the nitro group. The two fragments were then coupled using HATU followed by deprotection of the benzyl group to provide the target compounds.
  • Biaryl compounds were synthesised from the pyridin-2-amine (1-5), which underwent amide coupling reactions to provide carboxylic acid intermediate (5-2). Further coupling with bromoaniline leads to intermediate (5-3), which were then reacted with substituted phenylboronic acid via the Suzuki coupling reaction to yield intermediate (5-4). Subsequent deprotection of the methyl group provided the target compounds.
  • HC87610 is structurally very similar to HC8761, but with the addition of an oxygen moiety in the central methyl group of the backbone. While HC87610 does show inhibition of fibril formation (see Figure 4), it inhibits to a lesser degree than both ZBBP92 and HC8761, possibly indicating a change in conformational flexibility around the central oxygen moiety which reduces its ability to bind and inhibit fibril formation.
  • HC8762, HC8765 and HC8769 each contain a carboxylic acid moiety on the left benzene ring in the meta position relative to the attached NH group. None of these compounds show good inhibition of fibril formation in the thioflavin-T assay.
  • HC9532, HC9533 and HC9534 are isomers, with the biphenyl hydroxy carboxylic acid moiety of each compound attached to the NH group at a different position. This positioning affects inhibition of hA fibril formation which may be due to steric hindrance.
  • the HC87682 structure is different to HC8768 in that the hydroxyl groups are replaced by ester groups on the left benzene ring.
  • Cytotoxicity Example 17 shows that compound HC87682 is cytotoxic while it was cultured alone with RINm5F and CM cells. Compounds HC956, HC9532, HC9533 and HC9534 alone were not cytotoxic and were subjected to analysis for anti-hA-mediated beta cell death. The cell death prevention assays that HC956 has no cell death prevention activity.
  • the invention relates in certain embodiments to compounds capable of preventing or reversing human amylin (hA) misfolding, aggregation and/or amylin plaque amyloid formation.
  • the invention relates to compounds capable of preventing and/or reversing the transition from soluble human amylin to insoluble human amylin, and/or of preventing and inhibiting and/or reversing cytotoxic amylin fibril formation.
  • Human amylin also known as islet amylin amyloid polypeptide (IAPP)
  • IAPP islet amylin amyloid polypeptide
  • proIAPP proamylin sequence
  • amyloids there is usually a relationship between the identity of the protein and where in the body an amyloidosis manifests. Consequently, several types of amyloids exist, each of which is classified depending on the protein it comprises, and specific types of amyloidoses are classified based on the site of amyloid accumulation. The deposition of amyloids in the body often involves the accumulation of insoluble amyloid fibrils that comprise misfolded proteins. Human amylin is one protein that may misfold leading to the conversion of soluble amylin monomers and soluble amylin oligomers into insoluble amylin-amyloid fibrils.
  • Amylin amyloidosis disruption maybe priori disruption or posteriori disruption of amylin amyloidosis.
  • Priori disruption refers to the interference of the compounds described herein with any part of the process involving the conversion of soluble monomers and oligomers, such as amylin monomers and oligomers, into insoluble amylin amyloids.
  • Posteriori disruption refers to the disaggregation of insoluble amylin amyloids that are already formed, for example islet amylin amyloids, which may include the re-solubilisation of the constituent protein. Disruption of insoluble amylin amyloids may occur directly or indirectly.
  • Direct disruption involves one or more compounds described herein or a metabolite thereof binding to a part of the protein monomers or oligomers, such as human amylin monomers or oligomers, or part of a pre-formed aggregate, and physically preventing further aggregation and/or reversing aggregation, for example by weakening interactions between the monomers and/or oligomers in the aggregate.
  • Indirect disruption in contrast, involves preventing fibril or aggregate formation via mechanisms that do not require direct contact between the compound and the protein, for example, by altering local conditions to favour a soluble form of the protein over an insoluble form, or by favouring a non-aggregating conformation of the monomers or oligomers.
  • direct disruption of aggregates, such as islet aggregates, by the compounds described herein involves binding via covalent interactions, and in other embodiments involves binding via non-covalent interactions.
  • the compounds described herein interact with the monomers or with oligomers of the proteins making up the amylin amyloids or to the amylin amyloids themselves, by a combination of one or more covalent interactions and/or one or more non- covalent interactions, for example van der Waals interactions.
