EP4680606A1 - Dérivés d'adénine en tant qu'inhibiteurs de hsp90 - Google Patents

Dérivés d'adénine en tant qu'inhibiteurs de hsp90

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Publication number
EP4680606A1
EP4680606A1 EP24710769.1A EP24710769A EP4680606A1 EP 4680606 A1 EP4680606 A1 EP 4680606A1 EP 24710769 A EP24710769 A EP 24710769A EP 4680606 A1 EP4680606 A1 EP 4680606A1
Authority
EP
European Patent Office
Prior art keywords
compound
methyl
disease
compound according
amine
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
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EP24710769.1A
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German (de)
English (en)
Inventor
Anita RAYAR
Jean-Philippe Annereau
Luis BRISENO-ROA
Nathan BECKOUCHE
Xénia PROTON DE LA CHAPELLE
Philippe Maillos
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Atmosr
Medetia
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Atmosr
Medetia
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Publication of EP4680606A1 publication Critical patent/EP4680606A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the present invention relates to adenine derivatives, especially compounds of formula (I) as detailed hereafter, which are useful as inhibitors of HSP90, in particular for the treatment of cancers, neurodegenerative diseases, and neurodegenerative diseases with proteins aggregates such as congenital central hypoventilation syndrome (CCHS).
  • CCHS congenital central hypoventilation syndrome
  • HSP90s Heat shock protein 90
  • the HSP90s are a ubiquitous family of ATP-dependent molecular chaperone proteins consisting of four paralogs: Hsp90 ⁇ and Hsp90 ⁇ in the cytosol, Grp94 in the endoplasmic reticulum, and Trap-1 in the mitochondria.
  • HSP90 Hundreds of client proteins, including growth factors, signaling kinases, transcription factors, and cell surface receptors depend on HSP90 family members for their conformational maturation, stabilization, and proper subcellular localization
  • HSP90s orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis.
  • HSP90s, and their secreted forms contribute to the development and progress of serious pathologies, including cancers, neurodegenerative diseases, and neurodegenerative diseases with proteins aggregates such as congenital central hypoventilation syndrome (CCHS).
  • CCHS congenital central hypoventilation syndrome
  • HSP90 inhibitors have been developed and tested, such as for example Debio0932 (also referred to as CUDC-305, corresponding to 2-((6-(dimethylamino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2-(neopentylamino)ethyl)-1H- imidazo[4,5-c]pyridin-4-amine).
  • Debio0932 also referred to as CUDC-305, corresponding to 2-((6-(dimethylamino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2-(neopentylamino)ethyl)-1H- imidazo[4,5-c]pyridin-4-amine.
  • HSP90 inhibitors such as Debio0932 display an improvable metabolization profile and thus suboptimal pharmacokinetic properties.
  • the cancer is selected from brain tumors, hematopoietic disorders, breast cancer, lung cancer, leukemia, lymphoma, pancreatic cancer, multiple myeloma, prostate cancer, glioma, colon cancer, gastric cancer, ovarian cancer, and any cancer with oncogene production chaperoned by HSP90.
  • the neurodegenerative disease is selected from Alzheimer's disease, Senile dementia of the Alzheimer type, dementia of head trauma and diffuse brain damage, dementia pugilistica, frontal lobe dementia, Pick's disease, Huntington's disease, Multiple system atrophy combining dementia with ataxia and/or manifestations of Parkinson's disease, Progressive supranuclear palsy, diffuse Lewy body disease, corticodentatonigral degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, familial tremor, Gilles de la Tourette syndrome, cerebellar cortical degeneration, olivopontocerebellar atrophy, spinocerebellar degeneration, Shy-Drager syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy (Kennedy'
  • Halogen or “halo” means fluoro, chloro, bromo, or iodo. Generally, halo groups of this invention are fluoro, chloro or bromo, preferably fluoro.
  • Haloalkyl by itself or as part of another substituent, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl and the like.
  • Heterocyclyl by itself or as part of another substituent, refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-member monocyclic, 7- to 11-member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • Heterocyclic groups may in particular be 3- to 7-membered, preferably 5- or 6-membered.
  • Heterocyclic groups may in particular be monocyclic or bicyclic, preferably monocyclic.
  • Heterocyclylalkyl refers to any group –alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as defined above.
  • “Pharmaceutically acceptable” means that the component not deleterious to the subject to which it is administered and is compatible with each other component administered together.
  • “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic, or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • Prodrug as used herein means the pharmacologically acceptable derivatives of the compounds of the invention, whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters.
