WO2008101824A1 - Imidazo[1',5':1,6] pyrido[3,4-b]indoles derivatives and therapeutical use thereof - Google Patents

Abstract

The present invention relates to a compound of the formula (I) in which: R1 is a hydrogen atom or a C<SUB>1</SUB>- C<SUB>6</SUB> alkoxy group; R2 is a hydrogen atom or a C<SUB>1</SUB>- C<SUB>6</SUB> alkyl group optionally substituted by a hydroxy group; R3 is a hydrogen atom, a C<SUB>1</SUB>- C<SUB>6</SUB> alkyl group optionally substituted by a hydroxy group, or an aryl group optionally substituted by a sulfonic group; the pointed line of the cycle is absent and ---R 6 is === O or __ R 6 in which R6 is a hydrogen atom, a hydroxy group or a C<SUB>1</SUB>- C<SUB>6</SUB> alkyl group; or the pointed line of the cycle is a bond and ---R 6 is R6 in which R6 is a hydrogen atom, a hydroxy group or a C<SUB>1</SUB>- C<SUB>6</SUB> alkyl group; ---R 4 is ===x in which X is a hydrogen or sulphur atom or - R 4 in which R4 is a hydrogen atom or a C<SUB>1</SUB>- C<SUB>6</SUB> alkyl group; R5 is a C<SUB>1</SUB>- C<SUB>6</SUB> alkyl group, a C<SUB>2</SUB>-C<SUB>6</SUB> alkenyl group, a C<SUB>3</SUB>-C<SUB>12</SUB> cycloalkyl group, an arl group, an arylcarbonyl group or an aralkyl group, the aryl group being optionally substituted by a halogen atom, a C<SUB>1</SUB>- C<SUB>6</SUB> alkoxy group or a C<SUB>1</SUB>- C<SUB>6</SUB> alkyl group optionally substituted by one or more halogen atoms. The invention also relates to the use of the compound as a drug, to a method for preparing the same and to the use thereof in pharmaceutical and/or cosmetic compositions, in particular for regulating the waking-sleeping circadian cycle.

Description

 DERIVATIVES OF IMIDAZO [1 ', 5': 1, 6] PYRIDO [3,4-b] INDOLES AND THEIR USE IN THERAPEUTICS

The present invention relates to novel imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole derivatives and their therapeutic use, advantageously as 5HT ₂ serotoninergic receptor agonists, by allosteric modulation, advantageously in the treatment of sleep disorders.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland isolated by Lerner et al. (J. Am Chem Soc., 80, 1958, 2587). Melatonin has been studied extensively for its circadian activity, particularly in the rhythm of sleep, for its effects on testosterone production, for its hypothalamus activity, and for psychiatric disorders.

It has thus been envisaged to use melatonin and its analogues, in particular for the treatment of depression and psychiatric disorders, in particular stress, anxiety, depression, insomnia, schizophrenia, psychoses, epilepsy, but also for the treatment of sleep disorders related to travel ("jet lag"), neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease, for the treatment of cancer, or as a contraceptive or as an analgesic. However, the direct use of melatonin in vivo has not been very satisfactory, given a first hepatic passage that extracts more than 90% of the active ingredient.

Various analogues of melatonin have been described, highlighting two research pathways that relate to either the melatonin substituents (WO-A-89/01472, US-A-5,283,343, US-A-5,093,352 or WO-A-93/11761), or on the aromatic ring by replacing the indole group with a naphthyl (FR-A-2 658 818, FR-A-2 689 124).

The present patent application therefore relates to the preparation and use as medicament of novel imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole derivatives. Moreover, the inventors have demonstrated that melatonin, with the exception of its antioxidant and free radical neutralization properties, which make melatonin an extremely effective pharmacological agent against free radical damage and neuronal loss, the goal of preventing neurodegenerative processes, does not directly regulate the circadian sleep-wake cycle, but is only a biological precursor of two compounds that exhibit pharmacological activities.

It has thus surprisingly been found by the inventors that, during the nocturnal sleep time, 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 step of enzymatic acetylation by N-acetyltransferases, successively giving 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-beta-carboline, called valentonine (VLT (Figure I)).

