FR2914924A1 - DERIVATIVES OF 4,5,11,11A-TETRAHYDRO-1H, 6H-OXAZOLO [3 ', 4': 1.6] PYRIDO [3,4-B] INDOL-3-ONE AND THEIR USE IN THERAPEUTICS. - Google Patents

Abstract

The present invention relates to a compound 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one of general formula (I ) following: in which: R <1> represents a hydrogen atom or a C1-C6 alkoxy group; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C4-C6 cycloalkene group, a heteroaryl or an aryl group, the aryl group being optionally substituted by one or more groups chosen from C1-C6 alkyl, C1-C6 alkoxy, cyano or with one or more halogen atoms; R4 represents a hydrogen atom or a C1-C6 alkoxy group; or their mixtures, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereomers or their mixtures, its method of preparation and its use in pharmaceutical and / or cosmetic compositions, in particular for the regulation of the circadian watch cycle. sleep.

Description

The present invention relates to novel derivatives of

4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-ones, as well as their use in therapy, advantageously as as agonists of serotoninergic 5-HT2 receptors, by allosteric modulation, advantageously in the treatment of sleep disorders.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone from the pineal gland, isolated by Lerner et al. (J. Am. Chem. Soc., 80, 1958, 2587). Melatonin has been the subject of numerous studies for its circadian activity, particularly in the rhythm of sleep, for its effects on testosterone production, for its activity in the hypothalamus and in 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 4"), neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease, for the treatment of cancers, or even as a contraceptive , or as a pain reliever. However, the direct use of melatonin in vivo has not been shown to be very satisfactory, given a first hepatic passage which extracts more than 90% of the active principle.

Different melatonin analogues have been described, highlighting two avenues of research which relate either to the substituents of melatonin (WO-A-89/01472, US-A-5 283 343, US-A-5,093,352 or WO-A-93/11761), or on the aromatic nucleus by replacing the indole group by 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 new derivatives of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-ones. Furthermore, the inventors have demonstrated that melatonin, with the exception of its antioxidant and free radical neutralizing properties, which make melatonin an extremely effective pharmacological agent against damage due to free radicals and against neuronal loss, in the aim of preventing neurodegeneration processes, does not directly regulate the circadian sleep-wake cycle, but is only a biological precursor of two compounds that exhibit pharmacological activities. It was thus surprisingly discovered by the inventors that, during the time of nighttime sleep, and whatever the season, the melatonin produced in the pineal gland, following a first acetylation of serotonin, facilitated by N-acetyltransferases , undergoes, as soon as it is produced, a second enzymatic acetylation step by N-acetyltransferases, giving successively two beta-carboline derivatives, namely 6-methoxy-1-methyl-3,4-dihydro-beta-carboline, called 6-methoxy-harmalan (6-MH), and 2-acetyl-6-methoxy-1-methylene-3,4-dihydro-betacarboline, called Valentonin (VLT (Figure 1)). The production of 6-methoxy harmalan (6-MH) in the pineal gland has been demonstrated by Farrell and Mc Isaac (Farrell, G., et al., Arch. Bioch. Bioph., 94, 1961, 543-544 û Mc Isaac, WM, et al., Science, 134, 1961, 674-675), in 1961, from pineal glands of oxen killed early in the morning in Chicago slaughterhouses. As indicated above, 6-MH, which is therefore produced together with VLT, is a serotonin antagonist towards the 5HT2 serotonin receptors, which are neuro-inhibitory (their activation by serotonin leads to a decrease in serotonin receptor 5HT2). alertness and mood). By blocking them, 6-MH inhibits their activation by serotonin. Therefore, increased vigilance maintains the state of wakefulness; this results in an increase in vigilance which gives 6-MH a psychostimulant activity. In addition, in the tests that the inventors carried out on chicks, unlike VLT, which exhibits significant hypnotic activity, as shown in Table VII below, 6-MH increases locomotricity, which corresponds to l psychostimulant activity. Its psychostimulant activity, slightly weaker than that of lysergic acid diethylamide (LSD), another 5HT2 serotonin receptor antagonist, allows the body to switch from the state of sleep unconsciousness to a state of consciousness of standby, increasing vigilance. For this reason, 6-MH can be considered the sleep hormone. Moreover, as shown in Table VII below, VLT exhibits important hypnotic properties, both from a qualitative point of view (EEG architecture of physiological sleep) and from a quantitative point of view; and, taking into account that the biosynthesis of VLT and nighttime sleep are associated over time, it can be considered that VLT, involved in the induction and maintenance of the nocturnal sleep state, is the hormone some sleep . Like most endogenous compounds, VLT cannot be administered orally, due to its hydrolysis in the acidic gastric medium; Various analogs which are stable in an acid medium called Valentonergics, which are most often derivatives of beta carboline, and therefore of melatonin, have been synthesized. Thus, all the studies carried out by the inventors show that VLT and Valentonergics (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 regard to the electroencephalographic structure of sleep, with hypnotic drugs available on the market, such as, for example, benzodiazepines and Zolpidem. In fact, benzodiazepines and Zolpidem produce non-physiological sleep, characterized by the predominance of light S1 sleep and very little REM sleep (see Table VII below), qualified as so-called anesthetic sleep, because it is less restorative for the patient. organism, and gives amnesias. On the contrary, VLT and Valentonergics produce sleep, whose EEG architecture is similar to that of physiological sleep, characterized by the predominance of slow deep sleep (SLP) (S2 + S3) and high percentages of REM sleep. VLT and Valentonergics induce sleep by reducing vigilance, as a consequence of the activation, by allosteric modulation, of serotonergic 5-HT2 receptors. For these reasons, Valentonergics can be used in the treatment of sleep disorders. VLT and Valentonergics are therefore activators of the 5HT2 receptor by allosteric modulation. The present invention therefore relates to novel Valentonergics: derivatives of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3- one is. The role of the [(Valentonin) - (6-methoxy harmalan)] system in the regulation of the circadian sleep-wake cycle can be summarized as follows: 1 - VLT, sleep hormone, produced in the pineal body, during the period of sleep, between 8 p.m. and 4 a.m. GMT, by enzymatic acetylation of MLT, induces and maintains the state of sleep as a result of its ability to decrease vigilance after the activation of 5-HT2 receptors by allosteric modulation, to using its allosteric ligand. VLT remains prevalent during the period of sleep, which means that the concentrations in the vicinity of 5-HT2 receptors are higher than those of 6-MH. 2 - Early in the morning, at 4 am GMT, the biosynthesis of both VLT and 6-MH stops, because NAT decreases in the pineal body; then, since the rate of elimination of VLT is greater than that of 6-MH (figure 2), the waking hormone becomes prevalent. Therefore, between 4 a.m. and 8 p.m. GMT, 6-MH exerts its antagonistic action on 5-HT2 receptors by blocking them, which inhibits their activation by serotonin. As a result, vigilance increases, and the waking state is maintained until 8 p.m. GMT. Thus, the combination of VLT and 6-MH in the [(Valentonin) - (6-methoxy harmalan)] system helps to regulate the circadian sleep-wake cycle. Indeed, the capacity of the VLT to bind then to activate, by allosteric modulation, the adrenergic receptors I2, as well as the dopaminergic receptors D1 and D2, explains how the blood pressure and the muscular tone decrease during the period of night sleep. On the contrary, 6-MH, when its concentrations are higher than those of VLT, during the period of activity (waking), by blocking the 5-HT2 receptors, adrenergic I2 and dopaminergic D1 and D2, induces pharmacological activities which are opposed to those, previously described, of the VLT. Therefore, the mechanism of 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 to date, of insomnia, depression and mood disorders, psychotic states, illnesses. Parkinson's and Alzheimer's. A decrease in the biosynthesis of VLT, and simultaneously of 6-MH, is observed in primary insomnia, in Parkinson's disease and in Alzheimer's disease. In depressions, VLT biosynthesis is normal, but insufficient to lower the alertness increased by the stress at the origin of the depressive state. In these conditions characterized by sleep disturbances, it seems necessary to treat such disturbances by administering a Valentonergic. In addition, the treatment of Parkinson's disease with Valentonergics is justified by their dopaminergic agonist properties. Furthermore, the authors found that psychotic states were due to excessive biosynthesis of 6-MH, resulting in heightened alertness and mood due to excessive blockade of serotonergic 5-HT2 receptors. These conditions could be treated by administering Valentonergics, which may displace excess 6-MH from its binding sites to 5-HT2 receptors, which should cause a decrease in vigilance. Moreover, when the dysfunction of the [(VLT) - (6-MH)] system corresponds to a decrease in the biosynthesis of VLT together with that of 6-MH, it seems necessary to treat such disorders by giving a combination of 'a Valentonergic and 6-methoxy harmalan. Indeed, taking into account that the circadian sleep-wake cycle is controlled by the [(Valentonin) - (6-methoxy harmalan)] system, VLT, sleep hormone, or synthetic Valentonergic analogues, must be given together with an appropriate amount of 6-MH, the wakefulness hormone, for proper regulation of the circadian sleep-wake cycle. In addition, the inventors have also discovered that the combination of VLT or Valentonergics with 6-MH or its analogues makes it possible to 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 with aging and in Alzheimer's disease (AD). MLT secretion is significantly lower in Alzheimer's patients, compared to healthy subjects of the same age. A disturbed sleep-wake rhythm is common in patients with Alzheimer's disease, and is correlated with reduced MLT concentrations and a disturbed circadian rhythm of MLT secretion. The direct consequences of the decrease in MLT secretion by the pineal gland in patients with AD are insomnia and cognitive dysfunction, linked to decreases in the biosynthetic pathways of VLT, the sleep hormone, and 6 -MH, the day before hormone, respectively.

In addition, Parkinson's disease could result from an insufficient biosynthesis of VLT during the period of sleep. Patients with Parkinson's disease have trouble sleeping. 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 with VLT or a Valentonergic, administered for its dopaminergic agonist properties, can only be done by administering the combination of VLT or Valentonergics with 6-MH or its analogues, in order to harmoniously regulate the sleep-wake cycle.

The subject of the present invention is therefore the synthesis of novel Valentonergics derived from 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol- 3-ones, as well as their use alone or in combination as medicaments.

The present invention therefore relates to a 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one of general formula (I ) following: R4 R1 in which: Rl represents a hydrogen atom or a C1-C6 alkoxy group; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C4-C6 cycloalkene group, a heteroaryl or an aryl group, the aryl group being optionally substituted by one or more groups chosen from C1-C6 alkyl, C1-C6 alkoxy, cyan or with one or more halogen atoms; R4 represents a hydrogen atom or a C1-C6 alkoxy group; or their mixtures, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereomers or mixtures thereof.

The term C1-C6 alkyl group is understood to mean, within the meaning of the present invention, any alkyl group of 1 to 6 carbon atoms, linear or branched, in particular the methyl, ethyl, n-propyl, isopropyl, n- groups. butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl. Advantageously, it is a methyl, ethyl or n-propyl group.

