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WO1993013100A1 - Procedes d'obtention des derives bis-pyridiniques ayant des proprietes d'inhibition de l'acetylcholinesterase - Google Patents

Procedes d'obtention des derives bis-pyridiniques ayant des proprietes d'inhibition de l'acetylcholinesterase Download PDF

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Publication number
WO1993013100A1
WO1993013100A1 PCT/ES1992/000086 ES9200086W WO9313100A1 WO 1993013100 A1 WO1993013100 A1 WO 1993013100A1 ES 9200086 W ES9200086 W ES 9200086W WO 9313100 A1 WO9313100 A1 WO 9313100A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
process according
tetrahydro
nmr
diquinoline
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.)
Ceased
Application number
PCT/ES1992/000086
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English (en)
Spanish (es)
Inventor
Pelayo Camps Garcia
Mª Dolores PUJOL DILME
Joan Contrepas Lascorz
Diana Marina GÖRBIG ROMEU
Diego MUÑOZ-TORRERO LOPEZ-IBARRA
Montserrat Simon Fornell
Albert Badia Sancho
Josep E. BANOS DIEZ
Félix BOSCH LLONCH
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.)
Boehringer Ingelheim Espana SA
Original Assignee
Boehringer Ingelheim Espana SA
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 Boehringer Ingelheim Espana SA filed Critical Boehringer Ingelheim Espana SA
Publication of WO1993013100A1 publication Critical patent/WO1993013100A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • This invention describes a process for obtaining bis-pyridine derivatives and their pharmaceutically acceptable acid addition salts having therapeutic applications.
  • a process for obtaining bis-pyridine compounds that produce an increase in acetylcholine at the central level either by inhibition of the action of acetylcholinesterase or by other mechanisms of action and which are useful for treating various dysfunctions of memory characterized by decreased function, such as Alzheimer's disease or senile dementia of the Alzheimer type.
  • tacrine (9-amino- 1,2,3,4-tetrahydroacridine) which is an acetyl cholinesterase inhibitor and administered in combination with lecithin (intravenously) is useful in the treatment of Alzheimer's disease has the disadvantage of its high toxicity [WK Summers, KR Kaufman, F. Altman, Jr. and JM Fischer, Clin. Toxicol., 16, 269 (1980)].
  • the present invention describes a process for obtaining bis-pyridine compounds, designed by molecular duplication of tricyclic anticholinesterics structurally related to tacrine, and their pharmaceutically acceptable acid addition salts, represented by general structures I and II
  • R is hydrogen, alkyl or aralkyl
  • m, n, p, q can take the values 0, 1, 2, 3, .. so that m + n --- p + q ⁇ 9.
  • X and Y represent "connection bridges" that can be independent or linked together, directly through a link, and / or through one or more "suitable moieties".
  • R x hydrogen, halogen, lower alkoxy or lower alkyl.
  • alkyl represents a hydrocarbon moiety of one to six carbon atoms with straight, branched, cyclic, substituted cyclic or cycloalkyl chains. alkyl (for example: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, etc.).
  • aralkyl means phenylalkyl or phenylalkyl substituted on phenyl, containing 7 to 13 carbon atoms.
  • alkyl in “phenylalkyl” or “phenylalkyl. Substituted in phenyl 11" means a straight chain alkylene group containing one to four carbon atoms (eg, methylene, ethylene, trimethylene, tetramethylene).
  • phenylalkyl substituted on phenyl is a phenyl group containing a substituent selected from the group consisting of halogen (for example fluorine, chlorine, bromine and iodine), lower alkyl which includes alkyl groups containing one to four carbon atoms with chains linear or branched (for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tere-butyl), and lower alkoxy which includes a linear or branched chain alkoxy group containing one to four carbon atoms (for example methoxy , ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy)
  • aralkyl groups include benzyl, phenethyl, 3-phenylpropyl, 4- phenylbutyl 2- (4-methoxyphenyl) ethyl, 2- (2-methylphenyl) ethyl, 2 - (4-fluor
  • connection bridges means a bond, an atom (for example: oxygen, sulfur, ...) or a substituted atom (for example: NR 2 or CH-R 2 , where R 2 can be hydrogen, alkyl or aralkyl with the same meanings given previously for R).
  • suitable residues that can connect the “connection bridges” means a grouping of the type (CH 2 ) rZ- (CH 2 ) s, where rys can take the values zero, one, two, three or four, and Z represents a bond, a vinyl, ortho-phenylene, ortho-phenylene group substituted with an R 3 group, an oxygen atom, sulfur or the NR 4 or CH-R 4 groupings.
  • the substituent R 3 can adopt the same values given previously to Rj ..
  • R 4 in NR 4 and in CH-R 4 can adopt the same values given above to R.
  • Examples of -X-, -Y- are set out in the following:
  • halogen represents a fluorine, chlorine, bromine and iodine atom.
  • lower alkoxy means a straight or branched chain alkoxy group containing one to four carbon atoms (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy).
  • lower alkyl means an alkyl group containing straight or branched chains of one to four carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tere-butyl).
