EP2958906A1 - 6h-benzo[c]chromén-6-ones 3 substituées et 7,8,9,10-tétrahydro-6h-benzo[c]chromén-6-ones 3 substituées contre la démence sénile - Google Patents

6h-benzo[c]chromén-6-ones 3 substituées et 7,8,9,10-tétrahydro-6h-benzo[c]chromén-6-ones 3 substituées contre la démence sénile

Info

Publication number
EP2958906A1
EP2958906A1 EP14718200.0A EP14718200A EP2958906A1 EP 2958906 A1 EP2958906 A1 EP 2958906A1 EP 14718200 A EP14718200 A EP 14718200A EP 2958906 A1 EP2958906 A1 EP 2958906A1
Authority
EP
European Patent Office
Prior art keywords
benzo
chromen
tetrahydro
compound
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14718200.0A
Other languages
German (de)
English (en)
Inventor
Serdar Unlu
Ilker ESIRINGU
Yasemin SAHIN
Tugba ERCETIN
Demet OZ
Fethi SAHIN
Hayrettin Ozan GULCAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NOBEL ILAC SANAYII VE TICARET A.S.
Original Assignee
Nobel Ilac Sanayii Ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nobel Ilac Sanayii Ve Ticaret AS filed Critical Nobel Ilac Sanayii Ve Ticaret AS
Publication of EP2958906A1 publication Critical patent/EP2958906A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • This invention relates to novel 3-substituted-6H-benzo[c]chromen-6-one and 3-substituted- 7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one compounds which are useful as pharmaceutical compositions.
  • This invention further relates to pharmaceutical compositions having benefit in the therapy for the senile dementia, such as Alzheimer senile dementia.
  • cognition has serious deleterious effects in life quality and expectancy of sufferers, concomitant to negative effects on patient relatives, and caregivers. Indeed, cognition deeply defines the social lives, natural habits, behaviors, and personal characteristics. The mental processes such as interaction (i.e., understanding, speaking, observation) with the environment, attention, problem-solving, remembering, reminding are all parts of cognition and a disability in cognition results in decline of previously-known personal characteristics. Thus, serious loss in cognitive abilities produces dementia.
  • Alzheimer senile dementia is the most common form in populations. It has variations depending on its etiology, but in particular, the Alzheimer senile dementia is the most common form. Numerous attempts have been examined so far not only to treat the symptoms of the disease but also to figure out the mechanism underlying in the formation of Alzheimer's disease. However, today, there is no single or combination drug that completely treats the Alzheimer's disease and the accompanying dementia. Therefore, there is a need to provide novel medicines in the treatment of the symptoms of Alzheimer's disease, particularly, the accompanying the Alzheimer senile dementia.
  • Alzheimer's disease arises from 10% to 35% of population for the people aged from 65 to 85 years old.
  • dementia associated decline in cognitive abilities requires serious patient healthcare which brings together heavy economical and socioeconomic burdens not only to patient relatives but also to national health economics of countries worldwide. Therefore, there is a certain need to new medicines that prevents the continuous decline in cognition of sufferers having dementia, in particular the Alzheimer senile dementia.
  • galantamine and donepezil are ACHE selective inhibitors, since their selectivity is around 30 and 800 times more for ACHE, respectively.
  • they have quite distinctive IC50 values, since donepezil has an IC50 for ACHE at a very low nM level in comparison to the IC50 of galantamine for ACHE which is close to 1 ⁇ level.
  • IC50 of rivastigmine for the both enzymes are above 10 ⁇ level, although this drug has selectivity for BCHE. This definitely indicates the need of novel medicines having the potential to inhibit the both enzymes with less selectivity.
  • new drugs that possess IC50 values for both enzymes at low ⁇ levels Furthermore, there is a need for new drugs that have from high n to low ⁇ IC 5 o values to inhibit BCHE.
  • Hydroxylated-6H-benzo[c]ch ' romen-6-ones also referred to as urolithins
  • urolithins are ellagitannin and ellagic acid-derived metabolites produced by human colonic microflora following the digestion of most of the berries, walnut, and pomegranate.
  • the ability of these xenobiotics in neuroprotection and their possible beneficiary effects on cognitive skills have been studied.
  • urolithins are not potential inhibitors of ACHE and BCHE enzymes in comparison to the current ACHE and BCHE inhibitor drugs (i.e., donepezil, rivastigmine, and galantamine).
  • urolitihins have no use in the treatment of dementia, particularly the Alzheimer senile dementia, via the employment of the cholinergic hypothesis that involves the inhibition of ACHE and BCHE enzymes. Furthermore, urolithins are not drugs used in the treatment of dementia, particularly in Alzheimer senile dementia.
  • these xenobiotics can be converted to potent ACHE and BCHE inhibitors that have activity comparable to the current ACHE and BCHE inhibitor drugs (i.e., donepezil, rivastigmine, and galantamine).
  • ACHE and BCHE inhibitor drugs i.e., donepezil, rivastigmine, and galantamine.
  • n is the number of carbon atoms.
  • n is from 2 to 6.
  • n is from 2 to 4;
  • R is selected from:
  • Ri is a lower alkyl group, cyclohexyl group, benzyl group, and 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof.
  • n is the number of carbon atoms.
  • n is from 2 to 6.
  • R is selected from: ⁇
  • Ri is a lower alkyl group, cyclohexyl group, benzyl group, and 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof.
  • Preferable compounds of the invention bearing the formula II structure include: 3- 2-(benzyl(methyl)amino)ethoxy)-6H-benzo[c]chromen-6-one
  • n is the number of carbon atoms.
  • n is from 2 to 6.
  • n is from 2 to 4.
  • R is selected from:
  • Ri is a lower alkyl group, cyclohexyl group, benzyl group, and 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof.
  • Preferable compounds of the invention bearing the formula III structure include:
  • the present invention provides a therapeutically composition which comprises a pharmacologically effective amount of the compound having the formula II or formula III or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier and then a method for preventing and treating a disease due to acetylcholinesterase or butyryicholinesterase activity by administering to a human patient the compound having the formula II or formula III or a pharmacologically acceptable salts thereof.
