WO2013139929A1 - Nouveaux moyens et méthodes pour le traitement de maladies du système nerveux central, de maladies cardiaques et métaboliques et du vieillissement - Google Patents

Nouveaux moyens et méthodes pour le traitement de maladies du système nerveux central, de maladies cardiaques et métaboliques et du vieillissement Download PDF

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WO2013139929A1
WO2013139929A1 PCT/EP2013/055969 EP2013055969W WO2013139929A1 WO 2013139929 A1 WO2013139929 A1 WO 2013139929A1 EP 2013055969 W EP2013055969 W EP 2013055969W WO 2013139929 A1 WO2013139929 A1 WO 2013139929A1
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alkyl
compound
substituted
phenyl
unsubstituted
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PCT/EP2013/055969
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Kamran HONARNEJAD
Alexander DASCHNER
Jochen Herms
Franz BRACHER
Jacek KUZNICKI
André Philipe GEHRING
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Ludwig-Maximilians-Universität München
International Institute Of Molecular And Cell Biology
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Publication of WO2013139929A1 publication Critical patent/WO2013139929A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • Novel means and methods for treating diseases of the central nervous system, metabolic and cardiac diseases and aging are novel means and methods for treating diseases of the central nervous system, metabolic and cardiac diseases and aging
  • This invention relates to a compound of formula (la) or (II a)
  • R 1 is I and R 2 is selected from substituted or unsubstituted piperidinyl, preferably N-substituted or unsubstituted piperidin-4-yl; substituted or unsubstituted cyclohexyl, cyclopentyl, or cyclohexyl alkyl; substituted or unsubstituted aryl-alkyl; alkyl; aryl; - CHO; and hydrogen; or (B) R 1 is selected from halogen; substituted or unsubstituted alkoxy; substituted or unsubstituted alkyl; cyano; and hydrogen; and R 2 is substituted or unsubstituted piperidinyl, preferably N-substituted or unsubstituted piperidin-4-yl; and R 3 , R 4 and R 5 independently are either H or defined as R 1 ; R 6 is H; alkyl or aryl-al
  • AD Alzheimer's disease
  • ⁇ amyloid beta
  • IP 3 inositol 1 ,4,5- trisphosphate
  • mitochondrial dysfunction is an early event in progression of AD, but also in many other neurodegenerative disorders as well as generally in the course of aging (Celsi, F. et al. Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochimica et biophysica acta 1787, 335-44 (2009); Mattson, M.P., Gleichmann, M. & Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron 60, 748-66 (2008)). Improving mitochondrial function is by itself a focus in AD drug development (Reddy, P.H. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease. Experimental neurology 218, 286-92 (2009)).
  • AD Alzheimer's disease
  • ⁇ the product of proteolytic cleavage of APP
  • amyloid plaques the major constituent of amyloid plaques
  • the present invention relates to a compound of formula (la) or (lla)
  • R 1 is I and R 2 is selected from substituted or unsubstituted piperidinyl, preferably N-substituted or unsubstituted piperidin-4-yl; substituted or unsubstituted cyclohexyl, cyclopentyl, or cyclohexyl alkyl; substituted or unsubstituted aryl-alkyl; alkyl; aryl; - CHO; and hydrogen; or (B) R is selected from halogen; substituted or unsubstituted alkoxy; substituted or unsubstituted alkyl; cyano; and hydrogen; and R 2 is substituted or unsubstituted piperidinyl, preferably N-substituted or unsubstituted piperidin-4-yl; and R 3 , R 4 and R 5 independently are either H or defined as R 1 ; R 6 is H; alkyl or aryl-alkyl, or R 2 and R
  • This embodiment is also referred to as "main embodiment".
  • the first aspect presents two alternative formulae (la) and (lla) which differ from each other only with regard to the position of the substituted amine group NR 2 R 6 . While preference is given to compounds of formula (la), it is at the same time envisaged that compounds of formula (lla) are modulators of calcium homeostasis.
  • R 1 and R 2 this aspect provides for two alternatives (A) and (B), wherein each alternative is characterized by specific combinations of R 1 and R 2 .
  • R 1 is limited to I
  • R 1 a variety of options is available for R 1 in case of alternative (B).
  • R 1 is I.
  • R 1 is CN.
  • Particularly preferred R 2 groups are in either case N-phenyl-methyl piperidin-4-yl and N- phenyl-ethyl piperidin-4-yl; see compounds ADM-43 and AD -44 in Table 3 as well as the compounds of Table 14.
  • R 2 is N-ethyl-piperidin-4-yl or N-n-propyl- piperidin-4-yl. All these preferred R 2 groups apply equally to both alternatives (A) and (B).
  • Preferred R 2 groups in case of (A) are benzyl, phenyl-ethyl and cyclohexyl.
  • R 3 , R 4 and R 5 preference is given to R 3 , R 4 and R 5 all being H.
  • the phenyl ring of formulae (la) and (lb) bears one substituent which is R 1 .
  • R 6 is H.
  • R 6 is alky!
  • Compound ADM-42 as shown in Table 3 is a specific example of a compound wherein R 6 is methyl.