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). 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 stated above, 6-MH, which is therefore produced in conjunction with the VLT, is a serotonin antagonist to serotonin 5HT ₂ receptors, which are neuroinhibitors (their activation by serotonin results in a decrease in alertness and mood). By blocking them, 6-MH inhibits their activation by serotonin. As a result, the increase in alertness maintains the state of awakening; this results in an increase in alertness that gives the 6-MH a psychostimulant activity. Moreover, in the tests that the inventors have carried out on chicks, unlike the VLT, which exhibits a significant hypnotic activity, as shown in Table VII below, the 6-MH increases locomotion, which corresponds to psychostimulant activity. Its psychostimulant activity, slightly weaker than that of lysergic acid diethylamide (LSD), another 5HT ₂ serotonin receptor antagonist, allows the body to move from the state of sleep unconsciousness to a state of wakefulness, by increasing vigilance. For this reason, 6-MH can be considered as "the hormone of the day before".

Moreover, as shown in Table VII below, the VLT has important hypnotic properties, both from a qualitative point of view (physiological sleep EEG architecture) and from a quantitative point of view; and, given that VLT biosynthesis and nocturnal sleep are associated over time, it may be considered that the VLT, which is involved in the induction and maintenance of nocturnal sleep status, is "the sleep hormone ".

Like most endogenous compounds, the VLT can not be administered orally because of its hydrolysis in the acidic gastric medium; Various acid stable analogues called "Valentonergic" which are, most often, beta carboline derivatives, and therefore melatonin have been synthesized. Thus, all the studies carried out by the inventors show that the 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 respect to the electroencephalographic structure of sleep, with hypnotic drugs available on the market, such as, for example, benzodiazepines and Zolpidem. Indeed, benzodiazepines and Zolpidem produce a non-physiological sleep, characterized by the predominance of light sleep Sl and very little paradoxical sleep (see Table VII below), referred to as "anesthetic sleep" because it is less " repairer "for the body, and gives amnesia. In contrast, the VLT and Valentonergics produce sleep, whose EEG architecture is similar to that of physiological sleep, characterized by the predominance of deep slow sleep (SLP) (S2 + S3) and high percentages of paradoxical sleep. VLT and Valentonergic drugs induce sleep by reducing alertness, as a result of allosteric modulation activation of serotonergic 5-HT ₂ receptors. For these reasons, Valentonergics can be used in the treatment of sleep disorders. The VLT and Valentonergic are thus activators of the 5HT ₂ receptor by allosteric modulation. The present invention thus relates to novel Valentonergics: imidazo derivatives [l ', 5': l, 6] pyrido [3,4-b] indoles. The role of the [(Valentonine) - (6-methoxy harmalan)] system in the regulation of the circadian sleep-wake cycle can be summarized as follows:

1 - The VLT, a sleep hormone, produced in the pineal body, during the period of sleep, between 20 hours and 4 hours GMT, by the enzymatic acetylation of the MLT, induces and maintains the state of sleep as a consequence of its ability to decrease alertness after activation of 5-HT ₂ receptors by allosteric modulation, using its allosteric ligand. VLT remains prevalent during the sleep period, meaning that concentrations in the vicinity of 5-HT ₂ receptors are higher than those of 6-MH.

2 - Early in the morning, at 4:00 GMT, the biosynthesis of both the VLT and 6-MH stops, as the NAT decreases in the pineal body; then, since the rate of elimination of the VLT is greater than that of 6-MH (Figure 2), the hormone of the day before becomes prevalent. Therefore, between 4 am and 8 pm GMT, 6-MH antagonizes the 5-HT ₂ receptors by blocking them, which inhibits their activation by serotonin. As a result, vigilance increases, and the waking state is maintained until 20 hours GMT. Thus, the combination of VLT and 6-MH in the [(Valentonine) - (6-methoxy harmalan)] system regulates the circadian sleep-wake cycle. Indeed, the capacity of the VLT to bind and then activate, by allosteric modulation, the adrenergic receptors CC ₂ , as well as the dopaminergic receptors Di and D ₂ , explains how the arterial tension and the muscle tone decrease during the period of sleep night. In contrast, 6-MH, when its concentrations are higher than those of the VLT, during the activity period (standby), by blocking the 5-HT ₂ , adrenergic CC ₂ and dopaminergic D ₁ and D ₂ receptors, induces pharmacological activities which are opposed to those previously described of the VLT. Therefore, the mechanism of circadian sleep-wake regulation is controlled by the [(VLT) - (6-MH)] system. The dysfunctions of the system [(VLT) - (O-MH)] make it possible to explain the biological mechanisms, unknown so far, insomnia, depression and mood disorders, psychotic states, diseases Parkinson's and Alzheimer's. A decrease in the biosynthesis of the VLT, and simultaneously of the 6-MH, is observed in "primary" insomnia, in Parkinson's disease and Alzheimer's disease. In depressions the biosynthesis of the VLT is normal, but insufficient to lower the vigilance increased by the stress at the origin of the depressive state. In these disorders characterized by sleep disorders, it seems necessary to treat such disorders by administering a Valentonergic. In addition, the treatment of Parkinson's disease by Valentonergic is justified by their dopaminergic agonist properties.

