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WO2010069069A1 - Inhibiteurs de cathepsine b - Google Patents

Inhibiteurs de cathepsine b Download PDF

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Publication number
WO2010069069A1
WO2010069069A1 PCT/CA2009/001852 CA2009001852W WO2010069069A1 WO 2010069069 A1 WO2010069069 A1 WO 2010069069A1 CA 2009001852 W CA2009001852 W CA 2009001852W WO 2010069069 A1 WO2010069069 A1 WO 2010069069A1
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optionally substituted
formula
pharmaceutically acceptable
compound
group
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Patrick Roy
Daniel J. Mckay
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Merck Canada Inc
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Merck Frosst Canada Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • This invention relates to compounds for use in the therapeutic treatment of the human body.
  • a class of novel compounds which are selective inhibitors of cathepsin B, and hence are suitable for use in treating a variety of diseases which are mediated by cathepsin B.
  • the cathepsins are a family of cysteine proteases belonging to the papain superfamily. Cysteine proteases function in the normal physiological as well as pathological degradation of connective tissue. Aberrant activity of cysteine proteases, e.g. as a result of increased expression or enhanced activation, may have pathological consequences, and cysteine proteases have been associated with numerous disease states such as arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease and others.
  • Cathepsins play a major role in intracellular protein degradation, turnover and remodelling, and 11 distinct human cysteine cathepsins are known (identified as cathepsins B, C, F, H, L, K, O, S, V, W and Z). Increased levels of cathepsin B and redistribution of the enzyme are found in tumors, suggesting a role for cathepsin B in tumor invasion and metastasis. Cathepsin B has been shown to be involved in the processing of prorenin and as such may play a role in hypertension. (FEBS Lett. 443(1) p. 48-52 (1999).
  • cathepsin B activity is implicated in rheumatoid arthritis, osteoarthritis, Pneumocystis carinii, acute pancreatitis, inflammatory airway disease, bone and joint disorders, and atherosclerosis.
  • Inhibitors of cathepsin B and/or cathepsin S have been discussed for use in treating chronic obstructive pulmonary disease (COPD) (WO
  • Cathepsin B inhibitors have also been published for the treatment of Type II diabetes and metabolic syndrome (WO/2005/097103).
  • AD Alzheimer's disease
  • DSM-TV Diagnostic and Statistical Manual of Mental Disorders
  • a ⁇ is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes ⁇ -secretase and ⁇ -secretase. Variability in the site of the proteolysis mediated by ⁇ -secretase results in A ⁇ of varying chain length, e.g. A ⁇ (1-38), A ⁇ (1-40) and A ⁇ (1-42). N-terminal truncations such as A ⁇ (4-42) are also found in the brain, possibly as a result of variability in the site of proteolysis mediated by ⁇ -secretase. For the sake of convenience, expressions such as “A ⁇ (1-40)” and "A ⁇ (1-42)" as used herein are inclusive of such N-terminal truncated variants.
  • APP amyloid precursor protein
  • a ⁇ After secretion into the extracellular medium, A ⁇ forms initially-soluble aggregates which are widely believed to be the key neurotoxic agents in AD (see Gong et al, PNAS, 100 (2003), 10417-22), and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD.
  • Other dementing conditions associated with deposition of A ⁇ in the brain include cerebral amyloid angiopathy, hereditary cerebral haemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
  • WO 2005/028429 discloses a class of compounds active against cathepsins B, K, L, F and/or S, but does not disclose the compounds of the present invention, and does not disclose selective inhibition of cathepsin B.
  • WO2008/037072 discloses a class of compounds that are different than the compounds disclosed herein, and are selective inhibitors of Cathepsin B.
  • Other cathepsin inhibiting compounds that have some structural features of the compounds herein are disclosed in WO 2001/087828, WO 1999/024460, and J Med. Chem., Vol. 44, 4524- 4534 (2001).
