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WO2025062143A1 - Stéroïdes 7-difluorés destinés à être utilisés dans le traitement de maladies neurologiques ou mitochondriales - Google Patents

Stéroïdes 7-difluorés destinés à être utilisés dans le traitement de maladies neurologiques ou mitochondriales Download PDF

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WO2025062143A1
WO2025062143A1 PCT/GB2024/052438 GB2024052438W WO2025062143A1 WO 2025062143 A1 WO2025062143 A1 WO 2025062143A1 GB 2024052438 W GB2024052438 W GB 2024052438W WO 2025062143 A1 WO2025062143 A1 WO 2025062143A1
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compound
difluoro
formula
alkyl
hydroxy
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Alexander Charles Weymouth-Wilson
Laura Louise WALLIS
Gemma Louise PARKER
Zofia KOMSTA
Elizabeth RAINBOW
Heather MORTIBOYS
Katy Amanda BARNES
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Nzp Uk Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • 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 novel compounds which are of use in the treatment of neurodegenerative disorders and other conditions in which mitochondrial dysfunction is implicated and/or conditions in which modulating mitochondrial function is useful.
  • the invention relates to bile acid derivatives, to pharmaceutical compositions containing them, process for preparing them and to the use of the compounds in the treatment or prevention of neurodegenerative and neuromuscular disorders and mitochondrial disease.
  • Neurodegenerative diseases are a group of disorders of the central nervous system (CNS) and include dementia (including Alzheimer’s disease, vascular dementia, frontotemporal dementia (FTD) and dementia with Lewy bodies), Parkinson’s disease, mild cognitive impairment, Huntington’s disease, amyotrophic lateral sclerosis (motor neurone disease), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and Wilson’s disease.
  • dementia including Alzheimer’s disease, vascular dementia, frontotemporal dementia (FTD) and dementia with Lewy bodies
  • Parkinson’s disease mild cognitive impairment
  • Huntington’s disease amyotrophic lateral sclerosis (motor neurone disease), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and Wilson’s disease.
  • MSA multiple system atrophy
  • PSP progressive supranuclear palsy
  • Wilson Wilson
  • Alzheimer’s disease leads to progressive cognitive impairment and is characterised by the presence of extracellular neuritic plaques and intracellular neurofibrillary tangles. It is thought that mitochondrial dysfunction leads to the deposition of the p-amyloid proteins which are the major component of the neuritic plaques and to the formation of the neurofibrillary tangles.
  • Alzheimer’s disease may be either sporadic or familial, with the most common cause of familial Alzheimer’s disease being mutations in the PSEN1 gene, which encodes presenilin-1 (Kelleher and Shen, 2017) as well as the PSEN2 (presenilin-2) and APP (amyloid precursor protein) genes (Petit et al (2022).
  • Presenilin-1 and 2 are associated with the mitochondrial membrane causing disease related pathology. Familial Alzheimer’s disease is associated with early onset, in which symptoms may manifest in patients as young as 24 years of age. Sporadic Alzheimer’s disease typically manifests much later, generally in patients over 65 years of age.
  • Parkinson’s disease The symptoms of Parkinson’s disease are resting tremor, bradykinesia and rigidity and these symptoms are caused by neurodegeneration and loss of dopaminergic neurons. There is a large body of evidence which suggests that there is a strong association between mitochondrial dysfunction and Parkinson’s disease.
  • a mild deficiency of mitochondrial electron transport chain NADH dehydrogenase (complex I) activity has been found in the tissues of Parkinson’s disease patients and a number of the proteins that are linked to the familial form of Parkinson’s disease are either mitochondrial proteins or are associated with mitochondria.
  • Amyotrophic lateral sclerosis is also thought to be linked to mitochondrial dysfunction. This disease targets motor neurons in the CNS resulting in muscle weakness, atrophy and, death within 2-3 years of diagnosis. Phase 3 clinical trials have been conducted on TLIDCA for ALS (Albanese et al, 2022).
  • bile acids such as LIDCA (ursodeoxycholic acid) exert a beneficial effect on mitochondrial dysfunction in tissue from certain patients suffering from Parkinson’s disease, in particular in tissue from parkin mutant Parkinson’s disease patients (Mortiboys, et al 2013) and LRRK2 G2019S mutant Parkinson’s disease patients (Mortiboys et al 2015).
  • LIDCA ursodeoxycholic acid
  • LRRK2 G2019S mutant Parkinson’s disease patients Mortiboys et al 2015
  • bile acids such as LIDCA exert a beneficial effect on fibroblasts from patients suffering from both sporadic Alzheimer’s Disease and familial Alzheimer’s Disease due to PSEN1 mutations (Bell et a/2018).
  • LIDCA is beneficial to cells from sporadic Parkinson’s patients (Carling et al 2020). Furthermore, an innovative Phase 2a clinical trial testing LIDCA in Parkinson’s patients has shown some positive effects of LIDCA treatment in this small patient group (Payne et al, 2023).
  • WO 2014/036379, WO 2015/061421 and WO 2016/145216 teach that bile acids may be of use in the treatment of neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis.
  • WO 2015/061421 relates to deuterated bile acids and WO 2016/145216 discloses fluorinated bile acids particularly bile acids fluorinated at the 3- and/or 7-positions, for example 7-fluoro, 3,7-difluoro and 3, 3,7,7- tetrafluoro analogues of ursodeoxycholic acid.
  • WO 2020/128514 relates to 2-fluorinated bile having mitochondrial rescue properties and WO 2023/233164 relates to further bile acid derivatives which also have mitochondrial rescue properties. If a compound is to be used for the treatment of a neurodegenerative disorder it is, of course, necessary for it to enter the plasma, cross the blood brain barrier and remain in the CNS in sufficient amounts for activity.
  • bile acids are transported from the gut to the liver where they are conjugated, especially with taurine or glycine residues, to form bile salts.
  • the bile salts are then exported to the gall bladder and enter the enterohepatic circulation (Dawson, 2009).
  • the result of the bile acids/salt entering the enterohepatic circulation is that only a small proportion of the administered compound enters the blood stream and is therefore available to cross the blood brain barrier.
  • the blood brain barrier is formed by a monolayer of endothelial cells joined at tight junctions and other elements including a basement membrane, glial cells, pericytes and neurons.
  • the function of the blood brain barrier is to prevent harmful substances from entering the brain, while allowing access to oxygen and nutrients such as glucose.
  • the ability of a drug molecule to achieve an effective concentration in the CNS depends on a number of factors, which are discussed in Banks, 2009. Most drugs cross the CNS by transmembrane diffusion and this is favoured by low molecular weight and lipophilicity.
  • the drug must be sufficiently lipid soluble to pass into the cell membrane but not so lipophilic that it remains in the blood brain barrier rather than passing through it or is taken up by peripheral tissues. Drugs can, of course, diffuse across the blood brain barrier in both directions and if the drug is to achieve an effective concentration in the brain, it is also preferable that the rate of passage from the plasma into the brain (influx) is higher than the rate of passage from the brain into the plasma (efflux) (Dolghih, 2013; Doan, 2002. Efflux may be enhanced by binding of the drug to P-glycoprotein (also known as MDR1), which is an active efflux transporter and brain penetration of a drug can be predicted by the efflux ratio, which is represented by the following equation:
  • P app ⁇ B-A represents the permeability coefficient in the apical to basolateral (A-B) direction, representing transport of the compound from the plasma to the CNS
  • P app ⁇ A-B represents the permeability coefficient in the basolateral to apical (B-A) direction, representing efflux from the CNS.
  • the efflux ratio should preferably be less than 2.5 (Doan, 2002), which is not the case with bile acids such as ursodeoxycholic acid (LIDCA).
  • a compound may achieve a pharmaceutically effective concentration in the CNS even if the efflux ratio is higher than the preferred value.
  • more suitable compounds have lower efflux ratios.
  • Another relevant factor is the degree of protein binding, since this can prevent a drug from diffusing across the blood brain barrier (Banks, 2009).
  • the problem of protein binding is particularly acute with bile acids, many of which are bound in plasma at high levels.
  • Neuromuscular disorders include conditions such as muscular dystrophies, myopathies, neuromuscular junction diseases, motor neurone diseases, peripheral nerve diseases, mitochondrial diseases and ion channel diseases. Many of these diseases arise because of mitochondrial defects (Canto-Santos, 2020) and therefore can be treated by compounds which are capable of rescuing dysfunctional mitochondria.
  • a bile acid derivative is intended for use in the treatment of neuromuscular diseases, the ability to cross the blood brain barrier is not so important as for compounds intended for the treatment of neurodegenerative diseases. However, it is still necessary to ensure that the bile acid derivative does not become trapped in the enterohepatic circulation and that the degree of binding to plasma proteins is not sufficiently high to prevent the compound from crossing the mitochondrial membrane.
  • Mitochondrial diseases include Barth syndrome, chronic progressive external opthalomplegia (CPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome, 3-methylglutaconic aciduria, deafness, encephalopathy, and Leigh-like syndrome (MEGDEL syndrome), myoclonic epilepsy and ragged-red fibers syndrome (MERRF syndrome), mitochondrial encephalomyopathy, lactic acidosis and stroke-like syndrome (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE) and Senger syndrome. These diseases can also be treated by compounds which are capable of rescuing dysfunctional mitochondria.
  • CPEO chronic progressive external opthalomplegia
  • KSS Kearns-Sayre syndrome
  • Leigh syndrome 3-methylglutaconic aciduria, deafness, encephalopathy, and Leigh-like syndrome
  • MEGDEL syndrome myoclonic epilepsy and ragged-red fibers syndrome
  • MELAS mitochondrial encephalomyopathy
  • MELAS mitochondrial neuro
  • bile acid derivatives which are able to rescue dysfunctional mitochondria, which are not recirculated in the enterohepatic circulation, which do not bind in large quantities to plasma proteins and which cross the blood brain barrier and are retained in the CNS in an effective concentration.
  • R 1 is C1.4 alkyl or O(Ci-4 alkyl), it is optionally substituted with one or more substituents selected from fluoro, chloro, OH, NH2, N3, O(Ci-4 alkyl) and NH(CI-4 alkyl); wherein each of R 1a and R 1 b is independently H or C1.4 alkyl optionally substituted with halo; when connected to R 1 is a double bond, R 1 is selected from CHR 8 and O; wherein R 8 is H or CH3;
  • R 2 is selected from C(O)OR 5 , C1.6 alkyl, C2-6 alkenyl and C(O)N(R 5a )(R 5b ); wherein R 5 is H, C1.4 alkyl or benzyl; each of R 5a and R 5b is H or C1.4 alkyl or R 5a and R 5b together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine or morpholine ring; and wherein alkyl and alkenyl groups of R 2 are optionally substituted with one or more substituents selected from OH, NH2, N3, fluoro and chloro; when connected to R 3 is a single bond, R 3 is OH; when connected to R 3 is a double bond, R 3 is O; each of R 4a and R 4b is independently H, F, Cl, C1.2 alkyl or C1.2 haloalkyl; or a salt or solvate thereof.
  • Compounds of formula (I) include all isotopic variants but, in particular, isotopic variants in which: in an alkyl group R 1 , one or more hydrogen atoms are present as 2 H (deuterium) or 3 H (tritium), especially deuterium; and/or when connected to R 3 is a single bond, the hydrogen atom at the 3-position of the bile acid skeleton is replaced by 2 H (deuterium) or 3 H (tritium), especially deuterium.
