WO2022175402A1 - Dérivés de quinuclidine-3-one - Google Patents

Dérivés de quinuclidine-3-one Download PDF

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WO2022175402A1
WO2022175402A1 PCT/EP2022/053987 EP2022053987W WO2022175402A1 WO 2022175402 A1 WO2022175402 A1 WO 2022175402A1 EP 2022053987 W EP2022053987 W EP 2022053987W WO 2022175402 A1 WO2022175402 A1 WO 2022175402A1
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methyl
oxoquinuclidin
acetamide
group
malignant neoplasms
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PCT/EP2022/053987
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English (en)
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Lars Hagberg
Tim BLIZZARD
Joakim Larsson
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Aprea Therapeutics Ab
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Publication of WO2022175402A1 publication Critical patent/WO2022175402A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to certain substituted quinuclidine-3-one compounds for use in the treatment of hyperproliferative disease, such as cancer, and diseases associated with inflammation. More particularly, the present invention relates to certain substituted 3-quinuclidinones, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and to methods for using such compounds. In this manner, these compounds are of use for treating hyperproliferative diseases and inflammatory diseases.
  • p53 halts the cell cycle and/or triggers apoptosis in response to various stress stimuli, including DNA damage, hypoxia, and oncogene activation (Ko & Prives (1996), Genes Dev 10:1054-1072; Sherr (1998), Genes Dev 12:2984-2991). Upon activation, p53 initiates the p53-dependent biological responses through transcriptional transactivation of specific target genes carrying p53 DNA binding motifs.
  • the multifaceted p53 protein may promote apoptosis through transactivation- independent effects; in the nucleus repression of certain genes, and in the cytoplasmic space involving sequestering the anti-apoptotic protein Bcl-xL (Bennett et a/ (1998), Science 282:290-293; Gottling & Oren (1998), Semin Cancer Biol 8:359-68; Ko & Prives (1996), supra ; Green etal (2009), Nature 458: 1127-1130).
  • EAE as a model for autoimmune inflammatory diseases of the central nervous system (CNS) is a widely used model for the human disease multiple sclerosis.
  • a 2,2-substituted quinuclidine-3-one derivative leads to suppression of both branches of the cellular defense against oxidative stress, which has been shown to have an anti-cancer effect (Wondrak (2009), Antioxid Redox Signal 11:3015-3069).
  • the redox effects of 2,2-substituted quinuclidine-3-one derivatives suggest that this type of compounds may have a beneficial effect in chronic inflammatory diseases, comprising allergy, asthma, atherosclerosis, coeliac disease, Crohn’s disease, gout, inflammatory bowel disease, rheumatoid arthritis, and transplant rejection.
  • WO2002/24692 W02003/070250, W02004/084893, W2005/090341 and W02020/058458.
  • WO2002/24692 W02003/070250, W02004/084893, W2005/090341 and W02020/058458.
  • WO201 5/150472 describes a method of treating melanoma using a 2,2-substituted quinuclidine-3-one in a combination therapy with a BRAF inhibitor.
  • W02007/062030 and CN104860994 describe a series of 2,2- substituted quinuclidine-3-one derivatives for the treatment of cancer by restoring the activity of mutant p53.
  • the present invention provides certain novel compounds, pharmaceutically acceptable salts, hydrates, solvates and combinations thereof and pharmaceutical compositions containing the same, as well as methods and uses for treating disease.
  • the quinuclidine-3-one derivatives of the present invention are useful in the treatment of hyperproliferative diseases, autoimmune diseases, inflammatory diseases and heart diseases.
  • the compounds of the present invention have advantageous properties relating to the ability to kill tumor cells, including apoptosis of tumor cells carrying mutant p53.
  • the compounds also display favorable pharmacokinetic and pharmacodynamic properties, a high potency, stability in formulation, low toxicity, and show synergistic effects with other anti-cancer agents.
  • R 1 and R 2 are different; R 1 or R 2 is H; and R 1 or R 2 is selected from from the group consisting of -CH 2 - NR 10 -CS-NR 4 R 5 , -CH 2 -S-R 4 , -CH 2 -S-R 11 , -CH 2 -NR 10 -SO 2 -R 4 , -CH 2 - NR 4 R 5 , -CH 2 -NR 10 -CO-R 4 , -CH 2 -O-CO-R 4 , -CH 2 -NR 10 -CO-NR 4 R 5 , -CH 2 -NR 10 - CO-OR 4 and -CH 2 -O-CO-NR 4 R 5 .
  • R 1 and R 2 are different; R 1 or R 2 is H; and R 1 or R 2 is selected from from the group consisting of -CH 2 -O- R 4 , -CH 2 -S-R 4 , -CH 2 -S-R 11 , -CH 2 -NR 10 -SO 2 -R 4 and -CH 2 -NR 10 -CO-R 4 .
  • R 1 and R 2 are different; R 1 or R 2 is H; and R 1 or R 2 is selected from from the group consisting of -CH 2 -S- R 4 , -CH 2 -S-R 11 , -CH 2 -NR 10 -SO 2 -R 4 and -CH 2 -NR 10 -CO-R 4 .
