US20080103158A1 - Methods for treating delaying the progression of alzheimer's disease with heterocyclic compounds - Google Patents

Methods for treating delaying the progression of alzheimer's disease with heterocyclic compounds Download PDF

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US20080103158A1
US20080103158A1 US11/872,418 US87241807A US2008103158A1 US 20080103158 A1 US20080103158 A1 US 20080103158A1 US 87241807 A US87241807 A US 87241807A US 2008103158 A1 US2008103158 A1 US 2008103158A1
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group
compound
pyridin
imidazo
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Yoshimasa Yamaguchi
Ryogo Yui
Toshiyuki Matsuno
Kenichi Saitoh
Hitoshi Miyashita
Takeshi Nagata
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Zenyaku Kogyo KK
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Zenyaku Kogyo KK
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Assigned to ZENYAKU KOGYO KABUSHIKI KAISHA reassignment ZENYAKU KOGYO KABUSHIKI KAISHA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MATSUNO, TOSHIYUKI, MIYASHITA, HITOSHI, NAGATA, TAKESHI, SAITOH, KENICHI, YAMAGUCHI, YOSHIMASA, YUI, RYOGO
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Definitions

  • the present invention is in the filed of medicinal chemistry and relates to amyloid ⁇ deposition inhibitor containing a heterocyclic compound having a specific structure.
  • Alzheimer' diseases is dementing neurodegenarative disorder for which there is no effective treatment at present. Genetic and biological studies provide evidence that the production and deposition of amyloid- ⁇ (A ⁇ ) contribute to the etiology of Alzheimer' disease (for example, see Drug News & Perspectives. Vol. 17, No. 5, June 2004, Trends Neurosci., 20. 154-159 (1997), and Science, 297, 353-356 (2002)). Therefore an amyloid ⁇ deposition inhibitor will be useful agent as Alzheimer's disease progression inhibitor
  • ⁇ -Secretase inihibitors are developing for inhibiting the production of amyloid ⁇ , but these compounds will have adverse side effects because of their inhibitory activity of Notch gene or N-Cadherin (for example, see J. Biol. Chem., 276, 45394-45402 (2001)).
  • Curcumin is a component of Curcuma longa contained in curry in a large amount and has antiinflammatory and antioxidative activity equivalent to prescribed nonsteroidal antiinflammatory drugs (NSAIDs).
  • NSAIDs nonsteroidal antiinflammatory drugs
  • curcumin inhibits amyloid-related pathologies.
  • curcumin does not inhibit ⁇ amyloid deposition at satisfactory levels (for example, see Pharmacia, Japanese Pharmacology Association, Vol. 38, No. 9, 891-892, 2002). Therefore there is a strong demand for development of effective drugs having an sufficient effect and fewer side effects.
  • the present invention provides an amyloid ⁇ deposition inhibitor containing a heterocyclic compound having the general Formula (I): or a pharmaceutically acceptable salt or hydrate thereof.
  • the structural unit having the general formula (II) is one or more structural units selected from multiple types of structural units having the general Formula (III).
  • R 1 and R 2 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, and —O—(CH 2 )n-R 5 , wherein R 5 is a vinyl group, C 3 -C 6 cycloalkyl group, or phenyl group, and n is 0 or 1.
  • R 3 and R 4 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, and —CH(R 7 )—R 6 ; alternatively, R 3 and R 4 together form a spiro ring having the general Formula (IV):
  • R 6 is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C 1 -C 6 alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group.
  • the above R 7 is a hydrogen atom or C 1 -C 6 alkyl group.
  • the structural unit B is one or more structural units selected from multiple types of structural units having the general Formula (V).
  • the structural unit B binds at a position marked by * in the general Formula (V) to form a spiro ring.
  • R 8 is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C 1 -C 6 alkoxy group, cyano group, and trifluoromethyl group.
  • the compounds of Formula (I) may be used as an a delayer of the progression of Alzheimer's disease.
  • the invention also relates to a method of inhibiting amyloid deposition in an mammal in need thereof, comprising administering to the mammal an effective amount of a compound having the general Formula (I).
  • the invention also relates to a method of delaying the progression of Alzheimer's disease in a human in need thereof, comprising administering to the human an effective amount of a compound having the general Formula (I).
  • FIG. 1 contains photographs for explaining the effect of Compound 1 on the number of amyloid ⁇ -immunoreactive cells in senescene accelerated mice (SAMP8).
  • FIG. 2 depicts a graphical representation for explaining the effect of Compound 1 on the number of amyloid ⁇ -immunoreactive cells in senescene accelerated mice (SAMP8).