  • R 6 is aryl-alkyl
  • R 7 As regards the number of occurrences of R 7 , particular preference is given to m being 0. Also preferred is that m is 1 or 2. To the extent m is 1 or greater than 1 , preference is given for R 7 to be methyl and ethyl. Particularly preferred is methyl. Position of R 7 is preferred at C-2, said n being 0, 1 or 2. Also preferred position for R 7 is at C-4 for n being 1 or 2; and at C-5 for n being 2.
  • Formulae (VII-0), (VI 1-1 ) and (VII-2) below indicate the numbering scheme of the cycle bearing NR 2 R 6 in compounds of formulae (la), (lb), (Ilia), (lllb), (Va) and (Vb).
  • R 7 may be present at any position(s) of the ring into which the free valence of the (R 7 ) m is pointing in formulae (la) and (lib) as well as in any of the further formulae presenting R 7 .
  • a "free position” in that context is a position bearing hydrogen, hydrogen not being specifically indicated in any of the formulae.
  • alkyi substituents d to C 4 alkyi is preferred over C 5 to C-
  • a preferred embodiment of R 1 according to option (B) of the main embodiment is -CF 3 .
  • aryl substitutents phenyl is most preferred.
  • Preferred aryl-alkyl substituents include benzyl and phenyl-ethyl.
  • the preferred alkoxy substituent is OCH 3 .
  • Preferred halogens, to the extent they fall under the term “substitutent” as used herein are F and CI.
  • n 1 or 2, in particular 1.
  • R 1 is CF 3 or CN. Also preferred is that R 1 is F or CI. Also preferred is a compound with the generic formula shown in Table 14 wherein R 1 is Br (herein also designated ADM-44; see Table 3).
  • the compounds according to the invention meet one, two or all three of the following functional criteria (1 ), (2) and (3).
  • a compound according to the invention when administered to HEK293 cells, preferably administered in situ and incubated for 16 hours, decreases the peak amplitude of at least 1.1 -fold, preferably 1.5, 2-, 3-, 4-, 5- or 10-fold amplified agonist-induced calcium release from endoplasmatic reticulum (said agonist preferably being carbachol) in cells expressing familial Alzheimer's disease presenilin mutation, said presenilin mutation preferably being PS1 -M146L, by a factor of at least 1.1 , preferably 1.2, 1.5, 2, 3, 4, 5, 10 or 100, in comparison to negative control, an example of a negative control being DMSO.
  • a compound according to the invention when administered to HEK293 cells, preferably administered in situ and incubated for at least 1 hour, increases the TMRM dye (Sigma Aldrich) fluorescence intensity by at least 1.8-fold, preferably 2-, 3-, 4-, 5-, 10- or 100- fold after accumulation into mitochondria in comparison to negative control, an example of a negative control being DMSO.
  • TMRM dye fluorescence intensity is proportional to the mitochondrial membrane potential.
  • beta amyloid peptides decreases by a factor of at least 1.3, preferably 1.5, 2, 3, 4, 5, 10 or 100, upon administration of a compound according to the present invention, preferably in situ, followed by 16 hours incubation, compared to a negative control, an example of a negative control being DMSO. More preferred is a reduction of beta amyloid formation below the threshold of detection. Preferred cells producing beta amyloid are described in the examples.
  • the compounds according to the invention typically show activity in assays for at least one of the following properties: (i) Stabilization of impaired endoplasmatic reticulum (ER) calcium homeostasis (ii) Improvement of mitochondrial function, more specifically of the mitochondrial membrane potential; and (iii) Lowering ⁇ levels.
  • Stabilization of impaired endoplasmatic reticulum (ER) calcium homeostasis ii) Improvement of mitochondrial function, more specifically of the mitochondrial membrane potential
  • iii) Lowering ⁇ levels are described above, known in the art and furthermore described in Examples 19 to 21.
  • said compound is a compound of formula (Ilia) or (IVa)
  • each of the m occurrences of R 7 is independently selected from d to C 4 alkyl; m being 0, 1 , 2, 3 or 4; and the remainder of groups and substituents being as defined above.
  • R 7 As regards the number of occurrences of R 7 , as stated further above, particular preference is given to m being 0. Also preferred is that m is 1 or 2. To the extent m is 1 or greater than 1 , preference is given for R 7 to be methyl and ethyl. Particularly preferred is methyl. Position of R 7 is preferred at C-2, said n being 0, 1 or 2. Also preferred position for R 7 is at C-4 for n being 1 or 2; and at C-5 for n being 2.
  • m is 0 or 1.
  • said compound is a compound of formula (Via)
  • R 1 is selected from halogen; substituted or unsubstituted Ci to C 4 alkoxy, preferably OCH 3 ; substituted or unsubstituted to C 4 alkyl, preferably methyl or CF 3 ; cyano; and hydrogen
  • R 2 is substituted or unsubstituted piperidinyl, preferably N-substituted or unsubstituted piperidin-4-yl; the substituents being alkyl, phenyl- alkyl or halogen; alkyl being Ci to C 4 alkyl, preferably methyl, ethyl, n-propyl, i-propyl or t- butyl; or a salt of hydrate thereof.