In addition, the authors found that psychotic states were due to excessive biosynthesis of 6-MH, resulting in an exaltation of alertness and mood due to excessive blocking of serotonergic 5-HT ₂ receptors. These conditions could be treated by administration of Valentonergic, likely to displace 6-MH in excess of its attachment sites to 5-HT ₂ receptors, which should cause a decrease in alertness. Moreover, when the dysfunction of the [(VLT) - (β-MH)] system corresponds to a decrease in the biosynthesis of the VLT in conjunction with that of 6-MH, it seems necessary to treat such disorders by giving a combination of a Valentonergic and 6-methoxy harmalan. Indeed, taking into account that the circadian sleep-wake cycle is controlled by the system [(Valentonine) - (6-methoxy harmalan)], the VLT, sleep hormone, or the synthetic Valentonergic analogues, must be given together with an appropriate amount of 6-MH, the hormone of the day before, for proper regulation of the circadian sleep-wake cycle.

In addition, the inventors have also discovered that the combination of VLT or Valentonergic with 6-MH or its analogs can treat Alzheimer's disease. Indeed, cognitive dysfunction is one of the most striking age-related disorders in humans and animals. This disorder is probably due to the vulnerability of brain cells to increasing oxidative stress during the aging process. The hormone secreted by the pineal gland, melatonin (MLT), has been described as an endogenous antioxidant, whose peak plasma concentration declines during aging and in Alzheimer's disease (AD). The secretion of MLT is significantly lower in Alzheimer's patients, compared with healthy subjects of the same age. A sleep-wake rhythm disorder is common in patients with Alzheimer's disease, and is correlated with a decrease in MLT concentrations and a circadian circulatory rhythm of disrupted MLT. The direct consequences of decreased secretion of MLT by the pineal gland, in patients with AD, are insomnia and cognitive dysfunction, related to decreases in biosynthetic pathways of the VLT, sleep hormone, and 6 -MH, hormone of the day before, respectively. In addition, Parkinson's disease may be due to insufficient biosynthesis of the VLT during the sleep period. Patients with Parkinson's disease, have sleep disorders. It is interesting to note that 30% of patients with Parkinson's disease subsequently contract Alzheimer's disease. Under these conditions, a treatment of Parkinson's disease by the VLT or Valentonergic, administered for its dopaminergic agonist properties, can only be done by administering the combination of the VLT or Valentonergic with 6-MH or its analogs, in order to harmoniously regulate the sleep-wake cycle.

The subject of the present invention is therefore the synthesis of novel Valentonergic derivatives of imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indoles, as well as their use alone or in combination as a medicament.

dans laquelle :The present invention thus relates to an imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole of general formula (I) below:

in which :

Rl represents a hydrogen atom or an alkoxy group-C _6; R2 represents a hydrogen atom or an alkyl group Ci-C _{6 alkyl} optionally substituted by hydroxy group, preferably CH 3 or CH ₂ OH;

R3 represents a hydrogen atom, an alkyl group Ci-C _{6 alkyl} optionally substituted by hydroxy group (such as CH ₂ OH), or an aryl group, the aryl group being optionally substituted by a sulfonic group (SO3) ; the dotted line is absent and ring ^^ ^ ^{R 6} is ⁰ or ^{R 6} wherein R 6 represents a hydrogen atom, a hydroxy group or an alkyl group Ci-C _6; or the dotted line ring represents a bond and ^{R 6} represents ^{R 6} wherein ^{R 6} represents a hydrogen atom, a hydroxy group or a C ₁ -C ₆ alkyl group; ^{"R 4} represents ^ ^x wherein X represents an oxygen or sulfur atom or - ^{R 4} wherein R 4 represents a hydrogen atom or an alkyl group Ci-C _6;

R5 represents an alkyl group Ci-C ₆ alkenyl, C ₂ -C ₆ cycloalkyl, Cs-Ci _2, an aryl group, an arylcarbonyl group or an aralkyl group, the aryl group being optionally substituted by a a halogen atom, such as fluorine or chlorine, a C ₁ -C ₆ alkoxy group or a C 1 -C ₆ alkyl group optionally substituted with one or more halogen atoms (such as the trifluoromethyl group); or their mixtures, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof.

