WO2023042177A1 - Enantiomères du 5-((7-chloroisoquinolin-1-yl)amino)-n-(6-méthoxy-1,2,3,4-tétrahydronaphtalène-2-yl)picolinamide - Google Patents

Enantiomères du 5-((7-chloroisoquinolin-1-yl)amino)-n-(6-méthoxy-1,2,3,4-tétrahydronaphtalène-2-yl)picolinamide Download PDF

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WO2023042177A1
WO2023042177A1 PCT/IB2022/058847 IB2022058847W WO2023042177A1 WO 2023042177 A1 WO2023042177 A1 WO 2023042177A1 IB 2022058847 W IB2022058847 W IB 2022058847W WO 2023042177 A1 WO2023042177 A1 WO 2023042177A1
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compound
pharmaceutically acceptable
solvate
acceptable salt
group
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Ana Maria GARCÍA COLLAZO
Roberto Maj
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Gt Gain Therapeutics Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present disclosure relates to enantiomers of isoquinoline compounds, processes for their preparation, and to the use thereof in the treatment and/or prevention of conditions associated with the alteration of the activity of beta galactosidase, specifically galactosidase beta-1 or GLB1, including GM1 gangliosidoses and Morquio syndrome, type B.
  • the present disclosure is directed to enantiomers of 5- ((7-chloroisoquinolin-l-yl)amino)-N-(6-methoxy- 1,2,3, 4-tetrahydronaphthalen-2- yl)picolinamide, and pharmaceutically acceptable salts and solvates thereof, and their use.
  • the present disclosure is directed to the S-enantiomer of 5-((7- chloroisoquinolin- 1 -yl)amino)-N-(6-m ethoxy- 1 ,2,3 ,4-tetrahydronaphthalen-2- yl)picolinamide, and pharmaceutically acceptable salts and solvates thereof, and their use.
  • WO 2018/122746 Al describes racemic mixtures of certain isoquinoline compounds, including 5-((7-chloroisoquinolin-l-yl)amino)-N-(6-methoxy-l, 2,3,4- tetrahydro-naphthalen-2-yl)picolinamide, and their use.
  • GM1 gangliosidosis and Morquio B syndrome are very rare lysosomal storage diseases with an incidence of about 1 : 100,000-1 :200,000 live births worldwide (Caciotti A. et al.. Biochim Biophys Acta 1812(7):782-890 (July 2011)). Said conditions associated with GLB1 are known to be caused by a deficiency of the enzyme P-galactosidase due to mutations in the GLB1 gene.
  • P-Galactosidase cleaves P-galactose from different substrates, and deficiencies in its activity cause said substrates (i.e., gangliosides, and oligosaccharides carrying terminal P-linked galactose, such as ganglioside GM1 and glycosaminoglycans such as keratin sulfate) to accumulate in patients suffering from conditions associated with GLB 1 activity such as GM1 gangliosidosis and Morquio B syndrome.
  • substrates i.e., gangliosides, and oligosaccharides carrying terminal P-linked galactose, such as ganglioside GM1 and glycosaminoglycans such as keratin sulfate
  • small molecules capable of binding allosterically or competitively to mutated P-galactosidase enzyme thereby stabilizing the enzyme against degradation constitute an important therapeutic target in conditions associated with the alteration of the activity of beta galactosidase, specially galactosidase beta-1 or GLB1.
  • the present disclosure is related to the discovery that compounds represented by Formula S-I or S-II, and pharmaceutically acceptable salts and solvates thereof, exhibit improved pharmacokinetic properties and better metabolic stability than the corresponding racemic compounds and corresponding R-isomers.
  • the present disclosure provides compounds represented by Formula S-I or S-II, as described herein, and pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as “Compounds of the Disclosure” (each individually referred to hereinafter as a “Compound of the Disclosure”).
  • Compounds of the Disclosure have an enantiomeric excess of no less than about 50%, no less than about 60%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 95%, or no less than about 99%.
  • the present disclosure provides a compound of Formula S-II substantially free from the corresponding R-enantiomer: or a pharmaceutically acceptable salt or solvate thereof.
  • the compound S-II is more than 99% free from the corresponding R-enantiomer.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, as defined herein and at least one pharmaceutically acceptable excipient.
  • the present disclosure provides a Compound of the Disclosure as defined herein, or pharmaceutically acceptable salts or solvates thereof, for use in the prevention or treatment of a condition associated with the alteration of the activity of GLB1.
  • the present disclosure provides use of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the preparation of a medicament for the prevention or treatment of a condition associated with the alteration of the activity of GLB1.
  • the present disclosure provides a method of treating or preventing a condition associated with the alteration of the activity of GLB 1 in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure provides a method of treating GM1 gangliosidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof.
  • the present method of treating GM1 gangliosidosis or Morquio B syndrome in a patient further comprises administering to the patient an effective amount of an enzyme for enzyme replacement therapy.
  • the enzyme is P-galactosidase or an analog thereof.
  • the method further comprises administering to the patient a small molecule chaperone.
  • the small molecule chaperone binds competitively to an enzyme.
  • the small molecule chaperone is selected from the group consisting of iminoalditols, iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase, glycosyl transferase, phosphatase, and peptidase inhibitors.
  • the present disclosure provides a method of increasing P- galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof.
  • FIG. 1 is a bar graph representing the concentration of the racemic mixture, the (S)-enantiomer, or the (R)-enantiomer of 5-((7-chloroisoquinolin-l-yl)amino)-N-(6- methoxy-l,2,3,4-tetrahydro-naphthalen-2-yl)picolinamide in brain tissue and in plasma after a single i.v. administration of each compound at 10 mg/kg in male C57/BL6 mice.