The term C1-C6 alkoxy group is understood to mean, within the meaning of the present invention, any alkoxy group of 1 to 6 carbon atoms, linear or branched, in particular the OCH3 group. By the term aryl group, is meant within the meaning of the present invention one or more aromatic rings having 5 to 10 carbon atoms, which can be joined 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 is understood to mean 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 or nitrogen atoms. or oxygen. The heteroaryl according to the present invention can consist of one or two aromatic rings fused or joined together, each ring possibly comprising 1 or 2 heteroatoms and at least one of the rings comprising one or two heterotaoms. Examples of heteroaryl groups are furyl, thiophenyl, isoxazyl, pyridyl, pyrimidyl, benzimidazole, benzoxazole, benzothiazole, methylenedioxyphenyl groups. Advantageously, the heteroaryl group is chosen from pyridyl, furyl, thiophenyl and methylenedioxyphenyl groups, advantageously from pyridyl, thiophenyl and methylenedioxyphenyl groups. The term C3-C6 cycloalkyl group is understood to mean, within the meaning of the present invention, any saturated hydrocarbon-based ring composed of 3 to 6 carbon atoms, in particular the cyclohexyl group. By the term C4-C6 cycloalkene group is meant within the meaning of the present invention any hydrocarbon-based ring composed of 4 to 6 carbon atoms which is not completely unsaturated but comprising one or more unsaturations, in particular the cyclohexylene group. For the purposes of the present invention, the term halogen atom is understood to mean any halogen atom, advantageously chosen from Cl, Br, I or F.

In the present invention, the term "isomers" is intended to denote compounds which have identical molecular formulas but which differ in the arrangement of their atoms in space. Isomers which 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 diastereomers, and stereoisomers which are non-overlapping mirror images are referred to as enantiomers, or sometimes optical isomers. A carbon atom bonded to four non-identical 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, by pharmaceutically acceptable is meant 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 human pharmaceutical use. . By pharmaceutically acceptable salts of a compound is 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, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, methanesulphonic acid, ethanesulphonic acid fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, ptoluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth 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. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline (polymorphic) forms as defined herein of the same acid addition salt. Crystal forms (or polymorphs) mean the crystal structures in which a compound can crystallize under different arrangements of crystal stacks, all of which have the same elemental composition. Different crystal forms usually have different x-ray diffraction patterns, infrared spectra, melting points, hardness, density, crystal shape, optical and electrical properties, stability and solubility. The recrystallization solvent, rate of crystallization, storage temperature and other factors can cause a crystalline form to dominate. Solvates mean addition forms of solvents which 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 molecules of water with one of the substances in which the water maintains its molecular state in the form of H20, such a combination being capable of forming one or more hydrates. Advantageously, the 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention is chosen from the following compounds of formulas 1 to 41: NNHONNHO MeO 1 2 MeO 10 3 4 MeO 6 MeO 15 7 8 9 10 MeO 11 12 MeO 13 14 MeO 15 16 MeO 17 18 OMe 19 20 OMe MeO 21 22 MeO MeO 23 24 MeO CN 25 CN 26 MeO CN 27 OMe 28 MeO OMe OMe 29 30 OMe MeO MeO 31 32 MeO 33 34 MeO 35 36 MeO 37 38 and 39 40 OMe 41 The present invention also relates to a process for preparing a compound 5 of formula general (I) according to the invention in which R2 and R4 represent a hydrogen atom by cyclization of the compound of general formula (II) below: OH N NH H R3 (II) in which Rl and R3 are as defined in general formula (I) with diethyl carbonate in the presence of sodium ethoxide, advantageously by heating under reflux in ethanol.

Advantageously, the compound of general formula (II) is obtained by cyclization of a compound of general formula (III) below: R1 OH N NH2 H (III) in which R1 is as defined in general formula (I), with a aldehyde of formula R3CHO or an acetal of formula R3CH (OCH3) 2, in which R3 is as defined in general formula (I), advantageously by the method of PICTETSPENGLER, by heating in the presence of 4-toluenesulfonic acid monohydrate. The present invention further relates to a process for the preparation of a compound of general formula (I) wherein R4 represents a hydrogen atom and R2 represents 16 R1 a C1-C6 alkyl group by alkylation with an alkyl halide. , of formula R2X in which R2 represents a C1-C6 alkyl group and X represents a halogen atom, of a compound of general formula (I) in which R2 and R4 represent a hydrogen atom, advantageously in the presence of NaH.

In the case where R3 represents a cycloalkene group, a variant of the method consists in operating by catalytic hydrogenation of the compound of formula (I) in which R4 represents a cycloalkyl group. The present invention further relates to a process for the preparation of a compound of general formula (I) wherein R2 and R4 represent a hydrogen atom by cyclization of a compound of the following general formula (IV): wherein R1 is as defined in general formula (I), with an aldehyde of formula R3CHO or an acetal of formula R3CH (OCH3) 2, wherein R3 is as defined in general formula (I), advantageously in the presence of EtONa in ethanol. Advantageously, the compound of general formula (IV) is obtained by cyclization of a compound of general formula (III) with diethyl carbonate in the presence of sodium ethoxide, advantageously by heating under reflux in ethanol. The present invention further relates to a process for the preparation of a compound of general formula (I) in which R2 represents a hydrogen atom and R4 represents a C1-C6 alkoxy group by cyclization of the compound of the following general formula (V): R1 18, COCH O 3 R1 in which R1 is as defined in general formula (I), with an acetal of formula R3CH (OCH3) 2 in which R3 is as defined in general formula (I), advantageously in the presence 4-Toluenesulfonic acid monohydrate.

Advantageously, the compound of general formula (V) is obtained by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone of the compound of general formula (IV), advantageously in a mixture of THF and acetic acid.

The present invention further relates to a process for preparing a compound of general formula (I) wherein R4 represents a C1-C6 alkoxy group and R2 represents a C1-C6 alkyl group by alkylation with an alkyl halide, of formula R2X in which R2 represents a C1-C6 alkyl group and X represents a halogen atom, of a compound of general formula (I) in which R2 represents a hydrogen atom and R4 represents a C1 alkoxy group -C6, advantageously in the presence of NaH.

Thus these processes can be represented by the following synthetic scheme: OEt o ~ OEt OH EtONa, EtOH R1 R1 OH OEt o OEt II R3 EtONa, EtOH R1 R1 R1 OEt R3ùCH R1 OEt IV DDQ AcOH THF R4 R1 R1 R4 R1 Another object of the present invention is the combination of a 4,5,11,11a-tetrahydro-5 1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3- one according to the invention and an antagonist of the 5HT2 receptor of general formulas (VIII) or (VIIIbis) following N ~~ ùR16 ù NOH R17 R18 H MeO VIII VII I bis in which R18 represents a C1-C12 alkyl group, phenyl or phenyl (C1-C6 alkyl), the phenyl group being optionally substituted by C1-C6 alkoxy, a halogen atom or a secondary amine, R16 and R17 are absent and the dotted line represents a bond or R16 and R17 represent a hydrogen atom and the dotted line is absent.

By the term phenyl (C1-C6 alkyl) group is meant within the meaning of the present invention any phenyl group linked through a C1-C6 alkyl group as defined above. Examples of phenyl (C1-C6 alkyl) groups include, but are not limited to phenylethyl, 3-phenylpropyl, benzyl and the like. The amounts of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol3-one according to the invention, activators of the 5HT2 receptor by allosteric modulation, in combination are advantageously greater than that of the 5HT2 receptor antagonist so that the effect of the activator predominates over the effect of the antagonist throughout the sleep period. Thus, in such a combination, 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to 1 The invention and the 5HT2 receptor antagonist should have appropriate pharmacokinetic profiles such that when administered in the evening they produce concentration versus time curves similar to the concentration versus time curve of VLT and 6-MH (Figure 2 ). Thus the pharmacokinetic parameters of the 4,5,11,11a-tetrahydro-1H, 6H-oxazolo 25 [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention and of the 5HT2 receptor antagonist must match, so that the concentration of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3, 4-b] indol-3-one according to the invention is prevalent during the period of nighttime sleep, and that, on the contrary, the concentration of the 5HT2 receptor antagonist in the body is higher than that of 4,5 , 11.1 1 a-tetrahydro- 1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention, during the diurnal period of activity , after awakening. Therefore, advantageously, the elimination of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention must be faster than that of the 5HT2 receptor antagonist (elimination half-life T1 / 2 z = 2.5 hours for 6-MH, in the Beagle dog), that is to say that the elimination half-life of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention must be inferior to that of the 5HT2 receptor antagonist; this means that it is possible to combine, together with 6-MH, a 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b ] indol-3-one according to the invention which has an elimination half-life (T1 / 2z) of less than 2 hours.

It is also possible to administer a 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention having an elimination half-life greater than or equal to that of the 5HT2 receptor antagonist, i.e. the elimination of which is slower than that of the 5HT2 receptor antagonist, but for this it is necessary also to administer upon awakening a dose of 5HT2 receptor antagonist so that the effect of the 5HT2 receptor antagonist is prevalent over that of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ' , 4 ': 1,6] pyrido [3,4-b] indol-3-one according to the invention until the 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention is eliminated.

Advantageously the 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention is present in an amount greater in weight than that of the antagonist. Advantageously, the 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention has a duration elimination in blood than that of the 5HT2 receptor antagonist, preferably less than 2 hours.

Advantageously, the antagonist of the 5HT2 receptor of general formula (VIII) or (VIIIbis) is chosen from 6-methoxy-harmalan of the following formula: MeO or the ethylated analogue of 6-methoxy-harmalan of the following formula: MeO or their analogs hydrogenated, of formulas: MeO MeO and 1 H CH3 or the compound of formula Ibis N 1 H (ibis) MeO (VIII) or (VIIIbis): MeO N - '"ùR16

1 R18 H R17

VIII MeO Viiibis in which R18 represents a C1-C12 alkyl, phenyl or phenyl (C1-C6 alkyl) group, the phenyl group being optionally substituted by a C1-C6 alkoxy, a halogen atom or a secondary amine, R16 and R17 are absent and the dotted line represents a bond or R16 and R17 represent a hydrogen atom and the dotted line is absent, as a combination product for time-separated use to regulate the circadian cycle sleep-wake. Advantageously, the combination according to the present invention is administered in the evening and the 5HT2 receptor antagonist of general formulas VIII or VIIIbis is administered in the morning. The present invention also relates to a pharmaceutical composition comprising a 4,5,11,1 1 a-tetrahydro- 1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3- one according to the invention or the combination according to the invention and at least one pharmaceutically acceptable excipient.

Pharmaceutical compositions according to the present invention can be formulated for administration to mammals, including humans. The dosage varies depending on the treatment and the condition in question. These compositions are produced 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 to humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous administration forms , topical, intramuscular, intravenous, intranasal or intraocular and rectal administration forms. 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 can be coated with sucrose or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle. A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules.

A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable color. The water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents 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 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 are used which contain pharmacologically compatible dispersing agents and / or wetting agents. The active principle can also be formulated in the form of microcapsules, optionally with one or more additive carriers.

Advantageously, the composition according to the invention is intended for administration by oral or intravenous route, advantageously by oral route. A subject of the present invention is also a cosmetic composition comprising a 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3 -one according to the invention and a cosmetically acceptable excipient.

The pharmaceutical or cosmetic composition according to the invention can also be formulated for topical administration. It can 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, milks. or creams, for example, with excipients allowing in particular skin penetration in order to improve the properties and accessibility of the active principle. this composition generally contains, in addition to the active principle according to the present invention, a physiologically acceptable medium, generally based on water or on a solvent, for example alcohols, ethers or glycols. It can also contain surfactants, preservatives, stabilizers, emulsifiers, thickeners, other active principles leading to a complementary or possibly synergistic effect, trace elements, essential oils, perfumes, dyes, collagen, chemical or mineral filters, moisturizing agents 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 for regulating the circadian sleep-wake cycle and / or for treatment. insomnia, mood disorders such as depression or anxiety, Parkinson's disease, Alzheimer's disease and diseases or disorders linked to the deregulation of the circadian sleep-wake cycle.

