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  • 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
  • C07D471/22—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 systems contains four or more hetero rings
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • 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
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  • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel triazabenzo [ ⁇ ] naphtho [2,1,8- ⁇ fe] azulene derivatives, process for their preparation and pharmaceutical compositions containing them.
• the patent application EP 0 658 557 discloses eburnane derivatives modified at position 14 and 15 of the skeleton of the skull.
• the patent application EP 0 563 916 describes 1H-indole-cyclohexanecarboxamide derivatives.
• the compounds of the present invention besides being new, have very interesting pharmacological properties. They prove to be particularly powerful tyrosine hydroxylase inducers, selectively or not.
• - Ri represents a hydrogen atom or an alkyl group (C 1 -C 6) linear or branched aminoalkyl (CpC 6) linear or branched, or hydroxy (Ci-C 6) linear or branched,
• R 2 represents a hydrogen atom, or R 1 and R 2 together with the carbon atoms that carry them form a carbon-carbon bond,
• R 3 represents a hydrogen atom
• R 4 represents a hydrogen atom or a methyl or alkyl group (C 3 -C 6) linear or branched, amino (C 1 -C 6) linear or branched, hydroxy (Ci-C 6) linear or branched aryl- ( Ci-C 6 ) linear or branched, heterocycloalkyl (C 1 -C 6 ) alkyl linear or branched, or R 3 and R 4 together with the carbon atoms that carry them form a carbon-carbon bond,
• R 5, R 6, R 7, R 8, identical or different, independently of one another represent a hydrogen atom, or two geminal substituents (R 5 and R 6 and / or R 7 and R 8 ) form an oxo, thioxo or imino group,
• R 9 represents a hydrogen or halogen atom or an optionally substituted linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) alkoxy, hydroxy, cyano, nitro or polyhaloalkyl (C 1 -C 6 ) group; C 6) linear or branched, amino (optionally substituted by one or two alkyl (Ci-C 6) linear or branched, alkenyl (C 2 -C 6) -straight or branched alkyl and alkenyl may be the same or different),
• Rn identical or different, independently of one another, represent a hydrogen or halogen atom or a linear (Ci-C 6 ) alkyl group or branched, straight or branched chain alkoxy (C 1 -C 6 ), linear or branched hydroxy, cyano, nitro, polyhaloalkyl (C 1 -C 6 ), amino (optionally substituted by one or two straight or branched (C 1 -C 6 ) alkyl, alkenyl (C) 2 -C 6 ) linear or branched, alkyl and alkenyl may be the same or different),
• n an integer between 0 and 4 (0, 1, 2, 3, 4),
• n an integer between 0 and 2 (0, 1, 2)
• p represents an integer between 0 and 3 (0, 1, 2,3)
• X represents a group NR 12 ,
• Ri 2 represents a hydrogen atom or an alkyl (Ci-C 6) linear or branched, optionally substituted alkenyl (C 2 -C 6) linear or branched, optionally substituted aryl (Ci-C 6) linear or branched polyhaloalkyl (Ci-C 6 ) linear or branched,
• arylalkyl means the aryl-alkyl group in which the alkyl group denotes a linear or branched chain of 1 to 6 carbon atoms and the aryl group denotes an optionally substituted phenyl or naphthyl group,
• alkyl (C 1 - C 6) linear, branched alkenyl or (C 2 -C 6) -straight or branched alkyl or arylalkyl group means that these groups may be substituted by one or more atoms of halogen, one or more hydroxyl groups, linear or branched (C 1 -C 6 ) alkoxy or amino optionally substituted with one or two groups, identical or different, alkyl (C 1 -C 6 ), C 6 ) linear or branched,
• hydrochloric hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methane acids. sulfonic, camphoric, etc.
• pharmaceutically acceptable bases mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, lysine, etc.
• An advantageous variant relates to the compounds of formula (I) for which X represents a group NR 12 in which R 12 represents a hydrogen atom.