  • FIGS. 2 A and 2B are line graphs representing the concentrations of the (S)- enantiomer and (R)-enantiomer in plasma of a C57/BL6 mouse after a single oral administration of 10 mg/kg of the racemic mixture, the (S)-enantiomer, or the (R)- enantiomer of 5-((7-chloroisoquinolin-l-yl)amino)-N-(6-methoxy-l,2,3,4-tetrahydro- naphthalen-2-yl)picolinamide.
  • FIG. 2A shows a concentration obtained for each enantiomer present in the racemic mixture.
  • FIG. 2B the concentrations of the (S)- and (R)-enantiomers obtained for the racemic mixture are combined to show the concentration for the racemic mixture.
  • FIG. 3 is a line graph representing a percent of the area of the tested compound, the racemic mixture, the (S)-enantiomer, or the (R)-enantiomer of 5-((7- chloroisoquinolin- 1 -yl)amino)-N-(6-m ethoxy- 1 ,2,3 ,4-tetrahydro-naphthalen-2- yl)picolinamide, remaining in human liver microsomes at various incubation times with respect to the area of the tested compound at time 0 min.
  • FIG. 4 is a line graph representing a percent of the area of the tested compound, the racemic mixture, the (S)-enantiomer, or the (R)-enantiomer of 5-((7- chloroisoquinolin- 1 -yl)amino)-N-(6-m ethoxy- 1 ,2,3 ,4-tetrahydro-naphthalen-2- yl)picolinamide, remaining in mouse liver microsomes at various incubation times with respect to the area of the tested compound at time 0 min.
  • the term “optionally substituted” refers to a group that can be unsubstituted or substituted.
  • halogen or “halo” refer to -F, -Cl, -Br, or -I.
  • hydroxyl or “hydroxy” refers to the group -OH.
  • alkyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, which is attached to the rest of the molecule by a single bond and, unless otherwise specified, an alkyl radical typically has from 1 to 4 carbon atoms, i.e., Ci-4 alkyl.
  • Ci-4 alkyl groups can be methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, i-butyl and sec-butyl.
  • the alkyl is C1-2 alkyl (methyl or ethyl).
  • Ci-4 alkoxy refers to oxygen substituted by one of the Ci-4 alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy, iso-propoxy, butoxy, tert-butoxy, iso-butoxy, and sec-butoxy), for example by one of the C1-2 alkyl groups.
  • cycloalkyl embraces saturated carbocyclic radicals and, unless otherwise specified, a cycloalkyl radical typically has from 3 to 6 carbon atoms.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. It is, for example, cyclopropyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl group is C3-10 cycloalkyl.
  • heterocyclyl or “heterocyclic group” embrace typically a monocyclic or polycyclic, non-aromatic, saturated or unsaturated C2-10 carbocyclic ring, such as a 5- to 10-membered radical, in which one or more, for example 1, 2, 3 or 4 of the carbon atoms, for example, 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • the heterocyclyl is a C3-7 heterocyclyl, i.e., a heterocycle having 3-7 carbon atoms and at least one heteroatom.
  • a heterocyclyl is a (5- to 10-membered)-Ci-9 heterocyclyl, i.e., a heterocycle having 5- to 10-members, of which 1-9 members are carbon.
  • the heteroatom is N.
  • the heteroatom is O.
  • heterocyclyl radicals are saturated.
  • a heterocyclic radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
  • the substituents may be the same or different.
  • a said optionally substituted heterocyclyl is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different.
  • heterocyclic radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pyrazolidinyl, quinuclidinyl, tetrazolyl, cromanyl, isocromanyl, imidazolidinyl, oxiranyl, azaridinyl, 4,5-dihydro-oxazolyl and 3-aza- tetrahydrofuranyl.
  • the substituents are, for example, selected from halogen atoms, for example, fluorine or chlorine atoms, hydroxy groups, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, hydroxycarbonyl groups, carbamoyl groups, nitro groups, cyano groups, Ci-4 alkyl groups optionally substituted by one or more halogen atoms, Ci-4 alkoxy groups, optionally substituted by one or more halogen atoms and Ci-4 hydroxyalkyl groups.
  • aryl designates typically a Ce-io monocyclic or polycyclic aryl radical such as phenyl and naphthyl.
  • the aryl is phenyl.
  • a said optionally substituted aryl radical is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different.
  • the substituents are, for example, selected from halogen atoms, for example, fluorine or chlorine atoms, hydroxy groups, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, hydroxycarbonyl groups, carbamoyl groups, nitro groups, cyano groups, Ci-4 alkyl groups optionally substituted by one or more halogen atoms, Ci-4 alkoxy groups, optionally substituted by one or more halogen atoms and Ci-4 hydroxyalkyl groups.
  • the substituents on an aryl group are typically themselves unsubstituted.
  • heteroaryl designates typically a 5- to 10-membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, typically 1, 2, 3, or 4 heteroatoms.
  • a heteroaryl group may comprise a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
  • a said optionally substituted heteroaryl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different.
  • the substituents are, for example, selected from halogen atoms, for example, fluorine, chlorine or bromine atoms, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, carbamoyl groups, nitro groups, hydroxy groups, Ci-4 alkyl groups, optionally substituted by one or more halogen atoms and Ci-4 alkoxy groups, optionally substituted by one or more halogen atoms.