  • the compound of the present invention may be prepared by various processes.
  • n is the number of carbon atoms.
  • n is from 2 to 6.
  • R is selected from:
  • Ri is a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof, comprises the steps where resorcinol is reacted with a halo benzoic acid compound to obtain the compound of formula IV;
  • n is the number of carbon atoms.
  • n is from 2 to 6.
  • n is from 2 to 4.
  • R is selected from:
  • -N N-R and Ri is a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group, or a pharmaceutical acceptable salt thereof, comprises the steps where resorcinol is reacted with ethyl 2-oxocyclohexanecarboxylate to obtain the compound of formula VI;
  • Ri a lower alkyl group, cyclohexyl group, benzyl group, or 3-methoxybenzyl group
  • Na(s) (1.9 gram, 82.6 mmol) is dissolved in 50 mL dry ethanol to give NaOEt solution.
  • 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (15 gram, 69.4 mmol) solution in 150 mL Ethanol, previously prepared NaOEt solution is added at ambient temperature. Ethanol is distilled out under reduced vacuum and then 100 mL dry DMF is added onto the residue. 100 mL 1 ,2-dichloroethane is put into the reaction mixture and the content is refluxed for 7 hours. The reaction mixture is cooled to room temperature and it is poured onto 250 mLcold 0.8 N NaOH solution.
  • 3-(2-chloroethoxy)-6H-benzo[c]chromen-6-one 3-(2-chloroethoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 3, except the employment of 3-hydroxy-6H-benzo[c]chromen-6-one instead of 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one. Yield obtained: 46.8 %.
  • 3-(3-chloropropoxy)-6H-benzo[c]chromen-6-one 3-(3-chloropropoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 4, except the employment of 3-hydroxy-6H-benzo[c]chromen-6-one instead of 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one. The reaction is completed in 40 min. Yield obtained: 79.3 %.
  • 3-(4-chlorobutoxy)-6H-benzo[c]chromen-6-one is synthesized according to procedure given in Example 4, except the employment of 3-hydroxy-6H-benzo[c]chromen-6-one instead of 3- hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one.
  • the reaction is completed in 40 min. Yield obtained: 83.6 %.
  • hydrochloride is synthesized according to procedure given in Example 10. Yield obtained: 86.2%, HPLC purity: 99.98 %, HRMS (ESI) C25H30NO3 calcd 392.2226 [M+H] + , found 392.2227, DSC: 150.7°C.
  • Example 50 UR0-2C-BPP.HCI 3-(2-(4-benzylpiperidin-1 -yl)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride 3-(2-(4-benzylpiperidin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one hydrochloride is synthesized according to procedure given in Example 9. Yield obtained: 88.3%, HPLC purity: 99.37%, HRMS(ESI) C27H28NO3 calcd 414.2069 [M+H] + , found 414.2075, DSC: 199.6°C.
  • the compounds of the present invention concomitant with the pharmaceutical salts thereof represented by the general formula II and the general formula III are useful in the treatment of various kinds of senile dementia, in particular Alzheimer's Disease accompanying senile dementia.
  • Related pharmacological experimental data are described.
  • the reactions were initiated by the addition of the substrate (either acetylthiocholine iodide or butyrylthiocholine iodide, respectively for ACHE and BCHE enzymes).
  • the enzyme catalyzed formation of the yellow color was measured at 412 nm in terms of the calculation of enzyme activity concomitant to the presence of an inhibitor activity.
  • the acetylcholinesterase and butyrylcholinesterase inhibitory activity of each sample was expressed in terms of inhibitory concentration 50% (ICso). Representative examples are shown in Table I:
  • Table I In general, the compounds of the present invention displayed strong potential for the inhibition of both ACHE and BCHE enzymes. As seen in the examples in Table 1 , most of the compounds have IC50 values for ACHE close to 1. This finding definitely points out these compounds more active than rivastigmine in terms of the potential to inhibit ACHE. On the other hand, these results also reveal that the compounds of the present invention possess comparable potential with respect to galantamine, another ACHE inhibitor drug, for the inhibition of ACHE.
  • the selectivity of the compounds of the present invention seems to be bias for the ACHE enzyme the selectivity ratio for some compounds have been found close to 1 which also definitely points out their difference from the current ACHE and/or BCHE inhibitor drug molecules. Indeed, compounds such as THU-3C-BA, THU-3C-BPP, THU-3C-MBPP, THU-3C-BPZ, THU-4C-BPZ, URO-3C-BPP, URO- 3C-BPZ, and URO-4C-BA have selectivity ratio considerably less than current drugs such as donepezil and galantamine.
  • the passive avoidance test evaluates the ability of a rat to learn and memorize.
  • Male Wistar rats at an age of approximately 2 months, and around 250 g body weight were used.
  • the rats were placed into the illuminated compartment while the door closed and allowed a habituation phase (30 seconds).
  • the door automatically opened and stayed open for 5 minutes experimental time.
  • Two seconds after the rat entering the dark compartment of the apparatus the door closed and after 2 seconds latency an electric stimulus took place lasting for 3 or 6 seconds.
  • the rat stayed in the dark compartment for another 30 seconds delay before it was placed into the home cage.
  • the rats were treated with 1 mg/kg (i.p.) of scopolamine, half an hour before the administration of the each test compound.
  • the rats were placed into the illuminated compartment with the door closed again for a habituation time of 30 seconds.
  • the time for the rats visiting the dark box was measured for 5 minutes.
  • the time difference between the no scopolamine administered group and the only scopolamine administered group was taken as 100% and the effect of each compound of the present invention was calculated accordingly in terms of the percentage antagonism.
  • Each test compound was assessed employing ten animals per dose.
  • the compounds of the present invention have considerable effect in the test of passive avoidance learning impairment induced by scopolamine.
  • the results obtained through both the in-vitro acetylcholinesterase and butyrylcholinesterase inhibition tests and the in-vivo passive avoidance test present the compounds of this invention as powerful, promising, and novel compounds effective for various kinds of dementia, particularly the Alzheimer senile dementia..