  • R 2 is (1.1 ) N-aryl-alkyl piperidin-4-yl, preferably N- phenyl-alkyl piperidin-4-yl, particularly preferred N-phenyl-methyl piperidin-4-yl or N-phenyl- ethyl piperidin-4-yl; (1.2) N-alkyl piperidin-4-yl, preferably N-ethyl piperidin-4-yl or N-prop-1-yl piperidin-4-yl; or (1.3) N-alkyl piperidin-4-ylalkyl or N-aryl-alkyl piperidin-4-ylalkyl, preferably N- benzyl piperidin-4-yl-ethyl; or (2) in conjunction with option (A) of the main embodiment, R 2 is (2.1 ) alkyl cyclohexyl, preferably 3-methyl cyclohexyl, 4-methyl cyclohexyl, 4-ethyl
  • Particularly preferred compounds in relation to various aspects of the present invention are those which have at least one "+" sign in at least one of the three columns on the right-hand side of Tables 1 to 3 below.
  • Tables 1 and 2 show compounds which are preferred for medical uses, such medical uses being further detailed below.
  • Table 3 as well as Tables 4 to 46 show preferred compounds in accordance with the first aspect.
  • the compounds designated ADM- 05, ADM-06, ADM-09, ADM-17, ADM-26, ADM-27, ADM-32 and ADM-35 are less preferred.
  • Tables 1 to 3 Semiquantitative data for the performance of a variety of compounds in accordance with various aspects of the present invention. For each compound, its effect on calcium homeostasis, the ⁇ -amyloid ( ⁇ ) levels ( ⁇ 38, ⁇ 40 and ⁇ 42), and the mitochondrial membrane potential has been determined; see the last three columns.
  • the respective assays used are those described herein above as well as in Examples 19 to 21.
  • ADM-11 , ADM-22, ADM-43, ADM-44, ADM-46, ADM-47, ADM-48, ADM-49, ADM-50, ADM-51 and ADM-52 are particularly preferred compounds of the present invention (see also table 45 and 46).
  • Tables 4 to 46 show further preferred compounds according to the invention including the first aspect thereof.
  • R 1 I, Br, F, CI, CF 3 , CN, H 3 C orH
  • R 1 I, Br, F, CI, CF 3 , CN, H 3 C orH
  • R 1 I, Br, F, CI, CF 3 , CN, H 3 C orH
  • R 1 I, Br, F, CI, CF 3 , CN, H 3 C orH
  • R 1 I, Br, F, CI, CF 3 , CN or H 3 C
  • R 1 F, CI, Br, I, CF 3 , CN, H 3 C orH
  • R 1 I, Br, F, CI, CF 3 , CN, H 3 C orH
  • R 1 I, Br, F, CI, CF 3 , CN, H 3 C orH
  • R 1 F, CI, CF 3 , CN, H 3 C or H
  • R 1 I, Br, F, CI, CF 3 , CN, H 3 C orH ⁇
  • any of the compounds according to the invention as disclosed herein, be it specific compounds or generic formulae, expressly include, where applicable, racemic mixtures as well as pure enantiomeric (both R and S forms) as well as, where applicable, pure diastereomeric forms. Also envisaged are mixtures of enantiomeric or diastereomeric forms with varying percentage of the respective pure compound, i.e. mixtures are not confined to racemates.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or salt or hydrate thereof, said compound being as defined in accordance with the first aspect including preferred embodiments thereof or a compound of Table 2.
  • compositions described herein can be administered to a patient to be treated or a subject in which prevention is to be effected at a suitable dose.
  • Administration of the compositions may be effected by different ways, e.g., oral, intravenous, intraperitoneal, subcutaneous, as well as transdermal administration.
  • the compounds may, accordingly, be administered orally, parenterally, such as subcutaneously, intravenously, intramuscularly, intraperitoneally, intrathecally, transdermally, transmucosaily, subdurally, locally or topically via iontopheresis, sublingually, by inhalation spray, aerosol or rectally and the like, for example in dosage unit formulations optionally comprising conventional pharmaceutically acceptable excipients.
  • dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient or subject depends upon many factors, including the patient's or subject's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • the pharmaceutical composition described herein may comprise further agents depending on the intended use of the pharmaceutical composition. It will be appreciated by the person of ordinary skill in the art that the compounds of the invention and, if applicable, any additional therapeutic agent may be formulated in one single dosage form, or may be present in separate dosage forms and may be either administered concomitantly (i.e. at the same time) or sequentially.
  • compositions according to the invention may comprise carriers, vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate; binders, adjuvants, solubilizers, thickening agents, stabilizers, disintergrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colourants, flavours, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium state, talc, monosaccharides, disaccharides, starch, gelatine, cellulose, methylcellulose, sodium carboxymethyl
  • Dosage forms for oral administration include tablets, capsules, lozenges, pills, wafers, granules, oral liquids such as syrups, suspensions, solutions, emulsions, powder for reconstitution.
  • Dosage forms for parenteral administration include solutions or emulsions for infusion, solutions, suspensions or emulsions for injection pre-filled syringes, and/or powders for reconstitution.
  • Dosage forms for local/topical administration comprise insufflations, aerosols, metered aerosols, transdermal therapeutic systems, medicated patches, rectal suppositories, and/or ovula.
  • a therapeutically effective dosage of a compound of the invention will generally be from about 1 to 1000 mg/day, preferably from about 5 to about 500 mg/day, and most preferably from about 10 to about 200 mg/day, which may be administered in one or multiple doses.