  • IZ compound of formula (IZ): wherein:
  • R 1Z is selected from H, fluoro, chloro, OH, C1.4 alkyl and O(Ci-4 alkyl), wherein when R 1Z is Ci- 4 alkyl it is optionally substituted with one or more substituents selected from fluoro, chloro, OH and O(Ci- 4 alkyl);
  • R 5 is H, Ci-6 alkyl or benzyl; or a salt or solvate thereof.
  • Compounds of formula (IZ) include all isotopic variants thereof.
  • references to “pharmaceutical use” refer to use for administration to a human or an animal, in particular a human or a mammal, for example a domesticated or livestock mammal, for the treatment or prophylaxis of a disease or medical condition.
  • pharmaceutical composition refers to a composition which is suitable for pharmaceutical use and “pharmaceutically acceptable” refers to an agent which is suitable for use in a pharmaceutical composition.
  • Other similar terms should be construed accordingly.
  • the term “Ci-e” alkyl refers to a straight or branched fully saturated hydrocarbon group having from 1 to 6 carbon atoms.
  • alkyl encompasses methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl.
  • Other alkyl groups for example C1.4 alkyl, C1.3 alkyl, or C1.2 alkyl are as defined above but contain different numbers of carbon atoms.
  • Ci-e alkylene refers to a straight or branched fully saturated hydrocarbon chain having from one to 6 carbon atoms.
  • the term encompasses -CH2-, -CH2CH2-, -CH(CH3)-CH2- , -CH 2 CH(CH 3 )-, -CH2CH2CH2-, -CH 2 CH(CH 2 CH3)- and -CH 2 CH(CH 2 CH3)CH 2 -.
  • Other alkylene groups for example C1.5 alkylene, C1.4 alkylene, C1.3 alkylene, or C1.2 alkylene are as defined above but contain different numbers of carbon atoms.
  • Other alkenyl groups for example C2-4 alkenyl and C2-3 alkyl are as defined above but contain different numbers of carbon atoms.
  • protected OH group refers to a hydroxyl protected by any known protecting group.
  • protected OH groups of this type include R 18 C(O)O, where R 18 is Ci-e alkyl or benzyl, especially methyl.
  • Silyl ether protecting groups may also be used and OH can also be protected as an ether, for example a Ci-e alkyl, benzyl or p-methoxybenzyl ether.
  • Other suitable protecting groups for OH are well known to those of skill in the art (see e.g. Wuts, PGM and Greene, TW (2006) “Greene’s Protective Groups in Organic Synthesis”, 4 th Edition, John Wiley & Sons, Inc., Hoboken, NJ, USA).
  • Salts of the compounds of formula (I) may be basic addition salts.
  • Any salts intended to be administered to a patient will be pharmaceutically acceptable but other salts may also be used during the synthesis of a pharmaceutically acceptable final product.
  • Pharmaceutically acceptable salts are known to those of skill in the art and are summarised in Gupta et al, Molecules, 23, 1719 (2016).
  • Pharmaceutically acceptable basic addition salts include sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, amine salts including triethylamine, /V,/V-diisopropylethylamine (DI PEA), diethanolamine, ethanolamine, ethyl diamine, meglumine and other well-known basic addition salts.
  • DI PEA triethylamine
  • ethanolamine ethanolamine
  • ethyl diamine meglumine
  • the compounds of formula (I) include all stereoisomers.
  • stereoisomers refers only to stereoisomers of the R 1 and/or the R 3 substituents in the compounds of formula (I) and not to stereoisomers of the bile acid ring system.
  • the compounds of formula (I) include all isotopic variants.
  • isotopic variant refers to isotopically-labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature, or in which the proportion of an atom having an atomic mass or mass number found less commonly in nature has been increased (the latter concept being referred to as “isotopic enrichment”).
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 2 H (deuterium), 3 H, 11 C, 13 C, 14 C, 18 F, 123 l or 125 l (e.g. 3 H, 11 C, 14 C, 18 F, 123 l or 125 l), which may be naturally occurring or non-naturally occurring isotopes.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 2 H (deuterium), 3 H, 11 C, 13 C, 14 C, 18 F, 123 l or 125 l (e.g. 3 H, 11 C, 14 C, 18 F, 123 l or 125 l), which may be naturally occurring or non-naturally occurring isotopes.
  • the invention provides a compound of formula (I) as defined above or a salt, solvate and/or isotopic variant thereof.
  • the compounds of formula (I) have significant advantages when compared to the prior art compounds such as ursodeoxycholic acid and the fluorinated derivatives described in WO 2016/145216.
  • the compounds of formula (I) have a side chain which is one carbon atom shorter than that of ursodeoxycholic acid and the ursodeoxycholic acid derivatives described in WO 2016/145216. Surprisingly, it appears that this prevents recognition of the compounds by the enzymes which control conjugation of bile acids in the liver. As a result, bile salts of the compounds of formula (I) are not formed in the liver and the compounds of formula (I) do not enter the enterohepatic circulation but pass to the bloodstream.
  • Example 3 For example, as shown in Biological Example 3 below, Compound 1 of Example 1 has an efflux ratio of 1.2, whereas LIDCA has an efflux ratio of 3.6. Because of this, the achievable concentration in the CNS is significantly greater for compounds of formula (I) than for LIDCA.
  • the compounds of formula (I) bind to proteins in lower amounts than LIDCA or the compounds of WO 2016/145216.
  • 89% of Compound 1 of Example 1 binds to plasma proteins but 99% of LIDCA is protein-bound in plasma. This means that the unbound concentration in the blood is significantly higher, for the compounds of the invention than for LIDCA meaning that penetration across the blood brain barrier is higher.
  • Biological Example 1 describes a dose response assay for mitochondrial membrane potential (MMP) and mitochondrial morphology as represented by the percentage of long mitochondria.
  • MMP mitochondrial membrane potential
  • Compound 1 which is a compound of formula (I) was compared with Comparative Compound A, which has the same difluoro substitution at the 7-positon of the steroid ring system but has a side chain one carbon atom longer.
  • Comparative Compound A which has the same difluoro substitution at the 7-positon of the steroid ring system but has a side chain one carbon atom longer.
  • the results showed that Compound 1 achieved a higher maximum MMP value than Comparative Compound A and a similar maximum for long mitochondria.
  • R 1 is suitably selected from H, fluoro, chloro, OH, NH2, N3, C1.4 alkyl, O(Ci- 4 alkyl), NH(CI- 4 alkyl) and C(O)OH.
  • R 1 is H.
  • R 1 is C1.4 alkyl which is unsubstituted or is substituted as described above.
  • the C1.4 alkyl group may be unsubstituted and, for example may be methyl or ethyl.
  • the C1.4 alkyl group may be substituted with one or more substituents selected from fluoro, chloro, OH, NH2, N3, and O(Ci-4 alkyl), especially fluoro, chloro, OH, NH2 and methoxy.
  • R 1 is methyl, ethyl, or methyl substituted with one or more substitutents selected from OH, methoxy, NH2 or F.
  • R 1 is methyl, ethyl, CH2OH, CH2F, CHF2, CH2OCH3 or CH2NH2.
  • the compound is an isotopic variant in which one or more of the hydrogen atoms of a substituted or unsubstituted alkyl group R 1 is replaced by 2 H (deuterium, D) or 3 H (tritium, T).
  • R 1 may be CD3.
  • R 1 is fluoro, chloro or azido (N3), especially fluoro or chloro.
  • R 1 is OH, NH2, O(Ci-4 alkyl) or NH(CI-4 alkyl), suitably OH, methoxy, ethoxy, NH2, methyl amino or dimethylamino.
  • R 1 is OH or methoxy and in other still more suitable compounds, R 1 is NH2.
  • R 1 is C(O)OH.
  • R 1 is C(O)NHR 1a or NHC(O)OR 1 b .
  • R 1a and R 1 b are each independently selected from H and methyl.
  • R 1 is CHR 8 , wherein R 8 is as defined above but is still more suitably H.
  • R 1 is O.
  • R 2 is C(O)OR 5 .
  • R 5 may be H, Ci-e alkyl or benzyl.
  • R 5 is H such that R 2 in formula (I) is C(O)OH and C(O)OR 5 in formula (IZ) is C(O)OH.
  • R 5 is a group R 6 , where R 6 is Ci-e alkyl or benzyl, and more suitably C1.4 alkyl, for example methyl.
  • R 2 is C1.4 alkyl or C2-4 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with one or more substituents selected from OH, NH2, N3, fluoro and chloro.
  • R 2 is methyl, ethyl or ethenyl, any of which is optionally substituted with one or more substituents selected from OH, NH2, N3, fluoro and chloro, for example unsubstituted ethyl, unsubstituted ethenyl or methyl substituted with one or more substituents selected from OH, NH2, N3, fluoro and chloro.
  • R 2 is unsubstituted ethyl, unsubstituted ethenyl, CH2OH, CH2NH2, CH2N3, CH 2 F or CHF 2 .
  • R 2 is C(O)NR 5a R 5b , where R 5a and R 5b are as defined above. More suitably, R 5a and R 5b are each independently H, methyl or ethyl, for example H or methyl. In some still more suitable compounds, R 5a is H and R 5b is methyl.
  • R 5a and R 5b together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine or morpholine ring, more suitably a piperidine, piperazine or morpholine ring, for example a morpholine ring.
  • each of R 4a and R 4b is independently H, F, Cl, methyl or methyl substituted with one or more fluoro substituents. More suitably, one of R 4a and R 4b is H and the other of R 4a and R 4b is H, F, Cl, methyl or methyl substituted with one or more fluoro substituents.
  • both R 4a and R 4b are H.
  • R 4a is H and R 4b is F, Cl, methyl or trifluoromethyl, more suitably F or Cl and especially F.
  • R 4b is H and R 4a is F, Cl, methyl or trifluoromethyl, more suitably F or Cl and especially F.
  • connected to R 3 is a double bond, and R 3 is O. More suitably, however, connected to R 3 is a single bond, and R 3 is OH.
  • R 3 is a-OH such that the compound of formula (I) is a compound of formula (IY):
  • R 1 , R 2 , R 4a and R 4b are as described above for compounds of formula (I).
  • Particularly suitable compounds of the invention include: 7,7-difluoro 24-norlithocholic acid (Compound 1);
  • R 2 is C(O)OR 5 , where R 5 is H, R 3 is a-OH and R 4a and R 4b are both H.
  • Compound 1 may be prepared from a protected compound of formula (II): wherein R 1 is as defined for formula (I), R 6 is Ci-e alkyl or benzyl and R 7 is a protected OH group; by hydrolysis, particularly base hydrolysis, for example by treatment with a strong base such as sodium or potassium hydroxide in an alcoholic solvent such as methanol, ethanol or isopropanol.
  • R 7 is R 18 C(O)O, where R 18 is Ci-e alkyl or benzyl, especially methyl.
  • R 18 is Ci-e alkyl or benzyl, especially methyl.
  • a compound of formula (II) may be prepared by fluorination of a compound of formula (III): wherein R 1 is as defined for formula (I) and R 6 and R 7 are as defined for formula (II).
  • the fluorination may be carried out using a fluorinating agent such as diethylaminosulfur trifluoride (DAST), a DAST alternative, for example morpholino-DAST, SF4 or Deoxo-Fluor® (bis(2-methoxyethyl)aminosulfur trifluoride solution).
