EP2718291A1 - Derives benzoquinolizidines, leur procede de preparation et leurs applications en therapeutique - Google Patents
Derives benzoquinolizidines, leur procede de preparation et leurs applications en therapeutiqueInfo
- Publication number
- EP2718291A1 EP2718291A1 EP12729076.5A EP12729076A EP2718291A1 EP 2718291 A1 EP2718291 A1 EP 2718291A1 EP 12729076 A EP12729076 A EP 12729076A EP 2718291 A1 EP2718291 A1 EP 2718291A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- radical
- pyrido
- isoquinolin
- hexahydro
- disorders
- 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.)
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Classifications
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- 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
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- 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
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
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- 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
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Definitions
- Alpha2 adrenergic receptors play a critical role in the regulation of neuronal activity and release of neurotransmitters.
- Alpha2 adrenergic receptors consist of three genetically and functionally distinct subtypes: alpha2A, alpha2B and alpha2C.
- the alpha2A subtype is the most abundant and is widely distributed in the body.
- the distribution of the alpha2C receptor in the central nervous system is limited mainly in areas such as the olfactory tubercle, the striatum and the hippocampus, the locus coeruleus, and other brain regions containing the noradrenergic neuron cell bodies, and in the dopaminergic centers of the midbrain, like the black substance and the ventral tegmental zone.
- the alpha2C receptor may also be of importance outside the central nervous system, and particularly in the regulation of cardiac homeostasis.
- Alpha2 adrenergic receptors modulate central nervous system functions, such as sympathetic tone, alertness, attention and responsiveness to a stressful environment.
- central nervous system functions such as sympathetic tone, alertness, attention and responsiveness to a stressful environment.
- pharmacological probes specific for alpha2 adrenergic receptor subtypes a vision of their roles has come from the development and use of genetically modified mice, either by inactivation, by targeted mutation or by over-expression of their genes. genes.
- alpha2A subtype is the main mediator of certain effects induced by non-selective subtype alpha2 adrenergic agonists, such as sedation, analgesia, hypothermia, sympathetic inhibition and reduction of blood pressure.
- alpha2C adrenergic subtype has a distinct inhibitory role in the development of sensory information, and in the control of cognitive, motor, emotional, or stress-related activities of the system central nervous system (Scheinin M, Sallinen J, Haapalinna A (2001) Evaluation of the alpha2C-adrenoceptor as a neuropsychiatry drug target: studies in transgenic mouse models Life Sci 68: 2277-2285).
- selective alpha2C receptor compounds may have therapeutic utility in disorders or conditions of the central nervous system, for example, to ameliorate symptoms associated with neurodegenerative diseases and their progression (including Parkinson's disease). , Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Do syndrome, corticobasal degeneration, pugilist dementia, multiple system atrophy, Y, Pick's disease), to treat the attention deficit and alertness of the elderly, mood disorders, depression, negative and cognitive symptoms of schizophrenia, bipolar disorder, anxiety disorder. attention with hyperactivity, post-traumatic stress disorder, anxiety disorders and mental illnesses spread by stress.
- ischemic and post-chemic brain disorders stroke and its consequences, narcolepsy and male sexual dysfunction, as well as disorders related to acquired immunodeficiency syndrome (MacDonald E, Kobilka BK, Scheinin M (1997) Gene targeting: homing in on alpha 2-adrenoceptor-subtype function Trends Pharmacol Sci 18: 211-219; Arnsten AF.
- alpha2c antagonists inhibit phencyclidine-induced PPI disruption (Sallinen J, Haapalinna A, Viitamaa T, Kobilka BK, Scheinin M (1998) Adrenergic alpha2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice. J Neurosci. 18 (8): 3035-42), compounds selective for alpha2C receptors may also be used for the treatment of disorders and conditions associated with sensory filtering deficits, particularly disorders and conditions in which such deficits result in flooding. sensory and cognitive fragmentation, producing a dysfunction of attention and perception.
- disorders and conditions involved include, but are not limited to others, schizophrenia, obsessive-compulsive disorder, Tourette's syndrome and other focal dystonia, temporal lobe epilepsy with psychosis, psychoses induced by drugs or drugs (eg, psychosis induced by chronic use of dopamine agonists), disorders caused by fluctuations in levels of sex hormones (eg, PMS) and "panic disorders".