  • compositions according to the present invention may comprise one compound according to the present invention as the only pharmaceutically active agent.
  • two or more compounds according to the present invention may be present as the only active agents.
  • further pharmaceutically active agents may be present, for example pharmaceutically active agents known in the art to be suitable in the treatment or prevention of one or more of the medical indications disclosed herein.
  • pharmaceutically active agents known in the art to be suitable in the treatment or prevention of one or more of the medical indications disclosed herein.
  • gamma secretase modulators e.g. GSM-01
  • inhibitors e.g.
  • BACE1 inhibitors e.g. LY 2811376
  • ADAM 10 activators e.g. Etazolate and Bryostatin-1
  • PPAR agonists e.g. Rosaglitazone
  • antibodies against ⁇ e.g. Bapineuzumab, Gammagard, LY- 2062430 and Ganteneurumab
  • Tau protein e.g. Anti-phospho tau antibodies
  • anti-aggregative compounds e.g. ELND-005 and Methylthioninium chloride
  • acetylcholinesterase inhibitors e.g.
  • NMDA receptor antagonists e.g. Memantine
  • Neurotrophins e.g. NGF
  • Neuroprotective and anti-oxidative stress agents e.g. Dimebon and EVT-302
  • further pharmaceutically active agents may provide synergistic beneficial effects and their combined use may be advantageous.
  • prodrug is a compound that is generally not biologically and/or pharmacologically active. After administration, the prodrug is activated, typically in vivo by enzymatic or hydrolytic cleavage and converted to a biologically and/or pharmacologically active compound which has the intended medical effect.
  • Prodrugs are typically obtained from compounds according to the present invention by chemical modification. Conventional procedures for the selection and preparation of the prodrugs are described, for example, in Design of prodrugs, ed.h. Buntgaard, Elsevier, 1984.
  • the present inventors considered that the above disclosed compounds as well as further compounds disclosed below such as those of Table 1 act on a cellular mechanism which mechanism is involved in the regulation of calcium homeostasis, mitochondrial activity and amyloid- ⁇ formation or clearance.
  • One such mechanism is considered to be the regulation of AMPK or ⁇ -secretase (BACE1 ) expression and/or activity.
  • a corresponding assay is described in Example 22.
  • Figure 4 displays corresponding data, the data showing activity of compounds of the invention on AMPK.
  • a further parameter according to the invention which is indicative of a compound's suitability in the treatment of specific medical indications is the mitochondrial activity.
  • the mitochondrial activity is known to be of particular relevance in central nervous system disorders, brain disorders, neural degenerative disorders, neuropsychiatric diseases, cardiovascular diseases and muscle disorders.
  • a reduction of beta amyloid ( ⁇ ) amounts and/or ⁇ -secretase expression/activity is particularly indicative of compounds suitable for treating or preventing Alzheimer's disease and/or mild cognitive impairment (MCI).
  • mild cognitive impairment represents an intermediate state of cognitive function between the changes seen in aging and those fulfilling the criteria for dementia and often Alzheimer's disease.
  • the present invention provides a compound or salt or hydrate thereof for use in a method of treating or preventing a disorder, said disorder being selected from central nervous system disorders, brain disorders, neurodegenerative disorders, neuropsychiatric diseases, obesity, metabolic syndrome, cardiovascular diseases, muscle disorders, cancer, inflammatory diseases, autoimmune diseases and age-associated disorders, or for use in a method of extending life-span, said compound being a compound of formula (lb) or (lib)
  • R 1 is selected from halogen; substituted or unsubstituted alkoxy; substituted or unsubstituted alkyl; cyano; N0 2 ; and hydrogen;
  • R 2 is selected from substituted or unsubstituted piperidinyl, preferably N-substituted or unsubstituted piperidin-4-yl; substituted or unsubstituted cyclohexyl, cyclopentyl, or cyclohexyl alkyl; substituted or unsubstituted aryl- alkyl; alkyl; aryl; -CHO; and hydrogen, R 3 , R 4 and R 5 independently are either H or defined as R 1 ;
  • R 6 is H; alkyl or aryl-alkyl, or R 2 and R 6 together with the N attached thereto form a 5- or 6- membered ring, preferably pyrrol; each of the m occurrences of R 7 is independently selected from d to
  • Formulae (lb) and (Mb) are distinguished from formulae (la) and (I Is), respectively, in that the options for substituents R and R 2 are different. Similar considerations apply mutatis mutandis to a comparison between formulae (Ilia) and (Illb), and so forth.
  • Central nervous system disorders brain disorders, neurodegenerative disorders, neuropsychiatric diseases are preferred. Cancer, obesity and metabolic syndrome are less preferred.
  • said compound is a compound of formula (Illb) or (IVb)
  • each of the m occurrences of R 7 is independently selected from d to C alkyl; m being 0, 1 , 2, 3 or 4; and the remainder of groups and substituents being as defined in the second aspect.
  • said compound is a compound of formula (Vb)
  • m is 0 or 1.