  • Embodiments of the present invention are described hereafter. Embodiments below relate to an amyloid ⁇ deposition inhibitor composition containing a heterocyclic compound having the above described specific structure (azaindolizinone derivatives) and pharmaceutically acceptable carriers or diluents, as well as methods for inhibiting amyloid deposition and methods for delaying the progression of Alzheimer's disease.
  • a heterocyclic compound having the above described specific structure azaindolizinone derivatives
  • pharmaceutically acceptable carriers or diluents as well as methods for inhibiting amyloid deposition and methods for delaying the progression of Alzheimer's disease.
  • the compounds useful in the present invention all contain a heterocyclic compound having the general Formula (I): or a pharmaceutically acceptable salt or hydrate thereof.
  • the structural unit having the general Formula (II) is one or more structural units selected from multiple types of structural units having the general Formula (III).
  • R 1 and R 2 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, and —O—(CH 2 )n-R 5 , wherein R 5 is a vinyl group, C 3 -C 6 cycloalkyl group, or phenyl group, and n is 0 or 1.
  • R 3 and R 4 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, and —CH(R 7 )—R 6 ; alternatively, R 3 and R 4 together form a spiro ring having the general formula (IV):
  • R 6 is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C 1 -C 6 alkylamino group, cyano group, nitro group, carboxy group, or phenyl group), phenethyl group, pyridyl group, thienyl group, and furyl group.
  • R 7 is a hydrogen atom or C 1 -C 6 alkyl group.
  • the structural unit B is one or more structural units selected from multiple types of structural units having the general Formula (V).
  • the structural unit B binds at a position marked by * in the general Formula (V) to form a spiro ring.
  • R 5 is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C 1 -C 6 alkoxy group, cyano group, and trifluoromethyl group.
  • heterocyclic compound having the general Formula (I) has asymmetric carbon atoms in the structure, its isomer from asymmetric carbon atoms and their mixture (racemic modification) is present. In such cases, all of them are included in the heterocyclic compound used in the embodiments described later.
  • the heterocyclic compound has the general Formula (I).
  • the following terms have the meanings specified below along with their examples.
  • C 1 -C 6 refers to 1 to 6 carbon atoms unless otherwise defined.
  • C 3 -C 8 refers to 3 to 8 carbon atoms unless otherwise defined.
  • C 1 -C 6 alkyl includes linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, and n-hexyl.
  • C 1 -C 6 alkoxy includes linear or branched alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, and n-hexyloxy.
  • C 3 -C 8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halogen atom includes fluorine, chlorine, bromine, and iodine.
  • heterocyclic compound useful in the practice of the present invention is not particularly restricted as long as it has the above described specific structure.
  • the following compounds can be used.
  • the heterocyclic compound of Formula (I) can be in the form of hydrate or acid addition salts as a pharmaceutically acceptable salt.
  • Possible acid addition salts include inorganic acid salts such as the hydrochloride, sulfate, hydrobromide, nitrate, and phosphate salts and organic acid salts such as acetate, oxalate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and salicylate salts.
  • the administration method, formulation, and dosage of the heterocyclic compound in mammals, particularly in human, are described hereafter.
  • the heterocyclic compound can be administrated orally or parenterally.
  • Formulations for oral administration include tablets, coated tablets, powder, granules, capsules, microcapsules, and syrups.
  • Formulations for parenteral administration include injectable solutions (including those freeze-dried and dissolved for use), adhesive skin patches, and suppositories.
  • formulations can be prepared using pharmaceutically acceptable fillers, binders, lubricants, disintegrators, suspending agents, emulsifiers, antiseptic agents, stabilizing agents, and dispersing agents such as lactoses, saccharoses, starches, dextrines, crystalline celluloses, kaolins, calcium carbonate, talc, magnesium stearate, and distilled water or saline.
  • Particular pharmaceutically acceptable components include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate.
  • the dosage varies according to the symptom, age, and body weight of patients. An adult can take 0.1 to 60 mg per day in one to three doses.
  • the invention provides an amyloid ⁇ deposition inhibitor composition comprising a compound having Formula (I).
  • the invention also provides a method of inhibiting amyloid deposition in an mammal in need thereof, comprising administration to the mammal an effective amount of a compound having the general Formula (I).
  • a compound of Formula (I) in particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan], exhibits inhibitory activity of amyloid ⁇ deposition in the hippocampus by amyloid ⁇ immunohistochemistry as described later in the examples.
  • Screening of derivatives of the compound for amyloid ⁇ deposition inhibitory activity showed that azaindolizinone derivatives in which an indan ring forms a spiro ring have potent amyloid ⁇ deposition inhibitory activity.