  • a subject is a mammal, preferably a human, suffering from the targeted disease and/or prone to develop the targeted disease.
  • the subject is a “patient”, i.e., a mammal, preferably a human, who/which is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure or is monitored for the development of the targeted disease.
  • “Therapeutically effective amount” refers to the amount of active agent or active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject in need of treatment, preventing, reducing, alleviating, or slowing down (lessening) one or more of the symptoms of the targeted disease.
  • “Treating” or “treatment” refers to a therapeutic treatment, to a prophylactic (or preventative) treatment, or to both a therapeutic treatment and a prophylactic (or preventative) treatment, wherein the object is to prevent, reduce, alleviate, and/or slow down (lessen) one or more of the symptoms the targeted disease, in a subject in need thereof.
  • This invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, wherein: X 1 is N or CH; X 2 is N or CH; provided that X 1 and X 2 are not both N; Y is S, SO, SO2, NH, O, or CH2; L 1 is a C1-4-alkyl; R 1 is a C 1-8 -alkyl; R 1’ is H or C 1-4 -alkyl; n is equal to 1 or 2.
  • R 2 and R 2’ are each independently H, D, methyl, or halo;
  • A is NR 3 R 3’ , OR 3 , or SO 2 R 3 ; wherein: R 3 is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, C1-4-haloalkyl, cyanoalkyl, cyanocarbonyl, aminocarbonylalkyl; wherein the cycloalkyl and heterocyclyl moieties are optionally substituted by one or more substituent selected from D, cyano, halo, hydroxyl, and C1-4-alkyl; R 3’ is C1-4-alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, C 1-4 -haloalkyl, cyanoalkyl, cyanocarbonyl, aminocarbonylalkyl; wherein the cycloal
  • X 1 and X 2 are both CH or X 1 is N and X 2 is CH. In one embodiment, X 1 and X 2 are both CH. In another embodiment, X 1 is N and X 2 is CH.
  • L 1 is ethyl. In one embodiment, R 1 is a C5-alkyl, preferably neopentyl. In one embodiment, R 1’ is H. In one specific embodiment, L 1 is ethyl, R 1 is neopentyl and R 1’ is H.
  • Y is S, SO or NH; preferably Y is S.
  • n is equal to 1.
  • R 2 and R 2’ are both H, both F, both D, or both methyl. In one embodiment, one of R 2 and R 2’ is F, D, or methyl and the other is H. In one embodiment, R 2 and R 2’ are both H, or both F. [0044] In one specific embodiment, n is equal to 1, and R 2 and R 2’ are both H or both F. [0045] In one embodiment, A is NR 3 R 3’ , OR 3 , or SO 2 R 3 . [0046] In one preferred, R 3 is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, or C1-4-haloalkyl.
  • R 3 is cycloalkyl, cycloalkylalkyl, alkenyl, or C 1-4 -haloalkyl.
  • R 3’ is C1-4-alkyl; more preferably, R 3’ is methyl.
  • R 3 is of formula (i): wherein Z is CH or N; each R 4 is independently H, D, cyano, halo, hydroxyl, or C1-4-alkyl; m is equal to 0, 1, 2, or 3; p is equal to 1, 2, 3, or 4; and represents the point of attachment to the rest of the compound.
  • Z is CH, m is equal to 0 or 1, and p is equal to 1 or 2.
  • the moiety of formula (i) is selected from cyclobutyl and cyclopropylmethyl.
  • R 3 is alkenyl; preferably R 3 is allyl.
  • R 3 is C 1-4 -haloalkyl; preferably R 3 is difluoroethyl.
  • R 3’ is methyl.
  • A is NR 3 R 3’ .
  • A is NR 3 R 3’ wherein R 3 is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, or C 1-4 -haloalkyl; and R 3’ is C 1-4 -alkyl.
  • A is NR 3 R 3’ wherein R 3 is cycloalkyl, cycloalkylalkyl, alkenyl, or C1-4-haloalkyl; and R 3’ is methyl.
  • A is NR 3 R 3’ wherein R 3 is of formula (i) as defined above, alkenyl, or C 1-4 -haloalkyl; and R 3’ is methyl.
  • A is NR 3 R 3’ wherein R 3 is of formula (i) as defined above and R 3’ is methyl.
  • R 3 is NR 3 R 3’ wherein R 3 is alkenyl, preferably allyl, and R 3’ is methyl.
  • A is NR 3 R 3’ wherein R 3 is C 1-4 -haloalkyl, preferably difluoroethyl, and R 3’ is methyl.
