EP1027350A1 - Aminomethylbenzochinolizidinderivate, ihre herstellung und ihre verwendung zur behandlung von neurodegenerativen krankheiten - Google Patents

Aminomethylbenzochinolizidinderivate, ihre herstellung und ihre verwendung zur behandlung von neurodegenerativen krankheiten

Info

Publication number
EP1027350A1
EP1027350A1 EP98951548A EP98951548A EP1027350A1 EP 1027350 A1 EP1027350 A1 EP 1027350A1 EP 98951548 A EP98951548 A EP 98951548A EP 98951548 A EP98951548 A EP 98951548A EP 1027350 A1 EP1027350 A1 EP 1027350A1
Authority
EP
European Patent Office
Prior art keywords
hexahydro
methoxy
methyl
benzo
quinolizinyl
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Withdrawn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
EP98951548A
Other languages
English (en)
French (fr)
Inventor
Patrice Mayer
Jean-Louis Vidaluc
Thierry Imbert
Marc Marien
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.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament 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 Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP1027350A1 publication Critical patent/EP1027350A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

Definitions

  • the present invention relates to new benzo [a] quinolizidine derivatives, and their preparation methods. It also relates to the use of these compounds as a medicament, as well as for the preparation of a medicament used as an antagonist of the ⁇ .2 adrenergic receptors and intended as such to treat neurodegenerative diseases.
  • Parkinson's disease Alzheimer's disease, Huntington's chorea, cognitive and memory disorders, deficits in attention and alertness of the elderly, as well as ischemic and post-ischemic cerebral disorders.
  • locus coeruleus plays a predominant role in the recovery of dopaminergic functions altered by administration of MPTP monkey (Mavridis, Neuroscience (1991). 41, 507). Its destruction results in reduced recovery.
  • compounds having an antagonist ⁇ .2 action are capable of reducing parkinsonian symptoms in monkeys (Colpaert, Brain Res. Bull.,
  • a substance activating the noradrenergic system can have the property of opposing the progression of the degeneration of the neurons involved, by reactivating the systems of the different cerebral localizations, whether they are dopaminergic, cholinergic, or whether it calls for release. growth factors. These compounds are therefore useful in the case of neurodegenerative diseases of the Parkinson or Alzheimer type and in their progression.
  • the compounds of the present invention are distinguished by the fact that it is a benzo [a] quinolizidine substituted in position 2 by an aminomethy group substituted with nitrogen to form ureas or amides.
  • These new products have particularly interesting pharmacological properties which distinguish them from other ⁇ compounds. 2 related antagonists. In particular, they are endowed with a central and selective action on the noradrenergic target.
  • Parkinson's disease is based on a dopaminergic agonist effect, to compensate for the too low levels of endogenous dopamine.
  • 1- Dopa has been used for almost 30 years. However, this treatment is not without side effects, both on the dopaminergic action itself (exhaustion of the effect), as on dyskinesias and undesirable peripheral cardiovascular disorders.
  • a compound with a dopaminergic agonist component can have a presynaptic effect on autoreceptors and, on this account, behave unfavorably for a desired increased release of dopamine.
  • agonists or partial dopamine agonists can have an adverse effect on the survival of neurons. Indeed, the survival of dopaminergic neurons seems to be linked to the increase in the formation of cyclic AMP at the level of the 2nd messenger (Michel P. Agid Y, J. Neurochem., (1996), .62, 1633). However, the D2 agonists will cause a decrease in the formation of cyclic AMP as has been shown by Weiner and Molinoff (1994) (Catecholamines in Basic Neurochemistry: Molecular, Cellular and Medical aspects; 5th Ed. GJ Siegal et al., Raven Press, NY. Pp 261-281).
  • the compounds of the present invention are devoid of dopaminergic effects and have the particularity of having an excellent passage at the central level, and a very long duration of action.
  • a compound having selectively antagonistic activity on a receptors. 2 adrenergics may by release of noradrenaline, reactivate the intrinsic functioning of other neurons, whether dopaminergic or cholinergic. Thus they can oppose the pathological degeneration and slow the progression of the disease, or even stop it.
  • the present invention particularly relates to the compounds of general formula I:
  • Ri represents a hydrogen atom or a C alkyl - ⁇ alkyl group, linear, branched or cyclic, a hydroxy or C ⁇ _6 alkoxy group, branched, linear or cyclic, a halogen atom such as F or Cl.
  • R2 represents a hydrogen atom or a C ⁇ _6- alkyl group
  • R4 and R5 may independently be a hydrogen atom or else a linear, branched, cyclic C - g alkyl group, an aryl, aralkyl, aroyl group. These aryl groups can also be substituted.
  • R4 and R5 may be linked by a carbon chain, optionally incorporating a heteroatom.
  • R3 can also represent an optionally substituted alkylsulionyl or arylsulfonyl group.
  • R3 can be a m am no; ulfor.yl.
  • Rg can also represent a linear, branched or cyclic C ⁇ _8 alkoxy group, an optionally substituted aralkoxy group.
  • Rg also represents an aryl or heteroaryl group, optionally substituted one or more times by a C ⁇ _g alkyl, C ⁇ _g alkoxy, hydroxy, halogen, Cl, F, NO2, CF3, CN, or a thiophene, furan, pyrrole, pyridine and their benzofused derivatives.