  • van der Waals interactions for example, without wishing to be bound by theory the inventors believe that in various embodiments the compounds described herein bind covalently to the monomeric forms of proteins, for example hA.
  • insoluble islet amylin amyloids begins with the aggregation of proamylin, which then serves as an initiation site for the deposition of insoluble islet amylin-amyloid fibrils.
  • disruption of islet amylin amyloids thus occurs by directly or indirectly disrupting the aggregation of or on proamylin.
  • hA may be reasonably unstructured and made up mostly of random coil structures. Under certain conditions often associated with pathogenesis, hA is expected to misfold to produce beta-sheets that stack to form highly structured aggregates comprising layers of beta- sheets.
  • disruption of islet amylin amyloids comprises the prevention or reversal of hA misfolding. Misfolding of the protein components of amylin amyloids is also thought to play a role in other diseases associated with amylin amyloidosis.
  • the compounds described herein disrupt amylin amyloid aggregates by one or more mechanisms selected from the group consisting of preventing, inhibiting and/or reversing amylin-amyloid fibril formation, preventing and/or reversing the transition from soluble human amylin to insoluble human amylin, and preventing, inhibiting and/or reversing cytotoxic amylin fibril formation.
  • the compounds described herein disrupt amylin-amyloid fibril formation by preventing, inhibiting and/or reversing protein misfolding.
  • the compounds described herein disrupt islet amylin-amyloid fibril formation by preventing, reversing and/or reversing hA misfolding.
  • the compounds described herein prevent, inhibit and/or reverse protein misfolding and/or prevent, inhibit and/or reverse protein aggregation.
  • the inventors believe that the aggregation potential of hA is promoted by the misfolding of amylin into structured Beta-sheets. Effect on disease states Amylin amyloids are thought to play a role in the pathogenesis of a number of diseases.
  • Amylin amyloid-associated diseases occur in a number of animals, including mammals, for example human beings.
  • the inventors have found that the compounds described herein are able to prevent, inhibit and/or reverse, for example, amylin-amyloid fibril formation, islet of Langerhans Beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation. Without wishing to be bound by theory, the inventors believe that these processes are associated with the development and/or progression of one or more amylin amyloid-associated diseases, such as, for example, type II diabetes.
  • prevent refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans beta- cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation that has not yet begun.
  • prevention is for a certain period of time – for example, for so long as the concentration of the compound or compounds as described herein, such as the concentration local to the hA, is maintained above a certain threshold. It will be appreciated that in such embodiments the term “prevent” does not contemplate prevention in perpetuity.
  • inhibitor as used herein is used in a similar manner to “prevent” but refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation, that has already begun.
  • the prevention, inhibition or reversal of processes associated with the development of one or more amylin amyloid-associated diseases may manifest in a number of ways.
  • the prevention, inhibition or reversal of processes such as for example amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation, leads to slowing of disease progression and improved quality of life in subjects with the disease.
  • the prevention, inhibition or reversal of processes associated with the development of one or more amylin amyloid-associated diseases manifests as an increased rate of survival.
  • prevention, inhibition or reversal of a process associated with hA amylin amyloid formation will in certain embodiments manifest as an increased rate of survival of islet beta-cells, for example.
  • treat refers to inhibiting or arresting the development of an amylin amyloid-associated disease and/or causing the reduction, remission or regression of an amylin amyloid-associated disease or one or more side effects thereof.
  • Methods of assessing treatment, including methods of assessing inhibition, arrest, reduction, remission and/or regression of disease states are known and will be apparent to a person skilled in the art.
  • reverse refers to the return of an amylin amyloid-associated disease to a former or less developed state.
  • remission and “regression” are to be interpreted in a similar manner.
  • administering refers to providing a therapeutically effective amount of a compound to a subject using one or more methods of administering compounds known in the art. These methods comprise administering compounds using oral, sublingual, intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like administration. In exemplary embodiments one or more active agents may be administered orally. It will be apparent to a person skilled in the art that the formulation of the compounds described herein will depend on the method of administration.