  • the compounds of the invention are of formula (Ia): or a pharmaceutically acceptable salt and/or solvate thereof, wherein X 1 , X 2 , Y, L 1 , R 1 , R 1’ , R 2 , R 2’ , R 3’ , R 4 , n, m, and p are as defined above.
  • the compounds of the invention are of formula (Ib): or a pharmaceutically acceptable salt and/or solvate thereof, wherein X 1 , X 2 , Y, L 1 , R 1 , R 1’ , R 2 , R 2’ , R 3’ , and n are as defined above.
  • the compound according to the invention is selected from those listed in Table 1: Table 1 001 2-((6- ((cyclopropylmethyl)(methyl)amino)benz o[d][1,3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5- c]pyridin-4-amine 002 8-((6- ((cyclopropylmethyl)(methyl)amino)benz o[d][1,3]dioxol-5-yl)thio)-9-(2- (neopentylamino)ethyl)-9H-purin-6- amine 003 8-((6- (allyl(methyl)amino)benzo[d][1,3]dioxol- 5-yl)thio)-9-(2-(neopentylamino)ethyl)- 9H-purin-6
  • references to compounds of formula (I) include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well.
  • a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.
  • Bonds from an asymmetric carbon in compounds are generally depicted using a solid line ( ), a solid wedge ( ), or a dotted wedge ( ).
  • the use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.
  • the use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.
  • All references to compounds of formula (I) include references to isotopically-labelled compounds of formula (I), including deuterated compounds of formula (I).
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, ammonia, arginine, benzathine, N-benzylphenethylamine, calcium, choline, chloroprocaine, N,N ’ -dibenzylethylenediamine, diethanolamine, diethylamine, 2-(diethylamino)ethanol, diolamine, ethylenediamine, ethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lithium, lysine, magnesium, meglumine, N-methyl-glutamine, morpholine, olamine, ornithine, potassium, piperazine, procaine, sodium, tetramethylammonium hydroxide, tris(hydroxymethyl)aminomethane, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the compounds of formula (I) may also form internal salts, and such compounds are within the scope of the invention.
  • the compounds of the invention contain a hydrogen-donating heteroatom (e.g., NH)
  • the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • compositions of formula (I) may be prepared by one or more of these methods: (i) by reacting the compound of formula (I) with the desired acid; (ii) by reacting the compound of formula (I) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or (iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. [0068] All these reactions are typically carried out in solution.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of formula (I) above.
  • the compound of invention can be synthesized by methods known in the art. Especially, the compound of invention can be synthesized by the methods detailed in the experimental part below.
  • Pharmaceutical composition [0071] This invention also relates to a pharmaceutical composition comprising a compound according to the invention, as described hereinabove, and at least one pharmaceutically acceptable carrier. [0072] According to a first embodiment, the pharmaceutical composition comprises the compound according to the invention as sole therapeutic agent. [0073] According to a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the other therapeutic agent is selected from therapeutic agents detailed hereafter regarding combination therapy.
  • the pharmaceutical composition of the invention may further comprise therapeutically active compounds other than those listed herein, which are usually applied in the treatment of the targeted pathological conditions. Medical use and methods of treatment [0075]
  • This invention also relates to a compound according to the invention, as described hereinabove, for use as a medicament.
  • This invention also relates to a compound according to the invention, as described hereinabove, for use as inhibitor of HSP90.
  • the compounds of the invention are advantageously specific inhibitors of HSP90. In some embodiments, the compounds of the invention are selective inhibitors of HSP90 alpha with regard to HSP90 beta.
  • the compounds of the invention are selective inhibitors of HSP90 alpha with regard to the three other paralogs of HSP90 (HSP90 beta, Grp94 and Trap-1).
  • the compounds of the invention present an improved penetration in brain compared to other HSP90 inhibitors.
  • This invention also relates to a compound according to the invention, as described hereinabove, for use in the treatment of a disease or disorder in which HSP90 is implicated.
  • diseases or disorders in which HSP90 is implicated include cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD (Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation), diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis.
  • ROHHAD Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation
  • diabetic atherosclerosis severe psoriasis
  • primary myelofibrosis primary myelofibrosis
  • acute pancreatitis atopic pancreatitis.
  • the invention thus provides a compound according to the invention, as described hereinabove, for use in the treatment of cancer.
  • the cancer is human cancer.
  • the cancer is a solid cancer.
  • the cancer is a non-solid cancer.
