FR2904973A1 - New methylidene-pyrido(3,4-b)indole derivatives are 5-hydroxytryptamine-2 receptor antagonists useful to treat e.g. sleep disorders, stress, depression, anxiety, insomnia, schizophrenia, Parkinson's disease and psoriasis - Google Patents

Abstract

Methylidene-pyrido[3,4-b]indole derivatives (I) and their salts, isomers, enantiomers and/or diastereoisomeres are new. Methylidene-pyrido[3,4-b]indole derivatives of formula (I) and their salts, isomers, enantiomers and/or diastereoisomeres are new. R1H (preferred) or 1-6C alkoxy; R2H (preferred) or 1-6C alkyl; R3H (preferred), 1-6C alkyl or aryl (optionally substituted by 1-6C alkyl); R43-10 member heteroaryl (optionally substituted by 1-6C alkyl and containing 1 or 2 heteroatoms of O, N or S atoms), -CN, -(C=O)R7, -(C=S)NH2, -(C=NOH)NH2 or -(C=NOH)NH(C=O)R5; R7NH2, 1-6C alkyl, phenyl (optionally substituted by 1-6C alkyl), halo or 1-6C alkoxy; and R5H or 1-6C alkyl (optionally substituted by halo). Independent claims are included for: (1) 9 preparations of (I); (2) a combination comprising (I) and 5-hydroxytryptamine-2 (5HT2) receptor antagonist, such as hexahydro-1H-beta-carboline compound of formula (XIV) or 1H-spiro[indole-3,3'-pyrrolidin]-2-one compound of formula (XIVa); and (3) a composition comprising (I), the 5HT2 receptor antagonist and an excipient, where the combination product is used in time interval to regulate the circadian sleep-wake cycle. R181-12C alkyl, phenyl (optionally substituted by 1-6C alkoxy) or phenyl(1-6C alkyl), halo or secondary amino; and dotted line : absent or a bond (where R16 and R17 are absent when the dotted is a bond or R16 and R17 are H, when dotted line is absent). [Image] [Image] ACTIVITY : Hypnotic; Neuroleptic; Neuroprotective; Tranquilizer; Antidepressant; Anticonvulsant; Antiparkinsonian; Nootropic; Cytostatic; Dermatological; Antipsoriatic; Antiseborrheic; Fungicide; Ophthalmological; Immunomodulator; Gynecological; Contraceptive. The hypnotic activity of (I) was tested in chicken. The result showed that 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-ethylidenecarboxamidoxime at 1 mg/kg caused a sleep time of 55 minutes. MECHANISM OF ACTION : 5-Hydroxytryptamine-2 (5HT2) receptor antagonist; Allosteric modulator.

Description

The present invention relates to novel derivatives of

  1-methylidene-pyrido [3,4-b] indole and their therapeutic use, advantageously as 5-HT2 serotonin receptor agonists, by allosteric modulation, advantageously in the treatment of sleep disorders. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland isolated by Lerner et al. (J. Am Chem Soc., 80, 1958, 2587). Melatonin has been studied extensively for its circadian activity, particularly in the rhythm of sleep, for its effects on testosterone production, for its hypothalamus activity, and for psychiatric disorders.