Abstract

Cette invention concerne la conversion de xénobiotiques en inhibiteurs d'ACHE et de BCHE puissants qui ont une activité comparable aux médicaments inhibiteurs d'ACHE et de BCHE actuels (par exemple donépézil, rivastigmine et galantamine).
EP14718200.0A 2013-02-21 2014-02-06 6h-benzo[c]chromén-6-ones 3 substituées et 7,8,9,10-tétrahydro-6h-benzo[c]chromén-6-ones 3 substituées contre la démence sénile Withdrawn EP2958906A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201302068 2013-02-21
PCT/TR2014/000027 WO2014129989A1 (fr) 2013-02-21 2014-02-06 6h-benzo[c]chromén-6-ones 3 substituées et 7,8,9,10-tétrahydro-6h-benzo[c]chromén-6-ones 3 substituées contre la démence sénile

Publications (1)

Publication Number Publication Date
EP2958906A1 true EP2958906A1 (fr) 2015-12-30

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EP14718200.0A Withdrawn EP2958906A1 (fr) 2013-02-21 2014-02-06 6h-benzo[c]chromén-6-ones 3 substituées et 7,8,9,10-tétrahydro-6h-benzo[c]chromén-6-ones 3 substituées contre la démence sénile

Country Status (2)

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EP (1) EP2958906A1 (fr)
WO (1) WO2014129989A1 (fr)

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CN109928963B (zh) * 2019-04-02 2020-08-25 武汉大学 一种抗菌药物三碳链甲基哌啶尿石素b及其盐酸盐的合成方法和应用
US20240139149A1 (en) * 2022-07-27 2024-05-02 Vandria Sa Therapeutic uses of urolithin derivatives

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ATE115953T1 (de) * 1987-12-11 1995-01-15 Mitsui Petrochemical Ind Amine und deren verwendung.
US20050171079A1 (en) * 2004-02-04 2005-08-04 Schrimpf Michael R. Amino-substituted tricyclic derivatives and methods of use
CA2620248A1 (fr) * 2005-10-21 2007-04-26 Merz Pharma Gmbh & Co. Kgaa Chromenones et leur utilisation en tant que modulateurs des recepteurs metabotropes au glutamate
CN102267971B (zh) * 2011-08-03 2013-03-27 华中科技大学 脂环并[c]苯并吡喃酮衍生物及其应用

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