Another object of the present invention is a 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to l 'invention or the composition according to the invention for its use as a medicament, advantageously as a medicament having muscle relaxant, hypnotic, sedative and / or analgesic activity, and / or intended for the treatment of diseases linked to disorders of the activity melatonin and / or the treatment of depression and psychiatric disorders, in particular stress, anxiety, insomnia, schizophrenia, psychosis or epilepsy, and / or the treatment of sleep disorders related to travel (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 the treatment of benign hyperplasia of prostate, skin conditions such as psoriasis, acne or yeast infection, glaucoma and / or at increase in immune resistance and / or prevention of symptoms of menopause, premenstrual syndromes, the effects of aging or sudden infant death syndrome.

Finally, the present invention relates to the use of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to the invention as a contraceptive in humans or animals and / or for regulating births in ruminant animals.

The examples of preparation of the compounds according to the present invention are given by way of indication. The raw materials and / or the various reagents used in these examples to synthesize the compounds according to the present invention are known products or products prepared according to known procedures. The structures of the compounds according to the present invention described in the various examples as well as in the various synthesis steps were determined by means of the usual spectrometric methods: IR spectrometry, NMR and mass spectrometry.

The following abbreviations will be used in the description of the experimental parts: APTS: 4-toluenesulfonic acid monohydrate. DDQ: 2,3-Dichloro-5,6-dicyanobenzoquinone. DCM: Dichloromethane. EP: Petroleum ether. THF: Tetrahydrofuran.

EXAMPLE 1: 4,5,11,11a-TETRAHYDRO-1H, 6H-OXAZOLO [3 ', 4': 1,6] PYRIDO [3,4-b] INDOL-3-ONES

The compounds whose structure is shown in the following Table I were synthesized: TABLE I EXAMPLES R3 R2 R1 R4 1 HHHH 2 HH OCH3 H 3 CH3 HHH 4 CH3 H OCH3 H C2H5 HHH 6 C2H5 H OCH3 H 7 n-C3H7 HHH 8 n-C3H7 H OCH3 H 9. HHH 5 CH3 HH 11 5 H OCH3 H 27 12 HHH 13 CH3 HH 14 H OCH3 H 15 HHH 16 H OCH3 H 17 CH3 HHH 18 CH3 H OCH3 H 19 CH3 CH3 HH 20 OMe HHH 21 OMe H OCH3 H 22 HHH 23 H OCH3 H ci 24 H OCH3 H 25 CN HHH 26 CN H OCH3 H 27 CN H OCH3 H 28 OMe HHH OMe 29 OMe CH3 HH OMe 30, ip,, OM e H OCH3 H OMe 31 OMe H OCH3 H OMe 32 i H OCH3 H 33 H OCH3 H 34 / s` / HHH 35 s HHH r 36 rs H OCH3 H 37 s H OCH3 H II 38 ~ s CH3 HH II 39 ~ sh C2H5 HH II 40 NHHH ..- • - 41 HH OCH3 Example 1 : 4,5,11,1 1 a-tetrahydro - 1 h, 6h-oxazo lo [3 'A': 1,6lpyrido [3,4-b] indol-3-one. A solution of sodium ethoxide (0.39 g, 5.83 mmol), diethyl carbonate (1.03 g, 8.75 mmol) and 3-hydroxymethyl-1,2,3,4-tetrahydro- pyrido [3,4-b] indole (1.18 g, 5.83 mmol) in ethanol (35 ml) is heated for 5 h at reflux with stirring. The solvent was removed under reduced pressure and to the residue was added a saturated aqueous solution of ammonium chloride (50 ml) and DCM (100 ml). Stirred for 20 min., Then the organic phase decanted and dried over magnesium sulfate is evaporated under reduced pressure. The solid residue is purified by chromatography on a silica column eluting with a mixture of CHCl 3 and acetone (90/10). White powder (0.86 g, 65%). F = 236 C. IR (KBr): 3393 (NH), 3309.3052 (CH), 1747 (CO), 1624 (C = C). 1H NMR (DMSO): 11.04 (1H, NH), 7.47 (1H, H10), 7.39 (1H, H7), 7.13 (1H, H8), 7.05 (1H, H9) , 4.75-4.60 (2H, CH2-5), 4.43, 4.28 (2H, CH2-1), 4.18 (1H, Hlla), 3.08.2.70 (2H, CH2-11).

MS (m / z): 228 (M +).

Example 2: 4,5,11,1 1 a-tetrahydro-1h, 6h-9-methoxy-oxazo lo [3 ', 4': 1,6] pyrido [3,3- b] indol-3-one. The operation is carried out as in the cases of Example 1 by heating for 5 h at reflux with stirring of a solution of sodium ethoxide (0.40 g, 5.98 mmol), of diethyl carbonate (1.06 g, 8.98 mmol) and 3-hydroxymethyl-6-methoxy-1,2,3,4-tetrahydro-pyrido [3,4-b] indole (1.39 g, 5.98 mmol) in ethanol ( 35 ml). Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (90/10). Beige powder (0.72 g, 40%) F = 202 C. IR (KBr): 3305 (NH), 2995.2954 (CH), 1747 (CO), 1636 (C = C), 1H NMR: (DMSO ): 10.85 (1H, NH), 7.28 (1H, H7), 6.97 (1H, H10), 6.76 (1H, H8), 4.73-4.60 (2H, CH2- 5), 4.40,4.26 (2H, CH2-1), 4.16 (1H, Hlla), 3.80 (3H2OCH3), 3.05,2.67 (2H, CH2-11). MS (m / z): 258 (M +).

Example 3: 4,5,11,1 1 a-tetrahydro- 1h, 6h-5-methyl-oxazolo [3 ', 4': 1: 6] pyrido [3,4- b] indol-3-one.

The operation is carried out as in the case of Example 1 by heating for 5 h at reflux with stirring of a solution of sodium ethoxide (0.36 g, 5.36 mmol), of diethyl carbonate (0.95 g, 8.05 mmol) and 1-methyl-1,2,3,4-tetrahydro-3-hydroxymethyl-pyrido [3,4-b] indole (1.16 g, 5.36 mmol) in ethanol ( 27 ml). Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (90/10). Beige powder (380 mg 38%) F 260 C. IR (KBr): 3271 (NH), 3115; 2932, 2890 (CH), 1732 (CO), 1621 (C = C). 1H NMR (DMSO): 11.05 (1H, NH), 7.42 (1H, H10), 7.31 (1H, H7), 7.06 (1H, H8), 6.98 (1H, H9) , 4.72 (1H, H5), 4.53,4.15 (2H, CH2-1), 4.08 (1H, Hlla), 3.02,2.55 (2H, CH2-11), 1 , 70 (3H, CH3-5). MS m / z): 242 (M +).

Example 4: 4,5,11,11 a-tetrahydro-1h, 6h-5-methyl-9-methoxy-Oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3- one. The operation is carried out as in the case of Example 1 by heating under reflux for 5 H with stirring of a solution of sodium ethoxide (0.44 g, 6.46 mmol), of diethyl carbonate (1.14 g, 10.3 mmol) and 1-methyl-1,2,3,4-tetrahydro-3-hydroxymethyl-6-methoxy-pyrido [3,4-b] indole (1.59 g, 6.46 mmol). Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (90/10). Beige powder (0.85 g, 48%). F = 224 C. IR spectrum (KBr): 3266 (NH), 2927, 2828 (CH), 1727 (CO), 1625 C = C). 1H NMR (DMSO): 10.86 (1H, NH), 7.19 (1H, H7), 6.91 (1H, H10), 6.69 (1H, H8), 4.69 (1H, H5) 4.52 (1H, CH2-1), 4.10-3.95 (CH2-1, Hlla), 3.73 (3H2OCH3), 2.98,2.52 (2H, CH2-11), 1, 68 (3H, CH3-5). MS (m / z): 272 (M +)

Example 5: 4,5,11,11a-tetrahydro-1h, 6h-5-ethyl-oxazolo [3 ', 4': 1,6] Pyrido (3, 4-b] indol-3-one. A solution of 'APTS (1.76 g, 9.25 mmol) and propionaldehyde (2 g, 9.25 mmol) in THF (36 ml) is stirred for 5 min. Then added with a solution of 4- (1H- indolyl-3-ylmethyl) -oxazolidin-2-one (2 g, 9.25 mmol) in CHCl 3 (18 ml). The mixture is refluxed for 3 H with stirring. After cooling, a saturated aqueous solution of NaHCO 3 ( 75 ml) and stirred for 20 min The decanted organic phase is evaporated to dryness under vacuum and the residue is purified by suspending in a mixture of EP and diethyl ether (60/40). 66%). F = 142 C. IR (KBr): 3282 (NH), 2966.2931 (CH), 1736 (CO), 1621 (C = C). 1H NMR (DMSO): 11.00 (1H, NH), 7.39 (1H, H10), 7.31 (1H, H7), 7.06 (1H, H8), 6.98 (1H, H9), 4.73 (1H, H5), 4, 54, 4.23 (2H, CH2-1), 4.15 (1H, H11a), 2.96, 2.61 (2H, CH2-11), 2.00, 1.75 (2H, CH2CH3), 0.94 (3H, CH2CH3) MS (m / z): 256 (M +).

Example 6: 4,5,11,11 a-tetrahydro-1h, 6h-5-ethyl-9-methoxy-Oxazolo [3 ', 4': 1,6lpyrido [3, 4-b] indol-3-one. A) 4- (1H-5-methoxyindol-3 ylmethyl) -oxazolidin-2-one. A solution of sodium ethoxide (3.67 g, 54.02 mmol), 5-methoxytryptophanol (11.9 g, 54.02 mmol) and diethyl carbonate (9.57 g, 81.04 mmol) in ethanol (270 ml) is heated for 5 h at reflux with stirring. Concentrate to dryness in vacuo then add to the residue a saturated aqueous solution of ammonium chloride (110 ml) and DCM (250 ml). Stirred for 20 min, the organic phase is decanted and dried over Mg504. It is filtered and concentrated until the start of crystallization. Beige powder (11.97 g, 90%). F = 160 C. IR (KBr): 3420.3284 (NH), 2959.2927 (CH), 1740 (CO), 1623 (C = C). 1H NMR (CDCl3): 10.73 (1H, NH), 7.71 (1H, NH), 7.21 (1H, H7-indole), 6.98 (1H, H4-indole), 6.90 ( 1H, H2-indole), 6.82 (1H, H6-indole), 4.43 (1H, CH-oxazole), 4.14 (2H, CH2-5-oxazole), 3.80 (3H, OCH3) , 2.92 (2H, CH2-indol-3-ylmethyl). MS (m / z): 246 (M +) B) 4,5,11, Il a-tetrahydro-1 H, 6H-5-ethyl-9-methoxy-oxazolo [3,4 ': 1, 6] pyrido [ 3, 4-b] indol-3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (580 mg, 3.04 mmol) and of propionaldehyde (0.3 ml, 4.56 mmol) in THF (10 ml). to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (750 mg, 3.04 mmol) in CHCl3 (10 ml) then heating to reflux for 4 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). Beige powder (405 mg, 54%). Mp = 100 C (dec.). IR (KBr): 3315 (NH), 2964.2929 (CH), 1734 (CO), 1626 (C = C) 1H NMR (DMSO): 10.77 (NH), 7.19 (1H, H7), 6.88 (1H, H10), 6.70 (1H, H8), 4.71 (1H, H5), 4.54,4.22 (2H, CH2-1), 4.14 (1H, Hl la ), 3.73 (3H, OCH3), 2.94.2.59 (2H, CH2-11). MS (m / z): 286 (M +).