  • the above compound exhibits amyloid ⁇ deposition inhibitory activity based on a novel mechanism different from antioxidative activity.
  • the compound has also been shown to be highly safe in the preclinical study.
  • amyloid ⁇ deposition inhibitor of Formula (I) in particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan], is effective at lower dosages based on a mechanism which is different from curcumin, a component of Curcuma longa contained in curry in a large amount and which has antioxidative activity. Therefore, it is a new amyloid ⁇ deposition inhibitor having a mechanism of action different from curcumin.
  • amyloid ⁇ deposition inhibitor of this embodiment is preferably spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan] as this compound was shown to have excellent inhibitory activity of amyloid ⁇ deposition in the hippocampus amyloid ⁇ immunohistochemistry, which is a typical animal model test for inhibitory activity of amyloid ⁇ deposition, as described later in the examples.
  • the amyloid ⁇ deposition inhibitor compound may be administered by any means which achieves reduction in amyloid ⁇ deposition in a mammal.
  • the amyloid ⁇ deposition inhibitor compound of this embodiment is orally administered.
  • the amyloid ⁇ deposition inhibitor compound may be administered as part of an adhesive skin patch.
  • the amyloid ⁇ deposition inhibitor compound may be formulated into tablets, coated tablets, powder, granules, capsules, microcapsules, and syrups, as the amyloid ⁇ deposition inhibitor in the form of oral formulations is easily administered in mammals, including human beings.
  • the amyloid ⁇ deposition inhibitor compound of this embodiment is preferably administered at an effective oral dosage of 0.0005 mg per kilogram of body weight or higher.
  • the compound is administered as part of a unitary pharmaceutical dosage form containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.
  • the amyloid ⁇ deposition inhibitor is administered at an effective oral dosage of this lower limit or higher, the amyloid ⁇ deposition inhibitory activity in mammals including human beings is improved compared to when lower doses are administered.
  • the invention provides an Alzhiemer's disease progression inhibitor composition comprising a compound of Formula (I).
  • the invention also provides a method of delaying the progression of Alzheimer's disease comprising administering to a human in need thereof an effective amount of a compound having Formula (I).
  • amyloid ⁇ deposition inhibitor of Formula (I) in particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan], exhibits excellent inhibitory activity of amyloid ⁇ deposition. Since amyloid ⁇ is neurotoxic and associated with the etiology of Alzheimer's disease, it is expected that administration of a compound of Formula (I) to a human patient in need thereof will slow or inhibit the progression of Alzheimer's disease. Such a human patient may exhibit the very early to late stages of Alzheimer's disease.
  • the human patient may exhibit very mild cognitive decline (stage 2), mild cognitive decline (early Alzheimer's disease, stage 3), moderate cognitive decline (mild or early-stage Alzheimer's disease, stage 4), moderately severe cognitive decline (moderate or mid-stage Alzheimer's disease, stage 5), severe cognitive decline (moderately severe or mid-stage Alzheimer's disease, stage 6), or very severe cognitive decline (severe or late-stage Alzheimer's disease, stage 7).
  • the Alzheimer's disease progression inhibitor compound may be administered by any means which achieves the slowing or inhibiting of the progression of Alzheimer's disease.
  • the Alzheimer's disease progression inhibitor compound of this embodiment is orally administered.
  • the Alzheimer's disease progression inhibitor compound may be administered as part of an adhesive skin patch.
  • the Alzheimer's disease progression inhibitor compound may be formulated into tablets, coated tablets, powder, granules, capsules, microcapsules, and syrups, as the amyloid ⁇ deposition inhibitor in the form of oral formulations is easily administered in mammals, including human beings.
  • the Alzheimer's disease progression inhibitor compound of this embodiment is preferably administered at an effective oral dosage of 0.0005 mg per kilogram of body weight or higher.
  • the compound is administered as part of a unitary pharmaceutical dosage form containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.
  • some preferable ranges of effective oral dosages are defined in the above embodiments. However, other ranges of effective dosages can be determined for other administration forms. For example, a preferable range of effective dosages for administration by injection can be determined as appropriate. Furthermore, preferable ranges of administration intervals can be determined for particular administration forms in addition to the effective dosages with no more than routine experimentation.
  • the sections were immunostained with streptavidin-biotin using a VECTASTATIN ABC kit. After one hour of incubation in 10% normal goat serum, the anti-amyloid ⁇ (A ⁇ ) antibody was diluted with PBS to ten fold and incubated at 4° C. overnight. The following day, PBS rinsing, 1.5 hours of incubation with biotinylated anti-rabbit secondary antibody, PBS rinsing, and 1.5 hours of incubation with peroxidase-labeled streptavidin were conducted. The immunoreaction was visualized with DAB and specimens were prepared.