  • halogen atoms for example, fluorine, chlorine or bromine atoms
  • alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, carbamoyl groups, nitro groups, hydroxy groups,
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, tetrazolyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, benzofurany
  • the heteroaryl is a (5- to 10-membered)-Ci-9 heteroaryl, i.e., a heteroaryl having 5- to 10-members, of which 1-9 members are carbon.
  • the heteroatom is N.
  • the heteroarom is O.
  • the heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -Ci-4alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally substituted Ce-io aryl, optionally substituted (5- to 10-membered)-Ci-9 heteroaryl, and (5- to 10-membered)-Ci-9 heterocyclyl; said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl is optionally fused to a further (second) ring.
  • 1, 2, or 3 groups independently selected from the group consisting of halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -Ci-4alkyl optionally substituted with 1, 2,
  • stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
  • chiral center or "asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
  • epimer refers to diastereomers that have opposite configuration at only one of two or more tetrahedral streogenic centers present in the respective molecular entities.
  • stereoisomer is an atom, bearing groups such that an interchanging of any two groups leads to a stereoisomer.
  • enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
  • absolute configuration refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
  • resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
  • enantiomeric excess refers to a measure for how much of one enantiomer is present compared to the other.
  • percent enantiomeric excess is defined as
  • *100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S 1.
  • the percent enantiomeric excess is defined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the mixture of enantiomers and [oc]max is the optical rotation of the pure enantiomer.
  • the value of ee will be a number from 0 to 100, 0 being racemic and 100 being pure, single enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
  • enantiomerically enriched refers to Compounds of the Disclosure having an enantiomeric excess of the S-enantiomer compared to the R- enantiomer.
  • Compounds of the Disclosure are enantiomerically enriched by having the ee of about 5% or more.
  • the ee is about 10%.
  • the ee is about 20%.
  • the ee is about 30%.
  • the ee is about 40%.
  • the ee is about 50%.
  • the ee is about 60%.
  • the ee is about 70%.
  • the ee is about 80%.
  • the ee is about 85%. In another embodiment, the ee is about 90%. In another embodiment, the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.
  • the term, "substantially free from the R-enantiomer” as used herein refers to a Compound of the Disclosure (such as, e.g., a compound of Formula S-II) that is at least about 85% or more, free from the corresponding R-enantiomer.
  • the Compound of the Disclosure is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% free from the corresponding R-enantiomer.
  • compositions and molecular entities that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavorable reaction, such as gastric disorders, dizziness and suchlike, when administered to a human or animal.
  • pharmaceutically acceptable means it is approved by a regulatory agency of a state or federal government or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • treatment refers to administering a therapy in an amount, manner or mode effective to improve a condition, symptom, or parameter associated with a condition or to prevent progression of a condition, to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • An effective amount, manner, or mode can vary depending on the subject and can be tailored to the patient.
  • an “effective” amount or a “therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect.
  • the amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • prevention refers to the reduction in the risk of acquiring or developing a given disease or disorder, or the reduction or inhibition of the recurrence or a disease or disorder.
  • the term “patient” as used herein refers to a human. In some embodiments, the patient is an adult. In some embodiments, the patient is a geriatric patient. In some embodiments, the patient is a child. In some embodiments, the patient is an infant. In some embodiments, the patient is a toddler. In some embodiments, the patient is a preadolescent. In some embodiments, the patient is an adolescent.
  • child is a human being between the stages of birth and puberty.
  • puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. On average, girls begin puberty around ages 10-11 and end puberty around 15-17; boys begin around ages 11-12 and end around 16-17.
  • infant is the synonym for "baby,” the very young offspring of a human.
  • infant is typically applied to young children under one year of age.
  • toddler refers to a child of 12 to 36 months old.
  • the term "preadolescent” refers to a person of 10-13 years old.
  • the term "adolescent” refers to a person between ages 10 and 19.
  • solvate means any form of the active compound of the disclosure which has another molecule (for example a polar solvent such as water or ethanol, a cyclodextrin or a dendrimer) attached to it through noncovalent bonds. Methods of solvation are known within the art.
  • a polar solvent such as water or ethanol, a cyclodextrin or a dendrimer
  • the disclosure also provides salts of the Compounds of the Disclosure.
  • Nonlimiting examples are sulphates; hydrohalide salts; phosphates; lower alkane sulphonates; aryl sulphonates; salts of C1-20 aliphatic mono-, di- or tribasic acids which can contain one or more double bonds, an aryl nucleus or other functional groups such as hydroxy, amino, or keto; salts of aromatic acids in which the aromatic nuclei may or may not be substituted with groups such as hydroxyl, lower alkoxyl, amino, mono- or di- lower alkylamino sulphonamido.
  • quaternary salts of the tertiary nitrogen atom with lower alkyl halides or sulphates and oxygenated derivatives of the tertiary nitrogen atom, such as the N-oxides.
  • oxygenated derivatives of the tertiary nitrogen atom such as the N-oxides.
  • Solvates and salts can be prepared by methods known in the state of the art. Note that the non-pharmaceutically acceptable solvates also fall within the scope of the disclosure because they can be useful in preparing pharmaceutically acceptable salts and solvates.
  • the Compounds of the Disclosure also seek to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a carbon enriched in U C, 13 C or 14 C or the replacement of a nitrogen by a 15 N enriched nitrogen are within the scope of this disclosure.
  • the term "enzyme replacement therapy,” or “ERT” refers to administering an exogenously-produced natural or recombinant enzyme or analog thereof to a patient in need thereof.