  • Rg represents an aralkyl group, aryloxyalkyl, the aryl part of which may be substituted and, the alkyl chain of which may be straight, branched or cyclic.
  • Rg can comprise several aromatic or non-aromatic ring systems, such as a 2-indanyl or a fluorenyl, a coumarinyl, a benzopyranyl.
  • Rg can also represent an aralcényl or aralcynyl group.
  • the aryl group conjugated with a double bond can be phenyl, naphthyl, polyaromatic such as biphenyl or fluorenyl, heteroaromatic and its benzo fused derivatives.
  • This aryl group can be optionally substituted one or more times with C 1 -C 6 alkyls, hydroxy, C 8 alkoxy, halogens such as Cl or F, NO 2, CF, CN, OCF 3, OCH 2 O or form a bicyclic system with a saturated or unsaturated cycle with or without a heteroatom such as O, N or S thus forming an indole, b ⁇ nzofuran or benzothiophene.
  • the alkenyl group can be optionally substituted by halogens, CT, alkyl, phenyl.
  • the motif (CX) -Rg thus forms a cinnamoyl group.
  • aryl represents a phenyl or naphthyl nucleus
  • aralkyl meaning an aryl group attached to an alkyl chain of at least one carbon atom and which may be linear, branched or cyclic.
  • the heteroaromatic group can be a 5 or 6-membered aromatic ring having one or more heteroatoms chosen from N, 0 or S, as well as their benzofused derivatives. They thus form a pyridine, furan, thiophene, indole, benzofuran, benzothiophene, benzoxazine, un ⁇ quinoxaiine, quinazoline, benzimidazole, benzopyrazole.
  • the transformation into 3,4-di H isoquinoline is done by treatment with NBS followed by NaOH.
  • the cyanation of the ketone in position 2 is carried out using tosylmethyl ⁇ -isonitril ⁇ in the presence of potassium tert-butoxide according to the method described by Oldenziel (J.O.C. (1977), 42, 3114).
  • the axial and equatorial nitriles are separated.
  • Each of the nitriles is used in the reduction with sodium borohydride in the presence of iCl2 or else with aluminum hydride to yield the aminomethyl (II) derivative.
  • the reaction of an acid chloride Rg COCl on this amine in the presence of base takes place in a conventional manner.
  • the invention also relates to the process for preparing a diastereomerically pure compound by chromatographic separation or by crystallization of the mixtures of diastereoisomers obtained during the synthesis from the appearance of the chiral center in position 2.
  • the enantiomerically pure compound thus obtained according to claim 10 can be subjected to separation on a HPLC chiral column.
  • the basic compound obtained can then be treated with a stoichiometric amount of the acid agent.
  • R3 represents, with the nitrogen to which it is attached, a group urea or thiourea, di, tri or tetra substituted or not substituted by alkyls or aryls.
  • the present invention also relates to their form salified by mineral or organic acids.
  • the invention relates to the various diastereoisomers obtained between the two asymmetrical centres in position 2 and 11b.
  • the invention relates to their enantiomerically pure levogyre and dextrorotatory form, as well as their addition salt, hydrochloride, sulfate, methanesulfonate, maleate, fumarate, oxalate, tartrate, succinate, citrate.
  • the compounds of the invention according to general formula I are thus shown as adrenergic receptor 2 antagonist agents and thus cause a release of noradrenaline. They can be used in human therapeutics and are of interest for the treatment of neurodegenerative diseases and their progression such as Parkinson's disease, Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, cognitive disorders linked to age, attention and memory disorders, brain damage due to central ischemic attacks.
  • the present invention also relates to pharmaceutical compositions comprising at least one compound of formula I and an appropriate excipient.
  • the pharmaceutical compositions can be presented, in a suitable manner, for oral, injectable or parenteral administration, in the form of capsules, capsules, tablets, or injectable preparations, at a dose of 0.1 to 200 mg per day.
  • the aqueous phase is basified with NaOH and then extracted with CH2Cl2.
  • the organic phase is then dried over MgSO 4, filtered and then evaporated to dryness.
  • reaction mixture After addition of 29.3 g of tBuOK (0.26 mole; 2 eq), the reaction mixture is maintained at 0 ° C for 1 h 30 then at room temperature for 1 h. The solution is then heated at 90 ° C for 2 h and then left at room temperature overnight.
  • H7a 2.12 ppm (m; 1H; Hla); 2.05 ppm (m; 1H; H2); 1.93 ppm (m; 1H; H3a); 1.83 ppm (m; 1H; H3b); 1.61 ppm (Hlb).
  • H7a, H6a, H4a 2.62 ppm (m; 1H; Hla); 2.45 ppm (m; 1H; H7b); 2.26 ppm (m; 2H; H4b and H6b); 1.71 ppm
  • a solution of 0.24 ml of dimethylcarbamoyl chlorides (280 mg; 2.6 mmol; 1.2 eq) in 2 ml THF is added dropwise to a solution of 530 mg of amino obtained in stage 5 of 1 ' ⁇ x ⁇ mpl ⁇ 1 (2.15 mmol) and 0.44 ml pyridin ⁇ (425 mg; 5.4 mmol; 2.5 eq) in 30 ml THF.
  • the reaction is maintained at room temperature for 2 days then heated to 80 ° C. for 5 days after addition of a tip of a DMAP spatula.
  • H7b 2.48 ppm (m; 1H H6b); 2.33 ppm (m; 2H; Hla H4b); 2.04 ppm (m; 1H H2); 1.78 ppm (m; 1H; H3a)
  • stage 3 of compound 96 The procedure is identical to that of stage 3 of compound 96.
  • the quantities used are 1.15 g (5 mmol) of keton from the previous stage, 20 ml of dimethoxyether, 1.03 g (leq) of tosylmethylisonitrile, 0.3 ml (leq ) ethanol and 1.18 g of tBuOK.
  • the operating mode is identical to that of stage 5 of Example 96.
  • the quantities used are 498 mg (5 mmol, leq) of the amine from the preceding stage, 15 ml of THF, 0.4 ml