  • the compounds described herein are in certain embodiments formulated as creams, lotions, tablets, capsules, pellets, dispersible powders, granules, suppositories, syrups, elixirs, lozenges, injectable solutions, sterile aqueous or non-aqueous solutions, suspension or emulsions, patches and the like.
  • the compounds described herein are formulated as tablets, capsules, pellets, dispersible powders, granules, syrups, suspensions or emulsions.
  • formulations that are suitable for a particular method of administration will be apparent to those skilled in the art.
  • the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the mammal to be treated. It is believed that the choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art.
  • care should be taken to ensure that the activity of the compound is not destroyed in the process and that the compound is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the compound by means known in the art, such as, for example, microencapsulation.
  • the route of administration chosen should be such that the compound reaches its site of action.
  • Those skilled in the art may readily determine appropriate formulations for the compounds of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art. Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof, may be prepared in parenteral dosage forms, including those suitable for intravenous, intrathecal, and intracerebral or epidural delivery.
  • the pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against reduction or oxidation and the contaminating action of microorganisms such as bacteria or fungi.
  • the solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for compound actives, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.
  • the formulation for injection will be isotonic with blood. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients such as those enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients.
  • Other pharmaceutical forms include oral and enteral formulations of the present invention, in which the active compound may be formulated with an inert diluent or with an assimilable edible carrier, or it may be enclosed in a hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal or sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, 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 a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum, 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
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of winter
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active compound to specific regions of the gut. Liquid formulations may also be administered enterally via a stomach or oesophageal tube.
  • Enteral formulations may be prepared in the form of suppositories by mixing with appropriate bases, such as emulsifying bases or water-soluble bases. It is also possible, but not necessary, for the compounds of the invention to be administered topically, intranasally, intravaginally, intraocularly and the like.
  • the invention also extends to any other forms suitable for administration, for example topical application such as creams, lotions and gels, or compositions suitable for inhalation or intranasal delivery, for example solutions, dry powders, suspensions or emulsions.
  • the compounds of the invention may be administered by inhalation in the form of an aerosol spray from a pressurised dispenser or container, which contains a propellant such as carbon dioxide gas, dichlorodifluoromethane, nitrogen, propane or other suitable gas or combination of gases.
  • a propellant such as carbon dioxide gas, dichlorodifluoromethane, nitrogen, propane or other suitable gas or combination of gases.
  • the compounds may also be administered using a nebuliser.
  • Pharmaceutically acceptable vehicles and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated.
  • compositions can also be incorporated into the compositions. It is especially advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • the principal active ingredient may be compounded for convenient and effective administration in therapeutically effective amounts with a suitable pharmaceutically acceptable vehicle in dosage unit form.
  • a unit dosage form can, for example, contain the principal active compound in amounts ranging from 0.25 ⁇ g to about 2000 mg. Expressed in proportions, the active compound may be present in from about 0.25 ⁇ g to about 2000 mg/mL of carrier.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • a therapeutically effect amount is a dose of a compound sufficient to result in one or more of the following; the prevention, inhibition or reversal of amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation.
  • the therapeutically effective amount of a compound will in certain embodiments be affected by a number of factors, and can be adjusted based on these factors. For example, the therapeutically effective dose may be affected by the bodyweight of the subject, metabolic capacity and synergy between combinations of actives administered.