  • R 1 and R 2 are different; R 1 or R 2 is H; and R 1 or R 2 is selected from from the group consisting of -CH 2 -O- CH 2 CH 3 , -CH 2 -S-CH 2 -CH(NHAc)-COOH, -CH 2 -NH-SO 2 -CH 3 , -CH 2 -N-CH 2 - CH 2 -CH 2 -SO 2 - wherein N and S together form a 5-membered ring, -CH 2 - N(CH 2 -CH 2 -O-CH 3 )-CO-CHF 2 , -CH 2 -N(CH 2 -CH 2 -O-CH 3 )-CO-CF 3 and -CH 2 - NH-CO-CF 3 .
  • R 1 and R 2 are different; R 1 or R 2 is H; and R 1 or R 2 is selected from from the group consisting of -CH 2 -S- CH 2 -CH(NHAc)-COOH, -CH 2 -NH-SO 2 -CH 3 , -CH 2 -N-CH 2 -CH 2 -CH 2 -SO 2 - wherein N and S together form a 5-membered ring, -CH 2 -N(CH 2 -CH 2 -O-CH 3 )- CO-CHF 2 , -CH 2 -N(CH 2 -CH 2 -O-CH 3 )-CO-CF 3 and -CH 2 -NH-CO-CF 3 .
  • R 1 and R 2 are different; R 1 or R 2 is H; and R 1 or R 2 is selected from from the group consisting of -CH 2 -S- R 4 , -CH 2 -S-R 11 , -CH 2 -NR 10 -SO 2 -R 4 and -CH 2 -NR 10 -CO-R 4 .
  • R 1 and R 2 are different; R 1 or R 2 is H; and R 1 or R 2 is selected from from the group consisting of -CH 2 -S- CH 2 -CH(NHAc)-COOH, -CH 2 -NH-SO 2 -CH 3 , -CH 2 -N-CH 2 -CH 2 -CH 2 -SO 2 - wherein N and S together form a 5-membered ring, -CH 2 -N(CH 2 -CH 2 -O-CH 3 )- CO-CHF 2 , -CH 2 -N(CH 2 -CH 2 -O-CH 3 )-CO-CF 3 and -CH 2 -NH-CO-CF 3 .
  • R 3 is selected from the group consisting of H, C 1 -C 6 alkyl and halogen, said alkyl being optionally substituted with one or more C 1 -C 6 alkoxy.
  • R 3 is selected from the group consisting of H, C 1 -C 6 alkyl and halogen.
  • R 3 is selected from the group consisting of H, methyl and fluoro.
  • R 1 and R 2 are the same or different and selected from the group consisting of H, -CH 2 -O-CH 2 CH 3 , -CH 2 - S-CH 2 -CH(NHAc)-COOH, -CH 2 -NH-SO 2 -CH 3 , -CH 2 -N-CH 2 -CH 2 -CH 2 -SO 2 - wherein N and S together form a 5-membered ring, -CH 2 -N(CH 2 -CH 2 -O-CH 3 )- CO-CHF 2 , -CH 2 -N(CH 2 -CH 2 -O-CH 3 )-CO-CF 3 and -CH 2 -NH-CO-CF 3 .
  • R 1 and R 2 are the same or different and selected from the group consisting of H, -CH 2 -S-CH 2 -CH(NHAc)- COOH, -CH 2 -NH-SO 2 -CH 3 , -CH 2 -N-CH 2 -CH 2 -CH 2 -SO 2 - wherein N and S together form a 5-membered ring, -CH 2 -N(CH 2 -CH 2 -O-CH 3 )-CO-CHF 2 , -CH 2 - N(CH 2 -CH 2 -O-CH 3 )-CO-CF 3 and -CH 2 -NH-CO-CF 3 .
  • a compound selected from the group consisting of: 4-methyl-2-methylenequinuclidin-3-one; 4-methylenehexahydro-2H-2,6-methanoquinolizin-3(4H)-one; 4-fluoro-2-methylenequinuclidin-3-one; 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6H)-one; 3-methylenehexahydro-2,5-methanocyclopenta[c]pyridin-4(3H)-one; 5-methylenehexahydro-3,7-methanoindolizin-6(5H)-one; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof.
  • the present invention provides a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment of a disease associated with a malfunctioning p53 signaling pathway, for example associated with mutant p53.
  • the present invention provides a method of treating a disease associated with a malfunctioning p53 signaling pathway, for example associated with mutant p53, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, to a subject in need thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, to a subject in need thereof.
  • the embodiments of the first, the second and the third aspects are also applicable here.
  • the present invention provides a method of preparing a compound according to the first aspect.
  • reaction scheme 1 The fused piperidone (iv) is constructed via a Robinson-Schöpf condensation starting from a masked dialdehyde, acetonedicarboxylic acid and an amine as described by Lowe III et al (1994), J Med Chem 37:2831- 2840.
  • the fused piperidone (ix) is made via a double Mannich reaction from N,N-Bis(methoxymethyl)benzylamine, or an amine and formaldehyde, plus a cyclic ketone as described by Mityuk et al (2010), Synthesis, 3:493-497 and Lowe III et al (1994), supra.