  • ERT refers to administering an exogenously-produced natural or recombinant enzyme or analog thereof to a patient in need thereof.
  • the patient accumulates harmful levels of a substrate (i.e., material stored) in lysosomes due to a deficiency or defect in an enzyme responsible for metabolizing the substrate, or due to a deficiency in an enzymatic activator required for proper enzymatic function.
  • Enzyme replacement therapy is provided to the patient to reduce the levels of (i.e., debulk) accumulated substrate in affected tissues.
  • Enzyme replacement therapies for treating lysosomal storage diseases are known in the art.
  • a lysosomal enzyme e.g., P-galactosidase
  • P-galactosidase can be used for enzyme replacement therapy to reduce the levels of corresponding substrate, e.g., GM1- ganglioside, glycoprotein, keratan sulfate, in a patient having GM1 gangliosidosis or Morquio B syndrome.
  • an "effective amount" of an enzyme when administered to a subject in a combination therapy of the disclosure, is an amount sufficient to improve the clinical course of a lysosomal storage disease, where clinical improvement is measured by any of the variety of defined parameters well known to the skilled artisan.
  • small molecule chaperone refers to a compound, other than a Compound of the Disclosure, that is capable of binding allosterically or competitively to a mutated enzyme, e.g., P-galactosidase, thereby stabilizing the enzyme against degradation.
  • the small molecule chaperone facilitates proper folding and transport of an enzyme to its site of action.
  • Small molecule chaperones for the treatment of lysosomal storage diseases are known in the art. See, e.g., US 2016/0207933 Al and WO 2011/049737 Al.
  • S-enantiomers of a certain group of isoquinoline compounds exhibit properties that are superior compared to the corresponding racemic compounds.
  • the S-enantiomer of 5-((7- chloroisoquinolin- 1 -yl)amino)-N-(6-m ethoxy- 1 ,2,3 ,4-tetrahydronaphthalen-2- yl)picolinamide also described herein as 5-[(7-chloro-l-isoquinolyl)amino]-N-[(2S)-6- methoxytetralin-2-yl]pyridine-2-carboxamide
  • Compounds of the Disclosure thus potentially offer an advantage over treating patients in need thereof with the corresponding racemic mixtures.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I: and the pharmaceutically acceptable salts and solvates thereof, wherein
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1, 2 or 3 independently selected halogen atoms;
  • R 3 is selected from the group consisting of halogen, -CN, -ORb, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1, 2 or 3 independently selected halogen atoms;
  • each R 4 is independently selected from the group consisting of halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -Ci-4alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally substituted -Ce-io aryl, optionally substituted -(5- to 10-membered)-Ci-9 heteroaryl, and -(5- to 10-membered)-Ci-9 heterocyclyl;
  • m is 0, 1, 2, or 3;
  • each Rb is independently selected from the group consisting of hydrogen, -Ci-4 alkyl, -C3-10 cycloalkyl, and -(5- to 10-membered)-Ci-9 heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl groups are optionally substituted by 1, 2 or 3 fluorine atoms.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein R 3 is selected from the group consisting of halogen, -CN, and -ORb, wherein Rb is as defined for Formula S-I.
  • R 3 is selected from the group consisting of halogen, -CN, -OH, and -O(Ci-4 alkyl) optionally substituted with 1, 2, or 3 fluorine atoms.
  • R 3 is a halogen.
  • R 3 is -Cl, -Br, or -F.
  • R 3 selected from the group consisting of -Cl, -CN, and -OCH3.
  • R 3 is -Cl.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 and R 2 are both H and R 3 is selected from the group consisting of halogen, -CN, and -ORb, wherein Rb is as defined for Formula S-I.
  • R 3 is selected from the group consisting of -Cl, -CN, and -OCH3.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein m is 0.
  • Compounds of the Disclosure are compounds of Formula S-I, and the salts and solvates thereof, wherein m is 1 or 2 and R 4 is independently selected from the group consisting of halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -Ci-4 alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally substituted -Ce-io aryl, optionally substituted -(5- to 10-membered)-Ci-9 heteroaryl, and - (5- to 10-membered)-Ci-9 heterocyclyl.
  • m is 1. In some embodiments, m is 2. In some embodiments, R 4 is independently selected from the group consisting of halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, and -Ci-4 alkyl optionally substituted with 1, 2, or 3 halogen atoms, wherein each Rb is independently selected from the group consisting of hydrogen and -Ci-4 alkyl optionally substituted by 1, 2 or 3 fluorine atoms. In some embodiments, R 4 is independently methyl, ethyl, methoxy, or ethoxy. In another embodiment, R 4 is methoxy.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein m is 1 and R 4 is at the 5-position of the tetrahydronaphthalen-2- yl ring:
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein m is 1 and R 4 is at the 6-position of the tetrahydronaphthalen-2- yl ring:
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein m is 1 and R 4 is at the 7-position of the tetrahydronaphthalen-2- yl ring:
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein m is 1 and R 4 is at the 8-position of the tetrahydronaphthalen-2- yl ring:
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 and R 2 are both hydrogen and R 3 is selected from the group consisting of halogen, -CN, -ORb, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1, 2, or 3 independently selected halogen atoms, and wherein Rb is as defined above for Formula S-I.
  • Rb is hydrogen or -Ci-4 alkyl optionally substituted by 1, 2, or 3 independently selected halogen atoms.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 is hydrogen and R 2 and R 3 are each independently selected from the group consisting of halogen, -CN, -ORb, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1, 2, or 3 independently selected halogen atoms, and wherein Rb is as defined above.