Example 7: 4,5,11,11 a-tetrahydro-1h, 6h-5-n-propyl-oxazolo [3 ', 4: 1,6] [3, 4-b] indol-3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.76 g, 9.25 mol) and of n-butyraldehyde (1 g, 13.87 mmol) in THF (36 ml) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (2 g, 9.25 mmol) in CHCl3 (18 ml) then heating for 2 H under reflux with stirring. Purification is carried out by suspending in a mixture of EP and diethyl ether (70/30) and filtration through sintered glass. Yellow powder (1.5 g, 60%). F = 180 C. IR (KBr): 3309 (NH), 2961.2931 (CH), 1714 (CO), 1620 (C = C). 1H NMR (DMSO): 10.99 (1H, NH), 7.38 (1H, H10), 7.31 (1H, H7), 7.06 (1H, H8), 6.97 (1H, H9) , 4.80 (1H, H5), 4.52,4,24 (2H, CH2-1), 4.14 (1H, Hl la), 2.96,2.59 (2H, CH2-11), 1.92, 1.76, 1.42, 0.94 (7H, C3H7). MS (m / z): 270 (M +). Example 8: 4,5,11,11 a-tetrahydro-1h, 6h-5-n-propyl-9-methoxy-Oxazolo 13 ', 4': 1, 6lpyrido [3,4-b] indol-3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (580 mg, 3.45 mmol) and of n-butyraldehyde (0.4 ml, 4.65 mmol) in THF (12 ml) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (750 mg, 3.045 mmol) in CHCl3 (20 ml) then heating for 2 h 30 min under reflux with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). Beige powder (375 mg, 42%); Mp = 98 C (dec.). IR (KBr): 3410 (NH), 2957, 2871 (CH), 1736 (CO). 1H NMR (DMSO): 10.75 (1H, NH), 7.19 (1H, H7), 6.88 (1H, H10), 6.70 (1H, H8), 4.78 (1H, H5) , 4.53, 4.33 (2H, CH2-1), 4.14 (1H, H11a), 3.73 (3H, OCH3), 2.93, 2.58 (2H, CH2-11), 1 , 88, 1.71, 1.42, 0.94 (7H, C3H7). MS (m / z): 300 (M +)

Example 9: 4,5,11,1 1 a-tetrahydro- 1h, 6h-5- (cyclohexen-3-yl) Oxazo lo [3 ', 4': 1,6] pyrido [3,4-b] indol -3-one The procedure is as in the case of Example 5 by adding a solution of APTS (1.76 g, 9.25 mmol) and of cyclohexen-3-yl-carboxaldehyde (1.53 g, 13.87 mmol) in THF (18 ml) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (2 g, 9.25 mmol) in CHCl3 (40 ml) then heating 3 h at reflux with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). White powder (1.29 g, 45%). F = 260 C. IR (KBr): 3294 (NH), 3021, 2914 (CH), 1732 (CO), 1621 (C = C). 1H NMR (DMSO): 10.97 (1H, NH), 6.94 (1H, H10), 6.85 (1H, H7), 7.08 (1H, H8), 6.97 (1H, H9) , 5.66 (2H, CH = CH cyclohexene), 4.79 (1H, H5), 4.55,4.22 (2H, CH2-1), 4.14 (1H, Hl la), 3.29 , 2.59 (2H, CH2-11), 2.49 (1H, H1 cyclohexene), 2.10-1.50 (6H, CH2 cyclohexene). MS (m / z): 308 (M +), 307.

Example 10: 4,5,11,11 a-tetrahydro-1h, 6h-5- (cyclohexen-3-yl) -6-methyl-oxazolo 13 ', 4': 1: 6lpyrido [3,4-b] indol -3-one. A solution of 4,5,11,11a -tetrahydro- 1H, 6H-5- (cyclohexen-3-yl) -oxazo lo [3 ', 4': 1,6] pyrido [3,4-b] indol -3-one (760 mg, 2.46 mmol) in a mixture of DCM (80 ml) and THF (20 ml) is added with vigorous stirring to an aqueous solution cooled to 0 C of 50% sodium hydroxide (30 ml) ). Benzyltributylammonium bromide (263 mg, 0.74 mmol) is then added, the mixture is stirred for 15 min. at 0 ° C. and methyl iodide (1.4 g, 9.86 mmol) is added dropwise. Stirring is continued for 1 hour 30 minutes at 0 C then 4 hours at 20 C. 100 ml of water are added, the organic phase is decanted and washed three times with water. It is dried over MgSO4 and the solvent is removed in vacuo. Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). Yellow powder (600 mg, 76%). Mp = 170 C. IR (KBr): 2958.2923 (CH), 1735 (CO). 1H NMR (DMSO): 7.41 (2H, H10, H7), 7.15 (1H, H8), 7.02 (1H, H9), 5.65 (2H, CH = CH cyclohexene), 5.01 (1H, H5), 4,57,4,22 (2H, CH2-1), 4.20 (1H, H11a), 3.70 (3H, NCH3), 3.01, 2.61 (2H, CH2 -11), 2.26-1.53 (7H, cyclohexene). MS (m / z): 322 (M +).

Example 11: 4,5,11,11a-tetrahydro-1h, 6h-5- (cyclohexen-3-yl) -9-Methoxy-oxazolo 13 ', 4': 1,6lpyrido [3,4-b] indol- 3-one.

The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.54 g, 8.12 mmol) and of cyclohexen-3-carboxaldehyde (1.54 g, 12.18 mmol) in THF (25 ml) to a solution of 4- (1H-5-methoxy-indol-3-ylmethyl) -2-oxazolidin-2-one (2 g, 8.12 mmol) in CHCl3 (32 ml) then heating at reflux for 4 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). Beige powder (420 mg, 33%). Mp = 120 C (dec.). IR (KBr): 3305 (NH), 3020.2916 (CH), 1732 (CO), 1626 (C = C); 1H NMR (CDCl3): 7.84 (1H, NH), 7.16 (1H, H7), 6.82 (1H, H10), 6.77 (1H, H8), 5.55 (2H, CH = CH cyclohexene), 4.88 (1H, H5), 4.52, 4.17, (2H, CH2-1), 4.06 (1H, Hl la), 3.78 (3H, OCH3), 2, 89, 2.66 (2H, CH2-11), 2.10-1.49 (7H, cyclohexene). MS (m / z): 338 (M +).

Example 12: 4,5,11,1 1 a-tetrahydro- 1h, 6h-5-cyclohexyl-oxazo lo- [3 ', 4': 1,6lpyrido [3,4-b] indol-3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.76 g, 9.25 mmol) and of cyclohexanecarboxaldehyde (1.56 g, 13.87 mmol) in THF (25 ml) ) to a solution of 4- (1H-indol-3-ylmethyl) -2-oxazolidin-2-one (2g, 9.25 mmol) in chloroform (36 ml) then heating at reflux for 7 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). White powder (1.62g, 56%). F = 266 C. IR (KBr): 3304 (NH), 2926.2851 (CH), 1736 (CO), 1621 (C = C). 1H NMR (DMSO): 10.61 (1H, NH), 7.09 (1H, H10) 7.00 (1H, H7), 6.73 (1H, H8), 6.65 (1H, H9), 4.32 (1H, H5), 4.20, 3.71 (1H, CH2-1), 3.88 (1H, Hl la), 3.00, 2.65 (2H, CH2-11), 2 , 19-0.97 (11H, cyclohexyl). MS (m / z): 310 (M +), 309.

Example 13: 4,5,11,11 a-tetrahydro-1h, 6h-5-cyclohexyl-9-methoxy-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3- one. A solution of 4,5,11,11a-tetrahydro-1H, 6H-5- (cyclohexen-3-yl) -9-methoxy-oxazolo [3 ', 4': 1,6] pyrido [3,4-b ] indol-3-one (200 mg, 0.59 mmol) in a mixture of methanol (15 ml) and THF (10 ml) is hydrogenated under ordinary pressure and temperature in the presence of 10% palladium / C . The solvents are evaporated until the start of crystallization. White powder (200 mg, 99%). F = 234 C. IR (KBr): 2925.2851 (CH), 1731 (CO), 1626 (C = C). 1H NMR (DMSO): 10.79 (1H, NH), 7.19 (1H, H7), 7.02 (1H, H10), 6.69 (1H, 1H, H8), 4.65 (1H, H5), 4.54, 4.22 (2H, CH2-1), 4.02 (1H, Hl la), 3.75 (3H, OCH3), 3.15, 2.90 (2H, CH2-11 ), 1.97-1.22 (1H, cyclohexyl). MS (m / z): 340 (M +).

Example 14: 4,5,11,1 1 a-tetrahydro - 1h, 6h-5-cyclohexyl-6-methyl-Oxazo lo [3 ', 4': 1,6] pyrido [3, 4-b} indol- 3-one. A solution of 4,5,11,1 a-tetrahydro - 1 H, 6H-5 - (cyclohex en-3 -yl) -6-methylo xazo lo [3 ', 4': 1,6] pyrido [ 3,4-b] indol-3-one (0.32 g, 0.99 mmol) in a mixture of methanol (25 ml) and THF (15 ml) is hydrogenated at ordinary pressure and temperature in the presence 10% palladium on charcoal. It is filtered and concentrated until the start of crystallization. White powder (256 mg, 80%). M = 188 C. IR (KBr): 3056.2926 (CH), 1730 (CO), 1614 (C = C). 1H NMR (DMSO): 7.44 (2H, H7, H10), 7.14 (1H, H8), 7.02 (1H, H9), 4.89 (1H, H5), 4.59, 4, 19 (2H, CH2-1), 4.22 (1H, Hl la), 3.38 (3H, NCH3), 3.01, 2.57 (2H, CH2-11), 2.07-1.24 (11H, Cyclohexyl). MS (m / z): 324 (M +), 323.

Example 15: 4,5,11,11a-tetrahydro-1h, 6h-5-phenyl-oxazolo [3 ', 4': 1,6lpyrido [3,4-b1 indol-3one. Anhydrous TFA (50 mg, 0.46 mol) is added then 4- (1H-indol-3 -ylmethyl) - oxazolidin-2-one (1g, 4.6 mmol) to a solution of benzaldehyde dimethylacetal (1, 06g, 6.9 mmol) in anhydrous THF (18 ml) and heated under reflux for 24 H. After cooling, it is poured into a saturated aqueous solution of NaHCO3 (50 ml), the organic phase is decanted and the mixture is extracted. aqueous phase three times with DCM. The combined organic phases are dried over MgSO4 and evaporated in vacuo. Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (95/5). Beige powder (770 mg, 56%). M = 90 C. IR (KBr): 3293 (NH), 3055.2914 (CH), 1740 (CO) 1618 (C = C). 1H NMR (CDCl3) 7.49 (1H, H10), 7.37 (1H, H7), 7.26 (7H, H8, H9, C6H5), 6.95 (1H, NH), 4.96 (1H , H5), 4.41 (1H, H11a), 4.11 (2H, CH2-1), 2.92 (2H, CH2-11). MS (m / z): 304 (M +).

Example 16: 4,5,11,1 1 a-tetrahydro- 1h, 6h-5-phenyl-9-methoxy-oxazo lo [3 ', 4': 1,6] pyrido [3,4-b] indol- 3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (618 mg, 3.25 mg) and of benzaldehyde dimethylacetal (740 mg, 4.87 mmol) in THF (18 ml) at a solution of 4- (1H-5-methoxy-indol-3ylmethyl) -oxazolidin-2-one (800 mg, 3.25mmol) in CHCl3 and refluxed for 5 hours with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and methanol (99/1). White powder (520 mg, 48%). IR (KBr): 3399 (NH), 2927.2832 (CH), 1755 (CO), 1611 (C = C). 1H NMR (CDCl3): 7.62 (1H, NH), 7.27 (5H, (C6H5)), 7.13 (1H, H7), 6.90 (1H, H10), 6.81 (1H, H8), 5.23 (1H, H5), 4.49 (1H, H11a), 4.16 (2H, CH2-1), 3.08, 2.82 (2H, CH2-11). MS (m / z): 334 (M +), 333,290,289,257.