  • Compound (xxv) can also be made by heating (xxiv) with dimethylamine, formalin and a base in an organic solvent, as described by Nielsen (1966), J Org Chem 31:1053-1059.
  • the substituted 2-(dimethylamino)methyl-3-quinuclidinone (xxxviii) can be isolated and used to generate the substituted 2-methylene-3- quinuclidinone (xxv) in situ for subsequent steps, according to below.
  • Reaction scheme 6 a substituted 2-methylene-3- quinuclidinone (xxv) can be used as starting material for the synthesis of compounds (xxvi) and (xxvii) and (xxviii).
  • the substituted 2-methylene-3- quinuclidinone (xxv) can be generated in situ from (xxxviii).
  • Compound (xxvii) may be made by reacting (xxv) with an amine in organic solvents as described by Malki et al (2017), supra; Singh et al (1969), J Med Chem 12:524-526 and US3726877, or in a mixture of an organic solvent and water in the presence of a phase transfer catalyst as described in WO2005/090341.
  • the synthesis of compound (xxviii) from compound (xxvi) may be performed by methods well known to the person skilled in the art by reacting (xxvi) with an alkyl halide and a base in an organic solvent as described by Declerck et al (2004), J Org Chem 69:8372-8381.
  • an alcohol may be used to alkylate the nitrogen under Mitsunobu conditions as described by Lee et al (2016), Org Lett 18:3678-3681.
  • compound (xxix) can be made by reacting water or an alcohol with (xxv) in the presence of an appropriate acid according to the example below.
  • compound (xxx) can be made by reacting a thiol with (xxv) in an appropriate solvent according to the examples below.
  • compounds (xxxi), (xxxii), (xxxiii) and (xxxiv) can be made by methods well known to the person skilled in the art from compound (xxvii).
  • Reaction scheme 10 According to Reaction scheme 10 compounds (xxxvi) and (xxxvii) can be made by methods well known to the person skilled in the art from compound (xxxv).
  • Compound (xxxv) in turn, can be made according to Reaction scheme 7, by reacting compound (xxv) with water in the presence of an appropriate acid.
  • C 1 -C 6 alkyl means both linear and branched chain saturated hydrocarbon groups with from 1 to 6 carbon atoms.
  • Examples of C 1 -C 6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, t-butyl, n-pentyl, 1-methyl-butyl, n-hexyl and 2-ethyl-butyl groups.
  • Non-limiting examples of unbranched C 1 -C 6 alkyl groups are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl groups.
  • Non-limiting examples of branched alkyl groups are iso-propyl, iso-butyl, sec-butyl, t-butyl, 1-methyl- butyl and 2-ethyl-butyl groups.
  • the term ”C 1 -C 3 alkyl means both linear and branched chain saturated hydrocarbon groups with from 1 to 3 carbon atoms.
  • Non- limiting examples of C 1 -C 3 alkyl groups include methyl, ethyl, n-propyl and isopropyl groups.
  • C 2 -C 6 alkenyl means both linear and branched chain unsaturated hydrocarbon groups with from 2 to 6 carbon atoms.
  • Non-limiting examples of C 2 -C 6 alkenyl groups include, ethyleneyl, 1- propene-1-yl, 2-butene-2-yl, 2-methyl-2-butene-1-yl and 3-metyl-2-pentene-2- yl.
  • C 1 -C 6 alkoxy means the group O-C 1 -C 6 alkyl, where “C 1 -C 6 alkyl” is used as described above.
  • Non-limiting examples of C 1 -C 6 alkoxy groups are methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, n-hexoxy and 3-methyl-butoxy groups.
  • C 1 -C 3 alkoxy means the group O-C 1 -C 3 alkyl, where “C 1 -C 3 alkyl” is used as described above.
  • Non-limiting examples of C 1 -C 3 alkoxy groups are methoxy, ethoxy, isopropoxy and n-propoxy groups.
  • C 1 -C 6 haloalkyl means both linear and branched chain saturated hydrocarbon groups with from 1 to 6 carbon atoms, having from one to all hydrogens substituted by a halogen of different or same type.
  • Non-limiting examples of C 1 -C 6 haloalkyl groups include methyl substituted with from 1 to 3 halogen atoms, ethyl substituted with from 1 to 5 halogen atoms, n-propyl or iso-propyl substituted with from 1 to 7 halogen atoms, n-butyl or iso-butyl substituted with from 1 to 9 halogen atoms, and sec-butyl or t-butyl substituted with from 1 to 9 halogen atoms.
  • C 1 -C 3 haloalkyl means both linear and branched chain saturated hydrocarbon groups with from 1 to 3 carbon atoms, having from one to all hydrogens substituted by a halogen of different or same type.
  • Non-limiting examples of C 1 -C 3 haloalkyl groups include methyl substituted with from 1 to 3 halogen atoms, ethyl substituted with from 1 to 5 halogen atoms, and n-propyl or iso-propyl substituted with from 1 to 7 halogen atoms.