  • Ar is phenyl or a 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from O, N, and S, wherein Ar is optionally substituted with 1-2 substituent groups independently selected from halogen, C i - ⁇ alkyl optionally substituted with 1-3 halogens, -OCi -3alkyl optionally substituted with 1-3 halogens, C2-3alkenyl optionally substituted with 1-5 halogens, and C3_6cycloalkyl;
  • Rl represents a group selected from H, Ci- ⁇ alkyl substituted optionally with 1-5 halogens and optionally with one C3-6cycloalkyl, C2-6alkenyl optionally substituted with 1-5 halogens, and C3-6cycloalkyl optionally substituted with 1-2 groups independently selected from F, CH3, CF3, -OCH3, and -OCF3;
  • R.2 represents a group selected from H, Ci-6alkyl optionally substituted with 1-5 halogens, C2-6 a lkenyl optionally substituted with 1-5 halogens, and C3-6cycloalkyl optionally substituted with 1-2 groups independently selected from F, CH3, CF3, -OCH3, and -OCF3; or Rl and R2 together with the N atom to which they are attached are connected to complete a 4-7-membered heterocyclic ring which also optionally includes a second heteroatom group in the ring selected from O, (NH), S, S(O), and S(O)2, wherein the heterocyclic ring is optionally substituted with 1-2 groups independently selected from F, CH3, CF3, -OCH3, and -OCF3; R3 and R4 are independently selected from H, Cl- ⁇ alkyl optionally substituted with 1-5 halogens, C2-6 a lkenyl optionally substituted with 1-5 halogens, and C3-6cycloalkyl
  • R5 is selected from the group consisting of halogen, Ci-6alkyl optionally substituted with 1-5 halogens, C2-6alkenyl optionally substituted with 1-5 halogens, and
  • C3_6cycloalkyl optionally substituted with 1-2 groups independently selected from F, CH3, CF3, -OCH3, and -OCF3; and n is an integer from 1-3.
  • variable occurs more than once in formula I, Ia, II, Ha, III, or IHa
  • identity taken by the variable at any particular occurrence is independent of its identity at any other occurrence in the same formula.
  • Alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert- butyl, pentyl, hexyl and the like.
  • alkenyl means carbon chains which may be linear or branched or combinations thereof containing at least 1 carbon to carbon double bond. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 1-hexenyl.
  • Cycloalkyl means saturated monocyclic carbocycles containing no heteroatoms.
  • Halogen or “halo” means fluorine, chlorine, bromine or iodine.
  • Heteroaryl means a 5-6-membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl
  • Compounds described herein contain at least two asymmetric centers and may thus exist as enantiomers and as diastereomers.
  • the present invention includes all such possible stereoisomers as substantially pure resolved enantiomers and racemic mixtures thereof, as well as individual diastereomers and mixtures of diastereomers.
  • the above formula I and later formula II and III are shown without definitive stereochemistry.
  • the present invention includes all stereoisomers of formulae I, II and III, including individual diastereomers thereof and mixtures thereof and pharmaceutically acceptable salts and hydrates thereof.
  • the structures in formulae Ia, Ha, and Ilia are provided showing the preferred stereochemistry at one of the two asymmetric centers.
  • Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or by using a chiral phase HPLC column.
  • any enantiomer or diastereomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • the compound of formula I has the stereochemistry shown in formula I(a):
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound is acidic, suitable salts can be conveniently prepared by neutralization with pharmaceutically acceptable non-toxic inorganic bases and organic bases.
  • suitable salts can be conveniently prepared by neutralisation with pharmaceutically acceptable non-toxic inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Xl and X2 are independently selected from CH and N;
  • R6 is selected from the group consisting of F, CH3, CF3, -OCH3, and -OCF3; m is an integer from 0-2;
  • Rl represents a group selected from H; Ci-3alkyl which is substituted optionally with 1-3 F atoms and optionally with one C3-6cycloalkyl; C2-3alkenyl which is optionally substituted with 1-3 F atoms; and C3_6cycloalkyl;
  • R2 represents a group selected from H and Ci_3alkyl which is optionally substituted with 1 -3 F atoms; or
  • Rl and R2 together with the N atom to which they are attached are connected to complete a 4-7-membered heterocyclic ring which also optionally includes a second heteroatom group in the ring selected from O and (NH), where the heterocyclic ring is optionally substituted with 1-2 groups independently selected from F, CH3, CF3, -OCH3, and -OCF3;
  • R3 and R4 are independently selected from H and Ci-3alkyl
  • R5 is selected from the group consisting of F, Ci_2alkyl, and CF3.