  • a fluorinating agent such as diethylaminosulfur trifluoride (DAST), a DAST alternative, for example morpholino-DAST, SF4 or Deoxo-Fluor® (bis(2-methoxyethyl)aminosulfur trifluoride solution).
  • fluorination using DAST or a DAST derivative is conducted at elevated temperature, for example at about 30 °C to 70 °C, for example about 40 °C to 60 °C and typically at about 50 °C.
  • Fluorination with SF4 is generally conducted at low temperature, typically about -78°C.
  • a compound of formula (III) may be prepared by oxidation of a compound of formula (IV): wherein R 1 is as defined for formula (I) and R 6 and R 7 are as defined for formula (II).
  • One suitable method is a Dess-Martin periodinane (1 , 1 ,1 -triacetoxy-1 ,1 -dihydro-1 , 2- benziodoxol) oxidation, which may be carried out in a chlorinated solvent such as chloroform or dichloromethane at a temperature of about 15 to 25 °C, suitably at room temperature.
  • a chlorinated solvent such as chloroform or dichloromethane
  • An alternative oxidation method is oxidation using a hypochlorite, for example sodium hypochlorite, under acidic conditions, for example provided by acetic acid.
  • the reaction may be carried out in an aqueous solvent and at a temperature of 0 to 15 °C, more usually at about O to 10 °C.
  • Other oxidation methods include a Jones reaction using sodium dichromate or, more usually, chromic trioxide in dilute sulfuric acid. This process is known to be reliable for the clean conversion of bile acid hydroxyl groups to the corresponding keto derivatives (Bortolini et al, J. Org. Chem., 2002, 67, 5802).
  • oxidation may be carried out using TEMPO ((2,2,6,6-Tetramethyl-piperidin-1-yl)oxy) or a derivative thereof.
  • a compound of formula (IV) may be prepared by protecting an ester of formula (V): wherein R 1 is as defined for formula (I) and R 6 is as defined for formula (II).
  • the compound of formula (V) may be reacted with a carboxylic acid of formula R 18 C(O)OH, or its acid chloride or anhydride.
  • the reaction may be conducted in an organic solvent, for example a solvent such as tetra hydrofuran, at the reflux temperature of the solvent.
  • organic solvent for example a solvent such as tetra hydrofuran
  • An ester of formula (V) may be prepared from a carboxylic acid of formula (VI): wherein R 1 is as defined for formula (I); by reaction with an alcohol of formula (VII):
  • R 6 -OH (VII) where R 6 is as defined for formula (II).
  • the reaction may be conducted at about 15 °C to 25 °C, for example at room temperature.
  • Compounds of formulae (VI) and (VII) are known and are commercially available or may be prepared by methods known to those of skill in the art.
  • R 1 is H and therefore this method is particularly suitable for preparing compounds of formula (I) in which R 1 is H, for example Compound 1 , which has the formula:
  • the starting material of formula (VI) is nor-ursodeoxycholic acid.
  • a compound of formula (II) in which R 1 is hydrogen and R 7 is R 18 C(O)O, where R 18 is Ci-e alkyl or benzyl, may be converted to a compound of formula (la), which is a compound of formula (I) in which R 2 is C(O)OR 5 and R 5 is a group R 6 : wherein R 6 is as defined for formula (II); by hydrolysis with a base such as an alkali metal alkoxide in an alcoholic solvent, for example with sodium or potassium methoxide in methanol. The reaction is suitably conducted at about 15 °C to 25 °C, for example at room temperature.
  • a base such as an alkali metal alkoxide in an alcoholic solvent, for example with sodium or potassium methoxide in methanol.
  • the hydrolysis is selective for the removal of the R 18 C(O) protecting group, while leaving the ester on the side chain intact.
  • transesterification may occur for example, hydrolysis of a compound of formula (II) in which R 6 is other than methyl with an alkali metal methoxide would result in the production of a compound of formula (la) in which R 6 is methyl.
  • a compound of formula (la) may be reacted with a compound of formula (XI) comprising an ether protecting group:
  • R 12 -O-X 2 -R 10 (XI) wherein R 10 is halo, especially chloro or bromo, X 2 is Ci-e alkylene and R 12 is Ci-e alkyl; to give a protected compound of formula (XII): wherein R 6 is as defined for formula (II) and R 12 and X 2 are as defined for formula (XI).
  • the reaction is carried out under an inert atmosphere such as nitrogen, in mildly basic conditions, for example using N,N-diisopropylethylamine (DIPEA).
  • DIPEA N,N-diisopropylethylamine
  • R 1a -R 13 (XIII) where R 1a is C1.4 alkyl optionally substituted as defined above for R 1 and R 13 is halo, for example chloro, bromo or iodo, especially iodo to give a compound of formula (XIV): wherein R 6 is as defined for formula (II) and R 12 and X 2 are as defined for formula (XI) and R 1a is C1.4 alkyl optionally substituted as defined above for R 1 .
  • the reaction is suitably carried out under strongly basic conditions, for example using lithium diisopropylamide (LDA) in the presence of hexamethylphosphoric triamide (HMPT), hexamethylphosphoramide (HMPA), tris(N,N-tetramethylene)phosphonic acid triamide (tripyrrolidinophosphoric acid triamide; TPPA).
  • LDA lithium diisopropylamide
  • HMPT hexamethylphosphoric triamide
  • HMPA hexamethylphosphoramide
  • TPPA tris(N,N-tetramethylene)phosphonic acid triamide
  • TPPA tripyrrolidinophosphoric acid triamide
  • the reaction is suitably conducted under an inert atmosphere, for example nitrogen.
  • the protecting group R 12 -O-X 2 may be removed by reaction of the compound of formula (XIV) with an acid, for example hydrochloric acid to give a compound of formula (lb): wherein R 6 is as defined for formula (II) and R 1a is C1.4 alkyl.
  • Compounds of formula (lb) are compounds of formula (I) in which R 1 is C1.4 alkyl and R 2 is C(O)OR 5 , where R 5 is C1.6 alkyl or benzyl.
  • the reaction is conducted at a temperature of about 30 °C to 50 °C.
  • the protecting group R 6 may be removed by reaction of the compound of formula (lb) with a strong base, such as a sodium or potassium hydroxide, in an alcoholic such as methanol to give a product of formula (I) in which R 2 is C(O)OH and R 1 is C1.4 alkyl.
  • a strong base such as a sodium or potassium hydroxide
  • an alcoholic such as methanol
  • the reaction is conducted at a temperature of about 50 °C to 70 °C.
  • a compound of formula (XII) may also be converted to compound of formula (XVI): wherein R 6 is as defined for formula (II), R 12 and X 2 are as defined for formula (XI) and R 1 b is fluoro or chloro by reaction with a fluorinating agent such as N-fluorobenzenesulfonimide (NFSI) or a chlorinating agent such as N-chlorosuccinimide.
  • the reaction is suitably carried out under strongly basic conditions, for example using LDA in the presence of an agent such as hexamethylphosphorous triamide (HMPT) hexamethylphosphoramide (HMPA) or tripyrrolidinophosphoric acid triamide (TPPA).
  • HMPT hexamethylphosphorous triamide
  • HMPA hexamethylphosphoramide
  • TPPA tripyrrolidinophosphoric acid triamide
  • Such agents enhance the rate and selectivity of lithiation reactions.
  • the reaction is suitably carried out under an
  • Removal of the protecting groups to give a compound of formula (I) may be carried out in two steps. Firstly, the compound of formula (XVI) may be reacted with an acid, for example hydrochloric acid to give a compound of formula (Ic): wherein R 6 is as defined for formula (II) and R 1 b is as defined for formula (XVI).
  • an acid for example hydrochloric acid
  • Compounds of formula (Ic) are compounds of formula (I) in which R 1 is fluoro or chloro and R 2 is C(O)OR 5 , where R 5 is Ci-e alkyl or benzyl.
  • the protecting group R 6 may be removed to give a product of formula (I) in which R 1 is fluoro or chloro and R 2 is C(O)OH by reaction of the compound of formula (XVII) with a strong base, such, for example sodium hydroxide, in an alcoholic such as methanol.
  • a strong base such as sodium hydroxide
  • the reaction is conducted at a temperature of about 35 °C to 55 °C.
  • the compound of formula (XII) is oxidised, for example by treating with a base such as1 M lithium diisopropylamide (LDA) 1 M in THF/hexanes, Davis reagent ((3-phenyl-2- (phenylsulfonyl)-1 ,2-oxaziridine or 2-(benzenesulfonyl)-3-phenyloxaziridine) and tris (N,N- tetramethlene)phosphonic acid triamide in tetra hydrofuran (THF) to give an OH substituted compound of formula (XXa) wherein R 6 is as defined for formula (II) and R 12 and X 2 are as defined for formula (XI).
  • a base such as1 M lithium diisopropylamide (LDA) 1 M in THF/hexanes
  • Davis reagent ((3-phenyl-2- (phenylsulfonyl)-1 ,2-oxaziridine or 2-(benz
  • R 2 is C(O)OR 5 , where R 5 is a group R 6 , which is Ci-6 alkyl or benzyl.
  • step (iv) Treatment of the product of step (iii) with sodium hydroxide in MeOH at 60 °C to give a compound of formula (I) in which R 1 is CH2OH and R 2 is C(O)OH or a compound of formula (I) in which R 1 is methyl in which one or more hydrogen atoms are replaced by F or Cl and R 2 is C(O)OH.
  • the products of steps (iii) are compounds of formula (I) in which R 2 is C(O)OR 5 , where R 5 is a group R 6 and is C1.6 alkyl or benzyl
  • the products of steps (iv) are compounds of formula (I) in which R 2 is C(O)OR 5 , where R 5 is H.
  • R 1 is CH2OH or methyl substituted with one or more F or Cl (e.g. CH2F, CH2CI, CHF2 or CF3).
  • the compound of formula (XXa) may be treated with methanesulfonyl chloride in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • the reaction is carried out in a solvent such as dichloromethane under an inert atmosphere such as nitrogen and at reduced temperature, for example about -5 °C to 5 °C, typically about 0 °C.
  • Conversion of the mesylate intermediate to an alkene may be achieved by treating a solution of the mesylate in a solvent such as DMF with Rubidium fluoride, suitably at elevated temperature, for example about 40 °C to 60 °C.
  • the product is a compound of formula (XXVIc) in which R 6 is as defined for formula (II) and R 12 and X 2 are as defined for formula (XI), connected to R 1 is a double bond and R 1 is CHR 8 .
  • oxidising agents vary depending on the nature of R 1 and R 2 but suitable oxidising agents include Jones reagent (chromium trioxide in aqueous sulfuric acid) and Dess Martin periodinane.
  • Jones reagent chromium trioxide in aqueous sulfuric acid
  • Dess Martin periodinane a solvent such as acetone
  • a more suitable solvent is dichloromethane.
  • oxidation of the R 3 group may also result in oxidation of the R 1 and/or R 2 groups.
  • CH2OH groups may be converted to C(O)OH as shown in Example 24 below.
  • Other suitable oxidising agents are as described above for the oxidation of a compound of formula (IV) to give a compound of formula (III).
  • an electrophilic fluorinating regent such as 1-(chloromethyl)-4-fluoro-1 ,4-diazabicyclo[2.2.2]octane-1 ,4-diium ditetrafluoroborate (sold under the trade mark Selectfluor®).