  • C 1 -C 3 haloalkoxy means both linear and branched chain saturated alkoxy groups with from 1 to 3 carbon atoms, having from one to all hydrogen atoms substituted by a halogen atom of different or same type.
  • Non-limiting examples of C 1 -C 3 haloalkoxy groups include methoxy substituted with from 1 to 3 halogen atoms, ethoxy substituted with from 1 to 5 halogen atoms, and n-propoxy or iso-propoxy substituted with from 1 to 7 halogen atoms.
  • C 1 -C 3 fluoroalkyl means both linear and branched chain saturated hydrocarbon groups with from 1 to 3 carbon atoms, having from one to all hydrogen atoms substituted by a fluorine atom.
  • Non- limiting examples of C 1 -C 3 fluoroalkyl groups include methyl substituted with from 1 to 3 fluorine atoms, ethyl substituted with from 1 to 5 fluorine atoms, and n-propyl or iso-propyl substituted with from 1 to 7 fluorine atoms.
  • C 1 -C 3 fluoroalkoxy means both linear and branched chain saturated alkoxy groups with 1 to 3 carbon atoms, having from one to all hydrogen atoms substituted by a fluorine atom.
  • Non-limiting examples of C 1 -C 3 fluoroalkoxy groups include methoxy substituted with from 1 to 3 fluorine atoms, ethoxy substituted with from 1 to 5 fluorine atoms, and n-propoxy or iso-propoxy substituted with from 1 to 7 fluorine atoms.
  • C 3 -C 6 cycloalkyl means a cyclic saturated hydrocarbon group with from 3 to 6 carbon atoms.
  • Non-limiting examples of C 3 -C 6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 1 -C 3 alkoxy C 1 -C 3 alkyl means both linear and branched chain saturated hydrocarbon groups with 1 to 3 carbon atoms, substituted with an alkoxy group with 1 to 3 carbon atoms.
  • Non-limiting examples of C 1 -C 3 alkoxy C 1 -C 3 alkyl groups are drawn below.
  • C1-C3 cyanoalkyl means both linear and branched chain cyano (CN) derivatives with one to three carbon atoms, including the carbon atom that is part of the cyano group.
  • C1-C3 cyanoalkyl groups are drawn below.
  • N-C1-C3 alkylamino means an C1-C3 alkyl substituent attached to the remainder of a molecule via nitrogen.
  • N-C1-C3 alkylamino are drawn below.
  • N,N-di C1-C3 alkylamino means two C1-C3 alkyl substituents attached to the remainder of a molecule via nitrogen. Non- limiting examples of N,N-di C1-C3 alkylamino are drawn below.
  • amino-C1-C3 alkyl means any amino derivative of a C 1 -C 3 alkyl radical. Non-limiting examples of amino-C 1 -C 3 alkyl are drawn below.
  • halogen means fluorine, chlorine, bromine or iodine.
  • aryl means a monocyclic aromatic carbocyclic group.
  • Non-limiting examples of such groups include phenyl.
  • heteroaryl means a monocyclic or bicyclic aromatic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. In a bicyclic aryl, one of the rings may be partially saturated.
  • Non-limiting examples of such groups include indolinyl, dihydrobenzofuranyl and 1,3-benzodioxolyl.
  • Non-limiting examples of monocyclic heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl.
  • bicyclic heteroaryl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuryl, indolyl, indazolyl, benzothiazolyl, pyridopyrimidinyl and isoquinolinyl.
  • heterocyclyl means a cyclic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples of heterocyclyl groups include 3- oxoquinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxanyl.
  • a “substituent” means an atom or group that replaces another atom or group in a molecule or can be regarded as replacing an atom in a parent compound.
  • the substituents R 1 and R 2 are replaced by the various listed alternative options.
  • the compounds of the present invention may form salts, which are within the scope of the present invention.
  • Salts of compounds of formula (I) suitable for use in medicine are for example those wherein a counter ion is pharmaceutically acceptable.
  • Suitable salts according to the invention include those formed with organic or inorganic acids or bases.
  • suitable acid addition salts according to the present invention include those formed with mineral acids, strong organic carboxylic acids, or with organic alkyl or aryl sulfonic acids, optionally substituted with halogen.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethane- sulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic or glutamic acids, as well as from lysine or arginine.
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or tri lower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono- ,di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine.
  • organic bases for example dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or tri lower alkylamine, for example ethyl, ter
  • Corresponding internal salts of the compounds of the present invention may furthermore be formed.
  • a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate or combination thereof, and a pharmaceutically acceptable diluent, carrier and/or excipient.
  • Such compositions may be suitable for oral or parenteral administration.