  • Rb is hydrogen or -Ci-4 alkyl optionally substituted with 1, 2, or 3 independently selected halogen atoms.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein R 2 is hydrogen and R 1 and R 3 are each independently selected from the group consisting of halogen, -CN, -ORb, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1, 2, or 3 independently selected halogen atoms, and wherein Rb is as defined above.
  • Rb is hydrogen or -Ci-4 alkyl optionally substituted with 1, 2, or 3 independently selected halogen atoms.
  • Compounds of the Disclosure are enantiomerically enriched compounds of Formula S-I, and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , and R 3 , when other than hydrogen, are each independently selected from the group consisting of chlorine, fluorine, -CN, unsubstituted -Ci-4 alkyl (such as methyl or ethyl), -Ci-4 alkyl substituted with 1, 2, or 3 fluorine atoms (such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 1,1-difluoroethyl, or 1,1,1 -trifluoroethyl), and -ORb, wherein Rb is hydrogen, unsubstituted -Ci-4 alkyl (such as methyl or ethyl), or -Ci-4 alkyl substituted with 1, 2, or 3 fluorine atoms (such as fluorine, -CN, un
  • R 1 , R 2 , and R 3 when other than hydrogen, are each independently selected from the group consisting of chlorine and -ORb, wherein Rb is hydrogen or unsubstituted -Ci-4 alkyl. In another embodiment, Rb is hydrogen or -Ci-4 alkyl.
  • a Compound of the Disclosure is enantiomerically enriched compound of Formula S-II: and the pharmaceutically acceptable salts and solvates thereof.
  • the Compound of the Disclosure is enantiomerically enriched compound of Formula S-II:
  • the Compound of the Disclosure is a pharmaceutically acceptable salt of the enantiomerically enriched compound of Formula S-II.
  • the Compound of the Disclosure is the hydrochloride (HC1) salt of the enantiomerically enriched compound of Formula S-II, or a solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess (ee) is about 5% or more.
  • the ee is about 10%.
  • the ee is about 20%.
  • the ee is about 30%.
  • the ee is about 40%.
  • the ee is about 50%.
  • the ee is about 60%.
  • the ee is about 70%.
  • the ee is about 80%.
  • the ee is about 85%.
  • the ee is about 90%.
  • the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess is no less than about 50%.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess is no less than about 60%.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess is no less than about 70%.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess is no less than about 80%.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess is no less than about 90%.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess is no less than about 95%.
  • Compounds of the Disclosure are compounds of any one of Formulae S-I or S-II, and the pharmaceutically acceptable salts and solvates thereof, wherein the enantiomeric excess is no less than about 99%.
  • the pharmaceutically acceptable salt of a compound of any one of Formulae S-I or S-II is a hydrochloride salt (a HCl-salt).
  • Compounds of the Disclosure can be synthesized, for example, by using methods described in WO 2018/122746 Al to obtain a racemic mixture followed by chiral column separation of the enantiomers.
  • Compounds of the Disclosure can be prepared by first preparing an acyl chloride intermediate by, for example using methods described in WO 2018/122746 Al, and then reacting the intermediate with a suitable chiral amine.
  • An exemplary reaction for synthetizing the intermediate (e) is presented in Scheme 1 and the reaction with a chiral amine to obtain compounds of Formula S-I is presented in Scheme 2 below.
  • S-enantiomer of 5- ((7-chloroisoquinolin-l-yl)amino)-N-(6-methoxy- 1,2,3, 4-tetrahydronaphthalen-2- yl)picolinamide (S-II) (also described herein as 5-[(7-chloro-l-isoquinolyl)amino]-N- [(2S)-6-methoxytetralin-2-yl]pyridine-2-carboxamide) is more brain penetrant than the racemic compound. As shown in FIG.
  • the brain tissue has about 40% higher concentration of S-enantiomer (S-II) than the racemic mixture or the R-enantiomer (R-II) after a single i.v. administration of each compound at 10 mg/kg in male C57/BL6 mice.
  • FIGS. 2 A and 2B show that the S-enantiomer has a lower in vivo clearance than the racemic mixture of the R-enantiomer after a single oral administration of 10 mg/kg of the racemic mixture, the (S)-enantiomer, or the (R)-enantiomer to C57/BL6 mice.
  • the racemic mixture exhibits about 58% higher clearance in this in vivo test than the S-enantiomer (S-II) and, thus, the racemic mixture is expected to have a lower systemic exposure in a human patient than the S-enantiomer.
  • the S-enantiomer (S-II) is more metabolically stable in human and mouse liver microsomes, respectively, than the racemic mixture. Therefore, Compounds of the Disclosure are expected to provide a more effective therapy for patients in need of treatment or prevention of a condition associated with the alteration of the activity of GLB1, such as GM1 gangliosidosis or Morquio B syndrome, than the corresponding racemic mixtures.
  • Compounds of the Disclosure described herein can be used/administered to treat and/or prevent conditions associated with the alteration of the activity of B-galactosidase, specifically galactosidase B-l or GLB1, including GM1 gangliosidoses and Morquio syndrome, type B, in a patient suffering from said condition.
  • the present disclosure is directed to a method of treating or preventing a condition associated with the alteration of the activity of GLB 1 in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof.
  • the Compound of the Disclosure is a compound of Formula S-I, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the Compound of the Disclosure is a compound of Formula S-II, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the present disclosure is directed to a method of treating GM1 gangliosidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof.