  • the agent may be a chlorinating agent such as N-chlorosuccinimide or carbon tetrachloride/triphenylphosphine.
  • the reagent may be an alkyl or haloalkyl iodide or trimethane sulfonate.
  • Preparation of the silyl enol ether may be achieved by treatment with trimethylsilyl trifluoromethanesulfonate under basic conditions, for example in the presence of a triethylamine, in a solvent such as dichloromethane and under an inert atmosphere, such as nitrogen.
  • an electrophilic reagent e.g.
  • fluorinations with Selectfluor® are suitably carried out under an inert atmosphere such as nitrogen and in a solvent such as acetonitrile.
  • the product is a mixture of isomers of formula (I) in which one of R 4a and R 4b is F, Cl, C1.2 alkyl or C1.2 haloalkyl and the other of R 4a and R 4b is H.
  • the isomers are suitably separated before the reduction step (ii), for example using column chromatography as described in Example 27.
  • Di-substituted compounds may be prepared from the monosubstituted products by repeating step (i).
  • step (ii) Reduction of the separate isomers isolated after step (i), for example using a hydride reducing agent such as sodium borohydride. Such reductions are suitably carried out under an inert atmosphere such as nitrogen, in a solvent such as THF and at reduced temperature, for example about -25 °C to -15 °C.
  • the product is a mixture of isomers 3a-0H and 3P-OH isomers, which can be separated as described in Example 27.
  • the compound of formula (I) may be reacted with ethyl chloroformate under basic conditions, for example in the presence of triethylamine, to form an acid anhydride, which may then be reacted with the compound of formula (XXVII).
  • both steps of the reaction are conducted at reduced temperature for example -5 °C to 5 °C, typically about 0 °C.
  • the compound of formula (XXVII) may be in aqueous solution under basic conditions, for example provided by sodium bicarbonate.
  • reaction may be carried out under basic conditions, for example using triethylamine and in the presence of a coupling agent.
  • Suitable coupling reagents include known peptide coupling agents such as O-(benzotriazol-1- yl)-/V,/V,/V’,/V’-tetramethyluronium hexafluorophosphate (HBTLI), O-(benzotriazol-l-yl)- /V,/V,/V’,/V’-tetramethyluronium tetrafluoroborate (TBTLI), O-(7-azabenzotriazol-1-yl)-A/,A/,A/’,A/’- tetramethyluronium hexafluorophosphate (HATLI), O-(7-azabenzotriazol-1-yl)- N,N,N’,N’- tetramethyluronium tetrafluoroborate (TATLI), (benzotriazol- 1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
  • R 1 is as defined for formula (I);
  • R 1a is C1.4 alkyl optionally substituted as defined above for R 1 ;
  • R 1 b is fluoro or chloro
  • R 6 is C1.6 alkyl or benzyl
  • R 7 is a protected OH group, for example R 18 C(O)O, where R 18 is C1.6 alkyl or benzyl;
  • R 8 is H or CH 3 ;
  • R 12 is Ci-6 alkyl
  • X 2 is Ci-6 alkylene.
  • the compounds of the invention are able to restore mitochondrial function. Surprisingly, it has been shown that they do not enter the enterohepatic recirculation, can cross the blood brain barrier in relatively high levels and bind to plasma proteins in lower levels than compounds such as LIDCA, meaning that they have excellent bioavailability in comparison with known bile acid derivatives. They are therefore of use in the treatment or prevention of neurodegenerative disorders including Parkinson’s disease, mild cognitive impairment, dementia (including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia (FTD)), Huntington’s disease, amyotrophic lateral sclerosis (motor neurone disease), progressive supranuclear palsy and Wilson’s disease.
  • Parkinson’s disease mild cognitive impairment
  • dementia including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia (FTD)
  • Huntington’s disease amyotrophic lateral sclerosis (motor neurone disease), progressive supranuclear palsy and Wilson’s
  • references to compounds of formula (I) for use in medicine, the use of compounds of formula (I) in the preparation of a medicament, methods of treatment employing compounds of formula (I) and pharmaceutical compositions comprising compounds of formula (I) apply equally to the pharmaceutically acceptable salts and solvates of compounds of formula (I).
  • the compounds of formula (I) are also useful in treating or preventing conditions in which modulating mitochondrial function is advantageous, particularly neurodegenerative disorders such as Parkinson’s disease, mild cognitive impairment, dementia (including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and FTD), Huntington’s disease, amyotrophic lateral sclerosis (motor neurone disease), multiple system atrophy, progressive supranuclear palsy and Wilson’s disease.
  • Parkinson’s disease mild cognitive impairment
  • dementia including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and FTD
  • Huntington’s disease amyotrophic lateral sclerosis (motor neurone disease), multiple system atrophy, progressive supranuclear palsy and Wilson’s disease.
  • neuromuscular diseases such as muscular dystrophies, myopathies, neuromuscular junction (NMJ) diseases, motor neuron diseases, peripheral nerve diseases, mitochondrial diseases and ion channel diseases.
  • NMJ neuromuscular junction
  • a compound of formula (I) for use in the treatment of a neuromuscular disorder • A compound of formula (I) for use in the treatment of a neuromuscular disorder
  • a compound of formula (I) for use in the prevention of a neuromuscular disorder • A compound of formula (I) for use in the prevention of a neuromuscular disorder.
  • the invention also provides:
  • the invention further provides:
  • a method for the treatment of a neurodegenerative disorder comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I);
  • a method for the prevention of a neurodegenerative disorder comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I);
  • a method for the treatment of a neuromuscular disorder comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I);
  • a method for the prevention of a neuromuscular disorder comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I).
  • neurodegenerative disorders which can be treated with the compounds of formula (I) include Parkinson’s disease, mild cognitive impairment, dementia (including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and FTD), Huntington’s disease, amyotrophic lateral sclerosis (motor neurone disease), multiple system atrophy (MSA), progressive supranuclear palsy and Wilson’s disease.
  • Disorders which are particularly suitable for treatment with the compounds of the present invention include Parkinson’s disease, mild cognitive impairment, dementia (including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and FTD), Huntington’s disease and amyotrophic lateral sclerosis and especially Parkinson’s disease, mild cognitive impairment and dementia (including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and FTD).
  • the compounds of the invention are particularly suitable for the treatment of dementia, for example Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and FTD and especially Alzheimer’s disease.
  • Examples of neuromuscular disorders which can be treated with the compounds of formula (I) include muscular dystrophies, myopathies, NMJ diseases, motor neuron diseases, peripheral nerve diseases, mitochondrial diseases and ion channel diseases.
  • Examples of muscular dystrophies include Becker muscular dystrophy (BMD), congenital muscular dystrophy (CMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDM D), Fasiosca-pulohume-ra1 muscular dystrophy (FSHD), limb-girdle muscular dystrophy (LGMD), Oculopha-ryngeal MD (OPMD) and distal muscular dystrophy (DD).
  • BMD Becker muscular dystrophy
  • CMD congenital muscular dystrophy
  • DMD Duchenne muscular dystrophy
  • EDM D Emery-Dreifuss muscular dystrophy
  • FSHD Fasiosca-pulohume-ra1 muscular dystrophy
  • LGMD limb-girdle muscular
  • myopathies include congenital myopathies, endocrine myopathies, inflammatory myopathies, metabolic myopathies, myofibrillar myopathies and scapula-peroneal myopathies.
  • NMJ diseases include congenital myasthenic syndromes (CMS), Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG).
  • CMS congenital myasthenic syndromes
  • LEMS Lambert-Eaton myasthenic syndrome
  • MG myasthenia gravis
  • motor neuron diseases include amyotrophic lateral sclerosis (ALS, also included in the list of neurodegenerative disorders above since it arises from degeneration of nerve cells in the brain and spinal cord), spinal-bulbar muscular atrophy (SBMA) and spinal muscular atrophy (SMA).
  • ALS amyotrophic lateral sclerosis
  • SBMA spinal-bulbar muscular atrophy
  • SMA spinal muscular atrophy
  • peripheral nerve diseases include Charcot-Marie-Tooth disease (CMT) and giant axonal neuropathy (GAN).
  • CMT Charcot-Marie-Tooth disease
  • GAN giant axonal neuropathy
  • mitochondrial diseases include mitochondrial myopathies and Friedreich’s ataxia as well as Barth syndrome, chronic progressive external opthalomplegia (CPEO), Kearns- Sayre syndrome (KSS), Leigh syndrome, 3-methylglutaconic aciduria, deafness, encephalopathy, and Leigh-like syndrome (MEGDEL syndrome), myoclonic epilepsy and ragged-red fibers syndrome (MERRF syndrome), mitochondrial encephalomyopathy, lactic acidosis and stroke-like syndrome (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE) and Senger syndrome.
  • CPEO chronic progressive external opthalomplegia
  • KSS Kearns- Sayre syndrome
  • MEGDEL syndrome 3-methylglutaconic aciduria
  • MEGDEL syndrome myoclonic epilepsy and ragged-red fibers syndrome
  • MELAS mitochondrial encephalomyopathy
  • MELAS mitochondrial neurogastrointestinal encephalopathy
  • Senger syndrome mitochondrial neurogastrointestinal encephalopathy
  • ion channel diseases include Andersen-Tawil syndrome, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, myotonia congenita, paramyotonia congenita and potassium-aggravated myotonia.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient or carrier.
  • composition may be formulated for administration by any route, for example parenteral, including intravenous, intramuscular, subcutaneous or intradermal; or oral, rectal, nasal, topical (including transdermal, eye drops, topical administration to the lung, buccal and sublingual) or vaginal administration.
  • parenteral including intravenous, intramuscular, subcutaneous or intradermal
  • oral rectal, nasal, topical (including transdermal, eye drops, topical administration to the lung, buccal and sublingual) or vaginal administration.
  • composition is formulated for parenteral administration or for oral administration.
  • the composition is formulated for oral administration.
  • the composition is formulated for parenteral administration, especially intravenous administration.
  • the composition may be prepared by bringing into association the above defined active agent with the carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of formula (I) in conjunction or association with a pharmaceutically acceptable excipient or carrier.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc.
  • compositions may be formulated for delayed, slow or controlled release of the compound of formula (I).
  • the term “acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate, stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of Wintergreen, cherry flavouring and the like can also be used. It may be desirable
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • compounds of formula (I) may be made up into a cream, ointment, jelly, solution or suspension etc.
  • Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
  • Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • CFC propellants include trichloromonofluoromethane (propellant 11), dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane (propellant 12).
  • Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227).
  • the propellant typically comprises 40%-99.5% e.g.
  • the formulation may comprise excipients including co-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Other possible excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine and the like. Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M or alternatively by Aptar, Coster or Vari). Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension.
  • co-solvents e.g. ethanol
  • surfactants e.g. lecithin, sorbitan trioleate and the like.
  • Other possible excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine and the like.
  • Aerosol formulations are packaged in canisters and a suitable
  • nebuliser e.g. one that can be hand-held and portable or for home or hospital use (ie nonportable).
  • the formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents.
  • Suspension liquid and aerosol formulations (whether pressurised or unpressurised) will typically contain the compound of the invention in finely divided form, for example with a D50 of 0.5-10 pm e.g. around 1-5 pm.
  • Particle size distributions may be represented using D10, D50 and D90 values.
  • the D50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half.
  • Dv values refer to particle size distributions measured using laser diffraction.