  • compositions for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers or other pH-adjusting components, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as polyethylene glycol, ethanol, 1,3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremophor®.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as polyethylene glycol, ethanol, 1,3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremophor®.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as polyethylene glycol, ethanol,
  • said cancer is selected from malignant neoplasms, stated or presumed to be primary, of the following sites: malignant neoplasms of lip, oral cavity and pharynx including head and neck cancer; malignant neoplasms of digestive organs including esophagus, colon, liver or pancreas cancer; malignant neoplasms of respiratory and intrathoracic organs including lung cancer; malignant neoplasms of bone and articular cartilage including osteosarcoma; melanoma and other malignant neoplasms of skin; malignant neoplasms of mesothelial and soft tissue including sarcoma; malignant neoplasm of breast; malignant neoplasms of female
  • said disease associated with a malfunctioning p53 signaling pathway is selected from autoimmune diseases, for example multiple sclerosis, and cardiac diseases, for example myocardial ischemia.
  • said disease is selected from the group consisting of pre-chronic inflammatory diseases, including allergy, asthma, atherosclerosis, coeliac disease, Crohn’s disease, gout, inflammatory bowel disease, rheumatoid arthritis and transplant rejection.
  • a method of treating a disease associated with a malfunctioning p53 signaling pathway, for example associated with mutant p53 comprising administering a therapeutically effective amount of a compound according to the present invention, to a patient in need thereof.
  • the amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated, as well as its severity.
  • An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Oral dosages of the present invention will range from about 0.1 to about 1000 mg per kg of body weight per day (mg/kg/day), preferably from 1 to 500 mg/kg/day, and more preferably from 10 to 250 mg/kg/day, for adult humans.
  • compositions may be provided in the form of tablets or other forms, such as capsules, to provide discrete units containing 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 500, 1000, 5000 or 10000 mg of active pharmaceutical ingredient.
  • An oral dosage unit typically contains from about 1 mg to about 5000 mg, preferably from about 1000 mg to about 2500 mg, of active pharmaceutical ingredient.
  • Parenteral dosages of the present invention when used for the indicated effects, will range from about 1 to about 1000 mg/kg/day, preferably from 1 to 500 mg/kg/day, most preferably from 10 to 100 mg/kg/day, for adult humans.
  • the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds and compositions of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the compounds and compositions of the present invention may be used or administered in combination with at least one of the following compounds (active pharmaceutical ingredients): platinum based antineoplastic agents (including cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin), nucleoside analogs and antimetabolites (including cytarabine, fludarabine, gemcitabine, 5FU), DNA intercalators (including danorubicin, doxorubicin, epirubicin and idarubicin, camptothecin), alkylating neoplastic agents (including cyclophosphamide, melphalan, bendamustine, carmustine, lomustine.
  • platinum based antineoplastic agents including cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin
  • nucleoside analogs and antimetabolites
  • ifosfamide topoisomerase inhibitors
  • PARP inhibitors including olaparib, niraparib, rucaparib
  • a substance interfering with microtubule dynamics including combrestatin, eribulin, docetaxel, taxane, vinoblastine, vincristine
  • a substance blocking the interaction between p53 and MDM2 or MDM4 including nutlins, idasanutlin, siremadlin (HDM201), milademetan (DS3032b), AMG-232 (CAS no.
  • kinase inhibitor including BRAF inhibitors vemurafenib, dabrafenib
  • PI3K and/or mTOR inhibitor including LY294002 (CAS no.
  • dactolisib, rapamycin and rapamycin analogs temsirolimus, everolimus, ridaforolimus an MRP1 inhibitor (including indomethacin, meloxicam, sulindac sulfide, GSK1904529A (CAS no.1089283-49-7), verlukast (MK571), verapamil), hypomethylation agents (including azacitidine, decitabine), histone deacetylase inhibitor (including cirtuins, hydroxamates including vorinostat, belinostat, dacinostat, panobinostat, valproic acid, benzamides including entinostat, mocetinostat), proteasome inhibitors (including bortezomib, ritonavir, carfilzomib), an antivascular or antiangiogenic agent (including 2aG4, bevacizumab), tyrosine kinase inhibitor (including la
  • brusatol trigonelline, luteolin, ascorbic acid, tretinoin (ATRA)
  • autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognize an extracellular cancer target (including CD19, PSMA, mesothelin), glucocorticoid receptor agonist (including dexamethasone), buthionine sulfoximine, folic acid, metformin, sorafenib, sulfasalazine, bleomycin, erlotinib, tunicamycin, wortmannin, pidilizumab, durvalumab, GSK3174998, tavolixizumab, deazaneplanocin A or piperlongumine.
  • CAR chimeric antigen receptor
  • Such combined administration may be concomitant and/or sequential.
  • the compounds and compositions of the present invention may be administered alone or administered in combination with other compounds (active pharmaceutical ingredients), wherein the administration is also in combination with an external beam irradiation by gamma or neutron radiation or targeted therapy with antibodies labeled with beta or alpha emitting radionuclides, including I-131, Y-90, Lu-177, Bi-213, Ac-225 and Th-227, or radiotherapy with Ra-223.
  • Example 2 Synthesis of N-((7-oxooctahydro-4,8-methanopyrido[2,1- c][1,4]oxazin-6-yl)methyl)methanesulfonamide 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6H)-one (33 mg, 0.18 mmol) was dissolved in DMF (0.5 mL) followed by addition of methanesulfonamide (23 mg, 0.24 mmol) and potassium carbonate (26 mg, 0.19 mmol).