  • Xl and ⁇ 2 are independently selected from CH and N, with the proviso that Xl and ⁇ 2 are not both N.
  • R6 is selected from the group consisting of F, CH3, and CF3.
  • m is an integer selected from 0 and 1.
  • Rl represents a group selected from H, Ci-3alkyl, and CH2-cyclopropyl.
  • R2 represents a group selected from H and Ci- 3alkyl.
  • Rl and R2 together with the N atom to which they are attached complete a 4-6-membered heterocyclic ring which also optionally includes in the ring a second heteroatom O.
  • R? and R4 are each H.
  • R5 is selected from the group consisting of F, CH3, and CF3. hi other subsets of formula II, R5 is CH3,
  • n is the integer 2.
  • a preferred subset of the compounds described above has Formula III, including individual diastereomers thereof and pharmaceutically acceptable salts and hydrates thereof:
  • I?? and R.8 are independently selected from H, F, CH3, and CF3, provided that R7 and R.8 are not both H.
  • a preferred subset of the compounds described above has Formula Ilia, including 10 individual diastereomers thereof and pharmaceutically acceptable salts and hydrates thereof:
  • R7 and RB are CH3.
  • Scheme 1 illustrates the synthetic method for preparing the chiral phenylalaninamide V.
  • the Boc protected aminomalonate I is deprotonated with NaH and 25 alkylated with 3,5-dimethylbenzyl bromide II.
  • Treatment with acetic acid and water at 150 °C for 16 hours results in mono-ester cleavage and decarboxylation.
  • Subsequent treatment with NaHCO 3 and the enzyme Alkalase 2.4 L results in selective cleavage of the S enantiomer to afford acid III. (See also reference 1.)
  • Scheme 2 shows the synthesis of the amino-substituted phenylacetic acids and pyridylacetic acids and their coupling with V to yield the compounds of the invention.
  • Phenylacetic acid or pyridylacetic acid VI is brominated with N-bromosuccinimide, and the bromide is subsequently displaced with amine VII to afford VIII.
  • Cleavage of the ester with a suitable base such as LiOH then yields acid IX which is coupled with V using a suitable coupling reagent such as HATU to give X as a diastereomeric mixture.
  • This diastereomeric mixture can further be separated into its component diastereomers XI by either normal-phase or reverse-phase chromatography.
  • novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as di-p-toluoyl- D-tartaric acid and/or di-p-toluoyl-L-tartaric acid, followed by fractional crystallisation and regeneration of the free base.
  • optically active acid such as di-p-toluoyl- D-tartaric acid and/or di-p-toluoyl-L-tartaric acid
  • the novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • racemic intermediates in the preparation of compounds of formula I may be resolved by the aforementioned techniques, and the desired enantiomer used in subsequent steps.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd ed., 1999.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds of the invention have the useful property of selectively inhibiting cathepsin B.
  • the compounds show selectivity for cathepsin B over cathepsins S, F, and K.
  • the compounds are therefore useful in the treatment or prevention of cathepsin B dependent diseases and conditions in mammals, especially humans.
  • the present invention provides a method for the prevention or treatment of cathepsin B dependent conditions in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof.
  • This aspect also encompasses the use of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of a medicament for the prevention or treatment of cathepsin B dependent conditions in a mammal.
  • cathepsin B dependent conditions include tumor invasion and metastasis, rheumatoid arthritis, osteoarthritis, Pneumocystis carinii, acute pancreatitis, inflammatory airway disease, COPD, bone and joint disorders, and diseases associated with deposition of ⁇ -amyloid in the brain.
  • the disease associated with deposition of A ⁇ in the brain is typically Alzheimer's disease (AD), cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistica or Down syndrome, and most typically is AD.
  • AD Alzheimer's disease
  • HCHWA-D cerebral amyloid angiopathy
  • multi-infarct dementia dementia pugilistica or Down syndrome
  • the invention provides the use of a compound of Formula I as defined above, or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for treating, preventing or delaying the onset of dementia associated with Alzheimer's disease, cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistica or Down syndrome.
  • the invention also provides a method of treating or preventing a disease associated with deposition of A ⁇ in the brain comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I as defined above or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention provides a method of treating, preventing or delaying the onset of dementia associated with Alzheimer's disease, cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistica or Down syndrome comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I as defined above or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention provides a method for attenuating the secretion of ⁇ -amyloid from a mammalian cell comprising contacting said cell with an effective amount of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof.