  • said compound is a compound of formula (VIb)
  • R 1 is selected from halogen; substituted or unsubstituted to C 4 alkoxy, preferably OCH 3 ; substituted or unsubstituted to C 4 alkyi, preferably CF 3 ; cyano; N0 2 ; and hydrogen;
  • R 2 is selected from substituted or unsubstituted piperidinyl, preferably N-substituted or unsubstituted piperidin-4-yl; substituted or unsubstituted cyclohexyl; and phenyl-alkyl; the substituents being alkyi or phenyl-alkyl; alkyi being Ci to C 4 alkyi, preferably methyl, ethyl, n- propyl, i-propyl or t-butyl; or a salt of hydrate thereof.
  • R 1 is Br, I, OCH 3 , F, CI, CF 3 ,
  • R 2 is (a) N-aryl-alkyl piperidin-4-yl, preferably N-phenyl- alkyl piperidin-4-yl, particularly preferred N-phenyl-methyl piperidin-4-yl or N-phenyl-ethyl piperidin-4-yl; (b) N-alkyl piperidin-4-yl, preferably N-ethyl piperidin-4-yl or N-prop-1-yl piperidin-4-yl; (c) N-alkyl piperidin-4-ylalkyl or N-aryl-alkyl piperidin-4-ylalkyl, preferably N- benzyl piperidin-4-yl-ethyl; (d) alkyi cyclohexyl, preferably 3-methyl cyclohexyl, 4-methyl cyclohexyl, 4-ethyl cyclohexyl or 4-tert-butyl cyclohexyl; aryl
  • said compound is selected from the compounds of Table 1 to 46. Further preferred compounds are those described as being preferred in relation to the first aspect of this invention.
  • the present invention provides in a fourth aspect a method of treating a patient suffering from a disorder or a subject at risk of developing a disorder, said disorder being selected from central nervous system disorders, brain disorders, neurodegenerative disorders, neuropsychiatric diseases, obesity, metabolic syndrome, cardiovascular diseases, muscle disorders, cancer, inflammatory diseases, autoimmune diseases and age-associated disorders, and/or of extending life-span, said method comprising the step of administering to said patient or subject a pharmaceutically effective amount of a compound or salt or hydrate thereof as defined in relation to the second aspect.
  • said central nervous system disorders, brain disorders, neural degenerative disorders and neuropsychiatric diseases are selected from mild cognitive impairment (MCI), dementia, Alzheimer's disease (AD), Parkinson's disease (PD), Amyothrophic lateral sclerosis (ALS), dementias with lewy bodies, Huntington's disease (HD), frontotemporal dementia (FTD), parkinsonism, tauopathies, aberrant/insufficient neurogenesis diseases, stroke, seizures, ataxia, migraine, schizophrenia, major depression, bipolar disorder, Down's syndrome, traumatic brain injury, posttraumatic stress disorder, chronic stress, alcohol and/or drug abuse, multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal degeneration (CBD), retinal ganglion degeneration, and prion-related disorders.
  • MCI mild cognitive impairment
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • ALS Amyothrophic lateral sclerosis
  • AD Alzheimer's disease
  • ALS Alzheimer's disease
  • ALS Alzheimer's disease
  • PD
  • MCI mild cognitive impairment
  • AD Alzheimer's disease
  • obesity and/or metabolic syndrome are further characterized in that they are associated with insulin resistance, type 2 diabetes, glucose intolerance, fatty liver disease, hypertension, diabetic myopathy, lipotoxicity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, and hypercholesterolemia.
  • Preferred cardiovascular diseases and muscle disorders include atherosclerosis, cardiac hypertrophy, cardiac arrhythmias, myocardial ischemia-reperfusion injury, arrhythmogenic right ventricular dysplasia type 2, catecholaminergic polymorphic ventricular tachycardia, sarcopenia diffuse atrophy, vascular restenosis, hypercalcemia, and ischemia.
  • Preferred forms of cancer include epithelial cancers, skin, lung, prostate, breast and adipose tumors and carcinomas, endometrial cancer, adenocarcinomas, squamous cell carcinomas, and leukaemia.
  • Inflammatory diseases and autoimmune diseases include lung, pancreas and intestine inflammation, chronic obstructive pulmonary disease, inflammatory bowel disease, pancreatitis, and rheumatoid arthritis.
  • Age associated disorders include common cancer, prostate enlargement, cardiovascular diseases, stroke, atherosclerosis, hypertension, osteoporosis, type 2 diabetes, mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, age-related macular degeneration and tauopathies. Mild cognitive impairment (MCI) and Alzheimer's disease are preferred.
  • Tauopathies are a group of neurodegenerative diseases with pathological deposition of abnormal tau protein isoforms in brain and central nervous system.
  • any of the above listed more specific indications is a disease or disorder which is independently amenable to treatment or prevention by the compounds of the present invention.
  • said neurodegenerative disorder is Alzheimer's disease, in particular familial Alzheimer's disease; mild cognitive impairment (MCI); or dementia.
  • MCI mild cognitive impairment
  • the present invention provides the use of a compound or salt or hydrate thereof as defined in relation to the second aspect in the manufacture of a medicament.
  • M and I stand for mesomeric and inductive effect, respectively.
  • Example 1 illustrate the invention but should not be construed as being limiting.
  • Example 1 illustrate the invention but should not be construed as being limiting.
  • 6-lodo-2,3,4,9-tetrahydro-1 /-carbazol-1-one was prepared from 4-iodoaniline and ethyl 2- oxocyclohexanecarboxylate in a similar manner as described in Example 1 to give a brown solid (26% yield).