  • Example 3 Synthesis of N-((6-oxooctahydro-3,7-methanoindolizin-5- yl)methyl)methanesulfonamide
  • N-((6-oxooctahydro-3,7-methanoindolizin-5- yl)methyl)methanesulfonamide To a solution of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)- one (22 mg, 0.13 mmol) in DMF (1 mL), methanesulfonamide (17 mg, 0.18 mmol) and potassium carbonate (21 mg, 0.15 mmol) were added. The reaction mixture was stirred for 48 hours whereafter 1 mL of acetonitrile was added and the reaction mixture was filtered and concentrated to give a yellow oil.
  • Example 5 Synthesis of N-acetyl-S-((4-methyl-3-oxoquinuclidin-2-yl)methyl)- L-cysteine 4-methyl-2-methylenequinuclidin-3-one (20.0 mg, 0.13 mmol) and 0.95 eq. of N-acetyl-L-cysteine (20.0 mg, 0.12 mmol) were suspended in DCM (0.50 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and diethyl ether was added to precipitate the product. The solid was washed with DCM and diethyl ether, and the title compound was obtained as an off-white solid (30 mg, 78%).
  • Example 8 Synthesis of N-acetyl-S-((4-fluoro-3-oxoquinuclidin-2-yl)methyl)-L- cysteine 4-fluoro-2-methylenequinuclidin-3-one (10.0 mg, 0.06 mmol) and N- acetyl-L-cysteine (10.5 mg, 0.06 mmol) was suspended in DCM (0.5 mL) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the title compound was obtained as a white waxy solid residue (20 mg, 98%). The title compound was isolated as a mixture of diastereomers. MS ESI+ m/z 319 [M+H] + .
  • Example 9 Synthesis of N-acetyl-S-((3-oxooctahydro-2H-2,6-methano- quinolizin-4-yl)methyl)-L-cysteine 4-methylenehexahydro-2H-2,6-methanoquinolizin-3(4H)-one (10.0 mg, 0.06 mmol) and N-acetyl-L-cysteine (8.7 mg, 0.053 mmol) were suspended in DCM (0.5 mL) and the reaction mixture was stirred at room temperature for 3 hours. After completion the solvent was evaporated and diethyl ether was added to precipitate the product.
  • Example 10 Synthesis of 4-methylenehexahydro-2H-2,6-methanoquinolizin- 3(4H)-one Step 1. Preparation of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-carbonitrile Potassium tert-pentoxide (1.7 M in toluene, 34 mL, 48 mmol) was mixed with monoglyme (50 mL) at 0°C.
  • Step 7 Preparation of hexahydro-2H-2,6-methanoquinolizin-3(4H)-one
  • the combined HCl phases were stirred at 90°C for 15 h.
  • Activated charcoal (2 g) was added and the reaction was further stirred at 90°C for 1 hour. The solution was allowed to cool and was then filtered through a pad of celite.
  • Example 12 Synthesis of 6-(ethoxymethyl)hexahydro-4,8-methanopyrido[2,1- c][1,4]oxazin-7(6H)-one 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6H)-one (5.8 mg, 0.03 mmol) was dissolved in a mixture of EtOH (0.50 mL) and 4M hydrochloric acid in 1,4-dioxane (16.2 ⁇ L, 0.06 mmol).
  • Example 13 Synthesis of N-acetyl-S-((7-oxooctahydro-4,8-methanopyrido- [2,1-c][1,4]oxazin-6-yl)methyl)-L-cysteine N-Acetyl-L-cysteine (30.6 mg, 0.19 mmol) was added to a solution of 6- methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6H)-one (21 mg, 0.12 mmol) in DCM (1 mL). The reaction mixture was stirred for 3 hours and then concentrated.
  • Step 2 Preparation of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid hydrochloride 9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carbonitrile (3.50 g, 14.4 mmol) was stirred in 12M HCl (60.2 mL, 722 mmol) at 100°C overnight.
  • Step 7 Preparation of hexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6H)- one
  • the combined HCl phases from step 6 above were heated at 90°C for 15 hours before activated charcoal (2 g) was added and the reaction mixture was further stirred at 90oC for 1 hour.
  • Example 15 Synthesis of N-acetyl-S-((6-oxooctahydro-3,7-methanoindolizin- 5-yl)methyl)-L-cysteine N-Acetyl-L-cysteine (30 mg, 0.18 mmol) in DCM (0.5 mL) was added to a mixture of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)-one (20 mg, 0.12 mmol) in DCM (1 mL). The obtained reaction mixture was stirred for 2 hours. The crude product was purified by preparative HPLC (Xbridge C18 19x50 mm, water/MeCN, 100:0 to 95:5) to yield 8 mg (20%) of the title compound.
  • the reaction mixture was diluted with DCM (2 mL), and 1 mL sat. NaHCO 3 (aq.) was added and the obtained two-phase mixture was stirred for 5 min.
  • the DCM layer was separated using a phase separator (IST) and the organic layer was concentrated at reduced pressure.