  • D10 and D90 values used in the context of laser diffraction, are taken to mean Dv and Dvgo values and refer to the particle size whereby 10% of the distribution lies below the D10 value, and 90% of the distribution lies below the D90 value, respectively.
  • Topical administration to the lung may also be achieved by use of a dry-powder formulation.
  • a dry powder formulation will contain the compound of the disclosure in finely divided form, typically with a mass mean diameter (MMAD) of 1-10 pm or a D50 of 0.5-10 pm e.g. around 1- 5 pm.
  • Powders of the compound of the invention in finely divided form may be prepared by a micronization process or similar size reduction process. Micronization may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument).
  • the formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose), usually of comparatively large particle size e.g. a mass mean diameter (MMAD) of 50 pm or more, e.g. 100 pm or more or a D50 of 40-150 pm.
  • a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose)
  • MMAD mass mean diameter
  • lactose refers to a lactose-containing component, including a- lactose monohydrate, p-lactose monohydrate, a-lactose anhydrous, p-lactose anhydrous and amorphous lactose.
  • Lactose components may be processed by micronization, sieving, milling, compression, agglomeration or spray drying.
  • lactose in various forms are also encompassed, for example Lactohale® (inhalation grade lactose; DFE Pharma), lnhaLac®70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose® (sieved inhalation grade lactose; DFE Pharma) products.
  • the lactose component is selected from the group consisting of a-lactose monohydrate, a-lactose anhydrous and amorphous lactose.
  • the lactose is a- lactose monohydrate.
  • Dry powder formulations may also contain other excipients.
  • a dry powder formulation according the present disclosure comprises magnesium or calcium stearate. Such formulations may have superior chemical and/or physical stability especially when such formulations also contain lactose.
  • a dry powder formulation is typically delivered using a dry powder inhaler (DPI) bevice.
  • DPI dry powder inhaler
  • Example dry powder delivery systems include SPINHALER®, DISKHALER®, TURBOHALER®, DISKUS®, SKYEHALER®, ACCUHALER® and CLICKHALER®.
  • dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.
  • a compound of formula (I) is provided as a micronized dry powder formulation, for example comprising lactose of a suitable grade.
  • composition comprising a compound of formula (I) in particulate form in combination with particulate lactose, said composition optionally comprising magnesium stearate.
  • a compound of formula (I) is provided as a micronized dry powder formulation, comprising lactose of a suitable grade and magnesium stearate, filled into a device such as DISKUS.
  • a device such as DISKUS.
  • a device is a multidose device, for example the formulation is filled into blisters for use in a multi-unit dose device such as DISKUS.
  • a compound of formula (I) is provided as a micronized dry powder formulation, for example comprising lactose of a suitable grade, filled into hard shell capsules for use in a single dose device such as AEROLISER.
  • a compound of formula (I) is provided as a micronized dry powder formulation, comprising lactose of a suitable grade and magnesium stearate, filled into hard shell capsules for use in a single dose device such as AEROLISER.
  • a compound of formula (I) is provided as a fine powder for use in an inhalation dosage form wherein the powder is in fine particles with a D50 of 0.5-10 pm e.g. around 1-5 pm, that have been produced by a size reduction process other than jet mill micronisation e.g. spray drying, spray freezing, microfluidisation, high pressure homogenisation, super critical fluid crystallisation, ultrasonic crystallisation or combinations of these methods thereof, or other suitable particle formation methods known in the art that are used to produce fine particles with an aerodynamic particle size of 0.5-10 pm.
  • the resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument).
  • the particles may either comprise the compound alone or in combination with suitable other excipients that may aid the processing.
  • the resultant fine particles may form the final formulation for delivery to humans or may optionally be further formulated with other suitable excipients to facilitate delivery in an acceptable dosage form.
  • the compound of the invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions and foams.
  • suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides.
  • the drug is mixed with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Parenteral formulations will generally be sterile.
  • Compounds of formula (I) may be used in combination with one or more other active agents which are useful in the treatment or prophylaxis of neurodegenerative disorders or neuromuscular disorders, for example the neurodegenerative and neuromuscular disorders described above.
  • a pharmaceutical composition as described above further comprising an additional active agent useful in the treatment or prophylaxis of neurodegenerative disorders or neuromuscular disorders, for example the neurodegenerative and neuromuscular disorders described above.
  • a product comprising a compound of formula (I) and an additional active agent useful in the treatment or prevention of a neurodegenerative or neuromuscular disorder as a combined preparation for simultaneous, sequential or separate use in the treatment or prevention of a neurodegenerative disorder or neuromuscular disorder, for example the neurodegenerative and neuromuscular disorders as described above.
  • FIGURE 1 is a plot showing blood concentrations of Compound 1 following IV Administration to male C57 mice at 1.00 (mg/kg) where reference numbers 19, 20 and 21 each refer to an individual mouse.
  • FIGURE 2 is a plot showing blood concentrations of Comparative Compound A following IV Administration to male C57 mice at 1.00 (mg/kg) where reference numbers 13, 14 and 15 each refer to an individual mouse.
  • FIGURE 3 is a plot showing blood concentrations of Compound 1 following oral administration to male C57 mice at 3.00 (mg/kg) where reference numbers 22, 23 and 24 each refer to an individual mouse.
  • FIGURE 4 is a plot showing blood concentrations of Comparative Compound A following oral administration to male C57 mice at 3.00 (mg/kg) where reference numbers 16, 17 and 18 each refer to an individual mouse.
  • NMR spectra were referenced using residual solvent peaks set to 5 7.26 and 77.16 ppm (CDC ), or 5 3.31 and 49.00 ppm (CD3OD), or 5 2.50 and 39.52 ppm (de- DMSO), or 5 2.05 and 29.82 ppm (acetone-de).
  • Low resolution ES mass spectra were recorded on a WATERS ZMD single quadrupole system or an Agilent 1260 Infinity II, iQ MSD single quadrupole system.
  • High resolution mass spectra were recorded on the Bruker Apex III FT-ICR-MS.
  • Optical rotations were recorded on an OPTICAL ACTIVITY POLAAR 2001 polarimeter at 589 nm.
  • Methyl 3a-acetylhydroxy-7-keto-5p-24-nor-cholan-23-oate (15 g, 0.034 mol, 1 equiv.) and water (1.87 g, 0.1 mol, 3 equiv.) were placed in a 300 mL autoclave made of Hastelloy nickel alloy.
  • the reaction vessel was cooled down by liquid nitrogen, and SF4 (37.5 g, 0.34 mol, 10 equiv.) was condensed into a reaction vessel. The cooling bath was removed, and the mixture was allowed to warm up to room temperature and stirred at this temperature for 24h. Then gaseous products were vented off into a trap with an aqueous solution of NaOH (1 M).
  • the product of this step is the starting material for Compound 25 of Example 25 (3-keto).
  • the product of this step is the starting material for Compound 3 of Example 3, Compound 4 of Example 4, Compound 5 of Example 5, Compound 6 of Example 6, Compound 12 of Example
  • the aqueous phase was extracted with DCM (2 x 15 mL) and the combined extracts were washed with 0.5 M HCI (3 x 15 mL, till pH ⁇ 5), 5% NaHCCh (25 mL), dried over MgSCU and concentrated in vacuo.
  • the residue was purified by column chromatography (SiC>2, 2-10% ethyl acetate in heptane) to afford the title compound as an off white solid (4.46, 86%).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-ethyl-cholan-23-oate from step i (198 mg, 0.41 mmol) was dissolved in MeOH (15 mL), 2 M HCI (1.0 mL, 2.0 mmol) was charged and the reaction mixture was heated to 40 °C for 18 h, then 50% NaOH (0.2 mL, 4.1 mmol) was charged and the solution was heated at 60 °C for 7 days. The solution was concentrated in vacuo, water (15 mL) was charged the aqueous solution was extracted with TBME (15 mL).
  • the mixture was diluted with ethyl acetate (30 mL) and quenched with 5% NaHCOs (10 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with 10% NaCI (30 mL), dried over MgSCU and concentrated in vacuo. The crude residue was obtained as mixture of fluoro- diastereomers (89:11), used without further purification (370 mg).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-fluoro-cholan-23-oate from step i (370 mg) was dissolved in MeOH (26 mL), 2 M HCI (1.0 mL, 2.0 mmol) was charged and the reaction mixture was heated to 40 °C for 18 h. After completion, the mixture was concentrated in vacuo, redissolve in water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with and 10% NaCI (30 mL), dried over MgSCU and concentrated in vacuo. The residue was purified by column chromatography (SiC>2, acetone/heptane) to afford the title compound as a mixture of fluoro-diastereomers (96:4) (51 mg, 18%).
  • Methyl 3a-hydroxy-7,7-difluoro-5p-24-nor-22-fluoro-cholan-23-oate from step ii (51 mg, 0.12 mmol) was dissolved in MeOH (5 mL), 50% NaOH (0.14 mL, 1.78 mmol) was charged and the solution heated at 45 °C for 18 h. The solution was concentrated in vacuo. The crude residue was diluted with water (15 mL), acidified with 2 M HCI and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with and 10% NaCI (30 mL), dried over MgSCU and concentrated in vacuo.
  • the product of this step is the starting material for Compound 8 of Example 8, Compound 9 of Example 9, Compound 10 of Example 10 and Compound 11 of Example 11.
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-hydroxy-cholan-23-oate from step i 50 mg, 0.11 mmol was dissolved in MeOH (5 mL), 2 M HCI (0.26 mL, 0.53 mmol) was charged and the reaction mixture was heated to 40 °C for 18 h, then to 50 °C for 4 h. After this time additional 2 M HCI (0.13 mL, 0.26 mmol) was charged and the reaction mixture was heated at 50 °C for a further 20 h. After completion, 50% NaOH (0.13 mL, 2.12 mmol) was charged and the solution heated at 50 °C for 24 h.
  • reaction was cooled to -78 °C and additional LDA (1.0 M in THF/hexanes, 0.55 mL, 0.55 mmol) was charged. After stirring for 40 minutes additional N-chlorosuccinimide (73 mg, 0.55 mmol). The reaction mixture was allowed to warm to ambient temperature then stirred under nitrogen for 18 h. The mixture was partitioned between 1 M HCI (30 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 30 mL).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-chloro-cholan-23-oate from step i (49 mg, 0.10 mmol) was dissolved in MeOH (5 mL), 2M HCI (0.25 mL, 0.5 mmol) was charged and the solution heated at 40 °C for 18 h, then heated at 50 °C and additional 2M HCI charged (0.13 mL, 0.25 mmol). After stirring at 50 °C for 22 h 50% NaOH (0.1 mL, 2 mmol) was charged and the heating continued for 22 h.
  • the aqueous phase was extracted with ethyl acetate (2 x 15 mL). The combined extracts were dried over MgSCU and concentrated in vacuo. The residue was purified by column chromatography (SiC>2, 5-15% ethyl acetate in heptane) to afford the intermediate as a 85:15 mixture with methyl 3a-hydroxy-7,7-difluoro-5p-24-nor-cholan-23-oate (70 mg). The intermediate was dissolved in MeOH (5 mL), 50% NaOH (86 pL, 1.63 mmol) was charged and the solution heated at 40 °C for 18 h, then heated at 65 °C and additional 50% NaOH charged (86 pL, 1.63 mmol).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5 -24-nor-22-keto-cholan-23-oate from step i (74 mg, 0.16 mmol) was dissolved in MeOH (2.6 mL). 2 M HCI (0.22 mL, 0.44 mmol) was charged and the reaction mixture was heated to 45 °C for 18 h. After this time additional 2 M HCI (0.20 mL, 0.40 mmol) was charged and the reaction mixture was heated at 45 °C for a further 21 h, then heated to 60 °C 5 h. After completion, 5 M NaOH (to pH 14) was charged and the solution was stirred at 30 °C for 5 days. The solution was concentrated in vacuo.