  • Examples of cancers include, without being limited to, brain tumors, hematopoietic disorders, breast cancer, lung cancer, leukemia, lymphoma, pancreatic cancer, multiple myeloma, prostate cancer, glioma, colon cancer, gastric cancer, ovarian cancer, and any cancer with oncogene production chaperoned by HSP90.
  • cancers driven by oncogenic proteins that are HSP90 clients, wherein the oncogenic proteins are for example selected from v-Src, Lyn, Lck, Yes, Fps, Fes, Bcr-Abl, Raf-1, AKT/PKB, ErbB2, Plk-1, MET, Wee1, Cdc2, Cdc4, Cdc6, Dnmt-1, Survivin, Mutant p53, c-Myc, hTERT, MOK, MAK, MRK, DNA polymerase ⁇ , Estrogen receptor, Androgen receptor, HIF-1 ⁇ , SV40 large T antigen, and SV40 small T antigen; and oncogenic translocations such as Alk-NPM, or Alk-EML4.
  • oncogenic proteins are for example selected from v-Src, Lyn, Lck, Yes, Fps, Fes, Bcr-Abl, Raf-1, AKT/PKB, ErbB2, Plk-1, MET, Wee1,
  • the present invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of a neurodegenerative disease.
  • neurodegenerative diseases include, without being limited to, Alzheimer's disease, Senile dementia of the Alzheimer type, dementia of head trauma and diffuse brain damage, dementia pugilistica, frontal lobe dementia, Pick's disease, Huntington's disease, Multiple system atrophy combining dementia with ataxia and/or manifestations of Parkinson's disease, Progressive supranuclear palsy, diffuse Lewy body disease, corticodentatonigral degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, familial tremor, Gilles de la Tourette syndrome, cerebellar cortical degeneration, olivopontocerebellar atrophy, spinocerebellar de
  • the present invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of a neurodegenerative disease with proteins aggregates.
  • a neurodegenerative disease with proteins aggregates include, without being limited to, congenital central hypoventilation syndrome (CCHS), Huntington's disease (HTT), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), alpha- synucleinopathies, and central hypoventilation syndrome (CHS).
  • CCHS congenital central hypoventilation syndrome
  • HTT Huntington's disease
  • ALS amyotrophic lateral sclerosis
  • PD Parkinson's disease
  • alpha- synucleinopathies and central hypoventilation syndrome
  • CHS central hypoventilation syndrome
  • the invention provides a compound according to the invention, as described hereinabove, for use in the treatment of congenital central hypoventilation syndrome (CCHS).
  • Congenital central hypoventilation syndrome “congenital central hypoventilation syndrome”, “CCHS”, “Ondine’s curse”, “congenital failure of autonomic control”, “Haddad syndrome” and “Ondine-Hirschsprung disease” are equivalent and refer to a rare neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia.
  • Congenital central hypoventilation syndrome is characterized by a sleep hypoventilation associated with a dysfunction of PHOX2B CO2/H + sensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG).
  • the patients are thus devoid of the interoceptive alarms that normally trigger awakening in the case of life-threatening hypoxia during sleep and in more severely affected individuals, during waking periods as well.
  • Congenital central hypoventilation syndrome is associated with a malfunction of the nerves that control involuntary body functions and abnormal development of early embryonic cells that form the spinal cord.
  • Hypercapnia, acidosis, and hypoxemia resulting from CCHS negatively affect physiological functions and can be life-threatening.
  • the present invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of an infectious disease.
  • infectious diseases include, without being limited to, viral infections such as infection by Enterovirus 71 (EV71), other virus from the picornavirus family, or COVID-19; and protozoan (Plasmodium) infections such as Malaria.
  • EV71 Enterovirus 71
  • COVID-19 Enterovirus 71
  • Plasmodium protozoan infections
  • Malaria Malaria.
  • This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for inhibiting HSP90.
  • This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a disease or disorder in which HSP90 is implicated, as defined above.
  • the invention provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD, diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis.
  • the invention thus provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of cancer, as defined above.
  • the invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a neurodegenerative disease, as defined above.
  • Step 2 8-((6-(allyl(methyl)amino)-2,2-difluorobenzo[d][1,3]dioxol- 5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine (Compound 004)
  • Step 2 (A, B and C): 2-((6-(cyclobutyl(methyl)amino)benzo[d][1,3]dioxol-5- yl)thio)-1-(2-(neopentylamino)ethyl)-1H-N,N-bis[(4-methoxyphenyl)methyl]imidazo [4,5-c]pyridin-4-amine
  • Step A [0198] Step A: To a solution of Intermediate IV-6 (500 mg, 820 ⁇ mol, 1.00 eq.) and compound b (367 mg, 1.64 mmol, 2.00 eq..) in DMF (5 mL) was added Cs 2 CO 3 (667 mg, 2.05 mmol, 2.50 eq.) at 25 °C under N2.