  It has thus been envisaged to use melatonin and its analogues, in particular for the treatment of depression and psychiatric disorders, in particular stress, anxiety, depression, insomnia, schizophrenia, psychoses, epilepsy, but also for the treatment of travel-related sleep disorders (jet lag), neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease, for the treatment of cancers, or as a contraceptive, or as an analgesic.  However, the direct use of melatonin in vivo has not been very satisfactory, given a first hepatic passage that extracts more than 90% of the active ingredient.  Various analogs of melatonin have been described, highlighting two research pathways that relate to either the melatonin substituents (WO-A-89/01472, US-A-5,283,343, US-A-5,093). 352 or WO-A-93/11761), or on the aromatic ring by replacing the indolyl group with a naphthyl (FR-A-2 658 818, FR-A-2 689 124).  The present patent application therefore relates to the preparation and use as medicament of novel 1-methylidene-pyrido [3,4-b] indole derivatives.  Furthermore, the inventors have demonstrated that melatonin, with the exception of its antioxidant and free radical neutralization properties, makes melatonin an extremely effective pharmacological agent against free radical damage and against neuronal losses. , in order to prevent neurodegenerative processes, does not directly regulate the circadian sleep-wake cycle, but is only a biological precursor of two metabolites that exhibit pharmacological activities.  It has thus surprisingly been found by the inventors that, during the nocturnal sleep time, and whatever the season, melatonin produced in the pineal gland, following a first acetylation of serotonin, facilitated by N-cells. acetyltransferases, undergoes, from its production, a second step of enzymatic acetylation by N-acetyltransferases, giving successively two derivatives of (3-carboline, namely 6-methoxy-1-methyl-3,4-dihydro-3 carbolin, called 6-methoxy-harmalan (6-MH), and 2-acetyl-6-methoxy-1-methylene-3,4-dihydro- (3-carboline, called valentonine (VLT (Figure 1)).  The production of 6-methoxy harmalan (6-Ml) in the pineal gland was demonstrated by Farrell and Mc Isaac (Farrell, G. , et al. , Arch. Bioch. BioPh. , 94, 1961, 543-544 - Mc Isaac, W. Mr. , et al. , Science, 134, 1961, 674-675), in 1961, from pineal glands of oxen killed early in the morning at slaughterhouses in Chicago.  As indicated above, 6-MH, which is therefore produced in conjunction with the VLT, is a serotonin antagonist to serotonin 5HT2 receptors, which are neuroinhibitory (their activation by serotonin causes a decrease in alertness and mood).  By blocking them, 6-MH inhibits their activation by serotonin.  As a result, the increase in alertness maintains the state of awakening; This results in an increase in alertness which confers on the 6-MH a psycho-stimulating activity.  Moreover, in the tests that the inventors performed on chicks, unlike the VLT, which exhibits significant hypnotic activity, as shown in Table VI below, 6-MH increases locomotion, which corresponds to psycho-stimulating activity.  Its psycho-stimulant activity, slightly weaker than that of lysergic acid diethylamide (LSD), another 5HT2 serotoninergic receptor antagonist, allows the body to go from the state of sleep unconsciousness to a state of wakefulness consciousness, increasing vigilance.  For this reason, 6-MH can be considered the hormone of the day before.  Moreover, as shown in Table VI below, the VLT exhibits important hypnotic properties, both from a qualitative point of view (EEG physiological sleep architecture) and from a quantitative point of view; and, given the fact that the biosynthesis of the VLT and night-time sleep are associated over time, it can be considered that the VLT, involved in the induction and maintenance of the nocturnal sleep state, is the hormone of sleep.  Like most endogenous compounds, the VLT can not be administered orally because of its hydrolysis in the acidic gastric medium; Various acid-stable analogues called valentonergic which are most often beta-carboline derivatives, and hence melatonin, have been synthesized.  Thus, all the studies conducted by the inventors show that VLT and valentonergic (WO 96/08490, WO 97/06140, WO 97/11056, US 6,048,868, WO 99/47521, WO 00/64897, WO 02 / 092598), reveal important hypnotic properties, never observed, with respect to the electroencephalographic structure of sleep, with hypnotic drugs available on the market, such as, for example, benzodiazepines and zolpidem.  Indeed, benzodiazepines and zolpidem produce a nonphysiological sleep, characterized by the predominance of light sleep S1 and very little paradoxical sleep (see Table VI below), referred to as so-called anesthetic sleep, because it is less restorative for organism, and gives amnesia.  In contrast, VLT and valentonergics produce sleep, whose EEG architecture is similar to that of physiological sleep, characterized by the predominance of deep slow sleep (SLP) (S2 + S3) and high percentages of paradoxical sleep.  VLT and valentonergic drugs induce sleep by decreasing alertness, as a result of allosteric modulation activation of serotonergic 5-HT2 receptors.  For these reasons, valentonergics can be used in the treatment of sleep disorders.  VLT and valentonergics are thus activators of the 5HT2 receptor by allosteric modulation.  The present invention thus relates to new valentonergic: 1-methylidene-pyrido [3,4-b] indole derivatives.  The role of the [(valentonine) - (6-methoxy harmalan)] system in the regulation of the circadian sleep-wake cycle can be summarized as follows: 1 - The VLT, sleep hormone, produced in the pineal body, during the period of sleep, between 20 hours and 4 hours GMT, by the enzymatic acetylation of the MLT, induces and maintains the state of sleep as a consequence of its capacity to decrease the vigilance after the activation of the 5-HT2 receptors by allosteric modulation , using its allosteric ligand.  The VLT remains prevalent during the sleep period, which means that concentrations in the vicinity of 5-HT2 receptors are higher than those of 6-MH.  2 - Early in the morning, at 4:00 GMT, the biosynthesis of both the VLT and 6-MH stops, as the NAT decreases in the pineal body; therefore, since the rate of VLT elimination is greater than that of 6-MH (FIG. 2), the hormone of the previous day becomes prevalent.  Therefore, between 4 am and 8 pm GMT, 6-MH antagonizes the 5-HT2 receptors by blocking them, which inhibits their activation by serotonin.  As a result, vigilance increases, and the waking state is maintained until 20 hours GMT.  Thus, the combination of VLT and 6-MH in the [(valentonine) - (6-methoxy harmalan)] system makes it possible to regulate the circadian sleep-wake cycle.  Indeed, the ability of the VLT to bind and thereafter activate, by allosteric modulation, the a2 adrenergic receptors, as well as the dopaminergic D 1 and D 2 receptors, explains how blood pressure and muscle tone decrease during the sleep period. night.  On the other hand, 6-MH, when its concentrations are higher than those of the VLT, during the activity period (standby), by blocking the 5-HT2, adrenergic α2 and dopaminergic D1 and D2 receptors, induces pharmacological activities which are opposed to those previously described of the VLT.  Therefore, the mechanism of the regulation of the circadian sleep-wake cycle is controlled by the [(VLT) - (6-MH)] system.  The dysfunctions of the system [(VLT) - (6-MH)] make it possible to explain the biological mechanisms, unknown until now, insomnia, depression and mood disorders, psychotic states, Parkinson's and Alzheimer's disease.  A decrease in the biosynthesis of VLT, and at the same time of 6-5 MH, is observed in primary insomnia, Parkinson's disease and Alzheimer's disease.  In depressions the biosynthesis of the VLT is normal, but insufficient to lower the vigilance increased by the stress at the origin of the depressive state In these disorders characterized by sleep disorders, it seems necessary to treat such disorders by administering a valentonergic.  In addition, the treatment of Parkinson's disease by valentonergic is justified by their dopaminergic agonist properties.  Furthermore, the authors found that psychotic states were due to excessive biosynthesis of 6-MH, resulting in an exaltation of alertness and mood due to excessive blockade of serotonergic 5-HT2 receptors.  These conditions may be treated by administration of valentonergic, which may displace 6-MH in excess of its attachment sites to 5-HT2 receptors, which should cause a decrease in alertness.  On the other hand, when the [(VLT) - (6-MH)] system dysfunction corresponds to a decrease in the biosynthesis of the VLT in conjunction with that of 6-MH, it seems necessary to treat such disorders by giving a combination of of valentonergic and 6-methoxy harmalan.  Indeed, taking into account that the circadian sleep-wake cycle is controlled by the [(valentonine) - (6-methoxy harmalan)] system, the VLT, sleep hormone, or synthetic valentonergic analogs, must be given together with an appropriate amount of 6-MH, the hormone of the day before, for good regulation of the circadian sleep-wake cycle.  In addition, the inventors have also discovered that the combination of VLT or valentonergic with 6-MH or its analogs can treat Alzheimer's disease.  Indeed, cognitive dysfunction is one of the most striking age-related disorders in humans and animals.  This disorder is probably due to the vulnerability of brain cells to increasing oxidative stress during the aging process.  The hormone secreted by the pineal gland, melatonin (MLT), has been described as an endogenous antioxidant, the peak plasma concentration of which declines during aging and in Alzheimer's disease (AD).  The secretion of MLT is significantly lower in patients with Alzheimer's, compared with healthy subjects of the same age.  A sleep-wake rhythm disorder is common in patients with Alzheimer's disease, and is correlated with a decrease in MLT concentrations and a circadian circulatory rhythm of disrupted MLT.  The direct consequences of the decrease in MLT secretion by the pineal gland, in patients with AD, are insomnia and cognitive dysfunction, related to decreases in the biosynthetic pathways of the VLT, sleep hormone, and 6-MH, hormone of the day before, respectively.  On the other hand, Parkinson's disease may be due to insufficient biosynthesis of the VLT during the sleep period.  Patients with Parkinson's disease, have sleep disorders.  It is interesting to note that 30% of patients with Parkinson's disease subsequently contract Alzheimer's disease.  Under these conditions, treatment of Parkinson's disease by VLT or valentonergic, administered for its dopaminergic agonist properties, can only be accomplished by administering the combination of VLT or valentonergic drugs with 6-MH. or its analogues, in order to harmoniously regulate the sleep-wake cycle.  The present invention therefore relates to the synthesis of new valentonergic derivatives of 1-methylidene-pyrido [3,4-b] indole and their use alone or in combination as a drug.  The present invention therefore relates to a 1-methylidene-pyrido [3,4-b] indole derivative of the following general formula (I): embedded image in which: R 1 represents a hydrogen atom or an alkoxy group C1-C6; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a hydrogen atom, a C1-C6 alkyl group, advantageously methyl or ethyl, or an aryl group, advantageously phenyl, the aryl group being optionally substituted with a C1-C6 alkyl group; R 4 represents: a heteroaryl group of 3 to 10 atoms, preferably 5 to 9 atoms, containing one or two identical or different heteroatoms selected from O, N or S, the other atoms being carbon atoms, the heteroaryl group optionally being substituted with a C1-C6 alkyl group; a -CN group; a group - (C = O) R7, in which R7 represents an NH2 group, a C1-C6 alkyl group, advantageously methyl, or a phenyl, the phenyl being optionally substituted with a C1-C6 alkyl group, advantageously methyl; a halogen atom, advantageously F or Cl, or a C1-C6 alkoxy group, advantageously methoxy; a group - (C = S) NH 2; A group - (C = NOH) NH 2; or a group - (C = NOH) NH (C = O) R5, in which R5 represents a hydrogen atom or a C1-C6 alkyl group, the alkyl group being optionally substituted with one or more halogen atoms, preferably fluorine (advantageously it is the group (CF3)); Or mixtures thereof, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof.  For the purposes of the present invention, the term "C1-C6 alkyl group" means any alkyl group of 1 to 6 carbon atoms, linear or branched, in particular the methyl, ethyl, n-propyl or isopropyl groups, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl.  Advantageously it is a methyl or ethyl group.  For the purposes of the present invention, the term "C1-C6 alkoxy group" means any alkoxy group of 1 to 6 carbon atoms, linear or branched, in particular the OCH 3 group.  By the term aryl group is meant in the sense of the present invention one or more aromatic rings having 5 to 10 carbon atoms, which can be contiguous or fused.  In particular, the aryl groups can be monocyclic or bicyclic groups, preferably phenyl, naphthyl, tetrahydronaphthyl or indanyl.  Advantageously, it is a phenyl or naphthyl group.  Even more advantageously, it is the phenyl group.  For the purposes of the present invention, the term "heteroaryl group" means any aromatic hydrocarbon group of 3 to 10 atoms, advantageously 5 to 9 atoms, containing one or two identical or different heteroatoms, such as, for example, sulfur atoms, nitrogen or oxygen, and may carry one or more substituents, such as, for example, a C1-C6 alkyl group.  The heteroaryl according to the present invention may consist of one or two fused or fused aromatic rings, each ring possibly having 1 or 2 heteroatoms.  Examples of heteroaryl groups are furyl, isoxazyl, pyridyl, pyrimidyl, benzimidazole, benzoxazole, benzothiazole.  Advantageously, the heteroaryl group is chosen from pyridyl, benzimidazole, benzoxazole and benzothiazole groups.  In the present invention is meant by isomers compounds which have identical molecular formulas but differ in the arrangement of their atoms in space.  Isomers that differ in the arrangement of their atoms in space are referred to as stereoisomers.  Stereoisomers which are not mirror images of each other are referred to as diastereoisomers, and stereoisomers which are nonimposable mirror images are termed enantiomers, or sometimes optical isomers.  A carbon atom bonded to four nonidentical substituents is called a chiral center.   Chiral isomer means a compound with a chiral center.  It has two enantiomeric forms of opposite chirality and can exist either as an individual enantiomer or as a mixture of enantiomers.  A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is referred to as a racemic mixture.  In the present invention, the term pharmaceutically acceptable is understood to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary as well as pharmaceutical use. human.  By pharmaceutically acceptable salts of a compound are meant salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound.  Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; either coordinates with an organic or inorganic base.  Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.  Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.  Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid, methanesulfonic acid and phosphoric acid.  Advantageously, it is methanesulfonic acid.  It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt.   Crystalline (or polymorphic) forms signify crystalline structures in which a compound can crystallize under different arrangements of crystalline stacks, all of which have the same elemental composition.  Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, hardness, density, crystal form, optical and electrical properties, stability and solubility.  The recrystallization solvent, crystallization rate, storage temperature, and other factors may cause crystalline form to dominate.   Solvates mean solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent.  Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.  If the solvent is water, the solvate formed is a hydrate, when the solvent is an alcohol, the solvate formed is an alcoholate.  Hydrates are formed by the combination of one or more water molecules with one of the substances in which the water retains its molecular state in the form of H 2 O, such a combination being capable of forming one or more hydrates.  Compounds of general formula I are 1-methylidene-1,2,3,4-tetrahydro-pyrido [3,4-b] indole derivatives of the following general formula: ## STR1 ## These novel compounds are useful because of their therapeutic activity and valuable intermediates for the elaboration of other related pyrido [3,4-b] indoles or heterocycles structures.  The subject of the present invention is also a methylidene-pyrido [3,4-b] indole derivative according to the present invention, characterized in that it is chosen from the compounds of general formulas (II), (III), ( IV) and (V): wherein R1 to R3 and R7 are as defined in the general formula (I), X represents a sulfur atom or NOH group, R6 represents an NH2 group or a group -NH (C = O) R5 in which R5 is as defined in the general formula (I), Het represents heteroaryl group of 3 to 10 atoms, advantageously 5 to 9 atoms, containing one or two identical or different heteroatoms selected from O, N or S, the other atoms being carbon atoms, the heteroaryl group being optionally substituted with a C1-C6 alkyl group; Or mixtures thereof, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof.  Advantageously, the methylidene derivative. -pyrido [3,4-b] -indole according to the present invention is chosen from the compounds of formulas 1 to 47 below: HCN MeO / H 10 1 2 CH 3 3 CN H 4 H MeO MeO, 6 N NH NNH N ' ## STR00005 ## ## STR2 ## ## STR2 ## ## STR15 ## ## STR2 ## 18 19 2904973 MeO 14 20 21 / H NH2 H NOH S / H / NH2 CH3 NOH 23 MeO ~~ 1 NNH NOH 22 NHCOCH3 NOH NOH 5 24 25 27 28 29 2904973 15 30 31 32 33 MeO 36 37 H3 5 38 39 2904973 The present invention also relates to a process for the preparation of a compound of general formula (II) according to the present invention in which R 2 represents a hydrogen atom by reaction of Bischler- Napieralski of the compound of the following general formula (VI): wherein R 1 and R 3 are as defined in the general formula (II), with phosphorus pentoxide or phosphorus oxychloride, by heating in toluene.  Advantageously, the compound of general formula (VI) amidification of the compound of general formula (VII) below: R 1 NH 2 H VII wherein R 1 is as defined in general formula (II), with the compound of general formula (VIII) next CN OEt R3 10 0 (VIII) wherein R3 is as defined in the general formula (II), preferably by heating without solvent or with dioxane.  It further relates to a process for the preparation of a compound of the general formula (II) according to the present invention in which R2 represents a C1-C6 alkyl group, by alkylation of the compound of the general formula (II) according to the present invention in which R2 represents a hydrogen atom, by means of an alkyl iodide of formula R 2 in which R 2 represents a C 1 -C 6 alkyl group, advantageously in a mixture of dichloromethane and an aqueous sodium hydroxide solution in the presence of benzyltrimethylammonium.  Thus, these processes can be represented by the following synthetic methods: ## STR1 ## R 1 is preferably obtained by the following methods: ## STR1 ## ## STR1 ## process for the preparation of a compound of general formula (III) according to the present invention in which R7 represents an NH2 group by heating at 80 ° C. in the polyphosphoric acid the compound of general formula (II) according to the present invention.  Thus, this process can be represented by the following synthesis method: The present invention furthermore relates to a process for preparing a compound of general formula (IV) according to the present invention in which X represents a sulfur atom and R 6 represents the NH 2 group by reacting the compound of the general formula (II) according to the present invention with the thioacetamide CH3CSNH2, advantageously in a solution of dimethylformamide in the presence of hydrochloric acid.  Thus, this process can be represented by the following synthetic method: ## STR1 ## The present invention also relates to a process for the preparation of a compound of general formula (IV) according to US Pat. wherein X is NOH and R6 is NH2 by refluxing the compound of the general formula (II) according to the present invention in an aqueous hydroxylamine solution.  It furthermore relates to a process for the preparation of a compound of the general formula (IV) according to the present invention in which X represents a NOH group and R6 represents the group -NHCOR5 in which R5 is as defined in the general formula (IV) by reacting the compound of the general formula (IV) according to the present invention wherein X is NOH and R6 is NH2 with the acid anhydride of the following general formula (IX) (R5CO) wherein R 5 is as defined in general formula (IV), advantageously in a solution of diethyl ether or benzene.  Thus, these processes can be represented by the following synthetic methods: ## STR1 ## The present invention furthermore relates to a process for the preparation of a compound of general formula (V) according to the present invention by Bischler-Napieralski reaction of the compound of general formula (X): HN Tf Het HX in which Het is as defined in general formula (V), with phosphoric anhydride or phosphorus oxychloride, advantageously by heating in toluene.  Advantageously, the compound of general formula (X) is obtained by paramidification of the compound of general formula (VII) according to the present invention in which R 1 represents a hydrogen atom with the compound of general formula (XI) below: Het O (XI in which Het is as defined in the general formula (V), advantageously by heating without solvent or with dioxane.  Thus, these processes may be represented by the following synthetic methods: ## STR2 ## The present invention further relates to a process for the preparation of a compound of the general formula (III) according to the present invention wherein R 7 is C 1 -C 6 alkyl or phenyl, the phenyl being optionally substituted by C 1 -C 6 alkyl, halogen or C 1 -C 6 alkoxy and R 2 represents a hydrogen atom, by treatment, advantageously in acetonitrile, of the compound of the following general formula (XII): wherein R 1 is as defined in the general formula (II), with a bromoacetone of general formula (XIII) R7 R3 O (XIII) wherein R3 and R7 are as defined in general formula (II), followed by treatment with an amine, advantageously triethylamine, and a phosphine, advantageously triphenylphosphine P (C6H5) 3, and by prolonged heating.  The present invention further relates to a process for the preparation of a compound of the general formula (III) according to the present invention wherein R 7 is C 1 -C 6 alkyl or phenyl, the phenyl being optionally substituted by an alkyl group C1-C6, a halogen atom or a C1-C6 alkoxy group and R2 does not represent a hydrogen atom, by reaction of a compound of general formula (III) according to the present invention wherein R7 represents a C1-C6 alkyl group or phenyl, the phenyl being optionally substituted by a C1-C6 alkyl group, a halogen atom or a C1-C6 alkoxy group and R2 represents a hydrogen atom, with a halogenide halogen; alkyl, advantageously in a solvent such as dichloromethane, in the presence of aqueous sodium hydroxide and N-benzyl-tri-n-butylammonium bromide.  Thus, these processes can be represented by the following synthetic methods: ## STR2 ## wherein R 2 is a hydrogen atom, R 2 R 2, R 2, R 3, R 3, R 3, R 3, R 3 Another object of the present invention is the combination of a methylidene-pyrido [3,4-b] -indole derivative according to the present invention and a 5HT2 receptor antagonist of general formulas (XIV) or (XIVbis) wherein R 18 represents a C 1 -C 12 alkyl, phenyl or phenyl (C 1 -C 6) alkyl group, the phenyl group being optionally substituted by a C 1 -C 6 alkoxy, a halogen atom or a secondary amine, advantageously a methyl or ethyl group; R16 and R17 are absent and the dashed line represents a bond or R16 and R17 represent a hydrogen atom and the dashed line is absent.  For the purposes of the present invention, the term "phenyl (C 1 -C 6) alkyl" means any phenyl group bonded via a C 1 -C 6 alkyl group as defined above.  Examples of phenyl (C1-C6) alkyl include, but are not limited to, phenylethyl, 3-phenylpropyl, benzyl and the like.  The amount of methylidene-pyrido [3,4-b] -indole derivative according to the invention, activators of the 5HT2 receptor by allosteric modulation, in the combination are advantageously greater than that of the 5HT2 receptor antagonist so that the effect of the activator predominates on the effect of the antagonist throughout the sleep period.  Thus, in such an association, the methylidene-pyrido [3,4-b] -indole derivative according to the invention and the 5HT2 receptor antagonist should have appropriate pharmacokinetic profiles so that, when administered in the evening, they produce concentration versus time curves similar to the concentration versus time curve of the VLT and 6-MH (Figure 2).  Thus the pharmacokinetic parameters of the methylidene-pyrido [3,4-b] -indole derivative according to the invention and of the 5HT2 receptor antagonist must be in agreement, so that the concentration of the methylidene-pyrido derivative [3 4-b] -indole according to the invention is prevalent during the nocturnal sleep period, and that, on the contrary, the concentration of the 5HT2 receptor antagonist in the body is higher than that of the methylidene-pyrido derivative. [3,4-b] -indole according to the invention, during the diurnal period of activity, after waking.  Therefore, advantageously, the elimination of the methylidene-pyrido [3,4-b] indole derivative according to the invention must be faster than that of the 5HT2 receptor antagonist (elimination half-life). T112 z = 2.5 hours for 6-MH, in the Beagle dog), that is to say that the elimination half-life of the methylidene-pyrido [3,4-b] -indole derivative according to the invention must be less than that of the 5HT2 receptor antagonist; this means that it is possible to combine, together with 6-MH, a methylidene-pyrido [3,4-b] -indole derivative according to the invention which has an elimination half-life (TI / 2). ) less than 2 hours.  It is also possible to administer a methylidene-pyrido [3,4-b] indole derivative according to the invention having an elimination half-life that is greater than or equal to that of the 5HT2 receptor antagonist; whose elimination is slower than that of the 5HT2 receptor antagonist, but for this it is also necessary to administer a dose of 5HT2 receptor antagonist upon awakening so that the effect of the antagonist of the 5HT2 receptor is prevailing over that of the methylidene-pyrido [3,4-b] -indole derivative of the invention and this until the methylidene-pyrido [3,4-b] -indole derivative according to the invention is eliminated.  Advantageously, the methylidene-pyrido [3,4-b] indole derivative according to the present invention is present in the combination in an amount by weight greater than that of the antagonist.  Advantageously, the methylidene-pyrido [3,4-b] -indole derivative according to the present invention has a lower blood elimination time than that of the 5HT2 receptor antagonist, advantageously less than 2 hours.  Advantageously, the 5HT2 receptor antagonist of general formula (XIV) or (XIVbis) is chosen from 6-methoxy-harmalan of the following formula: or the ethyl analogue of 6-methoxy-harmalan of the following formula: MeO MeO or The present invention further relates to a pharmaceutical composition comprising the combination of the present invention and a 5HT2 receptor antagonist of the general formulas (XIV) or (XIVa): wherein R 18 represents a C 1 -C 12 alkyl, phenyl or phenyl (C 1 -C 6) alkyl group, the phenyl group being optionally substituted by a C 1 -C 6 alkoxy, an atom of halogen or a secondary amine, R16 and R17 are absent and the dashed line represents a bond or R16 and R17 represent a hydrogen atom and the dashed line is absent as a combination product for a single use. n separated in time to regulate the circadian sleep-wake cycle.  Advantageously, the combination according to the present invention is administered in the evening and the 5HT2 receptor antagonist of general formulas XIV or XIVbis is administered in the morning.  The present invention also relates to a pharmaceutical composition comprising a methylidene-pyrido [3,4-b] indole derivative according to the present invention or a combination according to the present invention and a pharmaceutically acceptable excipient.  The pharmaceutical compositions according to the present invention can be formulated for administration to mammals, including humans.  The dosage varies according to the treatment and the condition in question.  These compositions are made so that they can be administered orally, topically, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally.  In this case 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, dosage forms of administration. -cutaneous, topical, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.  When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.  The tablets may be coated with sucrose or other suitable materials or may be treated so that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.  A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.  A syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant.  The water-dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.  For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.  For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents are used.  The active ingredient may also be formulated as microcapsules, optionally with one or more additive carriers.  Advantageously, the pharmaceutical composition according to the present invention is intended for oral or intravenous administration, advantageously orally.  The present invention further relates to a cosmetic composition comprising a methylidene-pyrido [3,4-b] indole derivative according to the present invention and a cosmetically acceptable excipient.  The pharmaceutical or cosmetic composition according to the invention may also be formulated for topical administration.  It may be in the forms which are usually known for this type of administration, that is to say in particular lotions, foams, gels, dispersions, sprays, shampoos, serums, masks, body milks or creams for example, with excipients including skin penetration to improve the properties and accessibility of the active ingredient.  this composition generally contains, in addition to the active ingredient according to the present invention, a physiologically acceptable medium, generally based on water or with a solvent, for example alcohols, ethers or glycols.  It may also contain surfactants, preservatives, stabilizing agents, emulsifiers, thickeners, other active ingredients leading to a complementary or possibly synergistic effect, trace elements, essential oils, perfumes, dyes, collagen, chemical or mineral filters, moisturizers or thermal waters etc.  The present invention also relates to the combination according to the present invention or the composition according to the present invention containing the combination according to the present invention for its use as a medicament, advantageously intended to regulate the circadian sleep-wake cycle and / or the treatment of insomnia, mood disorders such as depression or anxiety, Parkinson's disease, Alzheimer's disease and diseases or disorders related to deregulation of the circadian sleep-wake cycle.  Another object of the present invention is a methylidene-pyrido [3,4-b] indole derivative according to the invention or the composition according to the invention for its use as a medicament, advantageously as a medicament having a myorelaxant, hypnotic, sedative and / or analgesic activity, and / or intended for the treatment of