  • the dose that can be administered to a subject may also be affected by other factors such as interactions with other medicines that the subject is taking and severity of/ability to tolerate any side effects of the compounds administered.
  • the desired result to be achieved by the therapeutically effective amount comprises the slowing of disease progression, an improvement in the quality of life of the subject and/or an increased rate of survival.
  • the desired result to be achieved by the therapeutically effective amount is the amelioration of one or more symptoms associated with an amylin amyloid-associated disease, for example reduction in loss of kidney function, heart failure, obstructive sleep apnoea, difficulty swallowing or synovitis.
  • the desired result to be achieved by the therapeutically effective amount is the amelioration of one or more symptoms associated with type II diabetes, for example weight loss, polyuria, polydipsia, polyphagia, blurry vision, headache, fatigue or diabetic dermadromes, and signs such as lowering of blood glucose levels and HbA1C.
  • the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
  • the compounds described herein are in certain embodiments administered individually, and in other embodiments are administered in combination, either with other compounds described herein, or with other therapeutic agents or both. The combination may allow for separate, sequential or simultaneous administration of a compound with another active ingredient.
  • the combination may be provided in the form of a pharmaceutical composition.
  • two or more compounds are administered to a subject together.
  • the dose of each individual compound may be less than the therapeutically effective amount such that the combined dose of the two or more compounds is equal to or greater than the therapeutically effective amount.
  • one or more compounds is administered to a subject together with one or more additional agents.
  • the additional agents may be, for example, agents that treat, inhibit and/or reverse amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation.
  • the one or more additional agents may be compounds that prevent or treat amylin amyloid-associated diseases, such as type II diabetes.
  • the one or more additional agents will in certain embodiments be selected from the group comprising blood glucose modulating agents, such as an insulin, an insulin analogue or derivative, Symlin, GLP- agonists, metformin, sulphonylureas, thiazolidinediones, SGLT2 inhibitors, and selective dipeptidyl peptidase (DPP-IV) inhibitors.
  • the GLP-1 agonist is exenatide, liraglutide, lixisenatide, albiglutide, or dulaglutide, or any combination of two or more thereof.
  • the selective dipeptidyl peptidase (DPP-IV) inhibitor is selected from the group comprising Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Gemigliptin, Dutogliptin, and Omarigliptin.
  • the selective dipeptidyl peptidase (DPP-IV) inhibitor is selected from the group comprising alogliptin, linagliptin, saxagliptin, sitagliptin, Nesina, Tradjenta, Onglyza, and Januvia.
  • the one or more additional agents may for example be agents that reduce side effects associated with the compounds described herein.
  • one or more compounds may be administered to a subject with one or more additional agents selected from the group comprising quinacrine, tetracycline and doxycycline.
  • one or more compounds may be administered to or contacted with a sample in vitro with one or more additional agents selected from the group comprising anthracene, phenanthrene, quinacrine, neutral red, chlorpromazine, acridine, acridine orange, methylene blue, phenodiazine, phenothiazine, tetracycline, doxycycline, Congo red, pyrene, chrysene, benz[a]anthracene, benz[m]anthracene, benzo[c]phenanthrene and tetracene.
  • additional agents selected from the group comprising anthracene, phenanthrene, quinacrine, neutral red, chlorpromazine, acridine, acridine orange, methylene blue, phenodiazine, phenothiazine, tetracycline, doxycycline, Congo red, pyrene, chrysene, benz[a]anth
  • the dose of each compound administered may be less than the dose that would be administered if the compounds were administered separately. In some embodiments when one or more compounds are administered in combination with one or more additional agents, the dose of each compound administered may be greater than the dose that would be administered if the compounds were administered separately. For example, this may be the case if the one or more additional agents leads to reduced side effects, allowing a greater dose to be tolerated.
  • Example 1 Synthesis of N-(3,4-dihydroxyphenyl)-N-(6-(methoxy-d3)pyridin-2- yl)cyclopropane-1,1-dicarboxamide (HC863O) Step 1.
  • Example 2 Synthesis of 2-hydroxy-5-(1-((6-(methoxy-d3)pyridin-2- yl)carbamoyl)cyclopropane-1-carboxamido)benzoic acid (HC863C) Synthesised by a similar procedure to Example 1 from 2-hydroxy-5-nitrobenzoic acid instead of 4-nitrobenzene-1,2-diol in step 1.
  • Example 10 Synthesis of N-(3,4-dihydroxyphenyl)-2-(2-((6-(methoxy-d3)pyridin- 2-yl)amino)-2-oxoethoxy)acetamide (HC87610) Synthesised by a similar procedure to Example 1 from 2-(2-methoxy-2- oxoethoxy)acetic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3.