- symptoms that are not normally associated with the disorders and conditions mentioned above include (and without the exclusion of others) hallucinations, delusions, parathymia, agitation, cognitive disturbance of psychosis. (including deficits in thinking and speaking), and withdrawal symptoms (including delirium) associated with quitting smoking, alcoholism, or substance abuse. These symptoms could be observed also in pets under certain exceptional circumstances, for example the separation of their masters, or during their transport.
- alpha2C antagonists are learning and socialization disorders and stress-related disorders in children and adolescents, whether they are associated with specified or unspecified Invasive Developmental Disorders. , Disintegrative Disorders of the Child and Adolescent, Early Psychosis, Psychotic Disharmony, Autism or Atypical Mood Disorders, according to the ICD-10 classifications (10th edition of the International Statistical Classification of Diseases and Related Health Problems, "ICD-10, Classification of Mental and Behavioral Disorders: Diagnostic Requirements for Research, World Health Organization, 1993 Revised 1997), in the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders).
- JP-1302 an alpha2C adrenergic antagonist compound (Sallinen J, Hoglund I, Engstrom M, Lehtimaki J, Virtanen R, Sirvio J, Wurster S, Savola JM, Haapalinna A (2007) Pharmacological characterization and CNS effects of a Novel highly selective to lpha 2 C-adrenoceptor antagonist JP-1302, Br J Pharmacol 150: 391-402), provided a pharmacological tool for testing these hypotheses.
- the compound JP-1302 has antidepressant and antipsychotic properties.
- Cardiovascular tolerance is a key factor in the selection of an alpha2 receptor antagonist candidate for clinical development.
- understanding the respective roles of alpha2 adrenergic receptors and other adrenergic receptors in the regulation of cardiovascular function is fundamentally important.
- alpha2C adrenergic receptors despite their distribution in strategic positions in the central nervous system and periphery, which could theoretically alter cardiovascular homeostasis, appear to have no significant functional impact, while least not in transgenic animal models.
- an alpha2 adrenergic receptor antagonist that would be selective for subtype C could have a reduced cardiovascular impact or better tolerance compared to an alpha2 nonselective antagonist of a subtype.
- Alpha-2 antagonists of the pyrido [2, 1-a] structure which have not been described in WO99 / 21856.
- the compounds of the present invention are distinguished by the fact that they are heterocyclic structures grafted on the 2-position of pyrido [2,1-a] isoquinoline and non-amides or linear urea. Selectivity for alpha-2 adrenergic receptor subtypes was not described in WO99 / 21856.
- Alpha 2C antagonists with triazole structure, tetrazole, imidazole, pyrazine and condensed pyrimidines have been reported (WO2006 / 067139, WO2007 / 135131, WO2008 / 043775, US2004 / 0110826).
- C 1 -C 6 alkyl radical means a linear or branched hydrocarbon-based chain containing from 1 to 6 carbon atoms, for example a methyl radical, an ethyl radical, a propyl radical or a butyl radical.
- C 1 -C 6 alkoxy radical means a linear or branched hydrocarbon-based chain containing from 1 to 6 carbon atoms and an oxygen atom, for example a methoxy radical, an ethoxy radical or a propoxy radical. a butoxy radical.
- amino-C 1 -C 6 alkyl amine means an amine connected to a linear or branched C 1 -C 6 alkyl radical.
- halogen is understood to mean fluorine, chlorine or bromine.
- alkoxyalkyl radical Ci_C 6 refers in the sense of the present invention an alkyl radical in CI_ 6 as defined above, attached to an alkoxy radical Ci_C 6 through a carbon atom, for example a methoxymethyl group, a Ethox YME thy 1 e, a thoxyether radical or an ethoxyethyl radical.
- C 1 -C 6 -haloalkyl radical means a C 1 -C 6 alkyl group monosubstituted, disubstituted or trisubstituted with a halogen, for example a radical CF 3 , a radical CHF 2 , a radical CH 2 F, a radical CCl 3 , a radical CHCl 2 , a radical CH 2 Cl, a radical CBr 3 , a radical CHBr 2 or a radical CH 2 Br.
- a radical CF 3 a radical CHF 2 , a radical CH 2 F, a radical CCl 3 , a radical CHCl 2 , a radical CH 2 Cl, a radical CBr 3 , a radical CHBr 2 or a radical CH 2 Br.