  • pharmaceutically acceptable inorganic or organic acid addition salts means salts formed with inorganic acids such as: hydrochloric, hydrobromic, sulfuric and nitric acids and organic acids such as: tartaric, succinic, maleic, aric and citric.
  • the process object of this patent involves the reaction of dicarbonyl compounds of general structure III with aminonitriles of general structure IV in the presence of a suitable solvent and an acid of Le is as a catalyst, a reaction that leads directly to compounds with the general structure I and / or II, with the values defined above for A, -X- and -Y, m, n, p, q, with R equal to hydrogen.
  • the compounds of general structure V derived from the reaction of III with a single equivalent of IV, are also obtained as by-products. Compounds V can become important, if the reaction conditions are conveniently chosen.
  • the compounds of general structure I, II and V obtained in these reactions are separable by conventional procedures, for example: column chromatography, or selective dissolution with different solvents and subsequent crystallization, either in the form of free bases or their addition salts of organic or inorganic acids.
  • dicarbonyl compounds of general structure III -X-, -Y-, m, n, p, q, they have the same meanings given above for I and II, being essential that in the pairs m / n, p / q, one of the values is equal to or greater than one, that is, that there is always at least one methylene group in alpha-carbonyl position with respect to each ketone grouping.
  • compounds of general structure IV A has the meaning given above in relation to I and II.
  • the Lewis acid used as a catalyst in the condensation of the diketones III with the aminonitriles IV to give the derivatives of general structure I and / or II and V, with R equal to hydrogen can be, among others, aluminum trichloride, dichloride Zinc, titanium tetrachloride, etc. All of them anhydrous.
  • aprotic solvents should be used, for example: nitrobenzene, 1,2-dichloroethane, dichloromethane, dimethylformamide, among others.
  • the reaction is carried out at temperatures between 0 and 150 [ deg.] C. with reaction times ranging from 1 to 48 hours, depending on the type of catalyst and solvent used.
  • the pharmaceutically acceptable salt formation reactions of the compounds of general structure I, II and V are carried out by conventional methods, by reacting the organic compound with an organic or inorganic acid in an appropriate solvent, such as water, alcohols (for example, methanol, ethanol, isopropanol, etc.) or ethers (ethyl ether, tetrahydrofuran, dioxane, etc.).
  • an appropriate solvent such as water, alcohols (for example, methanol, ethanol, isopropanol, etc.) or ethers (ethyl ether, tetrahydrofuran, dioxane, etc.).
  • Derivatives I, II and V and their acid addition salts may be administered orally or parenterally in the form of conventional pharmaceutical preparations, such as tablets, capsules, syrups and suspensions. Alternatively, they can be administered parenterally in the form of solutions or emulsions, etc. They can be applied directly to the rectum, in the form of suppositories.
  • the preparations may contain physiologically acceptable carriers, excipients, activators, chelating agents, stabilizers. etc. In the case of injectables, physiologically acceptable buffers, solubilizing or isotonic agents may be incorporated.
  • the daily dose may vary depending on the symptoms of the disease, age, body weight of patients, mode of administration, etc., and the normal dose of an adult varies between 1 and 500 mg divided into several doses. up to date.
  • the mono and bis-pyridine derivatives were tested at the following concentrations ( ⁇ M): 0.1; 0.3; one; 3; 10; 30. The results are expressed as the average of at least six experiments considering the corresponding standard deviation.
  • the compound 6,7,8,15-Tetrahydro-7,15-methane-cyclooctene [1,2-b: 5,4-b '] diquinoline-14,16-diamine has the following antagonism indices: at concentration 3 ⁇ M, 19.7 + 5.8; at 10 ⁇ M, 52.7 + 1 and at 30 ⁇ M, • 68.1 + 5.1.
  • the ability to inhibit acetylcholinestera from mono- and bis-pyridine derivatives was determined by the colorimetric method of Ellman et al.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé permettant d'obtenir des dérivés bis-pyridiniques de formules (I) et (II) dans lesquelles R représente hydrogène, alkyle ou aralkyle, m, n, p, q peuvent avoir les valeurs 0, 1, 2, 3,... à condition que m + n + p + q < 9. X et Y représentent des 'ponts de connexion' qui peuvent être indépendants ou être unis entre eux, directement par une liaison, et/ou par l'intermédiaire d'un ou plusieurs 'restes adéquats'. (a) est (b) ou (c), R1 étant hydrogène, halogène, alcoxy ou alkyle. Les tests pharmacologiques des dérivés mono-et bis-pyridiniques objets de cette invention ont commencé avec l'étude de la réversion de l'effet bloquant de la tubocurarine, ce qui a permis de mesurer l'activité anticholinestérase.
PCT/ES1992/000086 1991-12-26 1992-12-24 Procedes d'obtention des derives bis-pyridiniques ayant des proprietes d'inhibition de l'acetylcholinesterase Ceased WO1993013100A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP9102873 1991-12-26
ES9102873A ES2042384B1 (es) 1991-12-26 1991-12-26 Procedimiento para obtener derivados bis-piridinicos.