  disorders related to disorders of melatonin activity and / or the treatment of depression and psychiatric disorders, in particular stress, anxiety, insomnia, schizophrenia, psychoses or epilepsy, and / or treatment of travel-related sleep disorders (jet lag) or neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease and / or the treatment of cancers such as skin cancer, and / or treatment of benign prostatic hyperplasia, skin conditions such as psoriasis, acne or fungal infections, glaucoma and / or increased immune resistance and / or the prevention of symptoms of menopause, premenstrual syndromes, effects of aging or sudden infant death.  Finally, the present invention relates to the use of the methylidenepyrido [3,4-b] -indole derivative according to the invention as a contraceptive in humans or animals and / or to regulate births in ruminant animals.  The examples of preparations of the compounds according to the present invention are given by way of nonlimiting indication.  The raw materials and / or the different reagents used in these examples to prepare the compounds according to the present invention are known products or prepared according to known procedures.  The structures of the compounds according to the present invention described in the examples as well as in the various synthesis steps were determined according to the usual spectrometric methods: infrared, NMR, mass spectrometry.  EXAMPLE I: 1-CYANOMETHYLIDENE-1,2,3,4-TETRAHYDRO-PYRIDO [3,4-b] INDOLES (METHANE SULFONATES) The compounds whose structure is indicated in the following Table I were synthesized: TABLE EXAMPLE R1 R2 R3 1 OCH3 HH 2 HHH 3 HH CH3 4 HH C6H5 5 OCH3 H CH3 6 OCH3 H C6H5 7 H CH3H8H CH3 CH3 9 OCH3 CH3H Example 1: 1-Cyanomethylidene-1,2,4 tetrahydro-6-methoxy-pyrido [3,4-b1 indole, methanesulfonate A) 5-methoxy-N- (indol-3-yl-ethyl) -cyanoacetamide A solution of 5-methoxytryptamine (5 g, 26 mmol) ) and ethyl cyanoacetate (3.9 g, 34 mmol) in 10 ml of anhydrous THF is heated at 70 ° C. with stirring for 16 h.  After cooling, the solid is filtered off and recrystallized from a mixture of ethanol and diethyl ether.  Colorless crystals (6 g, 90%).  F: 126C.  IR (KBr) 3454 (NH), 2259 (CN), 1648 (C = O).  B) 1-Cyanomethylidene-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole 2904973 A solution of 5-methoxy-N- (indol-3-yl-ethyl) cyanoacetamide (6 g, 23 mmol) in 270 ml of anhydrous toluene is added with 12 g of silica (silica gel 60).  Phosphorus oxychloride (6 g, 65 mmol) is then added at the temperature of 95 ° C. with stirring and dropwise, and heating is continued for 7 hours after the end of the addition.  After cooling, the toluene phase is decanted.  The lower phase is washed once with 150 ml of toluene and then added ice water and basified to pH 10 with a 5% aqueous sodium hydroxide solution.  The precipitate is filtered off and extracted with hot chloroform to remove the silica.  The combined organic phases are dried over magnesium sulphate.  The solvent was evaporated to give a red solid (2.75 g, 50%).  F: 244 C.  IR (KBr): 3423, 3320 (NH), 2181 (CN), 1617 (C = C).  MS (mez): 239 (M +), 238, 212, 181.  C) Methanesulfonate 2 g of 1-cyanomethylidene-1,2,3,4-tetrahydro-6-methoxypyrido- [3,4-b] indole are dissolved in 50 ml of ethanol at 50 ° C.  1.1 g of methanesulfonic acid are added and the mixture is stirred for 2 hours while allowing to return to ambient temperature.  It is drained, washed with water and recrystallized in ethanol.  Yellow crystals (1.7 g, 60%).  F: 200 C.  IR (KBr): 3422, 3320 (NH), 2182 (CN), 1646 (C = C).  1 H NMR (DMSO): 11.33 (1H, NH), 7.30 (1H, NH), 7.28 (1H, H8), 7.0 (1H, H5), 6.87 (1H, H7); ), 4.44 (1H, CH-CN), 3.39 (2H, CH2-3), 2.85 (2H, CH2-4).  EXAMPLE 2 1-Cyanomethyl-diene-1,2,3,4-tetrahydropyridone [3,4-b] indole, methanesulfonate The procedure is as in Example 1, using tryptamine and cyanoacetate as starting materials. ethyl to give N-indol-3-yl-ethyl-cyanoacetamide and then cyclizing it with phosphorus oxychloride in toluene.  1-Cyanomethylidene-1,2,3,4-tetrahydropyrido [3,4-b] indole is then salified with methanesulfonic acid in ethanol.  Red crystals.  F = 185C.  IR (KBr): 3420, 3305, (NH), 2180 (CN), 1622, 1606 (C = C).  1 H NMR (DMSO): 11.47 (1H, NH), 7.56 (1H, H5), 7.40 (1H, H8), 7.23 (1H, H7), 7.66 (1H, H6); ), 6.76 (1H, NH), 4.50 (1H, HC =), 3.41 (2H, CH2-3), 2.88 (2H-CH2-4), 2.49 (3H, CH3SO3H).  MS (m / z): 209 (M +), 208, 194.  EXAMPLE 3 1-Cyano-ethylenedene-1,2,3,4-tetrahydro-pyridone [3,4-b] indole methane sulfonate The procedure is as in Example 1, using as raw materials the starting material. tryptamine and ethyl cyanopropanoate.  A) N- (Indol-3-yl-ethyl) -2-cyanopropionamide White solid.  F = 132C.  IR (KBr): 3381, 3291 (NH), 2248 (CN), 1673 (CO).  1H NMR (DMSO): 10.82 (1H, NH), 7.52 (1H, H5), 7.33 (1H, H8), 7.14 (1H, indole H2), 7.06 (1H, H7); ), 6.97 (1H, H6), 3.69 (1H, CH-CH3), 3.38 (2H, CH2-3), 2.84 (2H, CH2-4), 1.36 (3H); , CH3).  B) 1-Cyanoethylidene-1,2,3,4-tetrahydro-pyrido [3,4-b] indole Yellow crystals.  F = 165 C.  IR (KBr): 3426, 3335 (NH), 2161 (CN), 1596 (C = C).  1H NMR (DMSO): 10.51 (1H, NH), 7.55 (2H, H5, H8), 7.17 (1H, H7), 7.06 (1H, H6), 6.56 (1H, NH), 3.33 (2H, CH2-3), 2.84 (2H, CH2-4), 1.82 (3H, CH3).  MS (m / z): 223 (M +), 222, 208, 194.  C) Methane Sulfonate Yellow crystals.  F = 188C.  IR (KBr): 3246 (NH), 2251 (CN), 1632 (C = C).  1H NMR (DMSO): 10.52 (1H, NH), 7.54 (2H, H5, H8), 7.17 (1H, H7), 7.03 (1H, H6), 4.92 (1H, NH), 3.31 (2H, CH2-3), 2.84 (2H, CH2-4), 2.49 (3H, CH3SO3H), 1.81 (3H, CH3).  Example 4: 1- (1-cyano-1-phenylmethylidene) -1,2,3,4-tetrahydro-pyridol-3,4-indol, methanesulfonate The procedure is as in Example 1, using as raw materials tryptamine and ethyl 2-cyanophenylacetate.  A) N- (Indol-3-yl-ethyl) -2-cyanophenylacetamide A solution of tryptamine (27.4 g, 144 mmol) and ethyl 2-cyano-phenylacetate (21.2 g, 111 mmol) in 70 1 ml of anhydrous dioxane is refluxed for 15 hours.  After cooling, the solvent is removed in vacuo.  The residual orange oil is taken up in diethyl ether and stirred for 30 minutes.  The formed precipitate is collected and recrystallized from chloroform.  White crystals (23.81 g, 46%).  F = 122 C.  IR (KBr): 3391, 3349 (NH), 1670 (CO), 1629 (C = C).  B) 1- (1-Cyano-1-phenylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole Yellow solid.  F = 192 C.  IR (KBr): 3391, 3349 (NH), 2166 (CN), 1589 (C = C).  1H NMR (CDCl3): 9.69 (1H, NH), 7.44 (1H. , H5), 7.35 (1H, H8), 7.30 (5H, C6H5), 7.24 (2H, H6, H7), 6.84 (1H, NH), 3.56 (2H, CH2), 3), 2.92 (2H, CH 2 -4).  MS (m / z): 285 (M +), 284, 208.  C) Methane sulphonate Beige solid.  Mp = 224 C.  IR (KBr): 3420 (NH), 2172 (CN).  1H NMR (DMSO): 10.97 (1H, NH), 7.59 (1H, H5), 7.44 (5H, C6H5), 7.26 (2H, H7, H8), 7.08 (1H); , H6), 3.36 (2H, CH2-3), 2.87 (2H, CH2-4), 2.49 (3H, CH3SO3H).  Example 5: 1-C1-cyanoethylidene) -1,2,3,4-tetrahydro-6-methoxy-ryridyl-3,4-b1indole, methanesulfonate The procedure is as in Example 1 using as raw materials 5-methoxytryptamine and ethyl 2-cyanopropanoate.  A) N- (5-methoxyindol-3-yl-ethyl) -2-cyanopropanamide A mixture of ethyl 2-cyanopropanoate (8 g, 63 mmol) and 5-methoxytryptamine (11, 98 g, 63 mmol).  Purify by chromatography on silica using dichloromethane as eluent.  White solid (14.70 g, 85%).  F = 162 C.  IR (KBr):  3391 (NH), 2247 (CN), 1667 (CO).  B) 1- (1-cyanoethylidene) -1,2,3,4-tetrahydro-6-methoxy [3,4-b] indole Yellow crystals.  Mp = 214 C.  IR (KBr): 3431, 3419 (NH), 2163 (CN), 1601 (C = C).  1H NMR (DMSO): 10.41 (1H, NH), 7.45 (1H, H8), 7.00 (1H, H5), 6.83 (1H, H7), 6.52 (1H, NH), 3.80 (3H, CH3O), 3.39 (2H, CH2-3), 2.89 (2H, CH2-4), 1.81 (3H, CH3-C).  MS (m / z): 253 (M +), 252, 238, 223.  C) Methane Sulfonate Yellow crystals.  Mp = 176 C.  IR (KBr): 3473, 3167 (NH), 2246 (CN), 1626 (C = C).  1H NMR (DMSO): 10.53 (1H, NH), 7.44 (1H, H8), 7.00 (1H, H5), 6.80 (1H, H7), 3.75 (3H, CH3O). ), 3.30 (2H, CH2-3), 2.80 (2H, CH2-4), 2.46 (3H, CH3SO3H), 2.1 (3H, CH3C).  EXAMPLE 6 1 - (1-Cyano-1-phenylmethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole, methanesulfonate The procedure is as in the example 4 using 5-methoxytryptamine and 2-cyanophenylacetate as starting materials.  A) N- (5-methoxyindol-3-yl-ethyl) -2-cyanophenylacetamide Beige solid.  Mp = 146 C.  IR (KBr): 3388, 3260 (NH), 2248 (CN).  B) 1- (1-Cyano-1-phenylmethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole Yellow solid.  F = 186 C.  IR (KBr): 3437 (NH), 2167 (CN), 1620 (C = C).  1H NMR (CDCl3): 9.52 (1H, NH), 7.48 (5H, C6H5), 7.33 (1H, H8), 7.06 (1H, H7), 6.96 (1H, H5) , 5.24 (1H, NH), 3.87 (3H, CH3O), 3.45 (2H, CH2-3), 3.00 (2H, CH2-4).  MS (m / z): 315 (M +), 314, 238, 223.  C) Methane Sulfonate 15 Intense yellow powder.  Mp = 198 C.  IR (KBr): 3437, 3344 (NH), 2168 (CN).  Example 7: 1- (1-Cyanomethylidene) -1,2,3,4-tetrahydro-9-methyl-pyrido [3,4-b] indole methanesulfonate A) 1- (1-cyanomethylidene) -1,2 3,4-tetrahydro-9-methylpyrido [3,4-b] indole to a solution of 1- (1-cyanomethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] indole (7 85 g, 37.6 mmol) in 1.2 l of dichloromethane is added at 0 C with vigorous stirring, a solution of 450 ml of 50% aqueous sodium hydroxide and then 4.02 g of benzyltributylammonium bromide.  The methyl iodide (21.3 g, 150.4 mmol) is then added and stirring is continued for 1 h at 0 ° C. and then 4 h at 20 ° C.  600 ml of water are added to the reaction mixture and extracted with dichloromethane after decantation of the aqueous phase.  The organic phase is washed with water until neutral pH.  The organic phases are combined and dried over magnesium sulfate.  After concentration, purify by chromatography on silica eluting with a mixture of dichloromethane (99) and methanol (1).  Yellow solid.  Mp = 176 C.  IR (KBr): 3434, 3326 (NH), 2182 (CN), 1599 (C = C).  1H NMR (DMSO): 7.64 (1H, H5), 7.57 (1H, H8), 7.34 (1H, H7), 7.15 (1H, H6), 4.50 (1H, HC = ), 3.89 (2H, CH2-3), 2.91 (2H, CH2-4), 2.55 (2H, NH).  MS (m / z): 223 (M +), 222, 208.  B) Methane sulfonate Yellow crystals.  Mp = 144C.  IR (KBr): 3437, 3218 (NH), 2255 (CN), 1621 (C = C).  Example 8: 1- (1-cyanoethylidene) -1,2,3,4-tetrahydro-9-methyl-pyridol [3,4-b] indole, methanesulfonate The procedure is as in the case of Example 7 using as the raw materials 1 - (1-cyanoethylenediol) -1,2,3,4-tetrahydro- [3,4-b] indole.  A) 1-O-cyanoethylidene, 1-butene, 2,3,4-tetrahydro-9-methylpyrido [3,4-b] indole Yellow crystals.  Mp = 175 C.  IR (KBr): 3380 (NH), 2170 (CN), 1595 (C = C).  1H NMR (CDCl3): 7.58 (1H, H5), 7.40 (1H, H8), 7.31 (1H, H7), 7.20 (1H, H6), 4.46 (1H, NH) , 3.89 (3H, CH3N), 3.37 (2H, CH2-3), 2.92 (CH2-4), 1.95 (3H, CH3C =).  MS (m / z): 237 (M +), 236, 222, 207.  B) Methane sulfonate Yellow powder.  M.p. 86-88 ° C.  IR (KBr): 3501, 3432 (NH), 2245 (CN), 1625 (C = C).  1H NMR (DMSO): 7.62 (1H, H5), 7.50 (1H, H8), 7.28 (1H, H7), 7.13 (1H, H6), 4.10 (1H, NH) , 3.73 (3H, CH3N), 3.22 (2H, CH2-3), 2.81 (2H, CH2-4), 2.49 (3H, CH3SO3H), 1.85 (3H, CH3C =) .  Example 9 1- (1-Cyanomethylidene) -1,2,3,4-tetrahydro-6-methoxy-9-methyl-pyridol [3,4-b] indole methane sulfonate The procedure is as in the case of Example 7 using as raw materials 1- (1-cyanomethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole.  A) 1- (1-cyanomethylidene) -1,2,3,4-tetrahydro-6-methoxy-9-methylpyrido [3,4-b] indole Yellow powder.  F = 197 C.  IR (KBr): 3353, 3308 (NH), 2178 (CN), 1600 (C = C).  1H NMR (CDCl3): 7.23 (1H, H8), 6.99 (2H, H5, H7), 5.43 (HC = C), 3.92 (3H, CH3N), 3.48 (2H, CH2-3), 2.94 (2H, CH2-4).  MS (m / z): 253 (M +), 252, 238, 207.  B) Methane sulfonate 2904973 35 Beige powder.  F = 148 C.  IR (KBr): 3435 (NH), 2211 (CN), 1614 (C = C).  1 H NMR (DMSO): 7.42 (1H, H8), 7.05 (1H, H5), 6.91 (1H, H7), 5.51 (1H, HC = C), 3.79 (3H); , CH3O), 3.77 (3H, CH3N), 3.42 (2H, CH2-3), 2.82 (2H, CH2-4), 2.41 (3H, CH3SO3H).  EXAMPLE 2: 1-CARBOXAMIDOMETHYLIDENE-1,2,3,4-TETRAHYDROPYRIDO [3,4-b] INDOLES (METHANESULFONATES) The compounds whose structure is shown in the following Table II were synthesized: TABLE II, CH3SO3H R1 EXAMPLE R1 R2 R3 10 OCH3 HH 11 HHH 12 HH CH3 13 HH C6H5 OCH3 H CH3 OCH3 H C6H5 16 H CH3 H 17 H CH3 CH3 18 OCH3 CH3 H Example 10: 1 -carboxamidomethylidene-1,2,3 4-Tetrahydro-6-methoxy-pyrido [3,5-bicarbonate, methanesulfonate A) 1-carboxamidomethylidene-1,2,3,4-tetrahydro-6-methoxypyrido [3,4-b] -indole 2904973 36 A suspension 1-cyanomethylidene-1,2,3,4-tetrahydro-6-methoxypyrido [3,4-b] indole (2.27 g, 9.5 mmol) in 17 g of polyphosphoric acid is stirred at 80 ° C. for 2 hrs.  After cooling, the minimum amount of ice is added to dissolve the black product obtained.  The mixture is basified to pH 8 with a 40% aqueous sodium hydroxide solution while cooling in an ice bath.  The mixture is stirred for 2 hours and the precipitate is filtered off, which is dried and recrystallized from THF.  Solid yellow orange (0.9 g, 40%).  F = 210 C.  IR (KBr): 3459, 3311 (NH), 1633 (CO).  MS (m / z): 257 (M +), 240, 213.  B) Methanesulfonate 1 g of 1-carbamoxamidomethylidene-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole is suspended in 30 ml of ethanol.  1 g of methanesulphonic acid are added dropwise with stirring.  The solution is stirred for 1 h at 50 ° C. and then for 1 h at 20 ° C.  It is concentrated to half volume, the precipitate obtained is filtered off and recrystallized in ethanol.  Yellow powder (0.8 g, 80%).  Mp = 227 C.  IR (KBr): 3385, 3182 (NH), 1687 (CO), 1612 (C = C).  1 H NMR (DMSO): 12.25 (1H, NH), 12.01 (1H, NH), 7.84 (1H, NH), 7.45 (2H, H5, H8), 7.17 (1H, HC = CO), 7.10 (1H, H7), 3.95 (3H, CH3O), 3.78 (2H, CH2-3), 3.17 (2H, CH2-4), 2.49 (3H; , CH3SO3H).  Example 11: 1-carboxamidomethylidene-1,2,3,4-tetrahydropyrido [3,4-b] indole, methane sulfonate The procedure is as in Example 10, treating 1-cyano-1,2-methylidene 3,4-tetrahydro-pyrido [3,4-b] indole with methanesulfonic acid in ethanol.  White solid.  F = 216 C.  IR (KBr): 3381, 3322 (NH), 1682 (CO), 1639 (C = C).  1H NMR (DMSO): 12.33 (1H, NH), 12.15 (1H, NH), 7.78 (1H, H5), 7.54 (2H, H7, H8), 7.46 (1H); , H6), 4.00 (1H, HC = CO), 3.96 (2H, CH2-3), 3.22 (2H, CH2-4), 2.49 (3H, CH3SO3H).  MS (m / z): 227 (M +), 210, 209, 183.  Example 12: (Z + E) -1-carboxamidoethylidene-1,2,3,4-tetrahydro-pyrido [3,4-b] indole, methanesulfonate The procedure is as in Example 10 by hydrolysis of 1-cyanoethylidene-1, 2,3,4-tetrahydro-pyrido [3,4-b] indole with polyphosphoric acid.  A) 1-carboxamidoethylidene-1,2,3,4-tetrahydro [3,4-b] indole Yellow crystals.  Mp 196 ° C-197 ° C.  IR (KBr): 3360, 3270 (NH), 1667 (CO), 1605 (C = C).  1 H NMR (DMSO): 10.67 (1H, NH), 7.53 (1H, H5), 7.43 (1H, H8), 7.18 (1H, H7), 7.03 (1H, H6); ), 3.77 (2H, CH2-3), 3.26 (2H, CH2-4), 1.33 (3H, CH3).  MS (m / z): 241 (M +), 224, 223, 197.  B) Methane sulphonate Yellow powder.  Mp = 224 C.  IR (KBr): 3412, 3427 (NH), 1695 (CO), 1633 (C = C).  1 H NMR (DMSO): 12.16 (1H, NH), 11.78 (1H, NH), 7.77 (2H, H5, H8), 7.47 (1H, H7), 7.19 (1H; , H6), 3.95 (2H, CH2-3), 3.23 (2H, CH2-4), 2.49 (3H, CH3SO3H), 1.56 (3H, CH3).  Example 13: 1- (1-carboxamido-1-phenylmethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-baurate, methane sulfonate The procedure is as in Example 10 by hydrolysis of 1- (1 -cyano-1-phenylmethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] indole with polyphosphoric acid.  A) 1- (1-Carboxamido-1-phenylmethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] indole Yellow solid.  F = 178 C.  IR (KBr): 3481, 3451 (NH), 1645 (CO), 1599 (C = C).  1 H NMR (CDCl 3): 10.06 (1H, NH), 7.45 and 7.09 (9H, H arom), 3.48 (2H, CH 2 3), 2.98 (2H, CH 2), 4), 1.72 (1H, NH).  MS (m / z) 303 (M +), 286, 285, 259.  B) Methane sulphonate Yellow solid.  F> 260 C.  IR (KBr): 3338 (NH), 1683 (CO), 1625 (C = C).  1 H NMR (DMSO): 11.18 (1H, NH), 8.35 (1H, NH), 7.47 and 7.16 (9H, H arom), 3.98 (2H, CH2-3), 3.27 (2H, CH 2 -4), 2.49 (3H, CH 3 SO 3 H).  Example 14: (Z + E) -1- (1-carboxamidoethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole methane sulfonate The procedure is as in Example 10 by hydrolysis of 1-cyanoethylidene-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole with polyphosphoric acid.  A) 1-carboxamidoethylidene-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole 2904973 Yellow powder.  Mp = 182 C.  IR (KBr): 3367, 3280 (NH), 1661 (CO), 1614 (C = C).  1 H NMR (DMSO): 10.96 (1H, NH), 7.38 (1H, NH), 7.34 (1H, H8), 6.99 (1H, H5), 6.83 (1H, H7); ), 3.75 (3H, CH3O), 3.67 (2H, CH2-3), 2.72 (2H, CH2-4), 1.31 (3H, CH3).  MS (m / z): 271 (M +): 254, 253, 227, 225, 212.  B) Methane sulfonate Yellow powder.  Mp = 144C.  IR (KBr): 3572, 3398, 3235 (NH), 1695 (CO), 1618 (C = C).  1 H NMR (DMSO): 8.30 (1H, NH), 7.76 (1H, NH), 7.58 (1H, NH), 7.49 (1H, H8), 7.18 (1H, H5); ), 7.12 (1H, H7), 3.78 (3H, CH3O), 3.94 (2H, CH2-3), 3.27 (2H, CH2-4), 2.49 (CH3SO3H), 1 , 56 (3H, CH3C).  Example 15: 1- (1-Carboxamido-1-phenylmethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole, methanesulfonate The procedure is as in Example 10 by hydrolysis of 1- (1-cyano-1-phenylmethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] indole with polyphosphoric acid.  A) 1- (1-Carboxamido-1-phenylmethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole Yellow solid.  F = 192 C.  IR (KBr): 3480, 3397 (NH), 1643 (CO), 1622 (C = C).  1 H NMR (CDCl3): 10.07 (1H, NH), 7.52, 7.45 (5H, C6H5), 6.88 (1H, H5), 6.76 (2H, H7, H8) , 3.76 (3H, CH3O), 3.58 (2H, CH2-3), 2.94 (2H, CH2-4).  B) Methane sulphonate Yellow solid.  Mp = 246 C.  IR (KBr): 3478, 3444, 3399 (NH), 1644 (CO), 1623 (C = C).  Example 16: 1-Carboxamidomethylidene-1,2,3,4-tetrahydro-9-methylpyrido- [3,4-b] indole methane sulphonate The procedure is as in the case of Example 10 by hydrolysis of the 1 - cyanomethylidene-1,2,3,4-tetrahydro-9-methyl-pyrido [3,4-b] indole with polyphosphoric acid.  A) 1-carboxamidomethylidene-1,2,3,4-tetrahydro-9-methylpyrido [3,4-b] -indole 2904973 Yellow solid.  F = 178 C.  IR (KBr): 3250, 3160 (NH), 1687 (CO), 1627 (C = C).  1H NMR (CDCl3): 9.41 (1H, NH), 7.57 (1H, H5), 7.28 (2H, H7, H8), 7.15 (1H, H6), 4.99 (1H, HC = C), 3.89 (3H, CH3), 3.47 (2H, CH2-3), 2.95 (2H, CH2-4).  MS (m / z): 241 (M +), 240, 226, 223, 197.  B) Methanesulfonate Yellow solid.  F = 186 C.  IR (KBr): 3260, 3136 (NH), 1699 (CO), 1527 (C = C).  1H NMR (DMSO): 12.38 (1H, NH), 8.06 (1H, NH), 7.66 (3H, H5, H7, H8), 7.22 (1H, H6), 4.19 ( 1H, HC = C), 3.95 (3H, CH3), 3.19 (2H, CH2-3), 2.36 (2H, CH2-4), 2.49 (3H, CH3SO3H).  EXAMPLE 17: (Z + E) -1- (1-carboxamidoetylmethyl) -1,2,3,4-tetrahydro-9-methyl-pyri) [3,4-b] indole methane sulfonate The procedure is as in the case of Example 10 by hydrolysis of the 10 (1-cyanoethylidene) -1,2,3,4-tetrahydro-9-methyl-pyrido [3,4-b] indole with the polyphosphoric acid.  A) 1- (1-carboxamidoethylidene) -1,2,3,4-tetrahydro-9-methylpyrido [3,4-b] indole Yellow solid.  F = 174C.  IR (KBr): 3360, 3271 (NH), 1667 (CO), 1616 (C = C).  1H NMR (DMSO): 7.58 (1H, H5), 7.48 (1H, H8), 7.31 (1H, NH), 7.25 (1H, H7), 7.07 (1H, H6) , 6.96 (1H, NH), 4.01 (1H, NH), 3.91 (3H, CH3N), 3.73-3.57 (2H, CH2-3), 2.68-2. , 49 (2H, CH2-4), 1.32 (3H, H3CC =).  MS (m / z): 255 (M +), 238, 212, 211, 196, 168.  B) Methane sulphonate Yellow solid.  F = 210 C.  IR (KBr): 3334, 3169 (NH), 1665 (CO), 1616 (C = C).  1H NMR (DMSO): 8.05 (1H, NH), 7.78 (1H, H5), 7.69 (1H, H8), 7.59 (1H, NH), 7.52 (1H, H7). ), 7.23 (1H, H6), 3.99 (3H, CH3N), 3.87 (2H, CH2-3), 3.15 (2H, CH2-4), 2.29 (3H, CH3SO3H) , 1.59 (3H, CH3C =).  Example 18 1 - (1-carboxamidomethylidene) -1,2,3,4-tetrahydro-6-methoxy-9-methyl-pyrido [3,4-bindol, methanesulfonate 2904973 The procedure is as in the case of the example By hydrolysis of 1- (1-cyanomethylidene) -1,2,3,4-tetrahydro-6-methoxy-9-methyl-pyrido [3,4-b] indole with polyphosphoric acid.  