- C1-C3 alkylenedioxy radical means a hydrocarbon chain comprising between 1 and 3 carbons and having at least one disubstituted unsaturation by an oxygen atom.
- aryl radical in the sense of the present invention an organic cyclic monovalent radical derived from an aromatic hydrocarbon which can be monocyclic such as phenyl or bicyclic such as naphthyl.
- aralkyl radical means an aryl radical as defined above, substituted with an alkyl radical as defined above, for example phenylemethyl or phenylethyl.
- heteroaryl radical means an aryl radical as defined above in which one or more carbon atoms has been substituted by a heteroatom such as, for example, nitrogen, oxygen or sulfur, for example pyridine, pyrimidine, imidazole, indole, furan or thiophene.
- heteroarylalkyl radical is meant in the sense of the present invention a heteroaryl radical as defined above, substituted with an alkyl radical as defined above.
- amino acid is understood to mean a molecule comprising an amino group NH 2, a radical R 'that varies according to the amino acid in question, and a carboxyl group COOH with the structure: NH 2 -CHR' -COOH, such as alanine, arginine, asparagine, aspartate, cysteine, glutamate, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine , threonine, tryptophan, tyrosine, valine and phenylglycine.
- alanine such as alanine, arginine, asparagine, aspartate, cysteine, glutamate, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine , threonine, tryptophan, tyros
- amino acid side chains are understood to mean the radical R 'of each of the amino acids as defined above.
- salts refers to the inorganic acid addition and base addition salts of the compounds of the present invention.
- the salts are pharmaceutically acceptable, that is, they are non-toxic to the patient to whom they are administered.
- pharmaceutically acceptable refers to molecular entities and compositions that produce no adverse, allergic or other adverse effects.
- the term "pharmaceutically acceptable excipient” includes any diluent, adjuvant or excipient, such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or agents. which would delay intestinal and digestive absorption and resorption.
- preservatives such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or agents. which would delay intestinal and digestive absorption and resorption.
- treatment means to prevent or inhibit the onset or progression of the condition to which the term applies, or one or more symptoms of this condition.
- the present invention relates to benzoquinolizidine derivatives (or pyrido [2,1-a] isoquinolin), their method of preparation and their application in human therapy.
- X represents an oxygen atom or a sulfur atom.
- RI may be one or more substituents, which may be identical or different, and represents a hydrogen atom, an OH radical or a C1-C6 alkoxy radical, or a C1-C6 alkyl radical or a C1-C3 alkylenedioxy radical; , or a C1-C6 haloalkyl radical or a halogen;
- the present invention relates to the compounds of general formula 1 characterized in that they are chosen from:
- the present invention also extends to the different stereoisomeric forms of the compounds of general formula 1, as well as their mixtures in all proportions.
- Mixtures of stereoisomeric forms in all proportions also include racemic mixtures.
- the subject of the invention also relates to the different stereoisomeric forms and their mixtures in all proportions of the compounds of general formula 1 as well as the pharmaceutically acceptable salts.
- the present invention also extends to the processes for the chemical preparation of the compounds of general formula 1 as well as the different stereoisomeric forms and their mixtures in all proportions.
- the present invention also relates to the compounds of general formula 1 as well as the various stereoisomeric forms and their mixtures in all proportions, and their pharmaceutically acceptable salts for their use as selective antagonists of the alpha 2 adrenergic receptor, and preferably the alpha subtype 2C.
- the present invention also relates to the compounds of general formula 1 as well as the various stereoisomeric forms and mixtures thereof in all proportions, and their pharmaceutically acceptable salts for their use as medicaments.
- the invention also relates to the compounds of general formula 1 as well as the various stereoisomeric forms and mixtures thereof in all proportions, and their pharmaceutically acceptable salts for use as a medicament for the treatment and / or prevention of diseases requiring selective antagonists. of the alpha 2 adrenergic receptor, and preferentially the alpha 2C subtype.
- the invention also relates to the compounds of general formula 1 as well as the various stereoisomeric forms and their mixtures in all proportions, and their pharmaceutically acceptable salts for their use as a medicament for the treatment and / or prevention of disorders or various conditions of the invention.