  • the compound of Formula I is administered to a patient suffering from AD, cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistica or Down syndrome, and typically AD.
  • the compound of Formula I is administered to a patient suffering from mild cognitive impairment or age-related cognitive decline.
  • a favourable outcome of such treatment is prevention or delay of the onset of AD.
  • Age-related cognitive decline and mild cognitive impairment (MCI) are conditions in which a memory deficit is present, but other diagnostic criteria for dementia are absent (Santacruz and Swagerty, American Family Physician, 63 (2001), 703-13). (See also "The ICD-IO Classification of Mental and Behavioural Disorders", Geneva: World Health Organization, 1992, 64-5).
  • age-related cognitive decline implies a decline of at least six months' duration in at least one of: memory and learning; attention and concentration; thinking; language; and visuospatial functioning and a score of more than one standard deviation below the norm on standardized neuropsychologic testing such as the MMSE. In particular, there may be a progressive decline in memory. In the more severe condition MCI, the degree of memory impairment is outside the range considered normal for the age of the patient but AD is not present.
  • the differential diagnosis of MCI and mild AD is described by Petersen et al., Arch. Neurol, 56 (1999), 303-8. Further information on the differential diagnosis of MCI is provided by Knopman et al, Mayo Clinic Proceedings, 78 (2003), 1290-1308. In a study of elderly subjects, Tuokko et al (Arch, Neurol., 60 (2003) 577-82) found that those exhibiting MCI at the outset had a three-fold increased risk of developing dementia within 5 years.
  • the compound of Formula I is advantageously administered to patients who suffer impaired memory function but do not exhibit symptoms of dementia.
  • impairment of memory function typically is not attributable to systemic or cerebral disease, such as stroke or metabolic disorders caused by pituitary dysfunction.
  • Such patients may be in particular people aged 55 or over, especially people aged 60 or over, and preferably people aged 65 or over.
  • Such patients may have normal patterns and levels of growth hormone secretion for their age.
  • Such patients may possess one or more additional risk factors for developing Alzheimer's disease.
  • Such factors include a family history of the disease; a genetic predisposition to the disease; elevated serum cholesterol; and adult-onset diabetes mellitus.
  • the compound of Formula I is administered to a patient suffering from age-related cognitive decline or MCI who additionally possesses one or more risk factors for developing AD selected from: a family history of the disease; a genetic predisposition to the disease; elevated serum cholesterol; adult-onset diabetes mellitus; elevated baseline hippocampal volume; elevated CSF levels of total tau; elevated CSF levels of phospho-tau; and lowered CSF levels of A ⁇ (l-42),
  • a genetic predisposition (especially towards early onset AD) can arise from point mutations in one or more of a number of genes, including the APP, presenilin-1 and presenilin-2 genes. Also, subjects who are homozygous for the ⁇ 4 isoform of the apo lipoprotein E gene are at greater risk of developing AD.
  • the patient's degree of cognitive decline or impairment is advantageously assessed at regular intervals before, during and/or after a course of treatment in accordance with the invention, so that changes therein may be detected, e.g. the slowing or halting of cognitive decline.
  • a variety of neuropsychological tests are known in the art for this purpose, such as the Mini-Mental State Examination (MMSE) with norms adjusted for age and education (Folstein et al , J Psych Res , 12 (1975), 196-198, Anthony et al , Psychological Med., 12 (1982), 397-408; Cockrell et al, Psychopharmacology, 24 (1988), 689-692; Crum et al., J. Am. Med. Assoc'n.
  • MMSE Mini-Mental State Examination
  • the MMSE is a brief, quantitative measure of cognitive status in adults. It can be used to screen for cognitive decline or impairment, to estimate the severity of cognitive decline or impairment at a given point in time, to follow the course of cognitive changes in an individual over time, and to document an individual's response to treatment.
  • Another suitable test is the Alzheimer Disease Assessment Scale (ADAS), in particular the cognitive element thereof (ADAS-cog) (See Rosen et al., Am. J Psychiatry, 141 (1984), 1356-64).