A) 1- (1-carboxamidomethylidene) -1,2,3,4-tetrahydro-6-methoxy pyrido [3,4-b] indole Orange solid.  F = 154 C.  IR (KBr): 3375 (NH), 1672 (CO), 1617 (C = C).  1H NMR (CDCl3): 9.42 (1H, NH), 7.23 (1H, H8), 6.98 (2H, H5, H7), 4.90 (1H, HC =), 4.87 (6H). , CH3O, CH3N), 3.49 (2H, CH2-3), 2.92 (2H, CH2-4).  MS (m / z): 271 (M +), 254, 253, 227.  B) Methanesulfonate Orange solid.  F = 84C.  IR (KBr): 3392, (NH), 1684 (CO), 1617 (C = C).  1 H NMR (DMSO): 12.23 (1H, NH), 8.02 (1H, NH), 7.59 (2H, H5, H8), 7.19 (1H, HC =), 7.15 ( 1H, H7), 4.14 (1H, NH), 3.92 (3H, CH3N), 3.88 (2H, CH2-3), 3.79 (3H, CH3O), 3.14 (2H, CH2) -4), 2.46 (3H, CH3SO3H).  EXAMPLE 3 1-THIOCARBOXAMIDOMETHYLIDENE-PYRIDO [3,4-b] INDOLES AND 1-PYRIDO [3,4-b] INDOLE-METHYLENECARBOXAMIDOXIMES The compounds whose structure is indicated in the following Table III were synthesized: EXAMPLE III ## STR2 ## - (1-thiocarboxamidoéthyli. dene) -1,2,3,4-tetrahydro-pyrido [3,4-b1 indole, methanesulfonate A) 1- (1-thiocarboxamidoethylidene) -1,2,3,4-tetrahydro pyrido [3,4-b] Indole A stream of hydrochloric acid is bubbled at 0 ° C. for 30 minutes in a solution of 1- (1-cyanoethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] ] indole (1 g, 4.5 mmol) and thioacetamide (0.67 g, 8.9 mmol) in 5 ml of dimethylformamide.  It is then stirred at 20 ° C. for 3 hours, 5 g of ice are added and the mixture is left at 0 ° C. for 12 hours.  It is basified with 10% aqueous sodium hydroxide solution, the precipitate is filtered off with suction and recrystallized from a mixture of chloroform (90) and methanol (10).  Yellow powder (0.46 g, 40%).  F = 170 C-172 C.  IR (KBr): 3435, 3298, 3233 (NH).  1 H NMR (DMSO): 12.25 (1H, NH), 10.87 (1H, NH), 7.57 (1H, H5), 7.53 (1H, NH), 7.47 (1H, H); ), 7.19 (1H, H7), 7.07 (1H, H6), 2.87 (2H, CH2-3), 2.48 (2H, CH2-4), 2.17 (3H, CH3) .  MS (m / z): 257 (M +), 256, 242, 239, 197.  B) Methanesulfonate To a solution of 1- (1-thiocarboxamidoethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole (0.25 g, 1 mmol) in 15 ml of ethanol, methanesulfonic acid (192 mg, 2 mmol) is added dropwise and the mixture is stirred for 1 hour at 20 ° C.  30 ml of petroleum ether are added, the mixture is filtered off with suction and the precipitate is rinsed with diethyl ether.  Yellow powder (0.30 g, 80%).  F (Dec. ) 200 C.  1 H NMR (DMSO): 12.03 (1H, NH), 11.65 (1H, NH), 10.11 (1H, NH), 7.75 (1H, H5), 7.54 (1H, H8); ), 7.44 (1H, H7), 7.18 (1H, H6), 3.16 (2H, CH2-3), 2.52 (2H, CH2-4), 2.49 (3H, CH3SO3H) 1.65 (3H, CH3).  Example 20: 1- (1-thiocarboxamidoethylidene) -1,2,3,4-tetrahydro-6-methoxy-pvrido [3,4-b] indole, methanesulfonate 2904973 42 A) 1- (1-thiocarboxamidoethylidene) -1,2,3,4-tetrahydro-6-methoxy pyrido [3,4-b] indole The procedure is as in the case of Example 19 by the action of thioacetamide (0.59 g, 7.9 mmol), 1- (1-cyanoethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole (1 g, 3.9 mmol).  The derivative is purified by chromatography on a silica column, eluting with a mixture of chloroform (98) and methanol (2).  Yellow powder (452 mg, 40%).  M.p. 152-154C.  IR (KBr): 3423, 3298 (NH), 1622 (C = C).  1H NMR (DMSO): 12.24 (1H, NH), 10.70 (1H, NH), 7.50 (2H, NH), 7.36 (1H, H7), 7.05 (1H, H5) , 6.83 (1H, H8), 3.75 (3H, CH3O), 3.33 (2H, CH2-3), 2.85 (2H, CH2-4), 2.17 (3H, CH3C) .  MS (m / z): 287 (M +), 253, 238, 228, 227.  B) Methanesulfonate The procedure is as in the case of Example 19.  Yellow powder.  F (Dec. ) 200 C.  IR (KBr): 3333, 3137 (NH), 1638 (C = C).  1H NMR (DMSO): 11.96 (1H, NH), 11.53 (1H, NH), 10.08 (1H, NH), 9.56 (1H, NH), 7.45 (1H, H7) , 7.17 (1H, H5), 7.11 (1H, 15H8), 3.79 (3H, CH3O), 3.90 (2H, CH2-3), 3.14 (2H, CH2-4) , 2.52 (3H, CH3SO3H), 1.63 (3H, CH3C =).  Example 21: 1,2,3,4-Tetrahydropyrido [3,4-b] indole-1-methylidene carboxamidoxime A solution of 1- (1-cyanomethylidene) -1,2,3,4-tetrahydropyrido- [3] , 4-b] indole (500 mg, 2.4 mmol) and 50% hydroxylamine in aqueous solution (1.57 g, 48 mmol) in 15 ml of ethanol is refluxed for 3 h.  After evaporation of the solvent, the solid residue is washed with 5 ml of water.  The insoluble material is drained and then washed with dichloromethane and diethyl ether.  Purify by column chromatography on silica eluting with a mixture of chloroform (90) and methanol (10).  Beige powder (230 mg, 40%).  F (Dec. ) = 160 C.  IR (KBr): 3394 (OH), 3338 (NH), 3217 (NH).  1 H NMR (DMSO): 11.54 (1H, NH), 10.81 (1H, NH), 8.76 (1H, NH), 8.29 (1H, NH), 7.43 (1H, H5) , 7.29 (1H, H8), 7.08 (1H, H7), 6.96 (1H, H6), 5.87 (1H, HC = C), 3.50 (2H, CH2-3), 2.97 (2H, CH 2 -4).  MS (m / z): 242 (M +), 241, 224, 207.  EXAMPLE 22 1,2,3,4-Tetrahydropyrido [3,4-b] indole-1-ethylidenecarboxamidoxime methane sulfonates A) 1,2,3,4-Tetrahydro pyrido [3,4-b] indole 1-ethylidene carboxamidoxime The procedure is as in Example 21 by the action of hydroxylamine on 1- (1-cyanoethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] indole.  Beige powder.  F = 95 C.  IR (KBr): 3301 (NH), 1655 (CN).  1H NMR (DMSO): 11.01 (1H, NH), 7.60 (1H, H5), 7.35 (1H, H8), 7.11 (1H, H7), 7.00 (1H, H6) , 6.52 (2H, NH), 2.81 (2H, CH2-3), 2.75 (2H, CH2-4), 1.79 (3H, CH3).  MS (m / z): 256 (M +), 241, 239, 212, 197.  B) Methanesulfonate To a solution of 1,2,3,4-tetrahydro-pyrido [3,4-b] indole-1-ethylidenecarboxamidoxime (0.77 g, 3 mmol) in 5 ml of ethanol is added dropwise methanesulfonic acid (0.29 g, 3 mmol) and stirred for 30 min at 20 ° C.  The precipitate formed is drained, rinsed with diethyl ether and dried.  White powder (0.82 g, 77%).  F (Dec. ) 200 C.  IR (KBr): 3374, 3329 (NH), 1658 (CO).  1 H NMR (DMSO): 11.22 (1H, NH), 7.75 (2H, NH), 7.64 (1H, H5), 7.42 (1H, H8), 7.16 (1H, H7). ), 7.06 (1H, H6), 6.64 (1H, OH), 3.04 (2H, CH2-3), 3.00 (2H, CH2-4), 2.31 (3H, CH3SO3H) , 1.86 (3H, CH3C).  C) Di-methane sulphonate The procedure is the same as in the case of mono-methane sulphonate with two equivalents of methanesulphonic acid.  White powder.  F (Dec. ) = 110 C.  IR (KBr): 3328 (NH), 1663 (C = N).  1H NMR (DMSO): 7.93 (2H, NH), 7.63 (1H, H5), 7.41 (1H, H8), 7.15 (1H, H7), 7.06 (1H, H6) , 4.88 (2H, NH, OH), 3.04 (2H, CH2-3), 3.01 (2H, CH2-4), 2.33 (6H, 2 CH3SO3H), 1.86 (3H, CH 3 C).  Example 23: 1,2,3,4-Tetrahydro-6-methoxy-pyrido [3,4-b] indol-1 - (1-ethylidene-2-carboxamidoxime) The procedure is as in the case of Example 19 by the action of hydroxylamine on 1 - (1-cyanoethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole.  White powder.  F = 95 C.  IR (KBr): 3453, (OH), 3381 (NH), 3152 (NH), 1651 (CN).  1H NMR (DMSO): 10.83 (1H, NH), 7.23 (1H, H8), 7.03 (1H, H5), 6.75 (1H, H6), 2904973 44 6.49 (2H); , NH), 3.76 (3H, CH3O), 2.77 (2H, CH2-3), 2.71 (2H, CH2-4), 1.82 (3H, CH3C).  MS (m / z): 286 (M +), 271, 269, 242, 200.  Example 24: 1,2,3,4-Tetrahydro-pyrido [3,4-b] indole-1-ethylidene-2-N-acetylcarboxamidoxime A) Anti-Form A suspension of 1,2,3,4 Tetrahydropyridone [3,4-b] indole-ethylidenecarboxamidoxime (400 mg, 1.56 mmol) in 25 ml of diethyl ether is added with stirring a solution of acetic anhydride (480 mg, 4.68 mmol) in 25 ml of diethyl ether.  Stirred at 20 ° C. for 2 hours, the precipitate is collected and washed with diethyl ether.  Cream powder (300 mg, 80%).  F = 100 C-102 C.  IR (KBr): 3398, 3272 (NH), 1645 (CO).  1 H NMR (DMSO): 7.60 (1H, H5), 7.37 (1H, H8), 7.13 (1H, H7), 7.03 (1H, H6), 6.53 (2H, NH4); ), 3.24 (2H, CH2-3), 2.88 (2H, CH2-4), 2.49 (3H, CH3CO), 1.76 (3H, CH3C).  MS (m / z): 298 (M +), 239, 226, 199.  B) Syn.  A suspension of 1,2,3,4-tetrahydro-pyrido [3,4-b] indole-1-2-N-acetyl carboxamidoxime, anti-form (220 mg, 0-74 mmol) in 50 ml of toluene is heated under reflux. with stirring for 30 min.  After cooling, the precipitate is filtered and rinsed with diethyl ether.  Cream powder (160 mg, 80%).  Mp = 164 C.  IR (KBr): 3452, 3420, 3277 (NH), 1655 (CO).  1 H NMR (DMSO): 11.06 (1H, NH), 7.94 (1H, OH), 7.60 (1H, H5), 7.37 (1H, H8), 7.13 (1H, H7); ), 7.03 (1H, H6), 6.55 (2H, NH), 3.28 (2H, CH2-3), 2.88 (2H, CH2-4), 2.49 (3H, CH3CO) 1.87 (3H, CH3C).  MS (m / z): 298 (M +), 239, 226, 199.  Example 25: 1,2,3,4-Tetrahydro-pyrido [3,4-b] indole-1-ethylidene-2-N-trifluoro-acetylcarboxamidoxime A solution of 1,2,3,4-tetrahydro-pyrido [3 , 4-b] indole-1- (1-ethylidene-2-carboxamidoxime) (700 mg, 2.7 mmol) and trifluoroacetic anhydride (1. 52 g, 8.2 mmol) in 10 ml of benzene is stirred at 20 ° C. C. for 6 h and then at 50 ° C. for 2 h.  After evaporation of the solvent, it is hydrolysed with ice and basified with a 5% aqueous sodium hydroxide solution.  The precipitate is collected and washed with dichloromethane and then with ethyl acetate.  White powder (365 mg, 40%).  F = 250 C.  IR (KBr): 3392, (OH), 3245 (NH), 1632 (CO), 1606 (C = C).  1H NMR (DMSO): 11.24 (NH), 7.63 (1H, H5), 7.41 (NH, H8), 7.07 (2H, H6, H7), 3.34 (2H, CH2) -3), 3.05 (2H, CH2-4), 1.90 (3H, CH3C).  MS (m / z): 352 (M +), 333, 255, 195.  EXAMPLE 4 1-HETEROARYL-METHYLIDENE-PYRIDO [3,4-b] INDOLES The compounds whose structure is indicated in the following Table IV were synthesized: TABLE IV V EXAMPLES Het 26 27 H3C \ NN 28 O ~ N 29 Example 26: 1- (2-Pyridylmethylidene) -1,2,3,4-tetrahydropyridin [3,4-b] indole A) N- (indol-3-yl-ethyl) pyridyl) 2-acetamide A mixture of tryptamine (23.76 g, 0.17 mmol) and 2-pyridyl-ethyl acetate (24.5 g, 0.15 mol) is heated for 8 hours at 100 ° C. and then 2 hours. at 120 C.  10 g (0.06 mol) of tryptamine are added and the mixture is again heated for 3 h at 120 ° C.  It is purified by chromatography on a silica column, eluting with a mixture of methanol (2) and dichloromethane (98).  Thick yellow oil (33 g, 80%), usable for the next reaction.  IR (KBr): 3400, 3289 (NH), 1651 (CO), 1593 (C = C).  1H NMR (CDCl3): 8.29 (2H, NH), 7.51 (1H, H5), 7.49 (1H, H8), 7.25 (1H, H7), 7.22-6.98. (6H, H3, H6, 4H pyridine), 6.82 (1H, HC = C), 3.61 (2H, CH2CO), 3.50 (2H, CH2-3), 2.85 (2H, CH2- 4).  B) 1- (2-pyridylmethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] indole A solution of N- (indol-3-yl-ethyl) -pyridyl-2-acetamide (900 mg 3.23 mmol) in 10 ml of phosphorus oxychloride is heated at 90 ° C for 1 hour.  It is evaporated to dryness, the residue is hydrolyzed by addition of ice and basified to pH 5 with 0.5N aqueous sodium hydroxide solution.  It is extracted 5 times with chloroform.  The combined organic phases are dried over magnesium sulphate and evaporated to dryness.  The residue is chromatographed on silica eluting with a mixture of dichloromethane (98) and methanol (2).  Orange powder (336 mg, 40%).  F = 190 C-192 C.  IR (KBr): 3411, 3205 (NH), 1631 (C = C).  1H NMR (CDCl3): 9.22 (1H, NH), 8.07 (1H, NH), 7.45 (1H, H5), 7.30 (1H, H8), 7.14 (1H, H7) , 7.05 (1H, H6), 8.34, 7.40, 6.93, 6.75 (4H, pyridine), 5.37 (1H, HC = C), 3.53 (2H, CH2) -3), 2.92 (2H, CH2-4).  MS (m / z): 261 (M +), 246.231.  Example 27: 1- (1-Methyl-2-benzimidazolylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole A) N- (indol-3-yl-ethyl) -1-methyl -2-Benzimidazolylacetamide A mixture of tryptamine (2.9 g, 18 mmol) and ethyl 1-methyl-2-benzimidazolylacetate (4 g, 18 mmol) is heated at 100 ° C. for 2 h.  After cooling, the solid residue is purified by suspending and stirring for 5 min in diethyl ether 3 times.  White powder (4.88 g, 80%).  F = 165 C.  IR (KBr): 3424, 3392, 3311 (NH), 1645 (CO), 1618 (C = C).  1 H NMR (DMSO): 10.82 (1H, NH), 8.42 (1H, NH), 7.16 (1H, indole H2), 7.52, 7.32, 7.21, 7.16, 7.05 and 6.95 (8H, arom H), 3.72 (3H, CH 3), 3.36 (2H, CH 2 3), 2.84 (2H, CH 2 -4), 3.88 (2H). , CH2CO).  B) 1- (1-methyl-2-benzimidazolylmethylidene) -1,2,3,4-tetrahydro pyrido [3,4-b] indole A solution of N- (indol-3-yl-ethyl) -1- Methyl-2-benzimidazolyl-acetamide (1 g, 3 mmol) and phosphorus oxychloride (0.93 g) in 50 ml of toluene was refluxed under nitrogen for 9 h.  The solvent is decanted and the residue is hydrolysed with ice.  After alkalinization with 1% aqueous sodium hydroxide, the mixture is extracted 5 times with dichloromethane.  The solvent is dried over magnesium sulfate and removed.  Purify by chromatography on silica eluting with a mixture of dichloromethane (99) and methanol (1).  Yellow solid (95 mg, 10%).  F = 220 C.  IR (KBr): 3401 (NH), 1602 (C = C).  1 H NMR (DMSO): 11.55 (1H, NH), 8.97 (1H, 15 NH), 7.53 (4H arom. ), 7.09 (4H arom. ), 5.94 (1H, HC = C), 3.72 (3H, CH3N), 3.59 (2H, CH2-3), 2.93 (2H, CH2-4).  MS (m / z): 314 (M +), 313, 299.  Example 28: 1- (2 -benzamazolylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole A) N- (indol-3-yl-ethyl) -2-benzoxazolylacetamide A mixture of ethyl 2-benzoxazolylacetate (4 g, 1.9 mmol) and tryptamine (3.1 g, 1.9 mmol) is heated at 110 C for 4 h.  After cooling, the mixture is extracted with acetone.  The solvent is evaporated and the residue is taken up in diethyl ether.  It is filtered off and purified by chromatography on silica eluting with a mixture of chloroform (95) and methanol (5).  White solid.  F = 136 C.  IR (KBr): 3458, 3278 (NH), 1651 (CO), 1615 (C = C).  1 H NMR (DMSO): 10.84 (1H, NH), 8.46 (1H, NH), 7.17 (1H, indole H2), 7.69, 7.52, 7.35, 7.05, 6.95 (8H arom. ), 3.88 (2H, CH2CO), 3.40 (2H, CH2-3), 2.85 (2H, CH2-4).  B) 1- (2-Benzoxazolylmethylidene) -1,2,3,4-tetrahydro pyrido [3,4-b] indole The procedure is as in the case of Example 27 starting from N- (indol-3-yl) ethyl) -2-benzoxazolylacetamide (1 g, 3.13 mmol) and phosphorus oxychloride (0.6 ml) in 250 ml of toluene.  It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (99.5) and methanol (0.5).  Yellow powder (100 mg, 11%).  F = 113 C.  IR (KI3r): 3401, 3297 (NH), 1616 (C = C).  1 H NMR (CDCl 3): 8.48 (1H, NH), 8.12 (1H, NH), 7.51, 7.34, 7.19, 7.09 (8H arom. ), 5.36 (1H, HC = C), 3.65 (2H, CH2-3), 2.98 (2H, CH2-4).  MS (m / z): 301 (M +), 172, 167.  Example 29: 1- (2-Benzothiazolylmethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b1 indole A) N- (indol-3-yl-ethyl) -2-benzothiazolylacetamide The procedure is as follows: in the case of N- (indol-3-yl-ethyl) -2-benzoxazolylacetamide (Example 28), from ethyl 2-benzothiazolylacetate (6.6 g, 2.9 mmol) and tryptamine ( 4.7 g, 2.9 mmol).  Yellow solid (4.4 g, 45%).  F = 172 C.  IR (KBr): 3269 (NH), 1677 (CO), 1633 (C = C).  1 H NMR (CDCl 3): 7.86, 7.55, 7.47, 7.41, 7.34, 7.19, 7.06 (8H arom. ), 6.86 (1H, indole H2), 4.00 (2H, CH2CO), 3.64 (2H, CH2-3), 2.97 (2H, CH2-4).  B) 1- (2-Benzothiazolylmethylidene) -1,2,3,4-tetrahydro-pyrido [3,4-b] indole The procedure is as in the case of Example 27 starting from Nù (indol-3-yl) ethyl) -2-benzothiazolylacetamide (1.8 g, 5.37 mmol) and phosphorus oxychloride (10.8 mmol) in 100 ml of toluene.  It is purified by chromatography on an alumina column with elution with dichloromethane.  Orange powder (0.34 g, 20%).  F = 60C-62C.  IR (KBr): 3286 (NH), 1597 (C = C).  1 H NMR (CDCl3): 8.56 (1H, NH), 8.19 (1H, NH), 7.58, 7.41, 7.31, 7.29, 7.18 (8H, H arom. ), 5.43 (1H, HC = C), 3.72 (2H, CH2-3), 3.06 (2H, CH2-4).  MS (ml'z): 317 (MI, 149.  EXAMPLE 5: 1-ACYLMETHYLIDENE-1,2,3,4-TETRAHYDROPYRIDO [3,4-b] INDOLES Compounds whose structure is shown in the following Table IV were synthesized: TABLE V 2904973 49 R1 III O EXAMPLES R1 R2 R3 R7 HHH 31 HHH CH3 32 HHH Cl 33 HHHF 34 HH CH3 -CH3 CH3O HH 36 CH3O HH CH3 CH3 H CH3 CH3 H CH3 39 H C2H5 H CH3 2904973 40 H CH3 H 41 H CH3 H Embedded image SCI 42 H C2 H5 HF 43 H C2 H5 HCl 44 CH3O HH 45 CH3O HH CI 46 HHH 47 HH Example 30: 1-Benzoylmethylidene-1,2,3,4-tetrahydro [3,4-bjindole A suspension of 1 -thioxo-1,2,3,4-tetrahydropyrido [3,4-b] -indole (2 g, 9.9 mmol) in 150 ml of acetonitrile, 2-bromoacetophenone (2.36 g, 11.88 mmol) in solution in 30 ml of acetonitrile and stirred for 72 hours at 20 ° C.  The insoluble material is filtered and the filtrate is evaporated to dryness in vacuo.  The residue is dissolved in 100 ml of acetonitrile, triethylamine (5.3 g, 14.85 mmol) is added and stirred for 2 hours at 20 ° C.  Triphenylphosphine (3.11 g, 11.88 mmol) is then added and heated under reflux for 24 hours.  It is evaporated to dryness under vacuum and the residue is purified by chromatography on a silica column eluting with a mixture of petroleum ether (50) and diethyl ether (50).  Orange yellow powder (1.71 g, 60%).  F: 194C  IR (KBr): 3434 (NH), 1600 (CO), 1583 (C = C).  1 H-NMR (CDCl3): 10.81 (1H, NH-9), 8.67 (1H, NH-2), 7.88 and 7.35 (5H, C6H5), 7.53 (1H, NH3); H5), 7.36 (1H, H8), 7.26 (1H, H7), 7.10 (1H, H6), 6.05 (1H, HC = C-1), 3.56 (2H, CH2) -3), 2.97 (2H, CH2-4).  MS (m / z): 288 (M +).  Example 31: 1- (4-toluoylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-bindole 5 The procedure is as in the case of Example 30 starting from 1-thioxo-1,2,3 , 4-Tetrahydropyrido [3,4-b] indole (2 g, 9.9 mmol) and 2-bromo-4'-methylacetophenone (2.53 g, 11.88 mmol) in 150 ml of acetonitrile.  Purification is by chromatography on a silica column eluting with a mixture of diethyl ether (50) and petroleum ether (50).  Yellow powder (1.9 g, 57%).  10 F: 242 C.  IR (KBr): 3449, 3138 (NH), 1601 (CO).  1 H-NMR (CDCl 3): 10.73 (1H, NH-9), 8.42 (1H, NH-2), 7.85 (2H, H 2 ', H 6', C 6 H 4 CH 3), 7.58 (1H, H5), 7.24 (5H, H6, H7, H8, H3 ', H5', C6H4CH3), 6.04 (1H, = CH-CO), 3.64 (2H, CH2-3), 3.05 (2H, CH2-4), 2, 37 (3H, CH3C6H4-).  MS (m / z): 302 (M +).  Example 32: 1- (4-Chlorobenzylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole The procedure is as in the case of Example 30 starting from 1-thioxo-1, 2,3,4-Tetrahydropyrido [3,4-b] indole (2 g, 9.9 mmol) and 2-bromo-4'-chloroacetophenone (2.31 g, 9.9 mmol) in 150 ml of acetonitrile.  The purification is done by chromatography on a silica column eluting with a mixture of diethyl ether (10) and petroleum ether (90).  Solid yellow orange (2.1 g, 65%).  F: 134C  IR (KBr): 3427, 3179 (NH), 1604 (CO).  1H NMR (CDCl3): 10.76 (1H, NH-9), 8.75 (1H, NH-2), 7.86 (2H, H5, H8), 7.57 (1H, H7), 7.27 (5H, H6, C6H4Cl), 6.05 (1H, = CH-CO), 3.63 (2H, CH2-3), 3.03 (2H, CH2-4).  MS (m / z): 322 (M +).  Example 33: 1- (4-fluorobenzoylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-blindole The procedure is as in the case of Example 30 starting from 1-thioxo-1,2,3 4-tetrahydropyrido [3,4-b] indole (2 g, 9.9 mmol) and 2-bromo-4'-fluorophenylacetophenone (2.15 g, 0.99 mmol) in 170 ml of acetonitrile.  The purification is done by chromatography on a silica column eluting with a mixture of diethyl ether (60) and petroleum ether (40).  Yellow powder (1.8 g, 60%).  F: 170 C.  IR (KBr): 3401 (NH), 1596 (CO).  1 H-NMR (CDCl3): 10.72 (1H, NH-9), 8.53 (1H, NH-2), 7.95 (2H, H5, H8), 7.58 (1H, H7), 7 , 28 (1H, H6), 7.08 (4H, C6H4F), 6.01 (1H, = CH-CO), 3.64 (2H, CH2-3), 3.05 (2H, CH2-4 ).  MS (m / z): 306 (M +).  Example 34: 1- (1-acetyl-1-methylmethylidene) -1,2,3,4-tetrahydropyridio-3,4-bindole The procedure is as in the case of Example 30 starting from 1-thioxo-1 , 2,3,4-Tetrahydropyrido [3,4-b] indole (2 g, 9.9 mmol) and 3-bromo-2-butanone (1.8 g, 11.8 mmol) in 200 ml of acetonitrile.  Purification is by chromatography on a silica column eluting with a mixture of diethyl ether (20) and petroleum ether (80).  Beige solid (0.48 g, 20%).  F: 198 C.  IR (KBr): 3390 (NH), 1617 (CO).  1 H-NMR (CDCl3): 8.94 (1H, NH), 7.53 (1H, H5), 7.43 (1H, H8), 7.26 (1H, H7), 7.07 (1H, H6) ), 3.67 (2H, CH2-3), 3.03 (2H, CH2-4), 2.20 (3H, CH3CO), 1.18 (3H, = CCH3).  MS (m / z): 240 (M +).  Example 35: 1-Benzoylmethylidene-6-methoxy-1,2,3,4-tetrahydropyrido [3,4-b] indole The procedure is as in the case of Example 30 starting from 1-thioxo-6- methoxy-1,2,3,4-tetrahydropyrido [3,4-b] indole (2 g, 8.62 mmol) and 2-bromoacetophenone (2.06 g, 10.34 mmol) in 200 ml of acetonitrile .  The purification is done by chromatography on a silica column with