By the term "C ₁ -C ₆ alkyl group" is meant for the purposes of the present invention any alkyl group of 1 to 6 carbon atoms, linear or branched, in particular, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl. Advantageously, it is a methyl, n-propyl or n-butyl group.

By the term "C ₁ -C ₆ alkoxy group" is meant in the sense of the present invention any alkoxy group of 1 to 6 carbon atoms, linear or branched, in particular, the group OCH ₃ .

By the term "aryl group" is meant in the sense of the present invention one or more aromatic rings having 5 to 8 carbon atoms, which can be contiguous or fused. In particular, the aryl groups can be monocyclic or bicyclic groups, preferably phenyl, naphthyl, tetrahydronaphthyl or indanyl. Advantageously, it is a phenyl or naphthyl group. Even more advantageously, it is the phenyl group.

For the purposes of the present invention, the term "C ₂ -C ₆ alkenyl group" means any alkenyl group of 2 to 6 carbon atoms, linear or branched, in particular the allyl group.

By the term "C3-C12 cycloalkyl group" is meant in the sense of the present invention any saturated hydrocarbon ring having from 3 to 12 carbon atoms, in particular the cyclohexyl group.

By the term "aralkyl group" is meant in the sense of the present invention any aryl group as defined above, linked through an alkyl group as defined above. In particular, an aralkyl group is a benzyl group.

For the purposes of the present invention, the term "arylcarbonyl group" is intended to mean any aryl group as defined above bonded via a carbonyl group. An example of an arylcarbonyl group is the benzoyl group. For the purposes of the present invention, the term "halogen atom" means any halogen atom, advantageously chosen from Cl, Br, I or F, advantageously Cl or F.

In the present invention, is meant by "isomers" compounds that have identical molecular formulas but differ in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoiso mothers who are not mirror images of each other are referred to as "diastereoisomers", and stereoisomers that are non-superimposable mirror images are referred to as "enantiomers", or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is called a "chiral center".

"Chiral isomer" means a compound with a chiral center. It has two enantiomeric forms of opposite chirality and can exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is referred to as a "racemic mixture".

In the present invention, the term "pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical.

The term "pharmaceutically acceptable salts" of a compound is intended to mean salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; either coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid, methanesulfonic acid and phosphoric acid.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt. "Crystalline forms" (or polymorphs) means crystalline structures in which a compound can crystallize under different arrangements of crystalline stacks, all of which have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, hardness, density, crystal form, optical and electrical properties, stability and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors may cause crystalline form to dominate.

"Solvates" means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which the water retains its molecular state in the form of H ₂ O, such combination being capable of forming one or more hydrates. The novel compounds according to the invention are heterocyclic structures which are attached to a basic heterocycle which is 5H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole of general structures (F) next :

r

r

These new compounds are both useful because of their therapeutic activity and valuable intermediates for the elaboration of other structures imidazo [l ', 5': l, 6] pyrido [3,4-b] indoliques

Advantageously, these compounds are distributed in the following six groups: 2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole-diones-1,3 (II)

1-hydroxy-2,3,6,11,1-la-hexahydro-1H-imidazo [5 ': 1,6] pyrido [3,4-b] indo-3-ones (III)

2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indol-3-ones (IV)

2,3,5,6,11 1-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indoles (V)

2,3,6,1-tetrahydro-5H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indol-3-ones (VI)

1-oxo-2,3,5,6,1,1,1-hexahydro [1 ', 5': 1,6] pyrido [3,4-b] indole-3-thiones (VII). Thus, the subject of the present invention is also an imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the present invention, characterized in that it is chosen from compounds of general formulas (II). ) to (VII):

dans lesquelles Rl à R3 et R5 sont tels que définis dans la formule générale (I), ou leurs mélanges, ou leurs sels d'addition pharmaceutiquement acceptables, ou leurs isomères, énantiomères, diastéréoisomères ou leurs mélanges.

wherein R1-R3 and R5 are as defined in general formula (I), or mixtures thereof, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof.

Advantageously, the imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the present invention is chosen from the following compounds of formulas 1 to 101:

8

10

11 12

13 14

15 16

17 18

19 20

21 22

23 24

25 26

27 28

29 30

31 32

33 34

35 36

37 38

41 42

45 46

47 48

49 50

51 52

53 54

55 56

57 58

59 60

61 62

63 64

65 66

67 68

69 70

71 72

73 74

75 76

77 78

79 80

81 82

83 84

85 86

87 88

89 90

91 92

93 94

95 96

97 98

99 100

101 The present invention also relates to a process for preparing a compound of general formula (II) according to the present invention by cyclization of the compound of general formula (VIII) below:

dans laquelle Rl à R3 sont tels que définis dans la formule générale (II) avec l'isocyanate de formule générale (IX) suivante :

in which R1 to R3 are as defined in the general formula (II) with the isocyanate of the following general formula (IX):

R5NCO (IX) wherein R5 is as defined in general formula (II).