  • the crude residue was purified by column chromatography on silica gel with IPA/DCM (1:18).
  • the material was further purified by preparative HPLC (XBridge C1819x50 mm; 50 mM NH 4 HCO 3 /MeCN; 99:1 to 80:20) to give 3.2 mg of the title compound (9%).
  • MS ESI+ m/z 164 [M+H] + MS ESI+ m/z 164 [M+H] + .
  • Example 17 Synthesis of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)- one Step 1. Preparation of 8-benzyl-8-azabicyclo[3.2.1]octane-3-carbonitrile 1.7 M Potassium tert-pentoxide in toluene (9.45 mL, 16.1 mmol) was added dropwise at 0°C to a mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3- one (1.38 g, 6.41 mmol) and TosMIC (1.63 g, 8.35 mmol) in diglyme/ethanol (54 mL / 1.6 mL). The reaction mixture was slowly allowed to reach room temperature.
  • Step 8 Preparation of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)- one A solution of N,N,N',N'-tetramethylmethanediamine (100 ⁇ L, 0.71 mmol) in DCM (0.6 mL) was added dropwise to a mixture of hexahydro-3,7- methanoindolizin-6(5H)-one (107 mg, 0.71 mmol) and acetic anhydride (134 ⁇ L, 1.42 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 days.
  • the reaction mixture was diluted with DCM (5 mL), NaHCO 3 (1 mL, aq., sat.) was added and the obtained two-phase mixture was stirred for 10 min.
  • the DCM layer was separated using a phase separator (IST) and concentrated.
  • the product was purified using column chromatography on silica gel with DCM/IPA (18:1) to give 78 mg (68%) of the title compound. MS ESI+ m/z 164 [M+H] + .
  • Example 18 Synthesis of 2-((1,1-dioxidoisothiazolidin-2-yl)methyl)-4- methylquinuclidin-3-one
  • Step 2 Preparation of 2,2-difluoro-N-(2-methoxyethyl)-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide hydrochloride
  • the crude product from the previous step was dissolved in 15 ml DCM.
  • Molecular sieves were added followed by difluoroacetyl chloride (55 ⁇ l, 0.53 mmol). The solution was stirred over night.
  • Example 20 Synthesis of 2,2,2-trifluoro-N-(2-methoxyethyl)-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide trifluoroacetate 2-((Dimethylamino)methyl)-4-methylquinuclidin-3-one (82 mg, 0.54 mmol) was dissolved in 5 ml THF followed by addition of 2- methoxyethylamine (470 ⁇ l, 5.41 mmol) and K 2 CO 3 (150 mg, 1.09 mmol). The mixture was stirred over night at ambient temperature. The mixture was diluted with 10 ml DCM, filtered and concentrated under reduced pressure. The crude product was dissolved in 5 ml DCM.
  • Example 21 Synthesis of 2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide
  • 2-((dimethylamino)methyl)-4-methylquinuclidin-3-one (112 mg, 0.571 mmol)
  • 2,2,2-trifluoroacetamide (645 mg, 5.71 mmol)
  • cesium carbonate (930 mg, 2.85 mmol) in MeCN (22.4 mL) was stirred for 1,5 days under nitrogen at ambient temperature.
  • the solids were removed by centrifuging the mixture in a 50 mL Falcon tube and drawing off the liquid. The solids were washed/centrifuged with 10 mL MeCN three times.
  • Example 22 Synthesis of N-cyclopropyl- ((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide N-Cyclopropylmethanesulfonamide (89.4 mg, 661 ⁇ mol) was added to a mixture of 4-methyl-2-methylenequinuclidin-3-one (50.0 mg, 331 ⁇ mol) and cesium carbonate (108 mg, 331 ⁇ mol) in acetonitrile (4.0 mL). and the reaction mixture was stirred at room temperature overnight. The solution was filtered and concentrated under reduced pressure.
  • Example 23 Synthesis of 2-((1,1-dioxido-1,2-thiazinan-2-yl)methyl)-4- methylquinuclidin-3-one
  • a mixture of N-Cyclopropylmethanesulfonamide (60.0 mg, 397 ⁇ mol), 1,2-thiazinane 1,1-dioxide (53.6 mg, 397 ⁇ mol) and cesium carbonate (323 mg, 992 ⁇ mol) in acetonitrile (12 mL) was stirred at room temperature for 3 days. The solution was filtered and concentrated under reduced pressure.
  • Example 24 Synthesis of 2-((3,3-difluoro-2-oxopiperidin-1-yl)methyl)-4- methylquinuclidin-3-one
  • a mixture of N-Cyclopropylmethanesulfonamide (60.0 mg, 397 ⁇ mol), 3,3-difluoropiperidin-2-one (53.6 mg, 397 ⁇ mol) and cesium carbonate (323 mg, 992 ⁇ mol) in acetonitrile (12 mL) was stirred at room temperature for 3 days. The solution was filtered and concentrated under reduced pressure.