  • the Compound of the Disclosure is a compound of Formula S-I, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the Compound of the Disclosure is a compound of Formula S-II, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the method of treating GM1 gangliosidosis or Morquio B syndrome in a patient further comprises administering to the patient an effective amount of an enzyme for enzyme replacement therapy.
  • the enzyme is P-galactosidase or an analog thereof.
  • the method further comprises administering to the patient a small molecule chaperone.
  • the small molecule chaperone binds competitively to an enzyme.
  • the small molecule chaperone is selected from the group consisting of iminoalditols, iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase, glycosyl transferase, phosphatase, and peptidase inhibitors.
  • suitable small molecule chaperones are selected from the group consisting of 1-deoxygalactonojirimycin (DGJ), N- nonyldeoxynojirimycin (NN-DNJ), N-butyldeoxygalactonojirimycin (NB-DGJ), galactose, fluorous iminoalditol, and epi-isofagomine.
  • the present disclosure is directed to a method of increasing P- galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof.
  • the Compound of the Disclosure is a compound of Formula S-I, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the Compound of the Disclosure is a compound of Formula S-II, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the present disclosure is also directed to the use of a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating and/or preventing a condition associated with the alteration of the activity of 13-galactosidase, specifically galactosidase 13-1 or GLB1, including GM1 gangliosidoses and Morquio syndrome, type B, in a patient suffering from said condition.
  • the Compound of the Disclosure is a compound of Formula S-I, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the Compound of the Disclosure is a compound of Formula S-II, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the present disclosure is directed to a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in treating GM1 gangliosidosis or Morquio B syndrome in a patient.
  • the Compound of the Disclosure is a compound of Formula S-I, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the composition is a compound of Formula S-I, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • Compound of the Disclosure is a compound of Formula S-II, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the compound of Formula S-II or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • the pharmaceutically acceptable salt or solvate thereof as described herein.
  • Compound of the Disclosure is administered to the patient in combination with an effective amount of an enzyme for enzyme replacement therapy.
  • the enzyme is P-galactosidase or an analog thereof.
  • the Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof is administered to the patient in combination with a small molecule chaperone.
  • the small molecule chaperone binds competitively to an enzyme.
  • the small molecule chaperone is selected from the group consisting of iminoalditols, iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase, glycosyl transferase, phosphatase, and peptidase inhibitors.
  • suitable small molecule chaperones are selected from the group consisting of 1 -deoxy galactonojirimycin (DGJ), N-nonyldeoxynojirimycin (NN-DNJ), N-butyldeoxygalactonojirimycin (NB-DGJ), galactose, fluorous iminoalditol, and epi-isofagomine.
  • DGJ 1 -deoxy galactonojirimycin
  • N-DNJ N-nonyldeoxynojirimycin
  • NB-DGJ N-butyldeoxygalactonojirimycin
  • compositions comprising an effective amount of a Compound of the Disclosure and at least one pharmaceutically acceptable excipient.
  • the composition comprises an effective amount of a compound of Formula S-I or Formula S-II, or a pharmaceutically acceptable salt or solvate thereof, as described herein, and at least one pharmaceutically acceptable excipient.
  • the Compounds of the Disclosure can be used in human medicine. As described above, the Compounds of the Disclosure are useful for treating or preventing a condition associated with the alteration of the activity of B-galactosidase.
  • the Compounds of the Disclosure can be administered to any patient suffering said condition.
  • patient refers to any human that may experience the beneficial effects of a Compound of the Disclosure.
  • a Compound of the Disclosure can be administered as a component of a composition that comprises a pharmaceutically acceptable excipient or carrier.
  • the Compound of the Disclosure can be administered in combination with at least one other therapeutic agent.
  • the therapeutic agent comprises an enzyme for enzyme replacement therapy.
  • the therapeutic agent comprises a small molecule chaperone.
  • Administration of the Compound of the Disclosure with at least one other therapeutic agent can be sequential or concurrent.
  • the Compound of the Invention and the at least one other therapeutic agent are administered in separate dosage forms.
  • the Compound of the Invention and the at least one other therapeutic agent are administered concurrently in the same dosage form.
  • excipient refers to a vehicle, diluent, or adjuvant that is administered with the active ingredient.
  • Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similar. Water or saline aqueous solutions and aqueous dextrose and glycerol solutions, for example, for injectable solutions, may be used as vehicles.
  • Suitable pharmaceutical vehicles are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin, 21 st Edition, 2005; or “Handbook of Pharmaceutical Excipients,” Rowe C.R.; Paul J.S.; Marian E.Q., sixth Edition, incorporated herein by reference.
  • compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid compositions (solutions, suspensions, or emulsions) for oral, topical, or parenteral administration.
  • pharmaceutical compositions are in an oral delivery form.
  • Pharmaceutical forms suitable for oral administration can be tablets and capsules, and can contain conventional excipients known in the art, such as binders, for example syrup, gum Arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, cornstarch, calcium phosphate, sorbitol, or glycine; lubricants for the preparation of tablets, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate, or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulphate.
  • binders for example syrup, gum Arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, cornstarch, calcium phosphate, sorbitol, or glycine
  • lubricants for the preparation of tablets, for example magnesium stea
  • Solid oral compositions can be prepared by conventional methods of blending, filling, or preparation of tablets. Repeated blending operations can be used to distribute the active ingredient in all the compositions that use large amounts of fillers. Such operations are conventional in the art.
  • the tablets can be prepared, for example, by dry or wet granulation and optionally can be coated by well known methods in normal pharmaceutical practice, in particular using enteric coating.
  • compositions can also be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in the appropriate unit dosage form.