  • Example 11 Synthesis of 4-(3-((6-(methoxy-d 3 )pyridin-2-yl)amino)-3- oxopropanamido)-1,2-phenylene dipropionate (HC87682)
  • HC87682 a solution of N 1 -(3,4-dihydroxyphenyl)-N 3 -(6-(methoxy-d3)pyridin-2- yl)malonamide (0.1 g, 0.3 mmol) in 1 mL THF was added triethylamine (0.09 g, 0.9 mmol) and propionyl chloride (0.09 g, 0.9 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h.
  • Example 12 Synthesis of 4-hydroxy-2'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (HC9532) Step 1. Synthesis of 3-((6-(methoxy-d3)pyridin-2-yl)amino)-3-oxopropanoic acid (5- 2) To a solution of 6-(methoxy-d3)pyridin-2-amine (0.50 g, 3.9 mmol) in 5 mL DCM was added triethylamine (0.80 g, 7.9 mmol) at room temperature.
  • reaction mixture was then allowed to warm to room temperature and stirred for additional 2 h. Upon completion, the reaction mixture was quench with water. The resulting participate was then filtered, washed with methanol and dried under reduced pressure to yield the title compound as white solid (0.15 g, 57%).
  • Example 13 Synthesis of 4-hydroxy-3'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (HC9533) Synthesised by a similar procedure to Example 12 from 3-bromoaniline instead of 2- bromoaniline in step 2.
  • Example 14 Synthesis of 4-hydroxy-4'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (HC9534) Synthesized by a similar procedure to Example 12 from 4-bromoaniline instead of 2- bromoaniline in step 2.
  • Example 15 Synthesis of N 1 -(3,4-bis(difluoromethoxy)phenyl)-N 3 -(6-(methoxy- d 3 )pyridin-2-yl)malonamide (HC956) To a solution of N 1 -(3,4-dihydroxyphenyl)-N 3 -(6-(methoxy-d 3 )pyridin-2- yl)malonamide (HC8768, Example 8, 0.05 g, 0.15 mmol) in 1 mL DCM was added an aqueous KOH solution (20 wt%, 0.26 mL, 0.9 mmol) with vigorous stirring.
  • Example 16 Inhibition of amylin fibril formation This example describes the analysis of representative compounds of Formula (I) using the thioflavin-T assay to assess compound-mediated inhibition of amylin fibril formation. All compounds were solubilised in aqueous solution with NaOH to a pH >10, then brought down to a pH of 7-8 with HCl. All compounds were 100% soluble and stable in solution under these conditions for at least 24 hours, with the exception of HC8768 which began to precipitate after 30 min at pH>10. The ability of the compounds to inhibit human amylin (hA) fibril formation was assessed using the thioflavin-T assay, as described in J.F.
  • Figure 1 shows that HC8768 significantly increased the inhibition of fibril formation over that of ZBBP92 ( ⁇ ) and both compounds showed inhibition of fibril formation compared to human amylin alone.
  • Figure 2 shows that HC87610 ( ) inhibits fibril formation, but to a lesser degree than ZBBP92 ( ⁇ ).
  • HC8762 showed no inhibition of fibril formation.
  • HC8768 showed significantly increased inhibition of fibril formation over that of ZBBP92 ( ⁇ ).
  • Figure 3 shows that HC8765 shows little inhibition of fibril formation.
  • HC8764 showed similar fibril inhibition to ZBBP92 ( ⁇ ).
  • HC8766 was less effective than ZBBP92 or HC8764.
  • Figure 4 shows that HC8769 ( ) did not inhibit fibril formation.
  • HC87610 ( ) showed inhibition of fibril formation, but to a lesser degree than ZBBP92 ( ⁇ ).
  • Figure 5 shows that HC8761 inhibits amylin fibril formation in a similar degree to ZBBP92 ( ⁇ ).
  • Figure 6 shows that HC9534 has inhibition of fibril formation activity comparable to ZBBP92 ( ⁇ ).
  • Figure 7 shows that HC9534 has a greater inhibitory effect on fibril formation activity than ZBBP92 ( ⁇ ) at 2.5 ⁇ M compared to activity levels at 25 ⁇ M (see Figure 6).
  • FIG. 8 shows that HC9532 shows some, but little inhibition, and HC9533 has a greater inhibitory effect on hA fibril formation, although not as strongly as HC9534 or ZBBP92 ( ⁇ ).
  • Figure 9 shows that HC87682 has a greater inhibitory effect on hA fibril formation, although not as strongly as HC9534 or ZBBP92 ( ⁇ ).
  • Example 17 Effect on prevention of human amylin-evoked beta-cell death
  • CM and RINm5F cells were plated in a 48-well plate and cultured o/n in RPMI medium (5%FBS and 10% FBS, respectively).
  • Human amylin (hA) stock solutions 500 ⁇ M were prepared freshly in water and diluted in medium to a final concentration of 10 ⁇ M.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés utiles pour traiter ou prévenir le diabète et des états apparentés, et pour prévenir, inhiber ou contrecarrer la formation de fibrilles amyloïdes d'amyline, prévenir la mort cellulaire des îlots de Langerhans (Beta), prévenir ou contrecarrer la transition d'amyline humaine soluble en amyline humaine insoluble, prévenir et inhiber ou contrecarrer la formation de fibrilles d'amyline cytotoxiques. L'invention concerne des composés de formule (I) : (I)
PCT/NZ2024/050094 2023-08-22 2024-08-20 Composés pour traiter le diabète et des états apparentés Pending WO2025042293A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NZ802977 2023-08-22
NZ80297723 2023-08-22