• Another advantageous variant relates to the compounds of formula (I) for which R 1, R 2 , R 3 and R 4 each represent a hydrogen atom.
• Another particular aspect of the invention relates to the compounds of formula (I) for which R 1 and R 2 together with the carbon atoms which carry them form a carbon-carbon bond.
• Rg advantageously represents a hydrogen or halogen atom.
• the preferred compounds of the invention are the compounds of formula (I) for which the two geminal substituents (R 5 and R 6 and R 7 and R 8 ) form an oxo group each.
• Another particular aspect of the invention relates to the compounds of formula (I) for wherein R 5 and R 0 each represent a hydrogen atom and the two geminal substituents (R 7 and R 8 ) form an oxo group.
• Enantiomers, diastereoisomers, N-oxides, as well as pharmaceutically acceptable acid or base addition salts of preferred compounds form an integral part of the invention.
• ⁇ -enantiomer and ⁇ -enantiomer are understood to mean the optically pure enantiomers of the corresponding racemic mixture.
• ⁇ -enantiomer and ⁇ -enantiomer are understood to mean the optically pure enantiomers of the corresponding racemic mixture.
• enantiomer ⁇ means that if the enantiomer ⁇ represents the (5a 123, 12bS, 12C5) -7-chloro-2,3,4,5,5a, 10,11,12a, 12b, 12c-decahydro-1H, 12H-3a, 9b, 11-triazabenzo [ ⁇ ] naphtho [2,1, 5-cde] azu-en-12-one (enantiomer ⁇ ) means that if the enantiomer ⁇ represents the (5a 123, 12bS, 12C5) -7-chloro-2,3,4,5,5a, 10,11,12a, 12b, 12c-decahydro-1H, 12H-3a, 9b, 11-triazabenzo [ ⁇ ] naphtho [2,1,8-c] azulen-12-one, then the ⁇ -enantiomer represents (5aS ', 12a / 12b / 12cc) - 7-chloro-2,3 4,5,5a, 10,11,12
• the present invention also extends to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) (the route of synthesis of which is described by RN Schut and Stuttgart, J. and Chem., 3 (1966), 101-102):
• R 1 represents a linear or branched (Ci-C 6 ) alkyl group and HaI represents a halogen atom, to yield the compound of formula (IV):
• R ', R 1, R 2, R n, n, m and p are as defined above, which are subjected to a hydrogenation reaction in the presence of sodium cyanoborohydride and acetic acid in anhydrous medium, to conduct to a mixture of cis enantiomers of formula (Vcis):
• R ', R 9 , Rio, Rn, n, m and p are as defined above, which are subject:
• R ' 5 and R' 6 each represent a hydrogen atom or together form an oxo group and R 9 , R 10 , R 11 , n, m and p are as defined above, which are reduced in the presence of an alkaline hydride to give the compound of formula (I / d), in particular the compounds of formula (I):
• R'5, R ' 6 , R 9 , R 1 Q, Rn, n, m and p are as defined above,
• the compounds of formula (I) have interesting pharmacological properties and in particular that of being powerful inducers of tyrosine hydroxylase (TH).
• Tyrosine hydroxylase is known to be a limiting enzyme that particularly controls the synthesis of neurotransmitters in central catecholaminergic and dopaminergic neurons.
• the speed of synthesis of these neurotransmitters is particularly related to the appearance of tonic brain dysfunctions that are many behavioral pathologies in humans, such as anxiety, psychosis, depression, stress, etc.
• the compounds of the invention therefore find their therapeutic use in the treatment of depressions, anxiety, memory disorders during senescence and / or neurodegenerative diseases, and in the palliative treatment of Parkinson's disease and for adaptation to stress.
• the subject of the present invention is also pharmaceutical compositions containing, as active ingredient, at least one compound of formula (I), its enantiomers, diastereoisomers, N-oxides or one of its addition salts with a base or a pharmaceutically acceptable acid, alone. or in combination with one or more inert, pharmaceutically acceptable, non-toxic excipients or carriers.