  • 6-Bromo-2,3,4,9-tetrahydro-1 -/-carbazol-1 -one was prepared from 4-bromoaniline and ethyl 2-oxocyclohexanecarboxylate in a similar manner as described in Example 1 to give a brown solid (60% yield).
  • 7,8-Dichloro-2,3,4,9-tetrahydro-1 H-carbazol-1 -one was prepared from 2,3-dichloroaniline and ethyl-2-oxocyclohexanecarboxylate in a similar manner as described in Example 1 to give a brown solid (30% yield).
  • A/-Benzyl-7,8-dichloro-2,3,4,9-tetrahydro-1 - -carbazol-1 -amine hydrochloride was prepared from 7,8-dichloro-2,3,4,9-tetrahydro-1 - -carbazol-1 -one in a similar manner as described in Example 7 to give a pale brown solid (42% yield).
  • A-Benzyl-6-iodo-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride was prepared from 6- iodo-2,3,4,9-tetrahydro-1 - -carbazol-1-one in a similar manner as described in Example 7 to give a pale yellow solid (42% yield).
  • A/-(1-Benzylpiperidin-4-yl)-6-bromo-2,3,4,9-tetrahydro-1/- -carbazol-1 -amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1 /-/-carbazol-1-one and 4-amino-1-benzylpiperidine in a similar manner as described in Example 7 to give a brown solid (25% yield).
  • 6-Brom-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride (220 mg, 0.73 mmol), magnesium perchlorate (84 mg, 0.3 mmol) and 1-(2-phenethyl)-4-piperidone (360 mg, 1.77 mmol) were stirred in dichloroethane (20 ml) and methanol (5 ml) over night, then sodium borohydride (1 12 mg, 3 mmol) was added. After stirring the mixture for another 5 hours, a saturated solution of sodium hydrogencarbonate (10 ml) was added, followed by extraction with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate and the solvents evaporated.
  • 6-lodo-2,3,4,9-tetrahydro-1 /-/-carbazol-1 -amine hydrochloride was prepared from 6-iodo- 2,3,4,9-tetrahydro-1 H-carbazol-1 -one and ammonium acetate in a similar manner as described in Example 5 to give a pale grey solid (56% yield).
  • 6-lodo-/V-(1-phenethylpiperidin-4-yl)-2,3,4,9-tetrahydro-1H-carbazol-1 -amine was prepared from 6-iodo-2,3,4,9-tetrahydro-1H-carbazol-1 -amine hydrochloride and 1-(2-phenethyl)-4- piperidone in a similar manner as described in Example 14 to give a dark red resin (18% yield).
  • HEK293 Human embryonic kidney 293 (HEK293) cells were cultured in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum and 1 % penicillin/streptomycin while being incubated at 37°C, 5% C0 2 and 90% humidity.
  • DMEM Dulbecco's modified eagle medium
  • the stable PS1 lines (generously provided by Dr. S. Lammich) were carrying PS1 variants that were cloned into pcDNA3.1/Zeo(+) and single cells were selected via Zeocin antibiotic resistance (S. Lammich et al., Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide.
  • the PS1 lines were then stably transfected with YC3.6/pcDNA3 construct (kindly provided by Dr. A. Miyawaki) and single cells were respectively isolated by G418 antibiotic resistance leading to generation of double stable lines.
  • the APP- , C99- and APPsw/PS1 -M146L-overexpressing HEK293 lines were kindly provided by Dr. S. Lichtenthaler and Dr. H. Steiner and cultured as previously described (S. Mitterreiter et al., Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms.
  • the readout for dysregulated ER calcium signaling are the potentiated IP 3 calcium signals in HEK293 cells carrying a disease-causing mutated form of PS1.
  • Agonist-induced IP 3 production by Carbachol (CCh) results in calcium being set free from the ER.
  • Various FAD- PS1 mutants show exaggerated CCh-induced calcium release compared to wild type PS1 expressing cells.
  • a genetically-encoded FRET-based calcium probe (Yellow Cameleon 3.6, Miyawaki Lab, Japan) (Nagai, T., Yamada, S., Tominaga, T., Ichikawa, M. & Miyawaki, A. Expanded dynamic range of fluorescent indicators for Ca 2+ by circularly permuted yellow fluorescent proteins. Proceedings of the National Academy of Sciences of the United States of America 101 , 10554-9 (2004)) has been introduced into these cells as a tool to monitor both the basal intracellular calcium concentration and the released calcium signals from the ER in real-time by
  • HEK293 cells stably expressing PS1 -M146L and YC3.6 were seeded at 13,000 cells/well in 40 ⁇ on collagen-coated 384-well CellCarrier plates (PerkinElmer) in growth medium consisting of DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% FCS, 1X penicillin-streptomycin, 1X GlutaMAX and selection antibiotics. After 6 hours, using pipetting robot (Bravo, Agilent Technologies), compounds according to the invention, positive controls (Thapsigargin, CPA, TMB-8 and Bepridil) and the vehicle were added into each well at the final concentration of 10 ⁇ and 1 % DMSO, each in 4 replicates.
  • DRAQ5 nuclear marker dye Biostatus
  • Biostatus was added into each well at the final concentration of 500 nM.