  • Suitable excipients such as fillers, buffering agents, or surfactants can be used.
  • the mentioned formulations can be prepared using standard methods, such as those described or referred to in the Spanish and U.S. Pharmacopoeias and similar reference texts.
  • the effective amount of a Compound of the Disclosure to be administered depends on the relative efficacy of the compound chosen, the severity of the condition or disorder being treated, and the patient’s weight.
  • the active compound can be administered one or more times a day, for example 1, 2, 3, or 4 times daily, with typical total daily doses in the range from about 0.01 mg/kg of body weight/day to about 1000 mg/kg of body weight/day.
  • the effective dosage amount of a Compound of the Disclosure is about 500 mg/kg of body weight/day or less.
  • the effective dosage amount of a Compound of the Disclosure is about 100 mg/kg of body weight/day or less.
  • the effective dosage amount ranges from about 0.01 mg/kg of body weight/day to about 100 mg/kg of body weight/day of a Compound of the Disclosure; in another embodiment, from about 0.02 mg/kg of body weight/day to about 50 mg/kg of body weight/day of a Compound of the Disclosure; and in another embodiment, from about 0.025 mg/kg of body weight/day to about 20 mg/kg of body weight/day of a Compound of the Disclosure.
  • a composition of the disclosure can be prepared by a method comprising admixing a Compound of the Disclosure with a pharmaceutically acceptable excipient or carrier. Admixing can be accomplished using methods known for admixing a compound and a pharmaceutically acceptable excipient or carrier. In another embodiment, the Compound of the Disclosure is present in the composition in an effective amount.
  • h means hours, “min” means minutes, “UPLC” means ultra-performance liquid chromatography, “UPLC-MS” or “HPLC-MS” means Liquid chromatography-mass spectrometry, “UV-DAD” means diode array ultraviolet detector method, “DMSO-de” means deuterated dimethyl sulfoxide, “DCM” means Di chloromethane, “MeOH” mean methanol, “EtOH” mean ethanol, “EtOAc” means ethyl acetate, “TEA” means triethylamine, “Pd2(dba)3” means tris(dibenzylideneacetone)- dipalladium(O), and “XantPhos” means 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene.
  • Method UPLC-MS Aquity UPLC BEH C18 (2.1 mm x 100 mm, 1.7 pm); wavelength: 210 nm - 400 nm; run time: 8.0 min; Mobile phase A: 0.1% of formic acid in water and B: 1.0% formic acid in acetonitrile; Time and mobile phase-gradient (time in min/%B): 0.00/3, 0.50/3, 7.00/97, 7.50/97, 7.60/3, 8.00/3; MASS: Agilent 1260 system coupled with diode array detector, and Q-Tof MS detector (G6540B).
  • Step 1 Synthesis of methyl 5-[(7-chloro-l-isoquinolyl)amino]pyri dinercarb oxy late (3).
  • Step 3 Synthesis of 5-[(7-chloro-l-isoquinolyl)amino]pyridine-2-carbonyl chloride (5).
  • Step a Synthesis of 5-[(7-chloro-l-isoquinolyl)amino]-N-[(2S)-6- methoxytetralin-2-yl]pyridine-2-carboxamide (S-II)
  • Step b Synthesis of 5-[(7-chloro-l-isoquinolyl)amino]-N-[(2S)-6- methoxytetralin-2-yl]pyridine-2-carboxamide (S-II) hydrochloride
  • Step a Synthesis of 5-[(7-chloro-l-isoquinolyl)amino]-N-[(2R)-6- methoxytetralin-2-yl]pyridine-2-carboxamide (R-II)
  • Step b Synthesis of 5-[(7-chloro-l-isoquinolyl)amino]-N-[(2R)-6- methoxytetralin-2-yl]pyridine-2-carboxamide (R-II) hydrochloride
  • Fibroblasts homozygous for a GM1 gangliosidosis missense mutation (GM11473) (canine fibroblasts homozygous for the GM1 gangliosidosis missense mutation p.R60H equivalent to human p.R59H mutation) were purchased from Coriell Institute for Medical Research (Camden, NJ, USA).
  • Fibroblasts were seeded at 4x104 cells per well in 12-well cell culture plates in Dulbecco’s Modified Eagle’s Media (DMEM) supplemented with 10% of fetal bovine serum (FBS), 1% penicillin/streptomycin (P/S) (Thermo Fisher Scientific, Waltham, MA, USA) and incubated at 37°C, 5% CO2 overnight for cell attachment. Subsequently, cells were incubated in the absence or presence of the compounds at the desired concentration for 4 days. After incubation, cells were washed twice with phosphate-buffered saline (“PBS”) and detached using Trypsin-EDTA solution (Sigma Aldrich, St. Louis, MO, USA) to prepare cell pellets. The pellets were stored at -80°C until activity assays were performed. Enzyme Activity Assay
  • D means that no increase compared with non-treated cells was detected in this method.
  • ND means “not determined.”
  • the S-enantiomer of 5-((7-chloroisoquinolin-l-yl)amino)-N-(6-methoxy-l,2,3,4- tetrahydronaphthalen-2-yl)picolinamide exhibits an improved brain penetration
  • Plasma and brain concentration-time data were used for the pharmacokinetic analysis.
  • Plasma, and brain samples were quantified by fit-for-purpose LC-MS/MS method (LLOQ: 1.00 ng/mL for plasma and 2.00 ng/mL for brain):
  • Dose volume i.v.: 5 mL/kg
  • Feeding regimen Food and water ad libitum,' and
  • Formulation used i.v.: 5% v/v NMP (N-methyl-2-pyrrolidone), 10% 5% v/v Solutol® HS-15, 30% v/v PEG-400 and 60% v/v normal saline. Formulation Preparation'.