- central nervous system for example, to improve the symptoms associated with neurodegenerative diseases and their progression (including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Do syndrome, corticobasal degeneration, pugilist dementia, multiple system atrophy, Le y body disease, Pick's disease), to treat attention deficit and vigilance deficits of the elderly subject, mood disorders, depression, negative and cognitive symptoms of schizophrenia, bipolar disorder ire, attention deficit hyperactivity disorder, post-traumatic stress disorder, anxiety disorders and mental illnesses spread by stress.
- neurodegenerative diseases and their progression including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear pal
- ischemic and ischemic cerebral palsy cerebrovascular accidents and their consequences, narcolepsy and male sexual dysfunction, as well as disorders related to the acquired immunodeficiency syndrome.
- Disorders and conditions associated with sensory filtering deficits particularly disorders and conditions in which these deficits lead to sensory flooding and cognitive fragmentation, producing a dysfunction of attention and perception.
- the disorders and conditions concerned include, but without the exclusion of others, schizophrenia, obsessive-c ompu 1 s ive, Tourette's syndrome and other focal dystonia, temporal lobe epilepsy with psychosis, psychoses induced by drugs or drugs (eg, psychosis induced by chronic use of agonists dop ami ner que s), disorders caused by fluctuations in levels of sex hormones (eg, PMS) and "panic disorders”.
- symptoms that are not normally associated with the disorders and conditions mentioned above include (and without the exclusion of others) hallucinations, delusions, parathymia, agitation, cognitive disturbance of psychosis. (including deficits in thinking and speaking), and withdrawal symptoms (including delirium) associated with quitting smoking, alcoholism, or substance abuse. These symptoms could be observed also in pets under certain exceptional circumstances, for example the separation of their masters, or during their transport.
- the invention also relates to the compounds of general formula 1 as well as the different stereoisomeric forms and their mixtures in all proportions, and their pharmaceutically acceptable salts for their use in the treatment of learning and socialization disorders and disorders related to stress in children and adolescents, whether associated with specified or unspecified Invasive Developmental Disorders, Child and Adolescent Integral Disorders, Early Disability Psychoses, Psychotic Disorders, Autism or Mood Disorders at Atypical Form.
- the invention also relates to the compounds of general formula 1 as well as the various stereoisomeric forms and their mixtures in all proportions, and their pharmaceutically acceptable salts in combination with antidepressants, anxiolytics and / or antipsychotics currently or possibly available to improve their effectiveness. and / or their time of action.
- the invention also relates to a pharmaceutical composition characterized in that it contains a compound of general formula 1 or one of its stereoisomeric forms and mixtures thereof in all proportions, or one of its pharmaceutically acceptable salts in combination with any excipient pharmaceutically acceptable.
- compositions according to the invention can be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally.
- the active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals or humans.
- Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration topical, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.
- Formulations suitable for the chosen form of administration are known in the art and described for example in Remington, the science and practice of pharmacy, l9 th edition, 1995, Mack Publishing Company.
- Assays of the compounds of Formula 1 in the compositions of the invention may be adjusted to provide an amount of active substance that is effective in achieving the desired therapeutic response for a particular composition in the method of administration.
- the effective dose of a compound of the invention varies depending on many parameters such as, for example, the chosen route of administration, weight, age, sex, nature of pathology and sensitivity of the subject. to treat. Consequently, the optimal pathology will have to be determined according to the parameters deemed relevant by the specialist in the field. Syntheses of the compounds of the invention
- the invention also extends to the non-exclusive process for preparing these compounds, characterized in that an amine compound of formula 2 is prepared with the specifications R1 as indicated above from the ketone of formula 3 .
- Benzo [a] quinolizidin-2-one of formula 3 is known and prepared according to J. Med. Chem. 1983, 26, 1426 or Brossi (Helv.Chim.Acta 1958, 41, 119). Depending on the substituent (s) RI at position 8 to 11, the process may be modified. It has been indicated in WO99 / 21856, the process for the preparation of the intermediates of formula 2 wherein the substituent R1 is at the 9-position of pyrido [2,1-a] isoquinoline. The same methodologies can be used here. Some variants are described to show the diversity of possible access to this type of conventional structure for the skilled person.
- the dihydroquinoquinol synthesis intermediates of formula 4, substituted on the homocycle are prepared according to the different methods set forth in Organic Reactions 1969, 6, 74.