  elution with a mixture of diethyl ether (20) and petroleum ether (80). Yellow powder (2.6 g, 94%). F: 190 ° C. IR (KBr): 3442, 3192 (NH), 1604 (CO). 1 H-NMR (CDCl3): 10.43 (1H, NH), 7.95 (1H, H8), 7.41 (1H, H5), 6.96 (1H, H7), 6.14 (1H, = CH-CO), 3.87 (3H, CH3O), 3.64 (2H, CH2-3), 3.02 (2H, CH2-4). MS (m / z): 318 (M +), 213.

Example 36: 1- (4-Toluoylmethylidene-6-methoxy-1,2,3,4-tetrahydropyridine [3,4-b] indole 2904973 The procedure is as in the case of Example 30 starting from 1 -thioxo-6-methoxy-1,2,3,4-tetrahydropyrido [3,4-b] indole (2 g, 8.62 mmol) and 2-bromo-4-methylacetophenone (2.2 g, 10, 34 mmol) in 250 ml of acetonitrile Purification is by chromatography on a silica column eluting with a mixture of diethyl ether (20) and petroleum ether (80) Orange powder (2 g, 60%) IR: 216 ° C (KBr): 3135 (NH), 1606 (CO) .1H-NMR (CDCl3): 10.73 (1H, NH-9), 8.46 (1H, NH-2), 7.83 (1H, H8), 7.29 (1H, H5), 7.19 (4H, C6H4CH3), 6.97 (1H, H7), 6.05 (1H, = CH-CO), 3, 86 (3H, CH3O), 3.64 (2H, CH2-3), 2.99 (2H, CH2-4), 2.37 (3H, C6H4CH3), MS (m / z): 332 (M +).