  • the compounds of Formula I are typically used in the form of pharmaceutical compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the principal active ingredient typically is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form
  • preformulation compositions When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • Tablets or pills of the composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, poly(ethylene glycol), poly(vinylpyrrolidone) or gelatin.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, and more preferably about 0.05 to 50 mg/kg of body weight per day, of the active compound.
  • the compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, a dosage outside these limits may be used.
  • the compounds of Formula I optionally may be administered in combination with one or more additional compounds known to be useful in the treatment or prevention of diseases or conditions for which compounds of formula I are useful, hi the case of AD, such additional compounds include cognition-enhancing drugs such as acetylcholinesterase inhibitors (e.g. donepezil and galanthamine), NMDA antagonists (e.g. memantine) or PDE4 inhibitors (e.g. ArifloTM and the classes of compounds disclosed in WO 03/018579, WO 01/46151, WO 02/074726 and WO 02/098878).
  • additional compounds also include cholesterol- lowering drugs such as the statins, e.g. simvastatin.
  • Such additional compounds similarly include compounds known to modify the production or processing of A ⁇ in the brain ("amyloid modifiers"), such as compounds which inhibit or modulate the secretion of A ⁇ (including ⁇ - secretase inhibitors, ⁇ -secretase modulators, and GSK-3 ⁇ inhibitors), compounds which inhibit the aggregation of A ⁇ , and antibodies which selectively bind to A ⁇ .
  • amloid modifiers compounds which inhibit or modulate the secretion of A ⁇ (including ⁇ - secretase inhibitors, ⁇ -secretase modulators, and GSK-3 ⁇ inhibitors), compounds which inhibit the aggregation of A ⁇ , and antibodies which selectively bind to A ⁇ .
  • additional compounds also include growth hormone secretagogues, as disclosed in WO 2004/110443.
  • the amyloid modifier may be a compound which inhibits the secretion of A ⁇ , for example an inhibitor of ⁇ -secretase (such as those disclosed in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, WO 2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO 02/47671), or any other compound which inhibits the formation or release of A ⁇ .
  • an inhibitor of ⁇ -secretase such as those disclosed in WO 01/90084, WO
  • GSK-3 inhibitors particularly GSK-3 ⁇ inhibitors, such as lithium, as disclosed in Phiel et al, Nature, 423 (2003), 435-9.
  • amyloid modifier is advantageously a ⁇ -secretase inhibitor, preferred examples of which include a compound of formula XI:
  • Such compounds may be prepared as described in WO 03/018543.
  • Preferred examples include those defined by formula XIa:
  • m is 0 or 1
  • X is Cl or CF 3
  • Y is OH, OQ- ⁇ alkyl, NH 2 or NHC ⁇ alkyl.
  • Particular examples include those in which m is 1 and Y is OH (or the sodium salts thereof), and those in which m is 0 and Y is NH 2 or NHC 1-6 alkyl.
  • ⁇ -secretase inhibitors for use in this embodiment of the invention is that defined by formula XII:
  • X is very aptly 5-substiruted-thiazol-2-yl, 5-substituted-4-methylthiazol-2-yl, 5- substituted- l-methylpyrazol-3-yl, l-substituted-imidazol-4-yl or l-substituted-l,2,4-triazol-3-yl.
  • R represents optionally-substituted phenyl or heteroaryl such as phenyl, monohalophenyl, dihalophenyl, trihalophenyl, cyanophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, monohalopyridyl and trifluoromethylpyridyl, wherein "halo" refers to fluoro or chloro.
  • R-X- Particularly preferred identities of R-X- include 5-(4-fluorophenyl)- 1 -methylpyrazol-3-yl, 5-(4-chlorophenyl)- 1 -methylpyrazol-3- yl and 1 -(4-fiuorophenyl)imidazol-4-yl.
  • Such compounds may be prepared by methods disclosed in WO 03/093252.
  • the amyloid modifier may be a modulator of ⁇ - secretase which selectively attenuates the production of A ⁇ (l-42). This results in preferential secretion of the shorter chain isoforms of A ⁇ , which are believed to have a reduced propensity for self-aggregation and plaque formation, and hence are more easily cleared from the brain, and/or are less neurotoxic.