Publications (1)

Publication Number Publication Date
WO2025042293A1 true WO2025042293A1 (fr) 2025-02-27

Family

ID=94732513

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NZ2024/050094 Pending WO2025042293A1 (fr) 2023-08-22 2024-08-20 Composés pour traiter le diabète et des états apparentés

Country Status (1)

Country Link
WO (1) WO2025042293A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007058927A1 (fr) * 2005-11-11 2007-05-24 The Scripps Research Institute Inhibiteurs d'histone desacetylase en tant que produits therapeutiques pour des maladies neurologiques
WO2010028193A1 (fr) * 2008-09-03 2010-03-11 Repligen Corporation Composés comprenant des dérivés d'acide pimélique en tant qu'inhibiteurs de hdac
WO2020080960A1 (fr) * 2018-10-19 2020-04-23 Auckland Uniservices Limited Composés pour le traitement du diabète et/ou d'états apparentés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007058927A1 (fr) * 2005-11-11 2007-05-24 The Scripps Research Institute Inhibiteurs d'histone desacetylase en tant que produits therapeutiques pour des maladies neurologiques
WO2010028193A1 (fr) * 2008-09-03 2010-03-11 Repligen Corporation Composés comprenant des dérivés d'acide pimélique en tant qu'inhibiteurs de hdac
WO2020080960A1 (fr) * 2018-10-19 2020-04-23 Auckland Uniservices Limited Composés pour le traitement du diabète et/ou d'états apparentés