Example 37: 1-B-enzoylmethylidene-9-methyl-1,2,3,4-tetrahydropyridine-1,3,4-indol A solution of 1-benzoylmethylidene-1,2,3,4-tetrahydropyrido- [3, 4-b] indole (1 g, 3.47 mmol) in 110 ml of dichloromethane cooled to 0 ° C., a 50% aqueous solution of sodium hydroxide solution (50 ml) is added successively with stirring, the tri-n-bromide is dissolved in water. butylbenzyl ammonium (370 mg) and methyl iodide (1.97 g, 13.88 mmol). The mixture is stirred for 1 h 30 at 0 ° C. and then 4 h at 20 ° C. 100 ml of water are added and the organic phase is decanted. After washing with 3 x 100 ml of water, it is dried over magnesium sulphate and evaporated to dryness in vacuo. It is purified by chromatography on a silica column eluting with a mixture of methanol (3) and dichloromethane (97). Yellow powder (0.80 g, 77%). M. IR (KBr): 3181 (NH), 1599 (CO). 1 H NMR (CDCl3): 11.33 (1H, NH-2), 7.84 (2H, H5), 7.53 (1H, H8), 7.37 (1H, H7), 7.29 ( 5H, C6H5), 7.11 (1H, H6), 6.12 (1H, = CH-CO), 3.99 (3H, NCH3), 3.53 (2H, CH2-3), 2.96 ( 2H, CH2-4). MS (m / z): 302 (M +).