  • the product of this step is the starting material for Compound 11 of Example 11.
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-hydroxy-cholan-23-oate 50 mg, 0.11 mmol was dissolved in DCM (2.5 mL), cooled to 0 °C and then MsCI (12 pL, 0.16 mmol) and Et 3 N (74 pL, 0.53 mmol) were charged. The reaction mixture was allowed to warm to ambient temperature, stirred for 18 h then additional MsCI (6 pL) and Et 3 N (37 pL) was charged. Upon completion, indicated by TLC analysis, water (5 mL) was added and extracted with DCM (2 x 10 mL).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-azido-cholan-23-oate from step i (33 mg, 0.06 mmol) was dissolved in MeOH (5 mL).
  • 2 M HCI (0.15 mL, 0.30 mmol) was charged and the reaction mixture was heated to 40 °C for 18 h.
  • 2 M NaOH (to pH 14) was charged and the solution was stirred at 40 °C for 21 h.
  • the solution was concentrated in vacuo.
  • the crude residue was diluted with water, acidified with 2 M HCI and extracted with EtOAc (x3).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-amine-cholan-23-oate from step i (22 mg, 0.05 mmol) was dissolved in MeOH (3 mL).
  • 2 M HCI (0.10 mL, 0.20 mmol) was charged and the reaction mixture was heated to 40 °C for 22 h.
  • 2 M NaOH (to pH 14) was charged and the solution was stirred at 40 °C for 18 h.
  • the solution was concentrated in vacuo.
  • the crude residue was diluted with water, acidified with 2 M HCI and extracted with EtOAc (x3). The aqueous phase was saturated with NaCI and extracted with THF.
  • the product of this step is the starting material for Compound 13 of Example 13 and Compound 15 of Example 15.
  • the starting material 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-cholan-23-ol (500 mg, 1.21 mmol) was dissolved in DCM (7.5 mL) and Et 3 N (0.84 mL, 6.03 mmol) then cooled to 0 °C. MsCI (107 pL, 1.82 mmol) was then charged, the reaction mixture was allowed to warm to ambient temperature and stirred for 18. Upon completion, indicated by TLC analysis, water (20 mL) was added and extracted with DCM (2 x 10 mL).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-formyl-cholan-23-oate from step i (0.3 g, 0.62 mmol) was dissolved in MeOH (12 mL) and cooled to 0 °C under nitrogen.
  • Sodium borohydride (47 mg, 1.2 mmol) was charged in one portion then the reaction was stirred at 0 °C for 5 minutes and then allowed to warm to ambient temperature and stirred for 18 h.
  • the reaction was quenched by the drop wise addition of 1 M HCI to pH 6.
  • the mixture was concentrated in vacuo, diluted with ethyl acetate (15 mL) and washed with NaHCCh (to pH 8).
  • Methyl 3a-methoxymethoxy-7,7-difluoro-5p-24-nor-22-hydroxymethyl-cholan-23-oate from step ii (100 mg, 0.21 mmol) was dissolved in MeOH (3.5 mL). 2 M HCI (0.5 mL, 1.0 mmol) was charged and the reaction mixture was heated to 45 °C for 19 h. After this time additional 2 M HCI (0.20 mL, 0.40 mmol) was charged and the reaction mixture was heated at 45 °C for a further 7.5 h. After completion, 50% NaOH (to pH 14) was charged and the solution was stirred at 45 °C for 3 days. The solution was concentrated in vacuo.
  • the product of this step is the starting material for Compound 19 of Example 19.
  • the product of this step is the starting material for Compound 20 of Example 20, Compound 21 of Example 21 , Compound 22 of Example 22 and Compound 23 of Example 23.
  • Triethylamine (0.263 mL, 1.89 mmol) and methanesulfonyl chloride (0.044 mL, 0.57 mmol) were charged then the reaction was stirred at 0 °C for 5 minutes and then allowed to warm to ambient temperature and stirred for 18 h.
  • the reaction was monitored by TLC, further triethylamine (0.130 mL) and methanesulfonyl chloride (0.022 mL) was added and stirred at room temperature for a further 18 h.
  • water 5 mL was added and extracted with DCM (2 x 10 mL).
  • Triethylamine (0.263 mL, 1.89 mmol) and methanesulfonyl chloride (0.044 mL, 0.57 mmol) were charged then the reaction was stirred at 0 °C for 5 minutes and then allowed to warm to ambient temperature and stirred for 18 h.
  • the reaction was monitored by TLC, further triethylamine (0.130 mL) and methanesulfonyl chloride (0.022 mL) was added and stirred at room temperature for a further 18 h.
  • water 5 mL was added and extracted with DCM (2 x 10 mL).
  • the crude residue was purified by preparative HPLC (C18, MeCN/FW, 0.1 % formic acid) to afford the f-butyl ester intermediates major diastereomer (3.9 mg), minor diastereomer (2.6 mg).
  • the f-butyl esters were reacted on separately, dissolve in 4 M HCI in dioxane (0.1 mL) and stirred at ambient temperature for 2 days until complete by TLC. After this time they were concentrated in vacuo to afford the major diastereomer (3.5 mg) and minor diastereomer (2.3 mg).
  • the product of this step is the starting material for Compound 24 of Example 24.
  • Example 27 Synthesis of 2P-fluoro-3a-hydroxy-7,7-difluoro-5P-24-nor-cholanic acid (Compound 27), 2P-fluoro-3P-hydroxy-7,7-difluoro-5P-24-nor-cholanic acid (Compound 28), 4P-fluoro-3a-hydroxy-7,7-difluoro-5P-24-nor-cholanic acid (Compound 29) and 4P- fluoro-3P-hydroxy-7,7-difluoro-5P-24-nor-cholanic acid (Compound 30)
  • Methyl 3-keto-7,7-difluoro-5p-24-nor-cholan-23-oate (410 mg, 1.0 mmol) was dissolved in anhydrous DCM (6 mL) under nitrogen and cooled to 0 °C. Triethylamine (0.28 mL, 2.0 mmol) was charged followed by TMSOTf (0.2 mL, 1.1 mmol) maintaining the temperature ca. 0 °C. The reaction mixture was stirred for 1 h at 0 °C then gradually warmed to ambient temperature.
  • the intermediate was dissolved in anhydrous MeCN (7 mL) under nitrogen, transferred to a flask containing Selectfluor (709 mg, 2.0 mmol) and stirred for 18 h at ambient.
  • the reaction was diluted with ethyl acetate, quenched by the addition of 5% NaHCOs (aq) (30 mL) and stirred for 1 h.
  • the phases were separated and the aqueous back extracted with ethyl acetate.
  • the combined extracts were washed with 10% NaCI (10 mL) dried over Na2SC>4 and concentrated in vacuo.
  • the residue was purified by column chromatography (SiC>2, ethyl acetate/heptane) to afford the 2-fluoro compound (85 mg, 20%) and 4-fluoro compound (260 mg, 61 %).
  • Methyl 4 -fluoro-3a-hydroxy-7,7-difluoro-5 -24-nor-cholan-23-oate from step ii. b (120 mg, 0.28 mmol) was dissolved in MeOH (10 mL). 2 M LiOH (2 mL) was charged and the reaction mixture was stirred at 40 °C for 3 days. Upon the completion indicated by TLC analysis, the solution was concentrated in vacuo. The crude residue was diluted with water, acidified with 1 M HCI and extracted with EtOAc (x3). The combined extracts were washed with 10% NaCI (10 mL) dried over MgSO4 and concentrated in vacuo to afford the crude compound.
  • TM RM tetramethylrhodamine, methyl ester
  • MEM phenol red free minimum essential media
  • a 9-point dose response was carried out, including the following concentrations: 1nm, 3nm, 10nm, 30nm, 100nm, 300nm, 1 pM, 3pM and 10pM. Each condition was repeated in four technical repeats.
  • the assay and analysis were carried out as previously described using the Opera Phenix® and Harmony® analysis software. EC50 values were calculated using GraphPad prism software using nonlinear regression analysis.
  • Compound 1 and Comparative Compound A were tested in cell lines PSEN1A, PSEN1B, PSEN1 D and PSEN1 E; Comparative Compounds B to G were tested in cell lines PSEN1A and PSEN1 B; and the remaining compounds were tested in cell lines PSEN1A, PSEN1 D and PSEN1E.
  • Table 1 The results from the primary screen and the dose response are set out in Table 1 below.
  • Table 1 mean values in the primary screen over the cell lines tested are provided for each compound for both MMP and Long Mitochondria data.
  • the columns headed “Activity” represent the EC50 in the dose response assays for MMP and Long Mitochondria.
  • the activity codes, AA, A1 and NA are used and the meanings for the activity codes are as follows:
  • % MMP is an indication of mitochondrial function. If mitochondrial function is lower than control levels, the mitochondria will function less efficiently. A substantial reduction in MMP may mean that the mitochondria are sufficiently dysfunctional to cause cell damage. Since the cell lines used in the assay show a reduction in MMP of 25%, an increase in MMP of 25% will restore the MMP in the PSEN1 mutant patient cell lines to that of controls.
  • the % long mitochondria is a measurement of mitochondrial morphology. Healthy mitochondria vary in size and shape depending on their environment and a mixture of different morphologies is found in healthy cells. The increase in the percentage of long mitochondria in the PSEN1 mutant patient lines indicates that the balance of different mitochondrial morphologies has been upset. Since the cell lines used show a 5% increase in long mitochondria, a reduction of 5% in % long mitochondria in will restore the patient phenotype to that of controls.
  • the results of the primary screen indicate that treatment with Comparative Compound A or with many of the Compounds of the invention elevates MMP to levels approaching those in controls, indicating that mitochondrial function is significantly improved. Treatment with Compound 1 is particularly effective. Treatment with Comparative Compounds B to G does not elevate MMP to such levels and so these compounds do not significantly improve mitochondrial function.
  • Compound A and the compounds of the invention appear to restore the balance of mitochondrial morphology, whereas Comparative Compounds B to G do not, restore the balance mitochondrial morphology to any great extent.
  • the dose response assay results for long mitochondria show that Compound A and the majority of the compounds of the invention have an activity rating of AA.
  • the remaining compounds of the invention have an activity rating of A1 , indicating that either they are active in only one of the Alzheimer’s disease cell lines tested or that they are active in multiple cell lines but at only one or two concentrations.
  • Comparative Compounds B to G are not active in the primary screen either for MMP or for long mitochondria. This is an indication that the nature of the R 2 substituent has considerable influence on the activity of the compounds.
  • Fibroblasts from sporadic PD patients were grown as described in Carling et al, 2020.
  • the ATP protocol is generally as described in Mortiboys et al 2008. Briefly, fibroblasts were cultured as and plated into white 384 well plates at a concentration of 5000 cells per well in 50 pl of media volume. The plates are left overnight in an incubator to allow the fibroblasts to adhere to the plate surface. The following morning the Glucose based medium is replaced with 25pl of Galactose based medium. The plates were then spiked with the compounds using a ECHO 550 liquid handling system. The wells were dosed to provide an 8-point concentration range of 1-10000nM of compound. After dosing the wells are topped up with a further 25pl of Galactose based medium and then left in an incubator for 24 hours.