Example 17: 4,5,11,11a-tetrahydro-1h, 6h-5- (4-tolyl) -oxazolo [3 ', 4': 1,6] pyrido [3,4- b] indol-3-one .30 The procedure is as in the case of Example 5 by adding a solution of APTS (1.76g, 13.87 mmol) and 4-tolylcarboxaldehyde (1.67g, 13.87 mmol) in THF (30 ml) in a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (2g, 9.25 mmol) in CHCl3 and heating for 3 H under reflux with stirring. It is purified by chromatography on silica column eluting with a mixture of CHCl3 and acetone (96/3). Pink powder (1.58g, 58%). F = 248 C. IR (KBr): 3272 (NH), 2923.2826 (CH), 1732 (CO), 1603 (C = C). 1H NMR (DMSO): 10.88 (1H, NH), 7.47 (1H, H10), 7.27 (1H, H7), 7.18 (4H, C6H4CH3), 7.09 (1H, H8) 7.05 (1H, H9) 5.90 (1H, H5), 4.52, 4.19 (2H, CH2-1), 4.21 (1H, Hl la), 3.15, 2.73 ( 2H, CH2-11), 2.28 (3H, CH3). MS (m / z): 318 (M +), 317, 227.

Example 18: 4,5,11,11 a-tetrahydro - 1 h, 6h-5 - (- 4-tolyl) -9-methoxy-Oxazolo [3 ', 4': 1,6] pyrido [3,4- b] indol-3-one. The procedure is as in the case of Example 5 by adding a solution of APTS (911 mg, 4.79 mmol) and 4-tolylcarboxaldehyde (864 mg, 7.19 mmol) in THF (10 ml) to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (1.18 g, 4.79 mmol) in CHCl3 (15 ml) and heating at reflux for 1 H with stirring. Green powder (634 mg, 38%). F = 230 C. IR (KBr): 3392 (NH), 2919 (CH), 1751 (CO). 1H NMR (DMSO): 10.47 (1H, NH), 7.12 (4H, C6H4CH3), 7.03 (1H, H7), 6.89 (1H, H10), 6.77 (1H, H8) , 5.22 (1H, H5), 4.45, 4.18 (2H, CH2-1), 4.07 (1H, Hlla), 3.79 (3H, CH3O), 3.09,2.69 (2H, CH2-11), 2.24 (3H, CH3C6H4). MS (m / z): 348 (M +) 257.

Example 19: 4,5,11,11 a-tetrahydro- 1h, 6h-5- (4-tolyl) -6-methyl-oxazolo j3 ', 4': 1,6lpyrido [3,4-b] indol-3 -one. The procedure is as in the case of Example 10 from 4,5,11,1la-tetrahydro-1H, 6H-5- (4-tolyl) -oxazolo [3 ', 4': 1,6] pyrido [ 3,4-b] indol-3-one (1g, 3.14 mmol), N-benzyltrimethylammonium bromide (335 mg, 0.94 mmol) and methyl iodide (1.78g, 12.56 mmol ) in a mixture of DCM (100 ml) and 50% aqueous sodium hydroxide solution (38 ml). Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). White powder (770 mg, 74%). M = 180 C. IR (KBr): 3023,2958,2871 (CH), 1734 (CO), 1613 (C = C). 1H NMR (CDCl3): 7.54 (1H, H10), 7.28 (1H, H7), 7.05-6.96, (6H, H8, H9, C6H4CH3), 5.99 (1H, H5) , 4.36, 4.07 (2H, CH2-1), 3.98 (1H, Hl la), 3.20 (3H, CH3N), 3.06, 2.75 (2H, CH2-11), 2.20 (3H, CH3C6H4). MS (m / z): 332 (M +), 241.

Example 20: 4,5,11,11a-Tetrahydro-1h, 6h-5- (4-Anisyl) -Oxazolo [3 ', 4': 1, 6] P. r ido [3,4-B] Indol- 3-One The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.32 g, 6.94 mmol) and of 4-anisyldimethylacetal (1.9 g, 10.4 mmol) in the CHCl3 (14 ml) in a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (1.5g, 6.94 mmol) in CHCl3 (14 ml) then heating at reflux for 3 H with restlessness. Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). White powder (1.1g, 47%). F = 250 C. IR (KBr): 3232 (NH), 2931.2837 (CH), 1725 (CO), 1609 (C = C). 1H NMR (DMSO): 10.89 (1H, NH), 7.47 (1H, H10), 7.28 (1H, H7), 7.18, 6.92 (4H, C6H4OCH3), 7.08 ( 1H, H8), 7.00 (1H, H9), 5.90 (1H, H5), 4.52, 4.22 (2H, CH2-1) 4.17 (1H, H11a), 3.76 ( 3H, CH3O), 3.14, 2.72 (2H, CH2-11). MS (m / z): 334 (M +), 333.

Example 21: 4,5,11,1 1 a-tetrahydro - 1 h, 6 h - 5- (4-anisyl) -9-methoxy ûOxazolo [3 ', 4: 1,6] pyrido [3,4-b ] indol-3-one.

The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.16 g, 6.09 mmol) and 4-anisyldimethylacetal (1.66g, 9, 13mmol) in CHCl3 (12 ml). ) to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (1.5g, 6.09 mmol) in CHCl3 then heating to reflux for 3 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). Beige powder (1.47g, 66%). F = 260 C IR (KBr): 3353 (NH), 2957.2933 (CH), 1739 (CO), 1610 (C = C). 1H NMR (DMSO): 10.47 (1H, NH), 7.03 (2H, H7, H8), 6.86 (4H, C6H4OCH3), 6.59, (1H, H10), 5.72 (1H , H5), 4.51 (1H, H11a), 4.18 (2H, CH2-1), 3.69 (3H, CH3OC6H4), 3.10, 2.69 (2H, CH2-11). MS (m / z): 364 (M +).

Example 22: 4,5,11,11 a-tetrahydro-1h, 6h-trans-5 - (3 -chlorophenyl) -oxazo lo [3,4: 1,6] pyrido [3,4-b] indol-3 -one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (0.70g, 5.55 mmol) and 3-chlorobenzaldehyde (0.78g, 3.7 mmol) in CHCl3 (8m1) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (0.80g, 3.7 mmol) in CHCl3 (8 ml) then heating to reflux with stirring for 1 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99.6 / 0.4). Green powder (0.69g, 55%). F = 262 C. IR (KBr): 3257 (NH), 2916.2847 (CH), 1718 (CO), 1620 (C = C). 1H NMR (CDCl3): 10.95 (NH), 7.52-7.15, (6H, C6H4Cl, H7, H10), 7.08 (1H, H8), 7.03 (1H, H9), 5 , 97 (1H, H5), 4.58, 4.28 (2H, CH2-1), 4.24 (1H, Hl la), 3.18, 2.74 (2H, CH2-11). MS (m / z): 338 (M +), 337.

Example 23: 4,5,11,11 a-tetrahydro-1h, 6h-trans-5 - (3-chlorophenyl) -9-methoxy-oxazolo [3'4 ': 1,6lpyrido [3,4-b] indol -3-one.

The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.16 g, 6.09 mmol) and 3-chlorobenzaldehyde (1.28 g, 9, 14 mmol) in THF (12 ml) to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (1.5g, 6.09 mol) in THF (24 ml) then heating under reflux for 5 H with stirring . Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). The separation of the cis and trans isomers is thus carried out. White powder (590 mg, 53%). F = 234 C. IR (KBr): 3289 (NH), 3064,2913,2829 (CH), 1717 (CO), 1625 (C = C). 1H NMR (DMSO): 10.05 (1H, NH), 7.41, 7.25 (4H, C6H4Cl), 7.22 (1H, H7), 6.98 (1H, H10), 6.74 ( 1H, H10), 5.94 (1H, H5), 4.57, 4.26 (2H, CH2-1), 4.23 (1H, Hl la), 3.75 (3H, CH3O), 3, 14, 2.70 (2H, CH2-11). MS (m / z): 368 (M +), 367.333.

Example 24: 4,5,11,11 a-tetrahydro-1h, 6h-cis-5 - (3 -chlorophenyl) -9-methoxy-oxazolo [3 ', 4': 1,6lpyrido [3,4-b] indol-3-one. This cis isomer is separated from the trans isomer by chromatography on a silica column as indicated in Example 23. White powder (514 mg, 45%). F = 224 C. IR (KBr): 3307 (NH), 3077.2989.2901 (CH), 1743 (CO). 1H NMR (DMSO): 10.56 (NH), 7.31, 7.10 (4H, C6H4Cl), 7.10 (1H, H7), 6.96 (1H, H10), 6.66 (1H, H8), 5.69 (1H, H5), 4.60, 4.23 (2H, CH2-1), 4.17 (1H, Hl la), 3.75 (3H, CH3O), 3.11, 2.87 (2H, CH2-11). MS (m / z): 368 (M +), 367, 333.

Example 25: 4,5,11,11 a-tetrahydro-1h, 6h-5- (4-cyanophenyl) -oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3- one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.51g, 7.95 mmol) and 4-cyanobenzaldehyde (1.56g, 11.93 mmol) in CHCl3 (16 ml) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (1.72g, 7.95 mmol) in CHCl3 (15 ml) then heating to reflux for 3 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). White powder (800 mg, 32%). F = 264 C. IR (KBr): 3338 (NH), 2963.2921 (CH), 2227 (CN), 1727 (CO), 1607 (C = C). 1H NMR (DMSO): 10.96 (1H, NH), 7.91 ((1H, H10), 7.36 (1H, H7), 7.16 (1H, H8), 7.08 (1H, H9 ), 6.10 (1H, H5), 4.64, 4.33 (2H, CH2-1) 4.27 (1H, H11a), 3.23, 2.82 (2H, CH2-11) .MS (m / z): 329 (M +), 328, 357.

Example 26: 4,5,11,11 a-tetrahydro-1h, 6h-trans-5- (4-cyanophenyl) 9-methoxy-oxazolo [3 ', 4': 1,6lpyrido [3,4-b] indol -3-one.

The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.16 g, 6.09 mmol) and 4-cyanobenzaldehyde (1.2 g, 9.14 mmol) in THF (12 ml) to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (1.5g, 6.09 mmol) in a mixture of THF 24 ml) and toluene (5m1) then heating at reflux for 5 hours with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). The separation of the cis and trans isomers is thus carried out. White powder (440 mg, 40%). F = 266 C. IR (KBr): 3325 (NH), 3065,2922,2832 (CH), 2228 (CN), 1735 (CO), 1626 (C = C). 1H NMR (DMSO): 7.84, 7.48 (4H, C6H4CN), 7.18 (1H, H7), 6.97 (1H, H10), 6.72 (1H, H8), 6.01 ( 1H, H5), 4.57, 4.25 (2H, CH2-1) 4.22 (1H, Hl la), 3.75 (3H, CH3O), 3.14, 2.72 (2H, CH2- 11). MS (m / z): 359 (M +), 358.