  • plates were measured for carbachol-induced calcium release from ER using PerkinElmer Opera high-throughput confocal imaging platform.
  • 442 nm laser the YC3.6 was excited and the CFP and YFP signals were separated using suitable filters.
  • 640 nm laser DRAQ5 dye was excited and its emission was collected in order to locate all nuclei for every time point. Time-lapse calcium imaging was performed at 1 second intervals.
  • the mitochondrial membrane potential ( ⁇ ) is used as a measure for mitochondrial activity which is typically reduced in AD (Rhein, V. et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proceedings of the National Academy of Sciences of the United States of America 106, 20057-62 (2009); Santos, R.X. et al. Alzheimer's disease: diverse aspects of mitochondrial malfunctioning. International Journal 3, 570-581 (2010). can be measured, for example, by utilizing a fluorescent cationic dye such as TMRM (tetramethylrhodamine methyl ester).
  • TMRM fluorescent relative light unit
  • the fluorescent relative light unit (RLU) of TMRM was used as a measure for ⁇ ⁇ , in HEK293 cells; see Figure 1 and last column of Table 1.
  • HEK293 cells were used to study the effect of the compounds according to the invention on the mitochondrial membrane potential as a measure of mitochondrial activity.
  • the measurement method for membrane potential with TMRM dye was adapted from Scaduto et al. (Scaduto Jr, R.C. & Grotyohann, L.W. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophysical journal 76, 469-477 (1999)).
  • HEK293 cells were seeded at the density of 50,000 cells/well in DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% FCS, 1X penicillin-streptomycin, 1X GlutaMAX on collagen/poly-L-lysine (PLL)-coated 96-well plates (Advanced-TC plates, Greiner) and incubated for 24 hours.
  • DMEM Dulbecco's Modified Eagle Medium
  • FCS 1X penicillin-streptomycin
  • PLL collagen/poly-L-lysine
  • Greiner Advanced-TC plates
  • the cells were loaded with 50 nM tetramethylrhodamine methyl ester (TMRM) dye in the presence or absence of compounds according to the invention which were pre-incubated on the cells (10 ⁇ ) one hour prior to adding TMRM dye. After 30 minutes each well was washed 3 times using PBS.
  • TMRM tetramethylrhodamine methyl ester
  • Fresh medium containing the corresponding compounds according to the invention (10 ⁇ ) was added into the wells. Live cell image acquisition was performed using inverted confocal microscope LSM510 with 25x magnification (Carl Zeiss Microimaging GmbH, Jena, Germany) and the images were analyzed using ImageJ software to quantify the intensity of TMRM fluorescence signal. The effect of each compound was analyzed in triplicate. The mitochondria uncoupler, CCCP (50 ⁇ ) and Dimebon (10 ⁇ ) were used as controls.
  • the conditioned medium was collected and the level of secreted ⁇ 38, ⁇ 40 and ⁇ 42 peptides were quantified using "Human (6E10) Abeta 3-Plex" sandwich ELISA immunoassay Kit (Meso Scale Disovery) according to the instructions of the manufacturer.
  • MSD blocker A 150 ⁇ was added into each well of the ELISA plate and incubated for 1 hour at the room temperature, followed by 3x washing using MSD wash buffer.
  • 25 ⁇ of detection antibody was added into each well.
  • each of samples or calibrators were added into separate wells of the MSD ELISA plate and incubated for 2 hours at the room temperature, followed by 3x washing using MSD wash buffer.
  • sAPPa and ⁇ fragments were measured using sandwich ELISA adapted from Colombo et al. (Constitutive alpha- and beta-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines. Neurobiol Dis 49C, 137 (Aug 24, 2012)). Wild type HEK293 cells were seeded at the density of 200,000 cells/well in collagen/poly-L-lysine (PLL)-coated 24-well plates and incubated for 24 hours in growth medium. Next, the medium was exchanged with 500 ⁇ of fresh medium containing either compounds or vehicle.
  • PLL collagen/poly-L-lysine
  • sAPPa/sAPP sandwich ELISA immunoassay kit (Meso Scale Discovery, MD, USA) according to the instructions of the manufacturer.
  • 150 ⁇ of blocker reagent was added to each well of the ELISA plate and incubated for 1 hour at room temperature, followed by 3x washing using TRIS wash buffer.
  • 25 ⁇ of samples or calibration standards were added to separate wells of ELISA plate and incubated for 1 hour at room temperature, followed by 3x washing using TRIS wash buffer.
  • 25 ⁇ of detection antibody was added to each well and incubated for 1 hour at room temperature, followed by 3x washing using TRIS wash buffer.
  • pAMPK phosphorylated AMP-activated protein kinase
  • AMP-activated protein kinase a potential player in Alzheimer's disease. Journal of neurochemistry 460-474 (201 1 ).doi:10.1 1 1 1/j.1471-4159.201 1.07331.) ⁇ Therefore we postulate that the activation of AMPK by our lead structure analogues to be a downstream effect of stabilizing ER calcium homeostasis, most likely through CaMKK . Interestingly, AMPK activation has been shown to be implicated in ⁇ clearance (Vingtdeux, V., Chandakkar, P., Zhao, H., Davies, P. & Marambaud, P.