- R1 represents a 9, 1 O-methylenedioxy group
- the raw material used dihydroisoquinoline is prepared according to Tetrahedron 1971, 27,2091, or Can. J. Chem. 1986, 64, 1031.
- the dihydroisoquinoline raw material is described in J. Org. Chem. 2007, 72, 5759.
- the ketone intermediate of formula 3 is prepared by cyclization of the intermediate of formula 4 with methyl vinyl ketone, according to the method described (J. Med Chem 1983, 26, 1426). . At this stage, a series of RI substituents can be obtained.
- the cyanation of the ketone at position 2 of the pyrido [2,1-a] isoquinoline structure of formula 3 is carried out with tosyylmethylisonitrile in a basic medium such as potassium tert-butoxide, according to the method described by Oldenziel (J. Org. Chem. 1977, 42, 3114) to give the diastereoisomeric nitriles of formula 5.
- N-alkyl or N-arylimidazolidinediones heterocycles or hydantoins prepared by reaction of the amine of formula 2 are prepared by reaction of the amine of formula 2 with an isocyanate derivative or glycine ester sothiocyanate followed by cyclization in basic medium.
- the corresponding thio derivatives can be prepared from their oxygenated counterparts by reaction with sulfurization reagents such as P2S5 or the test reagent.
- the invention therefore also extends to the process for preparing the compounds of formula 1 wherein condensing the amine of formula 2, with RI as defined above, with alkyloxycarbonylalkylisocyanate capable in a 2nd time cyclize in basic medium to imidazolidinedione.
- the cyclic imide derivatives may also be prepared by cyclizing a corresponding acid ester or anhydride with the primary amine of Formula 2.
- Another synthetic process for the preparation of the compounds of Formula 1 may be used. It consists in preparing a primary alcohol of formula 7. This compound consists of 2 diastereoisomers similarly to the amine of formula 2.
- the compound of formula 7 may be prepared from nitriles of formula 5, which they either diastereoisomerically pure or not, by esterification in the presence of ethanol and HCl, followed by a reduction of the esters formed by a reducing agent of the esters to alcohols, for example the lithium aluminum hydride.
- the primary alcohol of formula 7 can be condensed with hydantoins by a Mitsunobu type reaction (Org React 1992, 42, 335, Chem Rev. 2009, 109, 2551).
- the hydantoins can be prepared from the amine of formula 2 by reaction with phosgene or its equivalent and an amino acid ester. The urea formed is then cyclized to the hydantoin in a basic medium, such as for example NaH, in a 2 nd time.
- a basic medium such as for example NaH
- the invention also relates to the process for the preparation of the compounds of formula 1, characterized in that the amine of formula 2 is reacted with a compound derived from amino acid N-chlorocarbamoyl resulting from the reaction of a secondary amine. derived from amino acid with phosgene or its equivalent, providing a urea and cyclic in a basic medium in a 2nd time.
- W representing a pyrido [2,1-a] isoquinolin-2-ylmethyl
- the present invention also extends to synthetic intermediates of formula 7.
- the present invention also relates to their salified form with inorganic or organic acids.
- the invention relates to compounds in their racemic form but also in their diastereoisomeric and enantiomerically pure form levorotatory and dextrorotatory, due to the presence of several asymmetric centers, and their addition salt.
- the separation of the racemic diastereoisomers can be carried out on a single column, but on the other hand the separation of the enantiomers on each of the pure diastereoisomeric forms can be done either by crystallization of chiral diastereoisomeric salts with optically active acids, or by chiral HPLC preparative column separation, whose chiral stationary phase forms with the racemic compound diastereoisomeric complexes in 2 forms whose elution rates by the mobile phase are different (WH Porter, Pure & Appl., Chem., 1991, 63, 1119 ).
- the basic compound obtained at the end of the synthesis can be treated with an inorganic or organic acid in a stoichiometric proportion to give a crystalline salt. Salts from non-chiral acids will separate racemic diastereoisomeric forms. Salts from chiral acids will separate the enantiomerically pure forms. If appropriate, the acid used may be one of the optically active organic acids such as, but not exclusively, tartaric acid or its derivatives.