EXAMPLE 38 1- (4-Toluoylmethylidene) -9-methyl-1,2,3,4-tetrahydropyrido [3,4-b] indole The procedure is as in the case of Example 37 starting from 1- (4 toluoylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole (0.8 g, 2.65 mmol) and iodomethane (1.5 g, 0.66 mmol) in 100 ml of dichloromethane. It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (99) and methanol (1). Yellow solid (0.57 g, 61%). F: 122 C. IR (KBr): 3400 (NH), 1599 (CO). 1 H-NMR (CDCl3): 11.28 (1H, NH-2), 7.74 (1H, H5), 7.52 (1H, H8), 7.40 (5H, H7, C6H4CH3), 7.08; (1H, H6), 6.12 (1H, = CH-CO), 3.94 (3H, CH3N), 3.52 (2H, CH2-3), 2.94 (2H, CH2-4), 2 , 33 (3H, C6H4CH3).

MS (m / z): 316 (M +). Example 39: 1- (4-Toluoylmethylidene) -9-methyl-1,2,3,4-tetrahydropyrido [3,4-b] indole The procedure is as in the case of Example 37 starting from 1- (4-toluoylmethylidene) 1,2,3,4-tetrahydropyrido [3,4-b] indole (0.8 g, 2.65 mmol) and iodoethane (1.65 g, 10.6 mmol) in 120 ml dichloromethane. It is purified by chromatography on a silica column, eluting with dichloromethane. Yellow solid (0.3 g, 35%). F: IR 160 C. (KBr): 3420 (NH), 1595 (CO). 1 H-NMR (CDCl3): 11.36 (1H, NH), 7.74 (1H, H5), 7.53 (1H, H8), 7.29 (5H, H7, C6H4CH3), 7.10 (1H , H6), 6.09 (1H, 15 = CH-CO), 4.40 (2H, NCH2CH3), 3.53 (2H, CH2-3), 2.94 (2H, CH2-4), 2, 93 (3H, C6H4CH3), 1.52 (3H, NCH2CH3). MS (m / z): 330 (M +), 211. Example 40: 1- (4-fluorobenzoylmethylidene) -1,2,3,4-tetrahydro-9-methylpyrido [3,4-armolole 20 The procedure is as in the case of Example 37 from 1- (4-fluorobenzoylmethylidene) -1,2,3,4-tetrahydropyridine [3,4-b] indole (0.5 g, 1.63 mmol) and from iodomethane (0.92 g, 6.52 mmol) in 50 ml of dichloromethane. It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (97) and methanol (3). Yellow solid (0.4 g, 77%). M. IR (KBr): 3420 (NH), 1593 (CO). 1 H-NMR (CDCl3): 11.27 (1H, NH), 7.83 and 7.52 (4H, C6H4F), 7.28 (2H, H5, H8), 7.10 (1H, H7), 7 , 02 (1H, H6), 6.05 (1H, = CHCO), 4.04 (3H, NCH3), 3, 51 (2H, CH2-3), 2.93 (2H, CH2-4). MS (m / z): 320 (M +).

Example 41: 1 (4-chlorobenzoylmethylidene) -1,2,3,4-tetrahydro-9-methylpyridone [3,4-b] indole 2904973 The procedure is as in the case of Example 37 starting from 1- (4-Chlorobenzoylmethylidene) -1,2,3,4-tetrahydropyridine [3,4-b] indole (0.7 g, 0.17 mmol) and iodomethane (1.23 g, 8.68 mmol) ) in 90 ml of dichloromethane. It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (97) and methanol (3). Yellow solid (0.55 g, 75%). F: 140 ° C IR (KBr): 3442 (NH), 1605 (CO). 1 H-NMR (CDCl3): 11.34 (1H, NH), 7.78 and 7.53 (4H, C6H4Cl), 7.31 (3H, H5, H7, H8), 7.11 (1H, H6) , 6.07 (1H, = CHCO), 3.97 (3H, NCH3), 3.54 (2H, CH2-3), 2.96 (2H, CH2-4). MS (m / z): 336 (M +).

Example 42: 1- (4-fluorobenzoylmethylidene) -1,2,3,4-tetrahydro-9-ethylpyrido [3,4-b] indole The procedure is as in the case of Example 37 starting from 1- ( 4-fluorobenzoylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole (0.7 g, 2.28 mmol) and iodomethane (1.41 g, 9.7 mmol) in 100 ml of dichloromethane. It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (99) and methanol (1). Yellow powder (0.3 g, 27%). F: 150 ° C. IR (KBr): 3420 (NH), 1592 (CO). 1 H-NMR (CDCl3): 11.45 (1H, NH), 7.92 and 7.64 (4H, C6H4F), 7.39 (2H, H5, H8), 7.12 (2H, H6, H7) , 6.12 (1H, = CHCO), 4.49 (2H, NCH2CH3), 3.61 (2H, CH2-3), 3.04 (2H, CH2-4), 1.62 (3H, CH2CH) ). MS (m / z): 334 (M +). Example 43: 1- (4-Chlorobenzoylmethylidene) -1,2,3,4-tetrahydro-9-ethylpyrido [3,4-b] indole The procedure is as in the case of Example 37 starting from 1- ( 4-chlorobenzoylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole (0.9 g, 27.9 mmol) and iodoethane (1.74 g, 11.6 mmol) in 100 ml dichloromethane. It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (98) and methanol (2). Yellow powder (0.35 g, 36%). F: 158 C.

IR (KBr): 1577 (CO). 1 H-NMR (CDCl3): 11.41 (1H, NH), 7.76 and 7.55 (4H, C6H4Cl), 7.35 (1H, H5), 7.31 (1H, H8), 7.29. (1H, H7), 7.11 (1H, H6), 6.04 (1H, 2904973 = CHCO), 4.36 (2H, CH2CH3), 3.54 (2H, CH2-3), 2.96 (2H, CH 2 -4), 1.52 (3H, NCH 2 CH). MS (m / z): 350 (M +). Example 44: 1- (4-fluorobenzylmethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole The procedure is as in the case of Example 30 starting from 1-thioxo-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole (1.6 g, 6.9 mmol) and 2-bromo-4-fluoroacetophenone (1 8 g, 8.28 mmol) in 250 ml of acetonitrile. Purify by chromatography on a silica column eluting with a mixture of diethyl ether (40) and petroleum ether (60). Orange powder (1.6 g, 69%). F: 214C IR (KBr): 3210 (NH), 1597 (CO). 1 H NMR (CDCl3): 10.68 (1H, NH), 8.70 (1H, NH), 7.88 and 7.21 (4H, C6H4F), 6.99 (1H, H8), 6, 96 (2H, H5 and H7), 6.00 (1H, = CHCO), 3.76 (3H, CH3O), 3.62 (2H, CH2-3), 2.94 (2H, CH2-4). MS (m / z): 336 (M +).

Example 45: 1- (4-Chlorobenzoylmethylidene) -1,2,3,4-tetrahydro-6-methoxy-pyri [3,4-b] indole The procedure is as in the case of Example 30 starting from 1-thioxo-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole (1.6 g, 6.9 mmol) and 2-bromo-4-chloroacetophenone (1, 93 g, 8.28 mmol) in 150 ml of acetonitrile. It is purified by silica column chromatography eluting with a mixture of diethyl ether (10) and petroleum ether (90). Orange powder (1.3 g, 65%). F: 114C IR (KBr): 3305 (NH), 1611 (CO). 1 H-NMR (CDCl3): 10.71 (1H, NH), 8.43 (1H, NH), 7.81 and 7.30 (4H, C6H4Cl), 7.22 (2H, H5, H8), 6 , 93 (1H, H7), 5.94 (1H, = CHCO), 3.78 (3H, CH3O), 3.59 (2H, CH2-3), 2.96 (2H, CH2-4). MS (m / z): 352 (M +).

EXAMPLE 46 1 - (4-anilylmethylidene) -1,2,3,4-tetrahydropyrido [3,4-b] indole The procedure is as in the case of Example 30 starting from 1-thioxo-1, 2,3,4-Tetrahydropyrido [3,4-b] indole (2 g, 9.9 mmol) and 2-bromo-4-methoxyacetophenone (2.7 g, 11.88 mmol) in 250 ml of acetonitrile . It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (99) and methanol (1). Yellow powder (1.88 g, 60%). F: 138 C.

IR (KBr): 3315 (NH), 1699 (CO). 1 H NMR (CDCl3): 11.20 (1H, NH), 7.65 (4H, C6H4OCH3), 7.68 (1H, H5), 7.48 (1H, H8), 7.25 (1H, H7), 7.18 (1H, H6), 6.06 (1H, = CHCO), 3.82 (3H, CH3O), 3.42 (2H, CH2-3), 2.96 (2H, CH2- 4). MS (m / z): 318 (M +).

Example 47: 1- (1-phenyl-benzoylmethylidene) -1,2,3,4-tetrahydropyryl [3,4-bindole The procedure is as in the case of Example 30 starting from 1-thioxo-1 , 2,3,4-Tetrahydropyrido [3,4-b] indole (2 g, 9.9 mmol) and 2-bromo-1,2-diphenylethanone (3.54 g, 12.87 mmol) in 250 ml of acetonitrile. It is purified by chromatography on a silica column, eluting with a mixture of diethyl ether (50) and petroleum ether (50). Yellow powder (1.25 g, 40%). F: 258 C. IR (KBr): 3445 (NH), 1586 (CO). 1 H-NMR (CDCl3): 12.23 (1H, NH). 7.46 (1H, H5), 7.18 (10H, 2, C6H5), 7.66 (2H, H7, H8), 7. , 00 (1H, H7), 3.56 (2H, CH2-3), 3.02 (2H, CH2-4). MS (m / z): 364 (M +). EXAMPLE 6: HYPNOTIC ACTIVITY TESTS IN CHICO The effect on the state of alertness of valentonin, 6-methoxy-harmalan and certain valentonergic compounds according to the present invention was tested in flesh strain chicks. JA657, aged 10 to 14 days. The animals are subjected to programs of alternating illumination including 12h of darkness (20h to 8h) and 12h of illumination (8h to 20h). The ambient temperature is 25 C during the first week of chick rearing and 22 C from the second week. During the day, the illumination is provided by a halogen lamp (300 2 5 W), placed 30 cm above the floor of the vivarium. During the tests, the live weight of the chicks ranged between 85 and 120 g. The tests are carried out between 14 and 15h. The chicks are allotted in groups of 3, in identical vivariums of 30 cm x 50 cm x 30 cm. The tested products are administered intramuscularly (IM) in the major pectoralis muscle, either in aqueous solution (for water-soluble compounds such as mesylates), or in ethanol / PEG 400 / water solution (25/50/25, V). / V / V), 0.2 ml of solution 2904973 per 100 g live weight. The doses administered for the tested products (valentonergic and reference substances) vary from 0.25 mol to 5 mol per 100 g of live weight Placebo corresponds to 0.2 ml of the solution per 100 g of live weight When ethanol is used in the solvent, its effect was compared before that of physiological saline (NaCl solution 0.9%) or distilled water. The solutions of the tested products were prepared extemporaneously by successive dilution of a stock solution, obtained from 2.5 to 50 M of exactly weighed product, added to either 2 ml for injection (for the water-soluble compounds) or successively 0.5 ml of pure ethanol and 1 ml of PEG 400, sonicated and then supplemented to 2 ml with 0.5 ml of distilled water for injection. In Table I below are presented the results obtained after IM administration of doses of between 0.25 and 5 moles of test products, in solution in 0.2 ml of distilled water or of the ethanol / PEG 400 / water mixture, for 100 g live weight. For each chick, the injected volume is adjusted, based on actual live weight, to 0.2 ml per 100 g body weight; which corresponds to doses between 1 and 10 mg / kg live weight The parameters observed are the locomotor activity and the waking state of the chicks during 2h, the equivalent of the 6 theoretical cycles sleep-wake of the chick of 2 0 this age. They are recorded by video camera for 90 minutes, the first 30 minutes being the time of adaptation to the device Five stages of vigilance have been defined: - stage 1: active watch; stage 2: animal lying down, maintaining the head with tonicity, open eye; Stage 5: light sleep, sleeping animal; closed eye with intermittent opening, motionless posture unmodified by stimulation; - stage 4: deep sleep recumbent: relaxation of the neck, characteristic posture head under the wing or back; - stage 5: sleep standing: closed eye, motionless, drooping head (catatonic).

These five stages roughly correspond to the vigilance and sleep stages defined by the examination of electroencephalographic plots in this species. The correspondence is as follows: ^ Deep sleep lying down: stage 4 = slow wave sleep (SWS) 5 ^ Sleep standing = sleep-like state I (SLSI). Stage 3, asleep, could correspond to phases of REM sleep, with head shaking, for example. The observation of the chicks is performed by a trained observer with continuous video monitoring for at least one hour after waking the animals.

Two stimuli were used to confirm the observations of the chicks' behavior at regular intervals: - the noise caused by the impact of a plastic object on the vivarium pane, comparable to that of the beak of a chick on the pane, corresponds to a moderate stimulus. It is practiced at each observation period (every 5 minutes); 15 - and the presentation of a metal feeder filled with the usual food, left 2 minutes in the vivarium. It is a powerful stimulus involving vision, hearing and smell. It is practiced every 15 minutes, that is to say 6 times, at least, with each test. The awakening is defined by the appearance of elaborate conscious behavior of research and consumption of food or drink. Sleep Time (TS) is defined as the sum of the duration of the phases of light sleep (stage 3), deep sleep (stage 4) and sleep (stage 5). The Sedation Time, after waking, corresponds to stage 2. The Dulling Time (TA) is equal (within 1 minute) to the time required for the transition from active standby state 2 5 (stage 1) to a non-watchful state (stages 3, 4 and 5). Sleep Time (TS) is equal to the duration of the sleep period from sleep to wake up. It is expressed in minutes and in difference (minutes) compared to placebo (A TS vs. placebo). The total sedation time over the period is expressed in% of the period (Sed).