  • AMPK AMP-Activated Protein Kinase
  • RSVA314 RSVA405
  • Inhibit Adipogenesis Molecular medicine (Cambridge, Mass.) 17, 1022-30 (201 1 )) and mitochondrial activity (Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056-60 (2009)).
  • HEK293 cells were seeded at the density of 200,000 cells/well in collagen/poly-L-lysine (PLL)- coated 24-well plates and incubated for 24 hours in DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% FCS, 1X penicillin-streptomycin, 1X GlutaMAX.
  • DMEM Dynamic Eagle Medium
  • FCS fetal calf serum
  • 1X GlutaMAX 1X GlutaMAX
  • Next medium was exchanged with 500 ⁇ of fresh medium containing either the compounds according to the invention (10 ⁇ ), or controls Resveratol (50 ⁇ ), AICAR (2 mM), Compound C (1 ⁇ ) or the vehicle in triplicates.
  • the assay was performed according to the manufacturer's instructions. In brief, into each well of the ELISA plate 100 ⁇ of the lysates or the standards was added and incubated for 2 hours at the room temperature, followed by 4x washing using the assay wash buffer. Next 100 ⁇ of detection antibody was added into each well and incubated for 1 hour at the room temperature, followed by 4x washing using assay wash buffer. Then 100 ⁇ of HRP anti-rabbit antibody was added into the wells and incubated for 30 minutes at the room temperature, followed by 4x washing using the assay wash buffer. Finally, 100 ⁇ of stabilized chromagen was added into the wells and the reaction was stopped after 30 minutes by adding the "stop" solution into the wells. The plate was read at 450 nm using FLUOstar OPTIMA plate reader. Based on the absorptions of the standards and their calibration curve, and the levels of pAMPK were calculated.
  • Tetrahydrocarbazoles attenuate the FAD-PS 1 mediated exaggerated ER calcium release
  • ADM-02, ADM-03, ADM-06, ADM- 39 diminish that effect, while additional attachment of an aromatic motif (e.g. phenyl group) is beneficial to the activity (e.g. ADM-1 1 , ADM-22).
  • Tetrahydrocarbazoles increase the mitochondrial membrane potential
  • FAD-PS mutations affect the physical interaction between ER and mitochondria (E. Area-Gomez et al., Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31 , 4106 (Nov 5, 2012)), leading to altered shuttling of calcium between the two organelles and affecting the mitochondrial calcium uptake (E. Zampese er a/., Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca 2+ cross-talk. Proc Natl Acad Sci U S A 108, 2777 (Feb 15, 201 1 )).
  • Tables 45 and 46 show preferred or exemplary compounds of the invention and their performance in the above described assays.
  • the performance data are relative values, wherein DMSO has been used as a negative control.
  • values above or below 1 indicate more activity in the respective assay compared to DMSO, and values reaching 1 indicate less activity similar to DMSO.
  • values above 1 are desirable in accordance with the present invention, and in the calcium assay as well as in the ⁇ and ⁇ assays values below 1 are desirable and indicative of compounds useful in accordance with the present invention.
  • ADM-30 1.002 1.207 1.056 0.712 0.874

Abstract

La présente invention concerne un composé de formule (la) ou (Iia) dans laquelle soit (A) R1 est I et R2 est choisie parmi la pipéridinyle, substituée ou non substituée de préférence pipéridin -4-yl N-substituée ou non substituée; cyclohexyle substitué ou non substitué, cyclopentyle, ou cyclohexyle alkyle; aryl-alkyle substitué ou non substitué; alkyle; aryle ;-CHO et de l'hydrogène; ou (B) R1 est choisi parmi un atome d'halogène; alcoxy substitué ou non substitué; alkyle substitué ou non substitué; un groupe cyano; et de l'hydrogène; et R2 est un pipéridinyle, substitué ou non substitué, de préférence pipéridin -4-yl N-substitué ou non substitué; et R3, R4 et R5 sont indépendamment soit H soit défini comme R1; R6 est H; alkyle ou aryl-alkyle, ou R2 et R6 ensemble avec le N fixé à celle-ci forment un cycle à 5-ou 6-chaînons, de préférence un pyrrol, chacune des m occurrences de R7 est indépendamment choisie parmi un alkyle C1-C4, un alcoxy Cl-C4 et un atome d'halogène, de préférence F; et m étant 0, 1, 2, 3 ou 4; X est choisi parmi NH; N-alkyle, de préférence NCH3; N-aryl-alkyle; S; et O; dans laquelle dans la formule (la) R2 et X ensemble peuvent en variante, former ou comprendre un cycle à 6 chaînons, ledit cycle à 6 chaînons étant de préférence pipérazine; n est 0, 1 ou 2; les substituants étant choisis indépendamment parmi alkyle, aryle-alkyle; alcoxy, aryle, hydroxy; halogène; un groupe oxo; et thio; alkyle étant ramifié, non ramifié et/ou, alkyle cyclique Cl à C10 de préférence méthyle, éthyle, n-propyle, i-propyle, i-butyle ou t-butyle; alcoxy étant alcoxy C1 à C4, de préférence un méthoxy ; aryle étant phényle, naphtyle ou tétrahydronaphtyle, de préférence phényle; ou un composé selon l'une quelconque des Tables 3 à 46; ou un sel ou un hydrate de celui-ci.
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