Example 27: 4,5,11,1 1 a-tetrahydro -cis-5 - (4-cyanophenyl) -9-methoxy oxazolo [3 ', 4'- 1,6lpyrido [3,4-b] indol-3- one. This isomer is separated from the trans isomer by chromatography on a silica column as indicated in Example 25. White powder (330 mg, 30%). Mp = 180 C (dec.). IR (KBr): 3317 (NH), 3061,2961,2924 (CH), 2227 (CN), 1746 (CO), 1626 (C = C). 1H NMR (DMSO): 10.58 (1H, NH), 7.81, 7.55 (4H, C6H4CN), 7.17 (1H, H7), 6.98 (1H, H10), 6.67 ( 1H, 1H, H8), 5.77 (1H, H5), 4.63, 4.22 (2H, CH2-1), 4.19 (1H, Hl la), 3.75 (3H, CH3O), 3.14, 2.87 (2H, CH2-11) MS (m / z): 359 (M +), 358.

Example 28: 4,5,11,1 1 a-Tetrahydro- 1h, 6h-5- (3, 4-Dimethoxyphenyl) -Oxazo lo [3 ', 4'- 1,6] Pyrido [3,4-B] Indol-3-One The procedure is as in the case of Example 4 by adding a solution of APTS (1.76 g, 9.25 mmol) and 3,4-dimethoxybenzaldehyde (2.3 g, 13, 87 mmol) CHCl3 (18 ml) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (2g, 9.25 mmol) in CHCl3 (18 ml) then heating under reflux for 5H with restlessness. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (90/10). Yellow powder (1.6 g, 47%). F = 260 C. IR (KBr): 3350 (NH), 3081,3007,2939 (CH), 1740 (CO). 1H NMR (DMSO): 10.93 (1H, NH), 7.54 (1H, H10), 7.35 (1H, H7), 7.14 (1H, H8), 7.09 (1H, H9) , 6.99, 6.78 (3H, C6H3), 5.95 (1H, H5), 4.61, 4.30 (2H, CH2-1), 4.29 (1H, H11a), 3.79 (3H, CH3O), 3.77 (3H, CH3O), 3.22, 2.79 (2H, CH2-11). MS (m / z): 364 (M +), 363, 227.

Example 29: 4,5,11,11 a-Tetrahydro-1h, 6h-5 - (3, 4-Dimethoxyphenyl) -6-Methyl- Oxazolo [3 ', 4': 1,6] Pyrido [3, 4- B] Indol-3-One

The operation is carried out as in the case of Example 10 from 4,5,11,11a-tetrahydro-1H, 6H- 5 - (3, 4-dimethoxyphenyl) -oxazo lo [3 ', 4: 1,6] pyrido [3,4-b] indol-3 -one (1g, 2.74 mmol), N-benzyltrimethylammonium bromide (292 mg, 0.82 mmol) and methyl iodide (1.56 g, 2 , 74 mmol) in a mixture of DCM (90 ml) and 50% aqueous sodium hydroxide solution (35 ml). Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). White powder (800 mg, 77%). F = 222 C. IR (KBr): 3052.2930.2835 (CH), 1742 (CO), 1603 (C = C). 1H NMR (DMSO): 7.52 (1H, H10), 7.38 (1H, H7), 7.16 (1H, H8), 7.06 (1H, H9), 6.92, 6.88, 6, 58 (3H, C6H3), 6.08 (1H, H5), 4.51, 4.21 (2H, CH2-1), 4.16 (1H, H11a), 3.72 (3H, CH3O), 3 , 68 (3H, CH3O), 3.29 (3H, CH3N), 3.19, 2.73 (2H, CH2-11). MS (m / z): 378 (M +).

Example 30: 4,5,11,11 a-tetrahydro-1h, 6h -trans-5 - (3, 4-dimethoxyphenyl) -9-methoxy-oxazolo [3 ', 4': 1: 6lpyrido [3,4- b] indol-3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.16 g, 6.09 mmol) and 3,4-dimethoxybenzaldehyde (1.52 g, 9.14 mmol) in THF (12 ml) to a solution of 4 - (- 1H-5-methoxy-indol-3-ylmethyl) -oxazolidin-2-one (1.5 g 6.09mmol) in a mixture of THF (24 ml) and toluene (5 ml) then heating for 5 h at reflux with stirring. The cis isomer is purified and separated by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). White powder (600 mg, 50%). F = 264 C. IR (KBr): 3316 (NH), 3080,2963,2932 (CH), 1746 (CO), 1624 C = C). 1H NMR (DMSO): 10.70 (1H, NH), 7.17 (1H, H7), 6.97 (1H, H10), 6.95 (1H, H8), 6.73 (1H, H9) , 6.84, 6.69 (3H, C6H3), 5.86 (1H, H5), 4.54, 4.24 (2H, CH2-1), 4.21 (1H, H11a), 3.75 (3H, CH3O), 3.65 (3H, CH3O), 3.11, 2.69 (2H, CH2-11). MS (m / z): 394 (M +), 257.

Example 31: 4,5,11,11 a-tetrahydro-1h, 6h-cis-5 - (3, 4-dimethoxyphenyl) -9-methoxyoxazolo [3 ', 4': 1,6lpyrido [3,4-b] indol-3-one.

This isomer is separated from the trans isomer by chromatography on a silica column as indicated in Example 30. White powder (300 mg, 25%). F = 126 C. IR (KBr): 3315 (CH), 3079,2935,2837 (CH), 1747 (CO), 1622 (C = C). 1H NMR (DMSO): 10.52 (1H, NH), 7.18 (1H, H7), 7.01 (1H, H10), 6.98, 6.74 (3H, C6H3), 6.73 ( 1H, H8), 5.66 (1H, H5), 4.67 (1H, H11a), 4.25 (2H, CH2-1), 3.80 (3H, CH3O), 3.40 (6H, CH3O ), 3.18, 2.89 (2H, CH2-11). MS (m / z): 394 (M +), 257.

Example 32: 4,5,11,11 a-tetrahydro-1h, 6h-trans-5 - (3, 4-methylenedio xy-phenyl-9-methoxy-oxazo lo [3 ', 4': 1,6lpyrido [3 , 4-b] indol-3-one The procedure is as in the case of Example 5 by adding a solution of APTS (1.16 g, 9.14 mmol) and 3,4-methylenedioxybenzaldehyde ( 1.37 g 6.09 mmol) in THF (12 ml) to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (1.37 g, 6.09 mmol) in THF (24 ml) then heating under reflux for 5 hours with stirring, the mixture is purified and the cis isomer separated by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (90/10). yellow (449 mg, 53%). F = 270 C. IR (KBr): 3306 (NH), 2923.2853 (CH), 1749 (CO), 1626 C = C). 1H NMR (DMSO): 10.47 (1H, NH), 7.11 (1H, H7), 6.94 (1H, H10), 6.86 (3H, C6H3), 6.67 (1H, H8) , 5.95 (2H, OCH2O), 5.57 (1H, H5), 4.57 (1H, Hl la), 4.17 (2H, CH2-1), 3.10, 2.51 (2H, CH2-11). MS (m / z) 378 (M +), 257.

Example 33: 4,5,11,11 a-tetrahydro-1h, 6h-cis-5 - (3, 4-methylenedio xy-phenyl) -9- methoxy-oxazo lo [3 ', 4': 1,6lpyrido [ 3,4-b] indol-3-one. This isomer is separated from the trans isomer by chromatography on a silica column as indicated in Example 32. White powder (280 mg, 33%). F = 250 C. IR (KBr): 3322 (NH), 3076, 2935.2887 (CH), 1723 (CO), 1607 C = C). 1H NMR (DMSO): 10.70 (1H, NH), 7.16 (1H, H7), 6.98 (1H, H10), 6.80 (1H, H10), 6.90, 6.70 ( 3H, C6H3), 5.99 (2H, OCH2O), 5.84 (1H, H5), 4.55, 4.22 (2H, CH2-1), 4.16 (1H, H11a), 3.76 (3H, CH3O), 3.11, 2.67 (2H, CH2-11). MS (m / z): 378 (M +), 257.

Example 34: 4,5,11,1 1 a-tetrahydro- 1h, 6h-5- (2-thienyl) -oxazo lo [3 ', 4': 1,6] pyrido [3,4-25 b] indol -3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.76 g, 9.25 mmol) and of 2-thiophenecarboxaldehyde (1.56 g, 13.87 mmol) in CHCl3 (18 mL) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (2 g, 9.25 mmol) in CHCl 3 (18 mL) and reflux for 5 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). Yellow powder (545 mg, 38%); F = 230 C. IR (KBr): 3308 (NH), 3100,2901,2838 (CH), 1732 (CO), 1619 (C = C). 1H NMR (DMSO): 11.07 (1H, NH), 7.50 (1H, H5-thiophene), 7.47 (1H, H10), 7.31 (1H, H7), 7.10 (1H, H8), 7.03 (3H, H9, H3, H4-thiophene), 6.21 (1H, H5), 4.59, 4.23 (2H, CH2-1), 4.18 (1H, Hl la ), 3.14, 2.73 (2H, CH2-11). MS (m / z): 310 (M +), 309, 227.

Example 35: 4,5,11,11a-tetrahydro-1h, 6h-5- (3-thienyl) -oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one . The operation is carried out as in the case of Example 5 by adding a solution of APTS (2.64 g, 13.87 mmol) and of 3-thiophenecarboxaldehyde (2.33 g 20.81 mmol) in CHCl3 (27 ml) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (3 g, 13.87 mmol) in a mixture of CHCl 3 (27 ml) and THF (18 ml) then heating at reflux for 5 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (96/4). White powder (3 g, 70%). F = 220 C. IR (KBr): 3313 (NH), 3103,2915,2847 (CH), 1722 (CO), 1621 (C = C). 1H NMR (DMSO): 11.05 (1H, NH), 7.61 (1H, H10), 7.52 (1H, H7), 7.42 (1H, H2-thiophene), 7.38 (1H, H7), 7.18 (2H, H4, H5), 7.08 (1H, H9), 6.07 (1H, H5), 4.66, 4.31 (2H, CH2-1), 4.26 (1H, Hl la), 3.20, 2.79 (2H, CH2-11). MS (m / z): 310 (M +), 309, 227.

Example 36: 4,5,11,11 a-tetrahydro - 1 h, 6h-5- (2-thienyl) -9-methoxy-oxazo lo [3 ', 4': 1,6] pyrido [3,4- b] indol-3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.5 g, 8.12 mmol) and of 2-thiophenecarboxaldehyde (1.37 g, 12.18 mmol) in CHCl3 (18 mL) to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (2 g, 8.12 mmol) in a mixture of CHCl3 (16 mL) and THF (12 ml) then heating for 3 h at reflux with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (gradient from 99/1 to 90/10). Beige powder (1.27 g, 47%). F = 230 C. IR (KBr): 3292 (NH), 3070.2921, 2831 (CH), 1736 (CO), 1626 C = C).

1H NMR (DMSO): 10.96 (1H, NH), 7.50 (1H, H5-thiophene), 7.19 (1H, H7), 7.04 (2H, H3, H4-thiophene), 6, 96 (1H, H10), 6.74 (1H, H8), 6.17 (1H, H5), 4.58 (1H, 11a), 4.22 (2H, CH2-1), 3.75 (3H , CH3O), 3.11, 2.70 (2H, CH2-11). MS (m / z): 340 (M +), 257.

Example 37: 4,5,11,11 a-tetrahydro-1h, 6h-5 - (3 -thienyl) -9-methoxy-Oxazo lo j3 ', 4': 1,6lpyrido [3,4-b] indol- 3-one. The procedure is as in the case of Example 5 by adding a solution of APTS (1.5 g, 8.12 mmol) and of 3-thiophenecarboxaldehyde (1.37 g, 12.18 mmol) in CHCl3 ( 16 ml) to a solution of 4- (1H-5-methoxyindol-3-ylmethyl) -oxazolidin-2-one (2 g, 8.12 mmol) in a mixture of CHCl 3 (16 ml) and THF (16 ml ) then heating to reflux for 5 H with stirring. Purification is carried out by chromatography on a silica column, eluting with a mixture of CHCl 3 and acetone (gradient from 99/1 to 85/15). Beige powder (1.44 g, 54%). F = 190 C. IR (KBr): 3289 (NH), 3098.2907.2830 (CH), 1740 (CO), 1624 (C = C).