  • NSAIDs non-steroidal antiinflammatory drugs
  • analogues see WO 01/78721 and US 2002/0128319 and Weggen et al Nature, 414 (2001) 212-16; Morihara et al, J Neurochem., 83 (2002), 1009-12; and Takahashi et al, J Biol. Chem., 278 (2003), 18644-70.
  • Compounds which modulate the activity of PP ARa and/or PPAR ⁇ are also reported to have the effect of lowering A ⁇ (l-42) (WO 02/100836).
  • US 2002/0015941 teaches that agents which potentiate capacitative calcium entry activity can lower A ⁇ (l-42).
  • Further classes of compounds capable of selectively attenuating A ⁇ (l-42) production are disclosed on WO 2005/054193, WO 2005/013985, WO 2006/008558, WO 2005/108362 and WO 2006/043064.
  • the amyloid modifier may be a compound which inhibits the aggregation of A ⁇ or otherwise attenuates is neurotoxicicity.
  • Suitable examples include chelating agents such as clioquinol (Gouras and Beal, Neuron, 30 (2001), 641-2) and the compounds disclosed in WO 99/16741, in particular that known as DP-109 (Kalendarev et al, J Pharm. Biomed. Anal., 24 (2001), 967-75).
  • inhibitors of A ⁇ aggregation suitable for use in the invention include the compounds disclosed in WO 96/28471, WO 98/08868 and WO 00/052048, including the compound known as ApanTM (Praecis); WO 00/064420, WO 03/017994, WO 99/59571 (in particular 3 -aminopropane- 1 -sulfonic acid, also known as tramiprosate or AlzhemedTM); WO 00/149281 and the compositions known as PTI-777 and PTI-00703 (ProteoTech); WO 96/39834, WO 01/83425, WO 01/55093, WO 00/76988, WO 00/76987, WO 00/76969, WO 00/76489, WO 97/26919, WO 97/16194, and WO 97/16191. Further examples include phytic acid derivatives as disclosed in US 4,847,082 and inos
  • Said antibody may be polyclonal or monoclonal, but is preferably monoclonal, and is preferably human or humanized.
  • the antibody is capable of sequestering soluble A ⁇ from biological fluids, as described in WO 03/016466, WO 03/016467, WO 03/015691 and WO 01/62801.
  • Suitable antibodies include humanized antibody 266 (described in WO 01/62801) and the modified version thereof described in WO 03/016466.
  • the expression "in combination with” requires that therapeutically effective amounts of both the compound of Formula I and the additional compound are administered to the subject, but places no restriction on the manner in which this is achieved.
  • the two species may be combined in a single dosage form for simultaneous administration to the subject, or may be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close in time or remote in time, e.g. one species administered in the morning and the other in the evening.
  • the separate species may be administered at the same frequency or at different frequencies, e.g. one species once a day and the other two or more times a day.
  • the separate species may be administered by the same route or by different routes, e.g. one species orally and the other parenterally, although oral administration of both species is preferred, where possible.
  • the additional compound is an antibody, it will typically be administered parenterally and separately from the compound of Formula I.
  • Enzyme activity assays Assays of Cat S (human, rat) were carried out in 50 mM MES pH 6.5, 100 mM NaCl, 2.5 mM DTT, 2.5 mM EDTA, 0.001% w/v BSA, 10 % DMSO and 40 ⁇ M Z-Val-Val-Arg-AMC as substrate. Assays of Cat B (human, rat) were carried out in 50 mM MES pH 6.0, 2.5 mM DTT, 2.5 mM EDTA, 0.001% Tween-20, 10 % DMSO and 83 ⁇ M Boc-Leu- Lys-Arg-AMC as substrate.
  • the assay of human Cat F was carried out in 50 mM MES pH 6.5, 100 mM NaCl, 2.5 mM EDTA, 10% DMSO, 2.5 mM DTT, 0.01% BSA (w/v), 20 uM Z-Phe- Arg-AMC.
  • Assays of humanized rabbit Cat K and Cat L were carried out in 50 mM MES pH 5.5, 2.5 mM DTT, 2.5 mM EDTA, 10 % DMSO and 2 ⁇ M Z-Leu-Arg-AMC as substrate.
  • Compounds of formula (I) generally have IC 50 values of about 1 ⁇ M or lower; more typically they have IC 50 values of about 100 nM or lower against rat cathepsin B.