- this compound is prepared in several stages described below:
- 1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl) -methylamine obtained in Example 1 of the patent application WO99 / 21856, is obtained after extraction at the last stage, 1-benzo [1,3] dioxol-5-yl-3 - ((2RS, 11bSR) -9-methoxy-1,3,6,7,11b-hexahydro-2f pyrido [2,1-a] -isoquinolin-2-ylmethyl) imidazolidine-2,4-di one in the form of an oil which is flash chromatographed on SiO 2 (elution CH 2 Cl 2 - eOH-NH 4 OH .
- the hydrochloride is formed in ethyl acetate by addition of a solution of HCl in isopropanol (3N) and precipitation in ethyl ether.
- the salt is obtained in the form of a white powder.
- F ° C: 176; C 24 H 27 N 3 O 3 , HCI; PM 456.37; hydrate with 3.16% H 2 0
- Theoric: (corr H 2 O) C% 63.16, H% 6.54, N% 9.21. exp. C% 63.24, H% 6.55, N% 7.93; MS: ESI + , m / z 406 (MH +).
- hydrochlorides of each enantiomer are formed in ethyl acetate by addition of a solution of HCl in isopropanol (3N) and precipitation of the hydrochloride crystals in ethyl ether.
- 3- ((2R, 11bR) -9-methoxy-1,3,4,7,7,11b-hexahydro-2 ⁇ -pyrido [2,1-a] isoquinolin-2-ylmethyl) hydrochloride is obtained) 1-phenylimidazolidine-2,4-dione, and the hydrochloride of 3- ((2S, 1 IbS) -9-methoxy-1,3,4,6,7,11-hexahydro-2ii-pyrido [2], 1- (Isoquinolin-2-ylmethyl) -1-phenylimidazolidine-2,4-dione, in the form of light beige powder, they have, under the experimental conditions described, the following characteristics:
- Racemic According to the same procedure as for example 6 but using amine (2 RS, 11b SR) -9-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2 , 1-a] isoquinolin-2-yl-methyl-amine obtained in Example 1 of the patent application WO99 / 21856 instead of (2RS, 11bSR) -1-1, 3, 4, 6, 7.11-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl-methyl-amine is obtained in 2 stages, after purification on flash chromatography (SiO 2, elution CH 2 Cl 2 - eOH).
- a suspension consisting of 18 g (0.078 mol) of the hydrochloride thus prepared in 20 ml (0.234 mol, 3 eq) of 3-buten-2-one is heated at 60 ° C for 3h. After cooling, the reaction medium is taken up in mass, and the precipitate is organized in acetone and then filtered to provide 17 g (83% yield) of 9,10-dimethoxy-3, 4,6,7-tetrahydro-1H-hydrochloride. pyrido [2,1-a] -isoquinolin-2 (11bH) -one.
- the hydrochloride salt is recrystallized from acetone F ° C: 215. TLC Si0 2 CH 2 Cl 2 - eOH 90-10 Rf 0.65.
- Diastereoisomer A weight lg (yield 13%) TLC Si0 2 Ethyl acetate-MeOH 95-5, Rf 0.46.
- Diastereoisomer B weight lg (yield 13%) TLC SiO 2 Ethyl acetate-MeOH 95-5, Rf 0.36.
- a solution of THF (40 mL) is cooled to 0 ° C.
- a solution of LiAlH 4 (1.0 M in THF, 33 mL, 0.032 mol, 2 eq.) Is added and then 1 mL of concentrated H 2 SO 4 is added dropwise.
- the mixture is stirred at 0 ° C. for 1 h.
- a solution consisting of 4.5 g (0.016 mol) of the diastereoisomeric nitrile A, prepared in Step 2 above, in 30 mL of THF is added dropwise.
- the mixture is allowed to return to room temperature and the stirring is maintained for 2 hours.
- the reaction medium is hydrolysed with a minimum of water and is then extracted with ethyl acetate.
- the hydrochloride is prepared from the base in acetone solution by the addition of HCl in isopropanol to give 0.954 g of 3- ((2RS, 11bRS) -9,10-dimethoxy-1, 3-chlorohydrate. , 4,6,7,11 Ib-hexahydro-2 ⁇ -pyrido [2,1-a] isoquinolin-2-ylmethyl) imidazolidine-2,4-dione as a white powder.
- This compound is obtained according to the procedure described in Steps 1 and 2 of Example 2, with the same raw material, but using the ethyl ester of N-benzyl-glycine in place of the ethyl ester of N-phenylglycine.