  • I .V. Accurately weighed 2.92 mg of a tested compound was added in a labeled bottle for i.v. dosing. Individual excipient volumes were calculated to prepare a solution formulation at strength of 2 mg/mL. The volume of NMP was added and vortexed. The volumes of Solutol® HS-15, PEG-400 and normal saline were added followed by vertexing after each addition. The final formulation was vortexed for 2 minutes to obtain a clear solution.
  • LC conditions Thermo ScientificTM AccucoreTM, C18 (2.7 p, 50 mm X 2.1 mm) run time: 1.6 min; Injection volume: 1 pL; Flow rate: 0.8 mL/min; Mobile phase A: 0.1% formic acid in acetonitrile and B: 10 mM ammonium formate; and Time and mobile phase-gradient (time in min/%B): 0.00/95, 0.30/95, 0.50/5, 1.20/5, 1.40/95, 1.60/95.
  • MS/MS Source parameters T 550°C, Gas 1 40, Gas 2 60, CUR 30, IS 5500, and CAD 8.
  • S-enantiomer of 5-((7-chloroisoquinolin-l-yl)amino)-N- (6-methoxy-l,2,3,4-tetrahydronaphthalen-2-yl)picolinamide exhibits an improved brain penetration when compared to that of the R-enantiomer (R-II) or the racemic mixture of 5-((7-chloroisoquinolin-l-yl)amino)-N-(6-methoxy- 1,2,3, 4-tetrahydro- naphthalen-2-yl)picolinamide.
  • FIG. 1 shows that the S-enantiomer (S-II) is present in brain at higher levels at 0.25 h than the R-enantiomer (R-II) or the racemate when administered intravenously (10 mg/kg) to the male mouse C57/BL6. Accordingly, the S-enantiomer shows to be more brain penetrant.
  • Blood samples (approximately 60 uL) were collected under light isoflurane anesthesia from retro orbital plexus from a set of three mice at pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hr after administration, in micro-centrifuge tubes containing K2 EDTA anticoagulant. Immediately after blood collection, plasma was harvested by centrifugation at 4000 rpm, 10 min at 40 °C and samples were stored at -70 ⁇ 10°C until shipment.
  • Brain samples were collected from mice at 1, 4 and 24 hr after administration time points. Brain samples were homogenized using ice-cold phosphate buffer saline (pH 7.4) and homogenates were stored below -70 °C until analysis. The total homogenate volume was three times the brain weight. All samples were stored at -70 ⁇ 10°C.
  • QC plasma samples were prepared in mouse blank plasma adding 5 pl of each stock solution to 45 pl plasma and precipitating the protein by addition of 150 pl of cold acetonitrile (ACN) containing verapamil 200 ng/mL as an internal standard (IS). Samples were kept under mixing for 10 min and centrifuged for 15 min at 3000 g at 5 °C. Supernatants were injected into LC-MS/MS. Samples from kinetic study were analogously prepared from 50 pl of plasma.
  • ACN cold acetonitrile
  • IS internal standard
  • Brain samples were homogenates in ammonium formate 20 mM 1 g/10 mL and samples were prepared as previously described for plasma.
  • S-II S-enantiomer
  • R-II R-enantiomer
  • test compounds in duplicate were dissolved in DMSO to obtain 1 mg/mL solutions and pre-incubated, at the final concentration of 1 pg/mL (2 pM), for 10 min at 37 °C in potassium phosphate buffer 50 mM, pH 7.4, 3 mM MgCh, with mouse and human liver microsomes (Sigma) at the final concentration of 0.5 mg/mL.
  • Mobile phase A H2O with 0.1% formic acid
  • Mobile phase B ACN 0.1% formic acid
  • Injection volume 20 pL
  • MS/MS Source parameters for PK study T 450 °C, Gas 1 45, Gas 2 55, CUR 25, IS 4500, CAD 4.
  • MS/MS Source parameters for liver microsome study T 450 °C, Gas 1 45, Gas 2 55, CUR 30, IS 5500, CAD 4.
  • FIG. 3 exhibits the percent of the area of each of the test compounds remaining at the various incubation times in human liver microsomes with respect to the area of the test compound at time 0 min.
  • S-II S-enantiomer
  • R-II R-enantiomer
  • FIG. 4 exhibits the percent of the area of each of the test compounds remaining at the various incubation times in mouse liver microsomes with respect to the area of the test compound at time 0 min.
  • S-II S-enantiomer
  • R-II R-enantiomer

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Abstract

La présente invention concerne des composés énantiomériquement enrichis de formule S-I : S-I, et, en particulier, de formule S-II : S-II, et leurs sels et solvates, où R1, R2, R3, R4 et m sont tels que définis dans la description, ainsi que les compositions pharmaceutiques les comprenant, et leur utilisation pour le traitement et/ou la prévention des pathologies associées à l'altération de l'activité de la β-galactosidase, particulièrement la galactosidase bêta-1 ou GLB1, y compris les gangliosidoses GM1 et le syndrome de Morquio, de type B.
PCT/IB2022/058847 2021-09-20 2022-09-19 Enantiomères du 5-((7-chloroisoquinolin-1-yl)amino)-n-(6-méthoxy-1,2,3,4-tétrahydronaphtalène-2-yl)picolinamide WO2023042177A1 (fr)

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