  • the medium is removed from the plate and the wells are washed twice with sterile PBS.
  • the wells are filled with 25pl of Sterile PBS followed by 12.5pl of Lysis solution from the ATPIiteTM Luminescence ATP detection assay system (Perkin Elmer), including 16 cell free wells to use as blank controls.
  • the plate is then placed on a rotary shaker for 5 mins at 700 rpm. Following the shaking 12.5pl of ATP substrate solution (Perkin Elmer) is added to each well and a further 5 min of shaking. The plate is then placed in darkness for 10 minutes prior to reading. Using a PHERAStar® plate reader, luminescence intensity is recorded.
  • Table 3 The results are shown in Table 3.
  • MKCK-MDR1 cells are derived from Madin Darby canine kidney (MDCK) cells and have been transfected with the MDR1 gene, which encodes the efflux protein, P-glycoprotein (P-gp).
  • MDCK Madin Darby canine kidney
  • P-gp P-glycoprotein
  • MDR1-MDCK cells were seeded into 24 well TranswellTM plates and cultured for 3 days to form a confluent monolayer .
  • the test compound was prepared at a concentration of 10 pM in Hanks’ Balanced Salt Solution containing 25 mM HEPES and loaded into the donor compartments of the TranswellTM plates bearing the cell monolayers (pH 7.4 for both donor and receiver compartments).
  • Lucifer Yellow was added to the apical buffer in all wells to assess integrity of the cell monolayer.
  • Duplicate wells were prepared and incubated at 37°C in a CO2 incubator. Samples were removed at times 0 and 60 minutes and the test compound analysed by LC-MS/MS. Concentrations of Lucifer Yellow in the samples were measured using a fluorescence plate reader.
  • the apparent permeability (P app ) values of the test compound were determined both in the apical to basolateral (A-B) direction, representing transport of the compound from the plasma to the CNS, and in the basolateral to apical (B-A) direction, representing efflux from the CNS.
  • the permeability coefficient P app in each direction may be calculated from the following equation. where is the rate of permeation of the drug across the cells;
  • Co is the concentration of the test compound at time zero and A is the area of the cell monolayer
  • A is the area of the cell monolayer.
  • the efflux ratio was calculated from using the permeability coefficients in each direction:
  • the efflux ratio should preferably be less than 2.5 (Doan, 2002), The results indicate that while Compound 1 , Compound 2 and Comparative Compound A all have an acceptable efflux ratio, the efflux ratio for LIDCA is too high for it to be present in a pharmaceutically effective concentration in the CNS.
  • MDR1-MDCK I cells were seeded onto polycarbonate membrane (PC) in 96-well Corning insert systems at 4.44 x 10 5 cells/ mL and cultured for 4-7 days for confluent cell monolayer formation.
  • the transport buffer in the study was HBSS with 10.0 mM HEPES at pH 7.40 ⁇ 0.05. Test compounds were tested at 2.00 pM bi-directionally in duplicate. Digoxin was tested at 10.0 pM bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 pM in A to B direction in duplicate. Final DMSO concentration was adjusted to less than 1 %. The plate was incubated for 1.5 hours in CO2 incubator at 37 ⁇ 1°C, with 5% CO2 at saturated humidity without shaking. And all samples after mixed with acetonitrile containing internal standard were centrifuged at 3220 x g for 10 min.
  • test and reference compounds were quantified by LC- MS/MS analysis based on the peak area ratio of analyte/IS.
  • Lucifer yellow rejection assay was applied to determine the cell monolayer integrity. Buffers are removed from both apical and basolateral chambers, followed by the addition of 75 pL of 100 pM lucifer yellow in transport buffer and 250 pL transport buffer in apical and basolateral chambers, respectively. The plate was incubated for 30 minutes at 37°C with 5% CO2 and 95% relative humidity without shaking. After 30 minutes incubation, 20 pL of lucifer yellow samples were taken from the apical sides, followed by the addition of 60 pL of Transport Buffer, and then 80 pL of lucifer yellow samples were taken from the basolateral sides. The relative fluorescence unit (RFU) of lucifer yellow was measured at 425/528 nm (excitation/emission) with a microplate reader.
  • REU relative fluorescence unit
  • V r is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side);
  • A is the surface area for the transport, i.e. 0.143 cm 2 for the area of the monolayer
  • Co is the initial concentration in the donor chamber (pM).
  • V r and Co are defined as above;
  • Vd is the volume in the donor chambers (0.075 mL on the apical side, 0.25 mL on the basolateral side);
  • Cd and C r are the final concentrations of transport compound in donor and receiver chambers, respectively.
  • test compositions were prepared by dissolving the test compounds in an amount of 20% w/v in a solvent comprising DMSO and HP-p-CD in a volume ratio of 5/95.
  • test compositions were administered to male C57 mice.
  • each test composition was administered intravenously in an amount of 1.00 mg/kg to three mice and blood sampling was carried out at 5 minutes (0.0833 hours), 0.25 hours, 1 hour, 2 hours, 4 hours, 7 hours and 24 hours after administration for Compound 1 and Compound A and 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration for the other test compounds.
  • each test composition was administered orally in an amount of 3.00 mg/kg to three mice and blood sampling was carried out at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 7 hours and 24 hours after administration for Compound 1 and Compound A and 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration for the other test compounds.
  • the concentration of each test compound was determined at each sampling timepoint.
  • the three mice used for IV administration of Comparative Compound A were given reference numbers 13, 14 and 15 and the three mice used for oral administration of Comparative Compound A were given reference numbers 16, 17 and 18.
  • the three mice used for IV administration of Compound 1 were given reference numbers 19, 20 and 21 and the three mice used for oral administration of Compound 1 were given reference numbers 22, 24 and 24.
  • Tables 6 and 7 shows the results for all compounds after IV administration and Figures 1 and 2 each illustrate the results for three individual mice treated with Compound 1 ( Figure 1) or
  • Tables 8 and 9 show the results for all compounds following oral administration and Figures 3 and 4 each illustrate the results for three individual mice treated respectively with Compound 1 ( Figure 3) and Comparative Compound A ( Figure 4).
  • animal 17 Due to animal 17's concentrations being significantly lower than the other animals in the PO dose group and the consistency of the other animals profiles and data, animal 17 has been excluded from averages and PK calculations.
  • Compounds 3, 4, 5, 6, 7 and 17 also demonstrated significantly longer half-life and greater AUCo-infthan Compound A when administered by IV bolus or orally.
  • test compositions 1 to 3 were prepared by the compound in amounts of 0.3 mg/mL, 1 mg/mL or 3 mg/mL in a solvent comprising: a) DMSO and b) HP-p-CD in water (20% w/v) in a volume ratio a/b of 5/95.
  • test compositions were administered orally to three groups of six male C57 mice at doses of 3.0 (G01), 10.0 (G02) and 30.0 (G03) mg/kg.
  • levels of the compound were measured in plasma, brain and cerebrospinal fluid in three mice at 0.25 hours and in the other three mice at 0.5 hours.
  • the plasma concentration achieved for nor UDCA is, in any case, lower than that achieved for Compound 1 and this, combined with the less favourable efflux ratio for nor UDCA leads to significantly lower concentrations of nor UDCA in the brain and CSF than can be achieved for Compound 1.
  • Compound 2 achieves slightly lower brain and CSF concentrations than Compound 1 , although the levels are still significantly higher than those for nor UDCA.
  • the brain/plasma and CSF/plasma ratios achieved by Compound 2 are similar to those achieved by Compound 1.
  • Biological Examples 1 and 2 demonstrate that the compounds of the invention are active in cells from both Alzheimer’s disease and Parkinson’s disease patients.
  • the compounds of the invention and Comparative Compound A are active in one or both MMP and long mitochondria in cells from Alzheimer’s disease patients.
  • Comparative Compound A has a similar efflux ratio to Compound 1
  • Biological Example 4 demonstrates that it becomes trapped in the enterohepatic circulation and is therefore not present in the plasma in sufficient levels for an effective amount of the compound to be available to enter the CNS.
  • the bioavailability of Compounds 1 , 3 to 7 and 17 is significantly greater than that of Comparative Compound A and they enter in the plasma in sufficient concentrations for them to be available to cross the blood brain barrier.
  • the results for LIDCA and nor LIDCA support the theory that the longer side chain present in LIDCA and Compound A results in entrapment of the compounds in the enterohepatic circulation, whereas this is avoided by nor LIDCA and Compounds 1 and 2, all of which have a shorter side chain.
  • Biological Example 5 demonstrates that Compounds 1 and 2 do indeed cross the blood brain barrier and can both be found in both brain tissue and in CSF 15 minutes and 30 minutes after oral dosing in mice. This is not the case for nor LIDCA even though the plasma concentrations achieved are comparable to those for Compounds 1 and 2. The inventors speculate that this is because nor LIDCA lacks the 7,7-difluoro substitution pattern present in the compounds of the invention.

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Abstract

L'invention concerne les composés de formule (I) : (I) dans laquelle R1, R2, R3, R4a et R4b sont tels que définis dans la description et sont capables de restaurer les mitochondries endommagées et sont utiles pour le traitement de maladies et de troubles neurodégénératifs et neuromusculaires.