NMR 10.87 (1H, NH), 7.60 (1H, H7), 7.41 (1H, H2-thiophene), 7.18 (2H, H4, H5), 7.01 (1H, H10), 6.79 (1H, H8), 6.05 (1H, H5) 4.65, 4.31 (2H, CH2-1), 4.24 (1H, Hl la), 3.80 (3H, CH3O) , 3.16, 2.76 (2H, CH2-11). MS (m / z): 340 (M +), 257.

Example 38: 4,5,11,11 a-tetrahydro-1h, 6h-5 - (3 -thienyl) -6-methyl-Oxazolo 13 ', 4': 1,6lpyrido [3,4-b] indol-3 -one. The procedure is as in the case of Example 10 from 4,5,11,1la-tetrahydro-1H, 6H-5- (3-thienyl) -oxazolo [3 ', 4': 1,6] pyrido [ 3,4-b] indol-3-one (1g, 3.22mmol) N-benzyltrimethylammonium bromide (343mg, 0.96mmol) and methyl iodide (1.83g, 12.89mmol) in a mixture of DCM (105 ml) and 50% aqueous sodium hydroxide solution (40 ml). Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). White powder (820 mg, 78%). Mp = 178 C. IR (KBr): 2960 (CH), 1743 (CO). 1H NMR (DMSO): 7.52 (2H, H4, H5-thiophene), 7.39 (1H, H10), 7.26 (1H, H2-thiophene), 7.16 (1H, H7) 7.07 (1H, H8), 7.02 (1H, H9), 6.20 (1H, H5), 4.55, 4.22 (2H, CH2-1), 4.12 (1H, Hl la), 3 , 36 (3H, CH3N), 3.18, 2.73 (2H, CH2-11). MS (m / z): 324 (M +).

Example 39: 4,5,11,11a-tetrahydro-1h, 6h-5- (3-thienyl) -6-ethyl-Oxazolo 13 ', 4': 1,6lpyrido [3,4-b] indol-3- one. The procedure is as in the case of Example 10 from 4,5,11,1la-tetrahydro-1H, 6H- 5 - (3 -thienyl) -oxazo lo [3 ', 4': 1,6] pyrido [3,4, b lindol-3 -one (1g, 3.22 mmol), N-benzyltrimethylammonium bromide (343 mg, 0.96 mmol) and iodoethane (2g, 12.89 mmol) in a mixture of DCM (105 ml) and 50% aqueous sodium hydroxide solution (40 ml). Purification is carried out by chromatography on a silica column, eluting with a mixture of DCM and methanol (99/1). White powder (700 mg, 64%). F = 168 C. IR (KBr): 3094,2972,2910 (CH), 17344 (CO), 1613 (C = C). 1H NMR (CDCl3): 7.48 (1H, H5-thiophene), 7.22 (2H, H2, H4-thiophene), 7.16 (1H, H10), 7.08, (1H, H7), 7 1.0 (1H, H9), 6.09 (1H, H5), 4.66, 4.08 (2H, CH2-1), 4.04 (1H, H11a), 3.86, 3.72 (2H , CH2CH3), 3.13, 2.77 (2H, CH2-11), 1.02 (3H, CH3CH2). MS (m / z): 338 (M +).

Example 40: 4,5,11,1 1 a-tetrahydro- 1h, 6h-5- (3-pyridyl) -oxazo lo- [3 ', 4': 1,6] pyrido [3, 4, b lindol- 3-one. The operation is carried out as in the case of Example 5 by adding a solution of APTS (1.76 g, 9.25 mmol) and of 3-pyridinecarboxaldehyde (0.99 g, 9.25 mmol) in toluene (18 ml) to a solution of 4- (1H-indol-3-ylmethyl) -oxazolidin-2-one (2g, 9.25 mmol) in a mixture of toluene (18 ml) and DMF (15 ml) then heating at reflux for 3 hours with stirring. White powder (1.13 g, 40%). F 260 C. IR (KBr): 3180 (NH), 2976 (CH), 1736 (CO), 1H NMR (DMSO): 10.93 (1H, NH) , 8.57 (2H, H2, H6-pyridine), 7.65 (1H, H4-pyridine), 7.40 (1H, H4-pyridine), 7.48 (1H, H10), 7.29 (1H , H7), 7.09 (1H, H8), 7.01 (1H, H9), 6.02 (1H, H5), 4.60, 4.29 (2H, CH2-1), 7.24 ( 1H, Hl la), 3.18, 2.75 (2H, CH2-11). MS (m / z): 305 (M +)

Example 41: 4,5, 11,1 1 a-tetrahydro - 1 h, 6h-5 -phenyl-9, 1 1 -dimethoxy-Oxazo lo [3 ', 4': 1,6lpyrido [3,4-b] indol-3-one. A) 4- (1 h-5-m ethoxy-indol-3 yl-acetoxymethyl) -oxazolidin-2-one. 30 Acetic acid (52 ml) is added dropwise with stirring to a partial solution of 4- (1H-5-methoxy-indol-3-yl-methyl) -oxazolidin-2-one (2g, 8.12 mmol) in THF (52 ml) cooled to -78 C. The cooling bath is removed and after dissolution acetic acid, cooled again to -78 ° C and a solution of DDQ (2.03 g, 8.93 mmol) in THF (52 ml) added dropwise with stirring. Stirred for 30 min. at -78 C then the cooling bath is removed and stirring is continued for 24 h at room temperature. Add toluene (100 ml) and concentrate. A brown solid is obtained which is taken up in ethyl acetate (150 ml), the mixture is stirred for 30 min. and the insoluble material is collected. Beige powder (1.9g, 76%). F = 130 C (dec.) IR (KBr): 3306 (NH), 3059,2961,2924 (CH), 1747 (CO), 1619 (C = C). 1H NMR (DMSO): 11.18 (1H, NH), 8.16 (1H, NH), 7.61 (1H, H4-indole), 7.36 (1H, H7-indole), 7.10 ( 1H, H6-indole), 7.01 (1H, H5-indole), 6.07 (1H, H2-indole), 4.36 (1H, indol-3-ylmethyl), 4.48, 4.19 ( 2H, CH2-5-oxazole), 3.90 (1H, H4-oxazole), 2.01 (3H, COCH3). B) 4,5, II, 11A-TETRAHYDRO-1 H, 6H-5-PHENYL-9,11-DIMETHOXY-OXAZOLO 15 [3 ', 4': 1, 6] PYRIDO [3, 4-B] INDOL- 3-ONE. A solution of APTS (166 mg) in DCM (15 ml) is added to a solution of benzaldehyde dimethylacetal (2 g, 13.13 mmol) in a mixture of DCM and methanol (15 ml, 9/1) and stirred for 5 min. then cooled to 0 ° C. Add a solution of 4- (1H-5-methoxyindol-3-ylacetoxymethyl) -oxazolidin-2-one (2.4 g, 8.75 mmol) in DCM and methanol ( 15 ml (9/1)) then stirred for 4 h at 0 C. after evaporation of the solvents, a brown oil is obtained which is dissolved in DCM (150 ml). Washed twice with a saturated aqueous solution of NaHCO3. Evaporated to dryness under vacuum after drying and purified by chromatography on a silica column, eluting with a mixture of DCM and ethyl acetate (95/5). Yellow powder (1.65 g, 52 25%). M = 170 C. IR (KBr): 2929 (CH), 1748 (CO). 1H NMR (CDCl3): 7.62 (1H, H10), 7.18 (5H, C6H5), 7.07 (3H, H7, H8, H9), 6.08 (1H, H5), 4.60 ( 2H, CH2-1), 4.22 (1H, Hll), 3.74 (3H, OCH3), 3.53 (1H, Hl la). MS (m / z): 334 (M +).

EXAMPLE 2 TESTS OF HYPNOTIC ACTIVITY IN CHICKS The effect on the state of vigilance of Valentonin, 6-methoxy-harmalan and certain Valentonergic compounds according to the present invention was tested in chicks of the JA657 label meat strain. , aged 10 to 14 days. The animals are subjected to alternating lighting programs comprising 12 hours of darkness (8 p.m. to 8 a.m.) and 12 hours of lighting (8 a.m. to 8 p.m.). The ambient temperature is 25 ° C during the first week of rearing the chicks and 22 ° C from the second week. During the day, the lighting is provided by a halogen lamp (300 W), placed 30 cm above the floor of the vivarium.

During the tests, the live weights of the chicks varied between 85 and 120 g. The tests are carried out between 2 p.m. and 3 p.m. The chicks are allotted in groups of 3, in identical vivariums of 30 cm x 50 cm x 30 cm. The products tested are administered intramuscularly (IM) into the pectoral major muscle, in ethanol / PEG 400 / water solution (25/50/25, V / V / V), for all the compounds tested and the reference compounds ( Ethyl.carbo 7 and CF 019 MS), at a rate of 0.2 ml of solution per 100 g of bodyweight. The doses administered for the products tested (Valentonergics and reference substances) vary from 0.25 mol to 5 mol per 100 g of body weight. The placebo corresponds to 0.2 ml of the solution per 100 g of bodyweight. Since ethanol is used in the solvent, its effect was compared beforehand with that of physiological saline (0.9% NaCl solution) or distilled water. The solutions of the products tested and of the reference compounds (Ethyl.carbo 7 and CF 019 MS) were prepared extemporaneously by successive dilution of a stock solution, obtained from 2.5 to 50 M of product exactly weighed, added successively 0.5 ml of pure ethanol then 1 ml of PEG 400, stirred with ultrasound and then made up to 2 ml with 0.5 ml of distilled water for injection. In Tables II to v below are presented the results obtained after IM administration of doses of between 0.25 and 5 mol of products tested, in solution in 0.2 ml of the ethanolPEG 400 / water mixture, per 100 g of body weight. . For each chick, the volume injected is adjusted, depending on the actual body weight, to 0.2 ml per 100 g of body weight, which corresponds to doses of between 1 and 10 mg / kg of body weight. The parameters observed are locomotor activity and the waking state of the chicks for 2 hours, ie the equivalent of the 6 theoretical sleep-wake cycles of the chick of this age. They are recorded by video camera for 90 minutes, the first 30 minutes being the adaptation time to the device. Five stages of vigilance have been defined: -stage 1: active watch; - stage 2: animal lying down, maintaining the head with tone, eye open; - stage 3: light sleep, sleepy animal; closed eye with intermittent opening, 10 immobile posture unmodified by stimulation; - stage 4: deep sleep lying down: relaxation of the neck, characteristic head posture under the wing or behind; - stage 5: standing sleep: eye closed, motionless, head drooping (catatonic). These five stages correspond approximately to the stages of alertness and sleep defined by examination of the electroencephalographic tracings in this species. The correspondence is as follows: ^ Deep sleep lying down: stage 4 = slow wave sleep (SWS) ^ Standing sleep = sleep-like state I (SLSI). Stage 3, drowsiness, could correspond to phases of REM sleep, with head shaking, for example. 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 behavior of the chicks at regular intervals: - the noise caused by the impact of a plastic object on the glass of the vivarium, comparable to that of a chick's beak on the glass, corresponds to a moderate stimulus. It is performed at each observation period (ie every 5 minutes); - and the presentation of a metal feeder filled with the usual food, left for 2 minutes in the vivarium. It is a powerful stimulus involving sight, hearing and smell. It is performed every 15 minutes, that is to say 6 times, at least, at each test.