  • Compounds exemplified herein have IC 50 values in the range of 8 nM to 125 nM against rat cathepsin B.
  • Compounds exemplified herein were typically found to be > 100-fold selective for rat cathepsin B over rat cathepsin S and > 50-fold selective for human cathepsin B over human cathepsin F or K.
  • This compound was prepared in analogous manner to compound 2 of reference 1, using 3,5- dimethylbenzyl bromide as the alkylating agent.
  • Step 2 N ⁇ -(?err-butoxycarbonyl)-N-(cyanomethyl)-3,5-dimethyl-L-phenylalaninamide(IV).
  • aminoacetonitrile hydrochloride (2.75 g, 29.7 mmol)
  • HATU (14.1 g, 37.2 mmol
  • DMF 200 mL
  • diisopropylethylamine 13 mL, 74.3 mmol
  • Step 4 N-(cyanomethyl)-3,5-dimethyl-N ⁇ -[mo ⁇ holin-4-yl(pyridin-3-yl)acetyl]-L- phenylalaninamide.
  • the second eluting isomer of Example 1 is very potent and has the NMR spectrum shown below.
  • the absolute stereochemistry of the carbon bearing the morpholine group is not known.
  • 1H NMR 400 MHz, Acetone-d6): ⁇ 8.51-8.48 (m, 1 H), 8.45-8.43 (m, 1 H), 8.06-8.00 (m, 1 H), 7.98-7.93 (m, 1 H), 7.51-7.47 (m, 1 H), 7.30-7.25 (m, 1 H), 6.91 (s, 3 H), 4.82-4.75 (m, 1 H), 4.31-4.19 (m, 2 H), 4.04 (s, 1 H), 3.57 (t, 4 H), 3.21-3.15 (m, 1 H), 3.02-2.95 (m, 1 H), 2.35-2.24 (m, 8 H), 2.20-2.20-2.13 (m, 2 H).
  • the second eluting isomer of Example 3 is very potent and has the NMR spectrum written below.
  • the absolute stereochemistry of the carbon bearing the morpholine group is not known.
  • 1 H NMR 400 MHz, Acetone-d6): ⁇ 7.99-7.93 (m, 1 H), 7.86-7.81 (m, IH), 7.30-7.26 (m, 3 H), 7.19-7.15 (m, 2 H), 6.93-6.89 (m, 3 H), 4.73-4.66 (m, 1 H), 4.31-4.18 (m, 2H), 3.84 (s, 1 H), 3.61-3.54 (m, 4 H), 3.17-3.10 (m, 1 H), 3.01-2.93 (m, IH), 2.38-2.30 (m, 2 H), 2.27 (s, 6H), 2.22-2.15 (m, 2 H).
  • Step 2 Morpholin-4-yl(pyridin-4-yl)acetic acid.
  • aqueous IM LiOH solution 1.2 mL, 1.2 mmol.
  • the mixture was added to a suspension of 1.5 g of Amberlite IRC-50 (mildly acidic resin) in 5 mL of MeOH. After stirring for 5 min, the suspension was filtered and the filtrate was evaporated to yield the title compound (95 mg).
  • Step 3 N-(cyanomethyl)-3,5-dimethyl-N ⁇ -[morpholin-4-yl(pyridin-4-yl)acetyl]-L- phenylalaninamide.
  • Step 3 (Methylamino)(pyridin-3-yl)acetic acid.
  • IM LiOH solution 0.124 mL, 0.124 mmol.
  • the reaction mixture was added to a suspension of Amberlite IRC-50 (150 mg) in 2 niL of MeOH. After stirring for 5 min, the suspension was filtered and the filtrate was concentrated to dryness to yield the title compound (12 mg).
  • Step 4 N-(cyanomethyl)-3,5-dimethyl-N ⁇ -[(methylamino)(pyridin-3-yl)acetyl]-L- phenylalaninamide.
  • Step 1 (5 mL, ⁇ 1.5 mmol) at room temperature was added cyclopropanemethylamine (0.21 g, 3.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was taken up in EtOAcZH 2 O. The organic phase was washed with H 2 O and brine, and was then dried (MgSO ⁇ , filtered, and evaporated. The crude material was purified by column chromatography on silica gel, eluting with 20-100% EtOAc (containing 1% MeOH)/hexane) to give 220 mg of the title compound.