PCT/GB2024/052438 2023-09-22 2024-09-20 Stéroïdes 7-difluorés destinés à être utilisés dans le traitement de maladies neurologiques ou mitochondriales Pending WO2025062143A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014036379A2 (fr) 2012-08-31 2014-03-06 Metselex Acides biliaires permettant de prévenir ou d'arrêter la progression de la maladie de parkinson et de maladies neurodégénératives associées
WO2015061421A1 (fr) 2013-10-22 2015-04-30 Metselex, Inc. Acides biliaires deutérés
WO2015181275A1 (fr) * 2014-05-29 2015-12-03 Bar Pharmaceuticals S.R.L. Dérivés de cholane à utiliser dans le traitement et/ou la prévention de maladies médiées par fxr et tgr5/gpbar1
WO2016145216A1 (fr) 2015-03-10 2016-09-15 Metselex, Inc. Acides biliaires fluorés et alkylés
WO2020128514A1 (fr) 2018-12-20 2020-06-25 NZP UK Limited Acides biliaires 2-fluorés pour le traitement de maladies neurodégénératives
WO2023083343A1 (fr) * 2021-11-15 2023-05-19 Hepaitech (Beijing) Biopharma Technology Co., Ltd. Composés polycycliques et leurs procédés
WO2023233164A1 (fr) 2022-06-01 2023-12-07 NZP UK Limited Composés 3-astéroïdes pour le traitement de maladies associées à la fonction mitochondriale

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014036379A2 (fr) 2012-08-31 2014-03-06 Metselex Acides biliaires permettant de prévenir ou d'arrêter la progression de la maladie de parkinson et de maladies neurodégénératives associées
WO2015061421A1 (fr) 2013-10-22 2015-04-30 Metselex, Inc. Acides biliaires deutérés
WO2015181275A1 (fr) * 2014-05-29 2015-12-03 Bar Pharmaceuticals S.R.L. Dérivés de cholane à utiliser dans le traitement et/ou la prévention de maladies médiées par fxr et tgr5/gpbar1
WO2016145216A1 (fr) 2015-03-10 2016-09-15 Metselex, Inc. Acides biliaires fluorés et alkylés
WO2020128514A1 (fr) 2018-12-20 2020-06-25 NZP UK Limited Acides biliaires 2-fluorés pour le traitement de maladies neurodégénératives
WO2023083343A1 (fr) * 2021-11-15 2023-05-19 Hepaitech (Beijing) Biopharma Technology Co., Ltd. Composés polycycliques et leurs procédés
WO2023233164A1 (fr) 2022-06-01 2023-12-07 NZP UK Limited Composés 3-astéroïdes pour le traitement de maladies associées à la fonction mitochondriale

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
ALBANESE, ALUDOLPH, A CMCDERMOTT, C JCORCIA, PVAN DAMME, PVAN DEN BERG, L HHARDIMAN, ORINALDI, GVANACORE, NDICKIE, B: "Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol", FRONTIERS IN NEUROLOGY, vol. 13, 2022, pages 1009113
ARBER CLOVEJOY CHARRIS LWILLUMSEN NALATZA ACASEY JMLINES GKERINS CMUELLER AKZETTERBERG H: "Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis", CELL REP., vol. 34, no. 2, 2021, pages 108615
ARBER CVILLEGAS-LLERENA CTOOMBS JPOCOCK JMRYAN NSFOX NCZETTERBERG HHARDY JWRAY S: "Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout", BRAIN COMMUN., vol. 1, no. 1, 2019, pages 024
BEN-GEDALYA TMOLL LBEJERANO-SAGIE MFRERE SCABRAL WAFRIEDMANN-MORVINSKI DSLUTSKY IBURSTYN-COHEN TMARINI JCCOHEN E.: "Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction", EMBO J., vol. 34, no. 22, 2015, pages 2820 - 2839
BORTOLINI ET AL., J. ORG. CHEM., vol. 67, 2002, pages 5802
CAMPION DDUMANCHIN CHANNEQUIN DDUBOIS BBELLIARD SPUEL MTHOMAS-ANTERION CMICHON AMARTIN CCHARBONNIER F: "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum", AM J HUM GENET., vol. 65, no. 3, 1999, pages 664 - 670, XP009049864, DOI: 10.1086/302553
CAMPION DFLAMAN JMBRICE AHANNEQUIN DDUBOIS BMARTIN CMOREAU VCHARBONNIER FDIDIERJEAN OTARDIEU S ET AL.: "Mutations of the presenilin I gene in families with early-onset Alzheimer's disease", HUM MOL GENET., vol. 4, no. 12, 1995, pages 2373 - 2377, XP002042860, DOI: 10.1093/hmg/4.12.2373
CANTO-SANTOS JGRAU-JUNYENT, J MGARRABOU G: "The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases", ANTIOXIDANTS, vol. 9, 2020, pages 964 - 992
CARLING PJMORTIBOYS HGREEN CMIHAYLOV SSANDOR CSCHWARTZENTRUBER ATAYLOR RWEI WHASTINGS CWONG S: "Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson's disease", PROG NEUROBIOL., vol. 187, 2020, pages 101772, XP086088497, DOI: 10.1016/j.pneurobio.2020.101772
D'AMORE, C.DI LEVA, F. S.SEPE, V.RENGA, B.DEL GAUDIO, C.D'AURIA, M. V.ZAMPELLA, A.FIORUCCI, F.LIMONGELLI, V.: "Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors", J. MED. CHEM., vol. 57, 2014, pages 937 - 954, XP055165457, DOI: 10.1021/jm401873d
DE JONGHE CCRUTS MROGAEVA EATYSOE CSINGLETON AVANDERSTICHELE HMESCHINO WDERMAUT BVANDERHOEVEN IBACKHOVENS H: "Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion", HUM MOL GENET., vol. 8, no. 8, 1999, pages 1529 - 1540
DUMANCHIN CTOURNIER IMARTIN CDIDIC MBELLIARD SCARLANDER BROUHART FDUYCKAERTS CPELLISSIER JFLATOUCHE JB: "Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques", HUM MUTAT., vol. 27, no. 10, 2006, pages 1063, XP071974545, DOI: 10.1002/humu.9458
E. DOLGHIHM.P. JACOBSON: "Predicting Efflux Ratios and Blood-Brain Barrier Penetration from Chemical Structure: Combining Passive Permeability with Active Efflux by P-Glycoprotein", ACS CHEM. NEUROSCI., vol. 4, 2013, pages 361 - 367
E. WOODK. H. HALLW. TATE: "Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 'long-haulers'?", CHRONIC DISEASES AND TRANSLATIONAL MEDICINE, vol. 7, no. 1, 2021, pages 14 - 26
GLIEBUS GROSSO ALIPPA CF: "Progranulin and beta-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier", AM J ALZHEIMERS DIS OTHER DEMEN., vol. 24, no. 6, 20 December 2009 (2009-12-20), pages 456 - 460
GUO, QSU XZHANG, XSHAO, MYU, HLI, D.: "Soft Matter.", vol. 17, 2021, THE ROYAL SOCIETY OF CHEMISTRY, article "A review on acoustic droplet ejection technology and system", pages: 3010 - 3021
GUPTA ET AL., MOLECULES, vol. 23, 2018, pages 1719
H. MORTIBOYSJ. AASLYO. BANDMANN: "Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson's disease", BRAIN, vol. 136, no. 10, 2013, pages 3038 - 3050, XP055671128, DOI: 10.1093/brain/awt224
H. MORTIBOYSK.J. THOMASW.J. H. KOOPMANS. KLAFFKEP. ABOU-SLEIMANS. OLPINN. W. WOODP.H.G.M. WILLEMSJ.A.M. SMEITINKM.R. COOKSON: "Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts", ANN NEUROL., vol. 64, no. 5, 2008, pages 555 - 65
H. MORTIBOYSR. FURMSTONG. BRONSTADJ. AASLYC. ELLIOTTO. BANDMANN: "UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2G2019S carriers and in vivo", NEUROLOGY, vol. 85, 2015, pages 846 - 852, XP055671134, DOI: doi.org/10.1212/WNL.0000000000001905
HOOK VPODVIN SMOSIER CBOYARKO BSEYFFERT LSTRINGER HRISSMAN RA: "Emerging evidence for dysregulated proteome cargoes of tau-propagating extracellular vesicles driven by familial mutations of tau and presenilin", EXTRACELL VESICLES CIRC NUCL ACIDS., vol. 4, no. 4, 2023, pages 588 - 598
JACQUEMONT MLCAMPION DHAHN VTALLAKSEN CFREBOURG TBRICE ADURR A: "Spastic paraparesis and atypical dementia caused by PSEN1 mutation (P264L), responsible for Alzheimer's disease", J MED GENET., vol. 39, no. 2, 2002, pages E2
K. M. DOANJ.E. HUMPHREYSL.O. WEBSTERS. A WRINGL.J SHAMPINEC.J SERABJIT-SINGHK.K. ADKINSONJW. POLLI: "Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 303, no. 3, 2002, pages 1029 - 1037, XP002334073, DOI: 10.1124/jpet.102.039255
KELLEHERSHEN: "Presenilin-1 mutations and Alzheimer's disease", PROC. NATL. ACAD. SCI., vol. 114, no. 4, 2017, pages 629 - 631
NELSON OTU HLEI TBENTAHIR MDE STROOPER BBEZPROZVANNY I.: "Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1", J CLIN INVEST., vol. 117, no. 5, 2007, pages 1230 - 1239
P. A. DAWSONT. LANA. RAO: "Bile acid transporters", JOURNAL OF LIPID RESEARCH, vol. 50, 2009, pages 2340 - 2357
PAYNE, TSASSANI, MBUCKLEY, EMOLL, SANTON, AAPPLEBY, MMARU, STAYLOR, RMCNEILL, AHOGGARD, N: "Ursodeoxycholic acid as a novel disease-modifying treatment for Parkinson's disease: protocol for a two-centre, randomised, double-blind, placebo-controlled trial, The 'UP' study", BMJ OPEN, vol. 10, 2020, pages e038911
PETIT DGUTIÉRREZ FERNANDEZ SZOLTOWSKA K MENZLEIN TRYAN N SO'CONNOR ASZARUGA MHILL EVANDENBERGHE RFOX N C: "Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset", NATURE MOLECULAR PSYCHIATRY, vol. 27, 2022, pages 2821 - 2832
PODVIN SJONES ALIU QAULSTON BMOSIER CAMES JWINSTON CLIETZ CBJIANG ZO'DONOGHUE AJ: "Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons", ACS OMEGA, vol. 6, no. 20, 2021, pages 13033 - 13056
RAUX GGUYANT-MARÉCHAL LMARTIN CBOU JPENET CBRICE AHANNEQUIN DFREBOURG TCAMPION D: "Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update", J MED GENET., vol. 42, no. 10, 2005, pages 793 - 795
S. D. MHATREJ. IYERS. PUUKILAA. M. PAULC.G.T. TAHIMICL. RUBINSTEINM. LOWEJ.S. ALWOODM. B. SOWAS. BHATTACHARYA: "Neuro-consequences of the spaceflight environment", NEUROSCIENCE AND BIOBEHAVIOURAL REVIEWS, vol. 132, pages 908 - 935
S. M. BELLK. BARNESH. CLEMMENSA. R. AL-RAFIAHE. A. AL-OFIV. LEECHO. BANDMANNP. J. SHAWD. J. BLACKBURNL. FERRAIUOLO: "Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with either Sporadic or Familial Alzheimer's Disease", JOURNAL OF MOLECULAR BIOLOGY, vol. 430, no. 21, 2018, pages 3942 - 3953, XP055671138, DOI: 10.1016/j.jmb.2018.08.019
SCHWARTZENTRUBER ABOSCHIAN CLOPES FMMYSZCZYNSKA MANEW EJBEYRATH JSMEITINK JFERRAIUOLO LMORTIBOYS H: "Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons", SCI REP, vol. 10, no. 1, 23 September 2020 (2020-09-23), pages 15485
TYSOE CWHITTAKER JXUEREB JCAIRNS NJCRUTS MVAN BROECKHOVEN CWILCOCK GRUBINSZTEIN DC: "A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease", AM J HUM GENET., vol. 62, no. 1, 1998, pages 70 - 76, XP000891202, DOI: 10.1086/301672
VANOVA TSEDMIK JRASKA JAMRUZ CERNA KTAUS PPOSPISILOVA VNEZVEDOVA MFEDOROVA VKADAKOVA SKLIMOVA H: "Cerebral organoids derived from patients with Alzheimer's disease with PSEN1/2 mutations have defective tissue patterning and altered development", CELL REP., vol. 42, no. 11, 2023, pages 113310
W. A. DA SILVEIRAH. FAZELINIAS. BRIN ROSENTHALE. C. LAIAKISM. S. KIMC. MEYDANY. KIDANEK. S. RATHIS. M. SMITHB. STEAR: "Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact", CELL, vol. 183, 2020, pages 1185 - 1201
W.A. BANKS: "Characteristics of compounds that cross the blood-brain barrier", BMC NEUROLOGY, vol. 9, 2009, pages S3, XP021057491, DOI: 10.1186/1471-2377-9-S1-S3
YANG JZHAO HMA YSHI GSONG JTANG YLI SLI TLIU NTANG F: "Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations", ONCOTARGET, vol. 8, no. 5, 2017, pages 7900 - 7913

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