Publications (1)

Publication Number Publication Date
WO1993013100A1 true WO1993013100A1 (fr) 1993-07-08

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Application Number Title Priority Date Filing Date
PCT/ES1992/000086 Ceased WO1993013100A1 (fr) 1991-12-26 1992-12-24 Procedes d'obtention des derives bis-pyridiniques ayant des proprietes d'inhibition de l'acetylcholinesterase

Country Status (3)

Country Link
AU (1) AU3258993A (fr)
ES (1) ES2042384B1 (fr)
WO (1) WO1993013100A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013754A1 (fr) * 1995-10-11 1997-04-17 Pelayo Camps Garcia Nouveaux composes aminopyridiniques polycycliques inhibiteurs d'acetylcholinesterase, procede de preparation et utilisation
EP2018874A2 (fr) 1998-08-07 2009-01-28 Targacept, Inc. compositions pharmaceutiques pour la prévention et le traitement de troubles du système nerveux central comprenant un analogue de la nicotine et un inhibiteur de l'acétylcholinestérase
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
WO2014090929A1 (fr) 2012-12-13 2014-06-19 H. Lundbeck A/S Compositions comprenant de la vortioxétine et du donépézil
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0311303A2 (fr) * 1987-10-05 1989-04-12 Pfizer Inc. Dérivés de la 4-aminopyridine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268871A1 (fr) * 1986-10-31 1988-06-01 Sumitomo Pharmaceuticals Company, Limited Dérivés de quinoléine
EP0287977B1 (fr) * 1987-04-23 1994-06-29 Hoechst-Roussel Pharmaceuticals Incorporated Hétéroalkylène quinoléine amines, un procédé et intermédiaires pour leur préparation et leur utilisation comme médicaments
EP0394950A1 (fr) * 1989-04-25 1990-10-31 Sumitomo Pharmaceuticals Company, Limited Dérivés de pyridine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0311303A2 (fr) * 1987-10-05 1989-04-12 Pfizer Inc. Dérivés de la 4-aminopyridine

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013754A1 (fr) * 1995-10-11 1997-04-17 Pelayo Camps Garcia Nouveaux composes aminopyridiniques polycycliques inhibiteurs d'acetylcholinesterase, procede de preparation et utilisation
ES2100129A1 (es) * 1995-10-11 1997-06-01 Medichem Sa Nuevos compuestos aminopiridinicos policiclicos inhibidores de acetilcolinesterasa, procedimiento para su preparacion y su utilizacion.
US5965569A (en) * 1995-10-11 1999-10-12 Medichem, S.A. Polycyclic aminopyridine compounds which are acetylcholinesterase inhibitors, process for preparing them and their use
EP2018874A2 (fr) 1998-08-07 2009-01-28 Targacept, Inc. compositions pharmaceutiques pour la prévention et le traitement de troubles du système nerveux central comprenant un analogue de la nicotine et un inhibiteur de l'acétylcholinestérase
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
WO2014090929A1 (fr) 2012-12-13 2014-06-19 H. Lundbeck A/S Compositions comprenant de la vortioxétine et du donépézil
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10925834B2 (en) 2015-05-22 2021-02-23 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam

Also Published As

Publication number Publication date
AU3258993A (en) 1993-07-28
ES2042384A1 (es) 1993-12-01
ES2042384B1 (es) 1994-06-01

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