  • Immunoreactive A ⁇ -like granules in the hippocampus were counted under the microscope. The A ⁇ -like immunoreactive granule was observed as brown deposits in the hippocampus. The count was made for one section per individual.
  • FIG. 1 contains photographs showing the influence of Compound 1 on the number of amyloid ⁇ -immunoreactive cells in senescene accelerated mice (SAMP8).
  • the photographs at the top show stained images of amyloid ⁇ -like granules in the hippocampus of senescene accelerated mice (SAMP8) given tap water as drinking water for 2 months from age od 8 months.
  • the photographs at the bottom show stained images of amyloid ⁇ -like immunoreactivity in the hippocampus of senescene accelerated mice (SAMP8) given Compound 1 in drinking water at an effective oral dosage of 0.1 mg per kilogram of body weight for 2 months.
  • FIG. 2 is a graphical representation showing the influence of Compound 1 on the number of amyloid ⁇ -immunoreactive cells in senescene accelerated mice (SAMP8).
  • the effective oral dosage of Compound 1 is plotted as abscissa and the number of amyloid ⁇ -immunoreactive granules is plotted as ordinate.
  • SAMP8 Nine senescene accelerated mice (SAMP8) were given no Compound 1.
  • Five, eight and seven senescene accelerated mice (SAMP8) were given Compound 1 at oral dosage of 0.002 mg, 0.01 mg and 0.1 mg per kilogram of body weight respectively.
  • an amyloid ⁇ -like immunoreactivity in the hippocampus was observed in senescene accelerated mice (SAMP8) given tap water as drinking water for 2 months from age of 8 months.
  • the amyloid ⁇ -like immunoreactivity was reduced in senescene accelerated mice (SAMP8) given Compound 1 in drinking water at oral dosage of 0.002 mg/kg/day, 0.01 mg/kg/day and 0.1 mg/kg/day for 2 months.
  • the number of amyloid ⁇ -immunoreactive granules was significantly (*) decreased as a result of dosing of Compound 1.
  • Compound 1 inhibits amyloid ⁇ deposition.
  • Amyloid-related pathologies for which Compound 1 may be used the method for inhibiting of the progression of Alzheimer's disease in which amyloid ⁇ is considered to be a factor of the disorder.
  • heterocyclic compound having the general Formula (I) and prepared by the method in examples of Booklet of International Publication No. 01/09131 are described hereafter by way of example. More specifically, they were synthesized with reference to Booklet of International Publication No. 01/09131 and Booklet of International Publication No. 2002/060907 Brochure.
  • Compounds 2 to 40 of Formulae (I) were each prepared from the respective starting materials in the same manner as in Exemplary Preparation 1. Results of analysis of the obtained compounds are given for each compound. The results show that the obtained compounds were the targeted Compounds 2 to 40.
  • mice used mice as a mammal.
  • other mammals including human can be used.
  • the above Compounds 1 to 83 exhibit antidepressant, neuroprotection, amyloid ⁇ deposition inhibitory, or age retardant activity in other mammals including human.

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US20090221554A1 (en) * 2008-02-28 2009-09-03 Zenyaku Kogyo Kabushiki Kaisha Method of treating cognitive impairment
US20100168135A1 (en) * 2008-12-15 2010-07-01 Kim Nicholas Green Method of Inducing Cleavage of Amyloid Precursor Protein to Form a Novel Fragment
US20100256173A1 (en) * 2009-04-02 2010-10-07 Eckard Weber Method of Treating Cognitive Impairment
US20100267763A1 (en) * 2009-04-14 2010-10-21 Kim Nicholas Green Method of Decreasing Pro-ADAM10 Secretase and/or Beta Secretase Levels
US20100298348A1 (en) * 2009-05-11 2010-11-25 Kim Nicholas Green Method of Decreasing Ubiquitylated Protein Levels

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US20080268067A1 (en) * 2007-03-09 2008-10-30 Llinas Rodolfo R Methods and Compositions for Treating Thalamocortical Dysrhythmia
JP5405764B2 (ja) * 2007-10-15 2014-02-05 全薬工業株式会社 特定の構造の複素環化合物を含むアルツハイマー病進行抑制剤
WO2009085216A2 (fr) 2007-12-20 2009-07-09 Squicor Compositions et méthodes de détection ou d'élimination de cellules sénescentes pour le diagnostic ou le traitement de maladies
JP2015502366A (ja) 2011-12-13 2015-01-22 バック インスティテュート フォー リサーチ オン エイジング 薬物療法を改善するための方法
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