• compositions thus obtained are generally in metered form. They may for example take the form of tablets, dragees, capsules, suppositories, injectable or oral solutions and be administered orally, rectally, intramuscular or parenteral.
• compositions according to the invention mention will be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular, or subcutaneous), per-or trans-cutaneous, intravaginal, rectal, nasal, perlingual, oral administration. , ocular or respiratory.
• compositions according to the invention for parenteral injections comprise, in particular, aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstituting injectable solutions or dispersions.
• compositions according to the invention for solid oral administrations, comprise, in particular, single or coated tablets, sublingual tablets, sachets, capsules, granules, and for oral, nasal, oral or ocular liquid administrations, especially comprising emulsions, solutions, suspensions, drops, syrups and aerosols.
• compositions for rectal or vaginal administration are preferably suppositories or ovules, and those for percutaneous or transdermal administration include, in particular, powders, aerosols, creams, ointments, gels and patches.
• compositions cited above illustrate the invention but do not limit it in any way.
• inert, non-toxic, pharmaceutically acceptable excipients or vehicles mention may be made, by way of indication and not limitation, of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, blowing agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, dyes, flavoring agents, etc.
• the dosage varies depending on the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the condition, and the taking of any associated treatments.
• the dosage ranges from 0.1 mg to 100 mg in one or more doses per day.
• the starting materials used are known products or prepared according to known procedures.
• the different preparations lead to synthetic intermediates useful for the preparation of the compounds of the invention.
• PREPARATION 1 (1SR, 7aRS, 12aSR, 12bSR) -9-Chloro-1,2,3,4,6,7,7a, 12,12a, 2b-decahydroindolo [2,3-lquinolizine-1-carboxylic acid ethyl ester
• Step A 1- [2- (5-Chloro-1-indol-3-vinyl-2-piperidin)
• Stage B 9-chloro-2.3.4,6,7,12-hexahydro-1H-indolo- [2,3-alquinolizin-5-ylium tetrafluoroborate
• 16 ml of acetic acid are added to a solution of 16 g of the product of Step D above in 300 ml of distilled THF.
• 4.4 g NaBH 3 CN are added in small portions under a nitrogen atmosphere and at 0 0 C, then the reaction mixture is stirred vigorously at room temperature for 12 h.
• a saturated solution of Na 2 CO 3 is then added at 0 ° C., and the solvent is then evaporated off under reduced pressure.
• 200 ml of CH 2 Cl 2 and 80 ml of water are added to the residue. After extraction with CH 2 Cl 2 , the organic phases are washed with a saturated solution of sodium chloride, dried over Na 2 SO 4 and then concentrated under reduced pressure.
• Stage G ⁇ SRJaRS ⁇ 2aSRq2bSR) -9-Chloro-1.23A6JJa, 12.12a, 12b-decahydroindolo [2,3-fl-quinolizine-1-ethyl carboxylate (trans-diastereoisomer)
• EXAMPLE 1 (5aRSJ2aSRa2bSR.12cSR) -7-Chloro-2,3,4,5,5a.l0.11.12aa2ba2c-decahydro-yl2H-3a, 9b, 11-triazabenzoflnaphthyl2, 1,8-crfglazulen-12-one
• Step A ⁇ SRJaRS, 12aSRa2bSR) -9-Chloro-1,2,3,4,6,7,7a, 12,12a, 12b-decahydroindolo [2,3- ⁇ -quinolizine-1-carboxamide
• the aqueous phase is basified with saturated Na 2 CO 3 solution to pH 10 and extracted with dichloromethane (3 x 100 ml).
• the organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure.
• the amide is purified by washing with diethyl ether (100 ml) to give 2.37 g of the expected product.