  • Example 25 Synthesis of N-cyclopropyl- ((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide
  • N-Cyclopropylmethanesulfonamide (60.0 mg, 397 ⁇ mol)
  • N-cyclopropylcyclopropanesulfonamide (64.0 mg, 397 ⁇ mol)
  • cesium carbonate (323 mg, 992 ⁇ mol) in acetonitrile (12 mL) was stirred at room temperature for 3 days. The solution was filtered and concentrated under reduced pressure.
  • Example 26 Synthesis of N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide
  • N-Cyclopropylmethanesulfonamide 60.0 mg, 397 ⁇ mol
  • N-methylcyclopropanesulfonamide 53.6 mg, 397 ⁇ mol
  • cesium carbonate 323 mg, 992 ⁇ mol
  • Example 27 Synthesis of N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide
  • 2-((dimethylamino)methyl)-4- methylquinuclidin-3-one 76.0 mg, 417 ⁇ mol
  • N,N-diisopropylethylamine 363 ⁇ L, 2.08 mmol
  • DCM 8.3 mL
  • methanesulfonyl chloride 38.7 ⁇ L, 500 ⁇ mol
  • Example 28 Synthesis of 2,2,2-trifluoro-N-methyl- ((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide
  • 2-((dimethylamino)methyl)-4- methylquinuclidin-3-one 76.0 mg, 417 ⁇ mol
  • N,N-diisopropylethylamine 363 ⁇ L, 2.08 mmol
  • trifluoroacetic anhydride 70 ⁇ L, 500 ⁇ mol
  • Example 29 Synthesis of 2,2,2-trichloro-N-(2-methoxyethyl)- ((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate Step 1. Preparation of 2-(((2-methoxyethyl)amino)methyl)-4- methylquinuclidin-3-one 2-methoxyethylamine (470 ⁇ l, 5.41 mmol) and potassium carbonate (150 mg, 1.08 mmol) was added to a crude solution of 4-methyl-2- methylenequinuclidin-3-one (82.0 mg, 540 ⁇ mol) in THF (5.0 mL). The reaction mixture was stirred at room temperature overnight.
  • Step 2 Preparation of 2,2,2-trichloro-N-(2-methoxyethyl)-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate
  • 2-(((2-methoxyethyl)amino)methyl)-4- methylquinuclidin-3-one 63.0 mg, 278 ⁇ mol
  • triethylamine (194 ⁇ L, 1.39 mmol) in DCM 5.6 mL
  • trichloroacetic anhydride 47 ⁇ L, 420 ⁇ mol
  • Example 34 In vitro efficacy study using the SaOS-2 His273 protocol SaOS-2 His273 mtp53 is a human osteosarcoma cell line which has been genetically engineered at OnkPat CCK to express His273 mutated p53. 3000 cells/well (50 ⁇ l) were seeded into masked (black or white with clear bottom) 96-well cell culture plates using Iscove’s Modified Dulbecco’s Medium supplemented with 10% heat inactivated (56°C for 60 min) fetal calf serum.
  • CTG CellTiter-Glo® Luminescent Cell Viability Assay
  • the average of the signal values for the untreated cells was calculated for each plate.
  • the % of growth suppression was calculated as: 100 - ((Signal sample / Signal untreated cells) x 100).
  • the results of the SaOs-2 His273 analyses were expressed as IC50 values, i.e. concentration that suppresses growth of at least 50% of the cells.
  • the IC50 values of various compounds according to the invention are shown in Table 1.
  • Table 1 Cell based activity in SaOS-2 His273
  • Example 35 In vivo efficacy study A compound of Table 1 is administered intraperitoneally twice daily at approximately 25 or 75 mg/kg to NSG mice (NOD.Cg-Prkdcscid Il2rgtm1WjI/SzJ) ortotopically xenografted with the acute myeloid leukemia cell line SKM-1- Luc, carrying mutant p53 (R248Q). To make SKM-1-Luc, the cell line SKM-1 is stably transfected with a synthetic gene for firefly luciferase, Luc2 (pGL4, Promega).
  • the tumor load is externally monitored by luminescence measurement (radiance values; photon/second/cm 2 /steradian).1 x 10 7 SKM- 1-Luc cells are injected, and six days later the animals are stratified into treatment groups and control, 6 animals in each group, based on luminescence measurement. Treatment is started on day 7 and done in 3 cycles of 5 days each, with 2 days recovery. Tumor progression is evaluated by non-invasive in vivo imaging at the end of each treatment cycle (day 11, 18 and 25).

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Abstract

L'invention concerne certains composés de quinuclidine-3-one substitués destinés à être utilisés dans le traitement d'une maladie hyperproliférative, telle que le cancer, et des maladies associées à une inflammation. Plus particulièrement, la présente invention concerne certains 3-quinuclidinones substitués, des sels pharmaceutiquement acceptables de ceux-ci, des compositions pharmaceutiques les contenant, et des procédés d'utilisation de tels composés. Ainsi, ces composés sont utiles pour traiter des maladies hyperprolifératives et des maladies inflammatoires.
PCT/EP2022/053987 2021-02-18 2022-02-17 Dérivés de quinuclidine-3-one WO2022175402A1 (fr)

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