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 17 November 2006 (2006-11-17), XP093284097, Database accession no. 913494-52-7 *
DATABASE REGISTRY 17 November 2006 (2006-11-17), XP093284098, Database accession no. 913494-36-7 *
DATABASE REGISTRY 2 November 2022 (2022-11-02), XP093284088, Database accession no. 2848463-46-5 *
DATABASE REGISTRY 2 November 2022 (2022-11-02), XP093284091, Database accession no. 2848273-66-3 *
DATABASE REGISTRY 24 June 2019 (2019-06-24), XP093284093, Database accession no. 2344796-42-3 *
DATABASE REGISTRY 25 May 2001 (2001-05-25), XP093284101, Database accession no. 338392-31-7 *
DATABASE REGISTRY 28 November 2022 (2022-11-28), XP093284085, Database accession no. 2861125-71-3 *

Similar Documents

Publication Publication Date Title
US20220079914A1 (en) Macrophages/microglia in neuro-inflammation associated with neurodegenerative diseases
DK1511710T3 (en) RELATIONSHIPS, PREPARATIONS AND METHODS FOR TREATING AMYLOID DISEASES AND SYNUCLEINOPATHES, SUCH AS ALZHEIMER'S DISEASE, TYPE 2-DIABETES AND PARKINSON'S DISEASE
CN103124724B (zh) Lsd1的基于芳基环丙胺的脱甲基酶抑制剂及其医疗用途
US7601876B2 (en) Compounds, compositions and methods for the treatment of amyloid diseases such as systemic AA amyloidosis
CN102170787B (zh) 用于治疗β-淀粉样蛋白病和突触核蛋白病的化合物、组合物和方法
US20070276034A1 (en) Compounds, compositions and methods for the treatment of synucleinopathies
US20190119203A1 (en) Compounds and compositions for treating conditions associated with nlrp activity
KR20170035911A (ko) Hsp90 저해제 및 hsp70 유도제로서의 개질된 에터기를 가진 바이페닐 아마이드
WO2000030683A1 (fr) Composes prophylactiques et/ou therapeutiques destines a des maladies du systeme nerveux central et possedant des composes antagonistes du recepteur de txa2 et/ou inhibiteurs de la txa2 synthase
US20110144124A1 (en) Compounds and Compositions for Use as Modulators of Tau Aggregation and Alleviation of Tauopathies
CN112714761A (zh) 用作分子伴侣介导的自噬调节剂的化合物
US20250144110A1 (en) Compositions of autophagy modulating agents and uses thereof
WO2025042293A1 (fr) Composés pour traiter le diabète et des états apparentés
WO2022079204A1 (fr) Dérivés de tétracycline pour le traitement de maladies neurodégénératives ou neuroinflammatoires
US20220041591A1 (en) Compounds for treating diabetes and/or related conditions
CN111072652A (zh) 用于治疗糖尿病和/或相关病症的化合物
US20130190370A1 (en) Novel Tetrahydronaphalene Antagonists to the Thromboxane A2 (TP) Receptor
JP6520019B2 (ja) 新規スチルベン誘導体
JP7734361B2 (ja) 化合物又はその塩及びその製造方法、化合物又はその塩を含む医薬品組成物及びその製造方法
CN102260187B (zh) 取代的氨甲酰基环己甲酸类化合物及其制法和用途
US20250197394A1 (en) Antibacterials based on monocyclic fragments coupled to aminopiperidine naphthyridine scaffold
KR102179406B1 (ko) 신규한 인다졸 유도체 및 이의 용도
US20250312362A1 (en) INHIBITORS OF MsbA AS ANTIBIOTICS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
WO2024102245A1 (fr) Modulation allostérique de l'efficacité du récepteur muscarinique de l'acétylcholine
US20110269953A1 (en) Nitrogen and Sulfur-Containing Heterocycle Derivatives

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: 24856888

Country of ref document: EP

Kind code of ref document: A1