- 1-Benzyl-3 - ((2RS), 11bSR) 9-methoxy-1,3,4,6,7,11b-hexahydro-2f-pyrido [2,1-a] isoquinolin-2 is then obtained.
- the compounds of formula 1 were evaluated in vitro, the demonstration of alpha 2 adrenergic antagonist activity, on their receptor subtypes, the products of the present invention was made on the basis of binding tests according to the method described by Wurch et al., (Wurch T, Colpaert FC, Pau PJ, G-protein activation by putative antagonists at mutant Thr373Lys alpha2A adrenergic receptors, Br J Pharmacol 1999, 226 (4): 939-948).
- the measurement is made on the C6 glial cells expressing the human adrenergic receptors (h) h or h 2 c- Briefly, the membranes of the cells comprising the human alpha 2 receptor (10-20 g of protein) are placed in Tris buffer ( 50 mM), at pH 7.6, and incubated at 25 ° C for 120 min with [ 3 H] -RX821002 as radioligand, at concentrations of 2 nM, 10 nM and 4 nM for alpha 2A, 2B and 2C receptors respectively with the test compound in a final volume of 0.5 mL. Nonspecific binding is performed with phentolamine (10 ⁇ ). After filtration, the radioactivity retained is determined by scintillation measurement.
- L the concentration of the radioligand
- K d dissociation constant on the alpha 2 adrenergic receptor subtype concerned.
- the products of the present invention are also evaluated in vivo on cognitive performance, in particular on the test for scopolamine-induced amnesia, according to the protocol described by Chopin et al. (Chopin P, Colpaert FC, Marien M. Effects of acute and subchronic administration of dexefaroxan, a 2- adrenoceptor antagonist, on memory performance in young adults and aged rodents J Pharmacol Exp.Ther 2002; 301: 187-196) which consists in teaching a rat to stop enter a dark compartment (his natural preference) where he previously received an electric shock (0.8 mA). The rat's reluctance to enter the dark compartment (called latency) is measured 48 hours after training.
- This latency is considered as an index of its explicit-declarative memory.
- Scopolamine administered just before training, induces in this model a profound deficit of memory (decrease in latency) that can be antagonized.
- compounds having promnesic properties such as tacrine or dexefaroxan, administered before scopolamine (Chopin et al, 2002, already cited).
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FR1155028A FR2976287B1 (fr) | 2011-06-09 | 2011-06-09 | Derives benzoquinolizidines, leur procede de preparation et leurs applications en therapeutique |
PCT/EP2012/060805 WO2012168368A1 (fr) | 2011-06-09 | 2012-06-07 | Derives benzoquinolizidines, leur procede de preparation et leurs applications en therapeutique |
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EP12729076.5A Withdrawn EP2718291A1 (fr) | 2011-06-09 | 2012-06-07 | Derives benzoquinolizidines, leur procede de preparation et leurs applications en therapeutique |
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EP (1) | EP2718291A1 (fr) |
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US4686226A (en) * | 1985-09-03 | 1987-08-11 | Merck & Co., Inc. | Substituted benzo[b]furo- and benzo[b]thieno quinolizines |
FR2770215B1 (fr) * | 1997-10-28 | 2000-01-14 | Pf Medicament | Derives d'aminomethyl-benzo[a]quinolizidine, leur preparation et leur application en therapeutique pour les maladies neurodegeneratives |
CA2430328A1 (fr) * | 2001-09-28 | 2003-04-10 | Kyowa Hakko Kogyo Co., Ltd. | Antagoniste de recepteur |
AR052342A1 (es) | 2004-12-21 | 2007-03-14 | Janssen Pharmaceutica Nv | Derivados sustituidos de triazolona,tetrazolona e imidazolona con actividad selectiva antagonista de alfa2c-adenoreceptores |
RU2008150485A (ru) | 2006-05-22 | 2010-06-27 | Янссен Фармацевтика Н.В. (Be) | Замещенные производные пиразинона для применения в качестве лекарственного средства |
JP2010505908A (ja) | 2006-10-12 | 2010-02-25 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 薬剤として用いるための置換ピラジノン誘導体 |
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FR2976287B1 (fr) | 2013-07-05 |
WO2012168368A1 (fr) | 2012-12-13 |
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