  • Step B The compound resulting from step A (550 mg, 730 ⁇ mol, 1.00 eq..) was added to HCl/MeOH (6.00 mL) (2 M) at 25 °C and stirred for 1.5 hrs under N 2 .
  • the reaction mixture was diluted with water (40.0 mL) and extracted with DCM (30.0 mL ⁇ 2).
  • the combined organic layers were washed brine (40.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the corresponding deprotected compound (390 mg, 503 ⁇ mol, 68.9% yield, 84.2% purity) as a yellow oil which was used to the next step.
  • Step 3 2-((6-(cyclobutyl(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 006) [0202]
  • the compound resulting from step C above (300 mg, 414.97 ⁇ mol, 1.00 eq.) was added to TFA (3 mL) at 25 °C and stirred for 12 hrs under N2. The reaction mixture was concentrated under reduced pressure to remove TFA.
  • HSR Heat shock response
  • MCF-7 cells were treated with Debio0932 or a compound according to the invention at 10 ⁇ M, and incubated for 24 hours. Cell lysates were then prepared in RIPA buffer and each condition was analyzed by western blot analysis for HSP70 expression. GAPDH was used as a loading control. Effect of each compound on HSP70 induction was evaluated as the ratio of HSP70 signal compared to GAPDH.
  • HSP70 levels at 10 ⁇ M are summarized in Table 3.
  • Table 3 Compound HSP70 level (10 ⁇ M) 001 4.2 002 3.23 003 1.79 Debio0932 1.85
  • Example 3 Metabolization – CYP inhibition profile
  • Purpose Cytochrome P450 enzymes inhibition assay is used to predict drug interaction with CYP enzymes, as this interaction is predictive of the compound metabolization.
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4-M were evaluated for the compounds of the invention and for the reference compounds Debio0932 by LC-MS/MS.
  • Material and method CYP isoform-specific substrates are incubated individually with human or mouse liver microsomes and a concentration range (0.05 – 50 ⁇ M) of either the tested compounds, or known CYP inhibitors used as controls. After a 10 minutes incubation at 37°C, the formation of metabolites is monitored by LC-MS/MS.
  • Liver microsome clearance assay consists in calculating the time it takes for a compound to be degraded in presence of liver microsomes in order to predict its metabolization and clearing rate in a living organism. In vitro clearances of the compounds of the invention and of the reference compound Debio0932 were calculated in presence of human liver microsome by LC-MS/MS. [0219] Material and method: Each compound was added to well containing human microsome preparation and mixed. Plates were then incubated at 37°C for different time points before adding quenching solution to stop the reaction. Plates were then sealed and shaken for 10 minutes prior to LC-MS/MS analysis.

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Abstract

La présente invention concerne des composés de formule (I), ou des sels et/ou solvates pharmaceutiquement acceptables de ceux-ci, dans laquelle X1, X2, Y, L1, R1, R1', R2, R2', n et A sont tels que définis dans les revendications, qui sont utiles en tant qu'inhibiteurs de HSP90, en particulier pour le traitement de cancers, de maladies neurodégénératives et de maladies neurodégénératives avec des agrégats de protéines tels que le syndrome d'hypoventilation central congénital (CCHS).
EP24710769.1A 2023-03-17 2024-03-15 Dérivés d'adénine en tant qu'inhibiteurs de hsp90 Pending EP4680606A1 (fr)

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PCT/EP2024/056937 WO2024194175A1 (fr) 2023-03-17 2024-03-15 Dérivés d'adénine en tant qu'inhibiteurs de hsp90

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US4166452A (en) 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
US4256108A (en) 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
CA2786715C (fr) * 2009-01-16 2019-05-21 Curis, Inc. Aminopyridines fusionnees pour le traitement de tumeurs cerebrales
ES2647889T3 (es) * 2011-04-05 2017-12-27 Sloan-Kettering Institute For Cancer Research Inhibidores de la Hsp90
WO2023006993A1 (fr) * 2021-07-30 2023-02-02 Atmosr Dérivés d'amino pyridine ou pyrimidine condensée pour le traitement du syndrome d'hypoventilation centrale congénitale

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WO2024194175A1 (fr) 2024-09-26

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