• Step B (5aRSa2aSRa2bS / ?, 12cSR) -7-Chloro-2,3,4,5.5a, 10,11,12a2b2c-decahydro-1H, 12H-3a, 9bai-triazabenzo [ ⁇ 1-naphtho [2a8-crfglazulen-12- one
• EXAMPLE 2 (5aRSa2aSRa2bSRa2cSR) -7-Chloro-2,3,5aa2aa2ba2c-hexahydro-1H, 4H-3a, 9bai-triazabenzoranaphtho [2a, 8-c] ociperene-10a2r5HaiH) -dione
• Step A (1SR, 7aRSa 2aSRa 2bSi 2) - 12-aminocarbonyl-9-chloro
• Step B (5aRSa2aSR, 12bSRa2cSR) -7-Chloro-2,3,5a, 12aa2ba2c-hexahydro-l J y, 4H-3a, 9, l l-triazahenzo
• EXAMPLE 5 (5aS, 12aRq2bR, 12cR) or (5aRa2aS, 12bSa2c5) -2,3,5aJ2aa2b, 12c-hexahydro-1,4H-3a, 9bai-triazabenzo [1H] naphtho [2a, 8-c] / oleolene-10a2 ( 5HaiH) - dione (enantiomer ⁇ )
• EXAMPLE 6 (5aSi2a / U2biU2cR) or f5aR.12aS, 12bSJ2cS) -2.3.5a.l2a, 12ba2c-Hexahydro-1 / r, 4H-3a, 9b, 11-triazabenzofanaphthor2.1.8-c ⁇ / glazulene 10.12 (5 / ⁇ ll / ⁇ -dione ( ⁇ -enantiomer)
• the compound of Example 4 is split by fractional crystallization of the diastereomeric salts prepared by adding to a methanolic solution of the compound of Example 4, or a solution of (-) - di-O, O '- / ⁇ -toluyl-L-tartaric acid, a solution of (+) - di-O, O'-p ⁇ ra-toluyl-D-tartaric acid. After separation of the diastereoisomeric salt, the base is isolated according to conventional treatment. Jusion PpM ⁇ 250 ° C
• TH protein tyrosine hydroxylase
• mice used are male mice of the Balb / C pure line (Charles River Laboratories), aged from 7 to 8 weeks at the time of treatment.
• mice receive a single intraperitoneal injection of the test compound, dissolved in a solution of 0.04 M HCl (corresponding control: 0.004 M HCl) if the compound is sufficiently soluble, or in 90% olive oil / DMSO 10% (corresponding control: olive oil 90% / DMSO 10%) for the insoluble compounds in aqueous medium.
• Coronal slices 8 microns thick are made along the postero-anterior axis of the LC and fixed. The sections are transferred to Immobilon-P membranes. TH is measured by immunodetection and image analysis. Results:
• the affinity for the receptors is determined according to the usual methods of relationship between the specific ligand and the receptor, which may be of animal origin or a human recombinant. It was determined by the method of displacement of the specific ligand labeled by the test compound, and expressed by the dissociation constant K 1.
• the receptor affinity for 28 standard receptors has thus been studied.
• the study shows that the induction of TH observed does not go through an affinity towards the receptors usually affected by psychotropic products, such as alpha ( ⁇ 2 type), 5HT (type 5HT2A) adrenergic receptors, dopaminergic (type D 1 and D 2 ).
• the prediction of metabolic stability is tested by incubation of the derivatives at a concentration of 10 -7 M in the presence of mouse, rat or human liver microsomes (0.33 mg prot / ml) After addition of NADPH (nicotinamide adenine dinucleotide) phosphate, reduced form), samples are taken at 0, 5, 15, 30 and 60 minutes. The enzymatic reaction is stopped with methanol (VfV) - The protein is precipitated by centrifugation and the supernatant analyzed by LC-MS-MS The good metabolic stability of these derivatives makes it possible to envisage an oral treatment.
• NADPH nicotinamide adenine dinucleotide

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