The reference products are the following valentonergic compounds: Ethyl carbo 7 (water insoluble product) and CF 054 MS (water soluble mesylate). For each product tested, several series of measurements were performed on batches of 3 animals, each indicated value is the average in each batch of 3 chicks. When the number of lots is greater than or equal to 2, the figures given are the average values observed. NNN, CH3SO3H CF 054-MS TABLE VI Compound Dose TA (minutes) TS (mg / kg) (minutes) Placebo - NA 0 Melatonin 1.16 NA 0 2.32 NA 0 4.64 NA 0 Pentobarbital 1.24 NA 0 2.48 13 36 Diazepam 2.85 2-7 24-70 Zolpidem 3.07 2 33 Valentinine 2.56 2-9 36-65 5.12 4-11 40-70 Ethyl carbo 7 1.48 9 18 2, 96 9-11 28-101 6-methoxy harmalan 3 NA 0 Legend: NA: Not Applicable. The animals remain vigilant throughout the observation period TA: Dulling time is equal to the time required to go from the active standby state to a non-watch state. H3CO 5 Ethyl carbo 7 2904973 61 TS: Sleep time is equal to the duration of the sleep period from sleep to wake up. Results: In the chick of this age, the duration of a sleep-wake cycle is 20 to 30 minutes during the day. It thus appears, from the dose of 1 mg / kg that 8 out of 17 compounds tested induce a very strong decrease in locomotor activity attested by a duration of the first sleep greater than 20 minutes. The animals do not sleep after administration of the placebo . The number of products tested in this case, at higher doses, increases to 12/17 and 10 to 14/17 at doses of 3 and 10 mg / kg, respectively, as evidenced by the review of Tables VII. at IX. There is a positive net dose-response relationship for most tested compounds, with a reduction in the drowsiness period as the dose increases. Over 90 minutes, the difference in sedation time, expressed as a percentage of the period of observation, with that observed after the administration of the placebo, is greater than 50 percent for 4 out of 17 compounds at the dose of 1 mg / kg, for 5 from 17 to 3 mg / kg and from 1 to 17 mg / kg. The compounds tested are methanesulfonates, with the exception of Example 2a which is the basic form of Example 2, Example 10a which is the basic form of Example 10 and examples 26, 28 and 29. TABLE VII (Dose: 1 mg / kg) TA TS Sed ATS / placebo compounds (minutes) (minutes) (% period) (minutes) Example 1 21.5 22.5 31.5 22.5 Example 2 15.0 17.5 38.5 17.5 Example 2a 12.5 18.5 50.0 18.5 Example 5 10.0 27.5 41.5 27.5 Example 6 10.0 15, 46.5 15.5 Example 8 12.5 46.0 46.0 52.0 2904973 62 Example 10 9.5 9.5 38.0 9.5 Example 10bis 14.0 19.0 55.0 17, 0 Example 11 28.5 11.0 30.7 9.0 Example 12 22.0 9.0 20.3 7.0 Example 13 14.0 45.0 67.0 43.0 Example 14 11.0 17, 0 48.0 15.0 Example 15 11.5 5.0 35.0 3.0 Example 22 15.0 55.0 66.0 55.0 Example 26 12.5 23.5 54.5 23.5 Example 28 17.5 38, 49.0 38.5 Example 29 25.0 27.5 45.0 27.5 Ethyl carbo 7 15.0 12.5 12.5 38.0 CF 054-MS 10.0 10 , 0 10.0 27.0 TABLE VIII (Dose: 3 mg / kg) TA TS Sed ATS / placebo compounds (minutes) (minutes) ( % period) (minutes) Example 1 16.5 25.0 40.0 25.0 Example 2 20.0 20.0 34.0 20.0 Example 2a 8.3 44.0 67.0 44.0 Example 11.0 20.0 30.0 20.0 Example 6 17.0 16.0 32.5 16.0 Example 8 10.5 27.5 36.0 27.5 Example 10 6.5 21.5 43 Example 11bis 12.0 36.5 48.0 34.5 Example 11 14.9 23.0 48.6 21.0 Example 12 20.0 24.0 50.0 22.0 Example 13 19 , 0 16.0 46.0 14.0 Example 14 12.0 29.0 56.0 27.0 Example 15 13.0 7.0 21.0 5.0 2904973 63 Example 22 12.0 38.0 60 Example 28 8.5 53.5 68.5 53.5 Example 29 20.0 25.0 42.5 25.0 Ethyl carbo 7 10.0 53.5 57.5 53.5 CF 054-MS 14.0 42.0 55.0 42.0 TABLE IX (Dose: 10 mg / kg) TA TS Sed ATS compounds / placebo (minutes) (minutes) ) (% period) (minutes) Example 1 17.5 15.5 39.0 15.5 Example 2 9.0 52.5 65.0 52.5 Example 2 bis 7.0 74.0 80.0 74, Example 5 15.0 21.5 40.5 21.5 Example 6 9.5 37.0 62.0 37.0 Example 8 9.0 52.0 61.5 52.0 Example 10 8.0 35, 0 57.0 35.0 Example 10bis 5.0 58.5 74.0 56.5 Example 11 9.5 58.5 82.6 56.5 Exe mple 12 13.5 45.0 57.5 43.0 Example 13 29.0 18.0 31.0 16.0 Example 14 9.0 28.0 46.0 26.0 Example 15 10.0 27.0 55.0 25.0 Example 22 10.0 60.0 80.0 60.0 Example 26 4.0 46.0 46.0 72.0 Example 28 13.5 31.5 69.0 31.5 Example 29 12.5 20.0 32.5 20.0 Ethyl carbo 7 7.0 67.5 76.5 67.5 CF 054-MS 9.5 42.0 55.0 42.0

Claims (26)

  1. Derivative of methylidene-pyrido [3,4-b] indole of the following general formula (I): R 1 1 (I) in which: R 1 represents a hydrogen atom or a C 1 -C 6 alkoxy group; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a hydrogen atom, a C1-C6 alkyl group or an aryl group, the aryl group being optionally substituted by a C1-C6 alkyl group; R4 represents a heteroaryl group of 3 to 10 atoms containing one or two identical or different heteroatoms selected from O, N or S the other atoms being carbon atoms, the heteroaryl group being optionally substituted with a C1-C6 alkyl group; a -CN group; a group - (C = O) R7, wherein R7 represents an NH2 group, a C1-C6 alkyl group or a phenyl, the phenyl being optionally substituted by a C1-C6 alkyl group, a halogen atom or a C1-C6 alkoxy group; a group - • (C = S) NH2; a group - (C = NOH) NH 2; or a group - (C = NOH) NH (C = O) R5, in which R5 represents a hydrogen atom or a C1-C6 alkyl group, the alkyl group being optionally substituted by one or more atoms of halogen; or their mixtures, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof.   2. A methylidene-pyrido [3,4-b] indole derivative according to claim 1, characterized in that it is chosen from the compounds of general formulas (II), (III), (IV) and (V) R 1 NH R 6 HH and R 1 N NH in which R 1 to R 3 and R 7 are as defined in claim 1, X represents a sulfur atom or the group NOH, R 6 represents an NH 2 group or a group - NH (C = O) R5 wherein R5 is as defined in claim 1, Het is heteroaryl of 3 to 10 atoms containing one or two identical or different heteroatoms selected from O, N or S, the other atoms being carbon atoms, the heteroaryl group being optionally substituted with a C1-C6 alkyl group or mixtures thereof, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof. 15   3. Derivative of methylidene-pyrido [3,4-b] indole according to claim 1 or 2, characterized in that it is chosen from the following compounds of formulas 1 to 47: MeO HelI NHNNH RI NH N p ## STR1 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## // ~~ / 1N HNH,. , NH2 / NH2 CH3 NOH 22 23 s NOH 2904973 68 NH NHCOCH3H NHCOCF3 NOH 24 NOH 25 NNH H 26 27 NNH H 28 29 30 31 CI 5 32 33 2904973 69 H3 35 MeO CH3 36 37 CH3 38 39 40 41 5 42 43 2904973 70 44 45 MeO MeO 10 46 and 47   4. Process for the preparation of a compound of general formula (II) according to claim 2, in which R2 represents a hydrogen atom by reaction of Bischler-Napieralski with the compound of the following general formula (VI): R1 / II R3 HN Wherein R 1 and R 3 are as defined in claim 1 together with phosphoric anhydride or phosphorus oxychloride, advantageously by heating in toluene.   5. Process according to claim 4, characterized in that the compound of general formula (VI) is obtained by amidification of the compound of general formula (VII) below: ## STR1 ## in which R 1 is as defined in the claim 1 with the compound of the following general formula (VIII) CN R3 OEt O (VIII) wherein R3 is as defined in claim 1, advantageously by heating without solvent or with dioxane.   6. A process for the preparation of a compound of the general formula (II) according to claim 2 wherein R2 represents a C1-C6 alkyl group, by alkylation of the compound of the general formula (II) according to claim 2 wherein R2 represents a hydrogen atom, by means of an alkyl iodide of formula R 2 in which R 2 represents a C 1 -C 6 alkyl group, advantageously in a mixture of dichloromethane and an aqueous sodium hydroxide solution in the presence of benzyltrimethylammonium. 15   7. Process for the preparation of a compound of general formula (III) according to claim 2, in which R7 represents an NH2 group by heating at 80 ° C. in the polyphosphoric acid the compound of general formula (II) according to claim 2.   8. Process for the preparation of a compound of general formula (IV) according to claim 2 wherein X represents a sulfur atom and R6 represents the NH2 group by reaction of the compound of general formula (II) according to claim 2 with thioacetamide CH3CSNH2, advantageously in a solution of dimethylformamide in the presence of hydrochloric acid. 2904973 72   A process for preparing a compound of the general formula (IV) according to claim 2 wherein X is NOH and R6 is NH2 by refluxing the compound of the general formula (II) according to claim 2 in an aqueous solution of hydroxylamine.   A process for preparing a compound of the general formula (IV) according to claim 2 wherein X is NOH and R6 is -NHCOR5 wherein R5 is as defined in claim 1 by reacting the compound of general formula (IV) according to claim 2 wherein X is NOH and R6 is NH2 with the acid anhydride of the following general formula (IX) (R5CO) 20 wherein R5 is as defined in the claim 1, advantageously in a solution of diethyl ether or benzene. 15   11. Process for the preparation of a compound of general formula (V) according to claim 2 by Bischler-Napieralski reaction of the compound of general formula (X) below: ## STR2 ## wherein Het is as defined in claim 2 with phosphorus pentoxide or phosphorus oxychloride, advantageously by heating in toluene.   12. Process according to claim 11, characterized in that the compound of the general formula (X) is obtained by amidification of the compound of the general formula (VII) according to claim 5 in which R1 represents a hydrogen atom with the compound of wherein: Het is as defined in claim 2, advantageously by heating without a solvent or with dioxane. 5   A process for the preparation of a compound of the general formula (III) according to claim 2 wherein R 7 is a C 1 -C 6 alkyl group or a phenyl, the phenyl being optionally substituted with a C 1 -C 6 alkyl group, an atom of halogen or a C1-C6 alkoxy group and R2 represents a hydrogen atom, by treatment, advantageously in acetonitrile, of the compound of the following general formula (XII): XII in which R1 is as defined in claim 2, with a bromoacetone of the following general formula (XIII): wherein R3 and R7 are as defined in claim 2, followed by treatment with an amine, advantageously triethylamine, and phosphine, advantageously triphenylphosphine P (C6H5) 3, and by prolonged heating.   A process for the preparation of a compound of the general formula (III) according to claim 2 wherein R 7 is C 1 -C 6 alkyl or phenyl, the phenyl being optionally substituted with a C 1 -C 6 alkyl group, halogen atom or a C1-C6 alkoxy group and R2 does not represent a hydrogen atom, by reaction of a compound of general formula (III) according to claim 2 wherein R7 represents an alkyl group; C1-C6 or phenyl, the phenyl being optionally substituted by C1-C6alkyl, halogen or C1-C6alkoxy and R2 is hydrogen, with an alkyl halide; , advantageously in a solvent such as dichloromethane, in the presence of aqueous sodium hydroxide and N-benzyltri-n-butylammonium bromide.   15. Combination of a methylidene-pyrido [3,4-b] -indole derivative according to any one of claims 1 to 3 and a 5HT2 receptor antagonist of the following general formulas (XIV) or (XIVbis) Wherein R 18 represents a C 1 -C 12 alkyl, phenyl or phenyl (C 1 -C 6) alkyl group, the phenyl group being optionally substituted with a C 1 -C 6 alkoxy, a C 1 -C 6 alkyl group; halogen atom or a secondary amine, R16 and R17 are absent and the dashed line represents a bond or R16 and R17 represent a hydrogen atom and the dashed line is absent.   16. Association according to claim 15 characterized in that the methylidene-pyrido [3,4-b] -indole derivative according to any one of claims 1 to 3 is present in an amount by weight greater than that of the antagonist .   17. Combination according to claim 15 or 16, characterized in that the methylidene-pyrido [3,4-b] indole derivative according to any one of claims 1 to 3 has a lower blood elimination period. to that of the 5HT2 receptor antagonist, advantageously less than 2 hours. 2904973 75   18. Combination according to any one of claims 15 to 17, characterized in that R18 represents a methyl or ethyl group, advantageously the 5HT2 receptor antagonist of general formula (XIV) or (XIVbis) is chosen from 6- methoxy-harmalan of the following formula: or the ethyl analogue of 6-methoxy-harmalan of the following formula: MeO MeO or their hydrogenated analogues, of formulas: MeO MeO, and or the compound of formula CH3 NH (50) Me 0   19. A pharmaceutical composition comprising a methylidenepyrido [3,4-b] indole derivative according to any one of claims 1 to 3 or a combination according to any one of claims 15 to 18 and a pharmaceutically acceptable excipient.   20. A pharmaceutical composition comprising the combination according to any one of claims 15 to 18 and a 5HT2 receptor antagonist of general formulas (XIV) or (XIVa): wherein R16 to R18 and the dashed line are as defined in claim 15 as a combination product for a time-separated use for regulating the circadian sleep-wake cycle.   21. Composition according to any one of claims 19 or 20, characterized in that it is intended for oral or intravenous administration, advantageously orally.   22. A methylidene-pyrido [3,4-b] indole derivative according to any one of claims 1 to 3 or a combination according to any one of claims 15 to 18 or a composition according to any one of claims 19 to 21 for its use as a medicine. 15   23. A combination according to any one of claims 15 to 18 or a composition containing the combination according to any one of claims 19 to 21 for its use as a medicament for regulating the circadian sleep-wake cycle and / or treatment insomnia, mood disorders such as depression or anxiety, Parkinson's disease, Alzheimer's disease, and diseases or disorders related to deregulation of the circadian sleep-wake cycle.   24. A methylidene-pyrido [3,4-b] indole derivative as claimed in any one of claims 1 to 3 for use as a medicament having myorelaxant, hypnotic, sedative and / or analgesic activity, and / or for the treatment of disorders related to disorders of melatonin activity and / or the treatment of depression and psychiatric disorders, in particular stress, anxiety, insomnia, schizophrenia, psychosis or epilepsy, and / or the treatment of travel-related sleep disorders (jet lag) or neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease and / or the treatment of cancers such as skin cancer, and / or treatment of benign prostatic hyperplasia, skin conditions such as psoriasis, acne, mycosis, glaucoma and / or increased immune resistance and / or symptom prevention menopause, premenstrual syndromes, the effects of aging and sudden infant death.   25. Use of a methylidene-pyrido [3,4-b] -indole derivative according to any one of claims 1 to 3 as a contraceptive in humans or animals and / or for regulating births in ruminant animals.   26. Cosmetic composition comprising a methylidene-pyrido [3,4-b] indole derivative according to any one of claims 1 to 3 and a cosmetically acceptable excipient. 15