  • the title compound was prepared in an analogous manner to Ex. 1, Step 4, using the amine of Ex 1, Step 3, and the [(cyclopropylmethyl)amino](pyridin-3-yl)acetic acid of Step 3 as the acid component of the coupling. Following column chromatography on silica gel (20-100% EtOAc containing 2% MeOH)/hexane), the title compound was obtained as a pink/orange foam mixture of diastereomers (32 mg).

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Abstract

Les composés de formule I, y compris leurs diastéréoisomères individuels et leurs sels et hydrates de qualité pharmaceutique, sont des inhibiteurs sélectifs de la cathepsine B, et peuvent être employés dans le traitement d'états pathologiques traités par inhibition de la cathepsine B.
PCT/CA2009/001852 2008-12-17 2009-12-16 Inhibiteurs de cathepsine b Ceased WO2010069069A1 (fr)

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Cited By (1)

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WO2013109675A3 (fr) * 2012-01-18 2013-09-19 FIRESTONE, Raymond, A Compositions et méthodes utilisables en vue du traitement de cancers et de maladies et affections associées à l'inflammation

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WO2001087828A1 (fr) * 2000-05-15 2001-11-22 Novartis Ag Utilisation de peptidyl nitriles a substitution- n comme inhibiteurs des cathepsines de cysteine
US6353017B1 (en) * 1997-11-05 2002-03-05 Novartis Ag Dipeptide nitriles
CA2498149A1 (fr) * 2002-09-20 2004-04-01 Axys Pharmaceuticals, Inc. Derives de 4-hydroxyphenyl-3-3,5-disubstitue-propionamide en tant qu'inhibiteurs de cathepsine b
WO2005028429A2 (fr) * 2003-09-18 2005-03-31 Axys Pharmaceuticals, Inc. Composes contenant un haloalkyle utilise comme inhibiteurs de cysteine protease
WO2005097103A2 (fr) * 2004-04-01 2005-10-20 Axys Pharmaceuticals, Inc. Traitement du diabete et du syndrome metabolique au moyen d'inhibiteurs de la cathepsine b

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US6353017B1 (en) * 1997-11-05 2002-03-05 Novartis Ag Dipeptide nitriles
WO2001087828A1 (fr) * 2000-05-15 2001-11-22 Novartis Ag Utilisation de peptidyl nitriles a substitution- n comme inhibiteurs des cathepsines de cysteine
CA2498149A1 (fr) * 2002-09-20 2004-04-01 Axys Pharmaceuticals, Inc. Derives de 4-hydroxyphenyl-3-3,5-disubstitue-propionamide en tant qu'inhibiteurs de cathepsine b
WO2005028429A2 (fr) * 2003-09-18 2005-03-31 Axys Pharmaceuticals, Inc. Composes contenant un haloalkyle utilise comme inhibiteurs de cysteine protease
WO2005097103A2 (fr) * 2004-04-01 2005-10-20 Axys Pharmaceuticals, Inc. Traitement du diabete et du syndrome metabolique au moyen d'inhibiteurs de la cathepsine b

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CAREY P.R. ET AL: "Identity of Acyl Group Conformations in the Active Sites of Papain and Cathepsin B by Resonance Raman Spectroscopy", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 259, no. 23, 1984, pages 14357 - 14360 *
FRLAN R. ET AL: "Inhibitors of Cathepsin B", CURRENT MEDICINAL CHEMISTRY, vol. 13, 2006, pages 2309 - 2327 *
GREENSPAN P.D. ET AL: "Identification of Dipeptidyl Nitriles as Potent and Selective Inhibitors of Cathepsin B through Structure-Based Drug Design", J MED. CHEM., vol. 44, 2001, pages 4524 - 4534 *
MOON J.B. ET AL: "Reversible Covalent Inhibition of Papain by a Peptide Nitrile. 13C NMR Evidence for a Thioimidate Ester Adduct", J. AM. CHEM. SOC., vol. 108, 1986, pages 1350 - 1351 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109675A3 (fr) * 2012-01-18 2013-09-19 FIRESTONE, Raymond, A Compositions et méthodes utilisables en vue du traitement de cancers et de maladies et affections associées à l'inflammation

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