Awakening is defined by the onset of the conscious developed behavior of seeking and consuming food or drink. Sleep Time (TS) and defined by the sum of the durations of the phases of light sleep (stage 3), deep sleep (stage 4) and standing sleep (stage 5). The Sedation Time, after waking up, corresponds to stage 2. The Sleeping Time (AT) is equal (to within 1 minute) to the time required for the passage from the active waking state (stage 1) to a non-sleep state. vigil (stages 3, 4 and 5). Sleep Time (TS) is equal to the length of the sleep period from falling asleep to waking 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 as a% of the period (Sed). The reference products are the following valentonergic compounds: Ethyl carbo 7 (product insoluble in water) and CF 019 MS (mesylate soluble in water). H3CO H3CO Ethyl carbo 7 CF 019-MS The compounds tested are in base form. For each product tested, several series of measurements were carried out on batches of 3 animals, each value indicated is the average in each batch of 3 chicks. When the number of batches is greater than or equal to 2, the figures indicated are the average limit values observed. IHHN, CH3SO3H TABLE II Compound Dose TA TS (mg / kg) (minutes) (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 Valentonin 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: Sleeping time is equal to the time necessary to pass from the active wakeful state to a non-vigilant state. TS: Sleep Time is equal to the length of the sleep period from falling asleep to waking up.

Results: In chicks of this age outside the test, the duration of a sleep-wake cycle is 20 to 30 minutes during the day. It therefore appears, from the dose of 1 mg / kg that the 5 compounds tested induce a very strong decrease in locomotor activity attested by a duration of the first sleep of between 18 and 68.5 minutes, as evidenced by examination of Table III. The animals do not sleep after administration of the placebo. At higher doses, the compounds tested induce durations of the first sleep of between 37.5 and 72 minutes, for the dose equal to 3 mg / kg, and between 66 and 80 minutes, for the dose equal to 10 mg / kg, as evidenced by examinations of the results of Tables IV and V. There is a net positive dose-effect relationship for most of the compounds tested, with a reduction in the time to doze off when the dose is increased. Over 90 minutes, the difference in the sedation time, expressed as a percentage of the observation period, with that observed after administration of the placebo, is greater than 50% for 5 compounds out of 5 starting at a dose of 1 mg / kg.

TABLE III (Dose: 1 mg / kg) Compounds TA TS Sed ATS / placebo (minutes) (minutes) (% period) (minutes) Example 4 16.0 18.0 79.4 18.0 Example 15 12.5 36 , 5 64.0 34.5 Example 16 12.5 29.0 51.0 29.0 Example 21 10.0 43.5 74.0 41.5 Example 36 14.0 68.5 84.0 66.5 Ethyl carbo7 4.5 28.5 63.0 26.5 CF 019-MS 10.0 50.0 78.0 48.0 15 20 TABLE IV (Dose: 3 mg / kg) Compounds TA TS Sed ATS / placebo ( minutes) (minutes) (% period) (minutes) Example 4 15.5 72.0 78.3 72.0 Example 15 11.0 46.5 62.0 44.5 Example 16 12.5 37.5 59, 0 35.5 Example 21 10.0 52.5 82.0 50.5 Example 36 15.0 67.5 83.0 65.5 Ethyl carbo7 4.0 47.5 91.0 45.5 CF 019-MS 12.0 45.0 77.0 43.0 TABLE V (Dose: 10 mg / kg) Compounds TA (minutes) TS (minutes) Sed ATS / placebo (% o period) (minutes) Example 4 12.5 77, 5 86.1 77.5 Example 15 9.0 66.0 76.0 64.0 Example 16 12.5 75.0 83.0 73.0 Example 21 10.0 77.0 86.0 75.0 Example 36 10.0 80.0 89.0 78.0 Ethyl carbo7 5.5 50.0 81.0 48.0 CF 019-MS 8.0 72.0 80.0 70.0

Claims (22)

1 4,5,11,1 1 a-tetrahydro- 1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one of the following general formula (I) : R4 R1 in which: Rl represents a hydrogen atom or a C1-C6 alkoxy group; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C4-C6 cycloalkene group, a heteroaryl or an aryl group, the aryl group being optionally substituted by one or more groups chosen from C1-C6 alkyl, C1-C6 alkoxy, cyano or with one or more halogen atoms; R4 represents a hydrogen atom or a C1-C6 alkoxy group; or their mixtures, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereomers or mixtures thereof. 2. 4,5,11,1 1 a-tetrahydro- 1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to claim 1 characterized in that that it is chosen from the following compounds of 20 formulas 1 to 41: NNHONNHO MeO 1 2MeO 3 4 MeO 6 MeO 5 7 8 9 10 MeO 11 12MeO 13 14 MeO 15 16 MeO 17 18 OMe 19 20OMe MeO 21 22 MeO MeO 23 24 MeO CN CN 25 26 MeO CN 27 OMe 28MeO OMe 29 OMe 30 OMe MeO MeO 31 32 MeO 33 34 MeO 35 36MeO 37 38 and 39 40 OMe 41 3. Process for the preparation of a compound of general formula (I) according to claim 1 in which R2 and R4 represent a hydrogen atom by cyclization of the compound of the following general formula (II): R1 OH NNH H R3 (II ) in which Rl and R3 are as defined in claim 1 with diethyl carbonate in the presence of sodium ethoxide, advantageously by heating under reflux in ethanol. 15 4. Method according to claim 3 characterized in that the compound of general formula (II) is obtained by cyclization of a compound of general formula (III) below: OH N NH2 H (III) R1 in which Rl is as defined in claim 1, with an aldehyde of formula R3CHO or an acetal of formula R3CH (OCH3) 2, in which R3 is as defined in claim 1, advantageously by the method of PICTETSPENGLER, by heating in the presence of 4- acid toluenesulfonic monohydrate. 5. Process for the preparation of a compound of general formula (I) according to claim 1 in which R4 represents a hydrogen atom and R2 represents a C1-C6 alkyl group by alkylation with an alkyl halide, of formula R2X in which R2 represents a C1-C6 alkyl group and X represents a halogen atom, of a compound of general formula (I) according to claim 1 in which R2 and R4 represent a hydrogen atom, advantageously in the presence of NaH. 6. Process for the preparation of a compound of general formula (I) according to claim 1 in which R2 and R4 represent a hydrogen atom by cyclization of a compound of the following general formula (IV): R1 in which R1 is. as defined in claim 1, with an aldehyde of the formula R3CHO or an acetal of the formula R3CH (OCH3) 2, wherein R3 is as defined in claim 1, preferably in the presence of EtONa in ethano 1. 5 7. Method according to claim 6 characterized in that the compound of general formula (IV) is obtained by cyclization of a compound of general formula (III) according to claim 5 with diethyl carbonate in the presence of sodium ethoxide, advantageously by heating under reflux in ethanol. 8. Process for preparing a compound of general formula (I) according to claim 1 in which R2 represents a hydrogen atom and R4 represents a C1-C6 alkoxy group by cyclization of the compound of general formula (V) below: , COCH O 3 R1 10 in which R1 is as defined in claim 1, with an acetal of formula R3CH (OCH3) 2 in which R3 is as defined in claim 1, advantageously in the presence of 4-toluenesulfonic acid monohydrate . 15 9. The method of claim 8, characterized the compound of general formula (V) is obtained by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone of the compound of general formula (IV), advantageously in a mixture of THF and acetic acid. 20 10. A process for preparing a compound of general formula (I) according to claim 1 wherein R4 represents a C1-C6 alkoxy group and R2 represents a C1-C6 alkyl group by alkylation with an alkyl halide, of formula R2X in which R2 represents a C1-C6 alkyl group and X represents a halogen atom, of a compound of the general formula (I) according to claim 1 in which R2 represents a hydrogen atom and R4 represents a C1-C6 alkoxy group, advantageously in the presence of NaH. 11. Association of a 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to any one. of claims 1 or 2 and of an antagonist of the 5HT2 receptor of the following general formulas (VIII) or (VIIIbis) R16 N ùR16 N o H R17 R18 H VIII VIIIx in which R18 represents a C1-C12 alkyl, phenyl or phenyl group (C1-C6 alkyl), the phenyl group being optionally substituted by a C1-C6 alkoxy, a halogen atom or a secondary amine, R16 and R17 are absent and the dotted line represents a bond or R16 and R17 10 represent a hydrogen atom and the dotted line is absent. 12. Combination according to claim 11 characterized in that the 4,5,11,11atétrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3one according to the any one of claims 1 or 2 is present in an amount greater by weight than that of the antagonist. 13. Combination according to claim 11 or 12, characterized in that 4,5,11,1 1 a-tetrahydro- 1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b ] indol-3-one according to any one of claims 1 or 2 has an elimination time in the blood less than that of the 5HT2 receptor antagonist, preferably less than 2 hours. 14. Combination according to any one of claims 11 to 13, characterized in that R18 represents a methyl or ethyl group, advantageously the antagonist of the 5HT2 receptor of general formula (VIII) or (VIIIbis) is chosen from 6- methoxy-harmalan of the following formula: MeO 64MeO or the ethylated analogue of 6-methoxy-harmalan of the following formula: MeO or their hydrogenated analogs, of the formulas: MeO MeO or the compound of the formula Ibis NH (Ibis) MeO 15. Pharmaceutical composition comprising a 4,5,11,1 l a-tetrahydro1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to any one. of claims 1 or 2 or a combination according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient. 16. Pharmaceutical composition comprising the combination according to any one of claims 11 to 14 and an antagonist of the 5HT2 receptor of general formulas (VIII) or (VIIIbis): MeO N R16 1 R18 H R17 VIII MeO Viiibis in which R18 represents a C1-C12 alkyl group, phenyl or phenyl (C1-C6 alkyl), the phenyl group being optionally substituted by a C1-C6 alkoxy, a halogen atom or a secondary amine, R16 and R17 are absent and the line dotted line represents a bond or R16 and R17 represent hydrogen and the dotted line is absent, as a combination product for time-separated use to regulate the circadian sleep-wake cycle. 17. Composition according to any one of claims 15 or 16, characterized in that it is intended for oral or intravenous administration, advantageously orally. 18. 4,5,11,1 1 a-tetrahydro- 1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to any one of claims 1 or 2 or a combination according to any one of claims 11 to 14 or a composition according to any one of claims 15 to 17 for its use as a medicament. 19. Combination according to any one of claims 11 to 14 or composition containing the association according to any one of claims 15 to 17 for its use as a medicament intended to regulate the circadian sleep-wake cycle and / or for treatment. insomnia, mood disorders such as depression or anxiety, Parkinson's disease, Alzheimer's disease and diseases or disorders linked to the deregulation of the circadian sleep-wake cycle. 20. 4,5,11,11 a-tetrahydro- 1 H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to any one of claims 1 or 2 for its use as a medicament having muscle relaxant, hypnotic, sedative and / or analgesic activity, and / or intended for the treatment of diseases linked to disorders of melatonin activity and / or for 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 the treatment of benign prostatic hyperplasia, skin conditions such as psoriasis, 'acne, yeast infection, glaucoma and / or increased immune resistance and / or prevention of menopa symptoms use, premenstrual syndromes, the effects of aging and sudden infant death syndrome. 21. Use of 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to any one of claims 1 or 2 as a contraceptive in humans or animals and / or for controlling births in ruminant animals. 22. Cosmetic composition comprising a 4,5,11,11a-tetrahydro-1H, 6H-oxazolo [3 ', 4': 1,6] pyrido [3,4-b] indol-3-one according to any one. of claims 1 or 2 and a cosmetically acceptable excipient.