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP98951548A 1997-10-28 1998-10-26 Aminomethylbenzochinolizidinderivate, ihre herstellung und ihre verwendung zur behandlung von neurodegenerativen krankheiten Withdrawn EP1027350A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9713499 1997-10-28
FR9713499A FR2770215B1 (fr) 1997-10-28 1997-10-28 Derives d'aminomethyl-benzo[a]quinolizidine, leur preparation et leur application en therapeutique pour les maladies neurodegeneratives
PCT/FR1998/002281 WO1999021856A1 (fr) 1997-10-28 1998-10-26 Derives d'aminomethyl-benzo[a]quinolizidine, leur preparation et leur application en therapeutique pour les maladies neurodegeneratives

Publications (1)

Publication Number Publication Date
EP1027350A1 true EP1027350A1 (de) 2000-08-16

Family

ID=9512729

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98951548A Withdrawn EP1027350A1 (de) 1997-10-28 1998-10-26 Aminomethylbenzochinolizidinderivate, ihre herstellung und ihre verwendung zur behandlung von neurodegenerativen krankheiten

Country Status (8)

Country Link
EP (1) EP1027350A1 (de)
JP (1) JP2001521034A (de)
CN (1) CN1278260A (de)
AU (1) AU9751798A (de)
BR (1) BR9813303A (de)
CA (1) CA2307748A1 (de)
FR (1) FR2770215B1 (de)
WO (1) WO1999021856A1 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0016454D0 (en) 2000-07-04 2000-08-23 Hoffmann La Roche Thienopyrrolidinones
JPWO2006054793A1 (ja) * 2004-11-19 2008-06-05 財団法人新産業創造研究機構 ベンゾフラン化合物、およびそれを含有してなる医薬組成物
NZ566011A (en) * 2005-08-06 2011-01-28 Biovail Lab Internat Barbados Srl 3, 11b cis dihydrotetrabenazine for the treatment of schizophrenia and other psychoses
CA2650904C (en) * 2006-05-02 2015-07-07 The Trustees Of The University Of Pennsylvania Radiolabeled dihydrotetrabenazine derivatives and their use as imaging agents
GB2463451A (en) * 2008-09-08 2010-03-17 Cambridge Lab 3, 11b cis-dihydrotetrabenazine compounds for use in the treatment of dementia
FR2976287B1 (fr) * 2011-06-09 2013-07-05 Pf Medicament Derives benzoquinolizidines, leur procede de preparation et leurs applications en therapeutique
CA2849057C (en) * 2011-09-19 2021-05-11 Vitas Pharma Research Pvt Ltd Heterocyclic compounds as inhibitors of fatty acid biosynthesis for bacterial infections

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8416432D0 (en) * 1984-06-28 1984-08-01 Wyeth John & Brother Ltd Benzoquinolizines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9921856A1 *

Also Published As

Publication number Publication date
WO1999021856A1 (fr) 1999-05-06
BR9813303A (pt) 2000-08-29
AU9751798A (en) 1999-05-17
FR2770215A1 (fr) 1999-04-30
FR2770215B1 (fr) 2000-01-14
JP2001521034A (ja) 2001-11-06
CA2307748A1 (fr) 1999-05-06
CN1278260A (zh) 2000-12-27

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