Advantageously, the cyclizations are carried out by heating in appropriate organic solvents and, in general, in mixtures of dimethylsulfoxide and acetone.

Advantageously, the present invention also relates to a process for the preparation of a compound of general formula (II) according to the present invention in which R5 represents a C ₄ -C ₆ alkyl group, by:

cyclization of the compound of general formula (VIII) in which R1 to R3 are as defined in general formula (II) with an alkenyl isocyanate of general formula (X) below:

^{^} NCO

(X) wherein R7 represents a C1-C3 alkyl group to obtain the compound of formula XI below

dans laquelle Rl à R3 sont tels que définis dans la formule générale (II) et R7 est tel que défini dans la formule générale (X) ; -suivie d'une hydrogénation catalytique du composé de formule (XI), avantageusement avec un catalyseur Pd/C.

wherein R1 to R3 are as defined in general formula (II) and R7 is as defined in general formula (X); followed by a catalytic hydrogenation of the compound of formula (XI), advantageously with a Pd / C catalyst.

Thus, these two processes can be represented by the following synthesis method:

The present invention further relates to a process for preparing a compound of general formula (III) according to the present invention by partial reduction of the compound of formula (II) according to the present invention chemically. Advantageously, the reduction is carried out using agents such as sodium borohydride (NaBH ₄ ) or lithium hydrobromide (LiAlH ₄ ) by heating in appropriate solvents. Thus this process can be represented by the following synthesis method:

dans laquelle Rl à R5 sont tels que définis dans la revendication 1 avec le phosgène, avantageusement par agitation à basse température de solutions des aminés (XII) et de triphosgène dans des solvants appropriés tels que le chloroforme.The present invention furthermore relates to a process for preparing a compound of general formula (IV) according to the present invention by cyclization of the compound of general formula (XII) below:

wherein R1 to R5 are as defined in claim 1 with phosgene, advantageously by low temperature stirring solutions of amines (XII) and triphosgene in suitable solvents such as chloroform.

Thus this process can be represented by the following synthesis method:

XII IV

The present invention furthermore relates to a process for the preparation of a compound of general formula (V) according to the present invention by total chemical reduction of the compound of formula (II) according to the present invention, advantageously with the aid of NaBH ₄ or LiAlH ₄ in suitable solvents such as tetrahydrofuran. Thus this process can be represented by the following synthesis method:

LiAlH,

The present invention furthermore relates to a process for the preparation of a compound of general formula (VI) according to the present invention by dehydration of the compound of formula (III) according to the present invention, advantageously by refluxing with azeotropic entrainment in toluene in presence of 4- to luenesulfonic acid. Thus this process can be represented by the following synthesis method:

III VI

The present invention relates to a process for the preparation of a compound of general formula (VII) according to the present invention by cyclization of the compound of general formula (VIII) with the isothiocyanate of general formula (XIII) below:

R5NCS (XIII) wherein R5 is as defined in general formula (VII), advantageously by heating in customary solvents and, in general, in mixtures of dimethylsulfoxide and acetone.

Thus this process can be represented by the following synthesis method:

VIII VII

Another object of the present invention is the combination of an imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to any one of claims 1 to 3 and an antagonist of the 5HT ₂ receptor of the following general formulas (VIII) or (VHIbis)

V I I I V I I I b 1 S in which

Rl 8 represents a C ₁ -C ₁₂ alkyl, phenyl or phenyl (C ₁ -C ₆ ) alkyl group, the phenyl group being optionally substituted by a C ₁ -C ₆ alkoxy, a halogen atom or a secondary amine, advantageously a methyl or ethyl group;

R16 and R17 are absent and the dotted line represents a bond or R16 and R17 represent a hydrogen atom and the dashed line is absent.

For the purposes of the present invention, the term "phenyl (C ₁ -C ₆₎ alkyl group" means any phenyl group bonded via a C ₁ -C ₆ alkyl group as defined above. Examples of phenyl-alkyl (Ci-C ₆₎ include, but are not limited to, phenylethyl, 3-phenylpropyl, benzyl and the like.

The amounts of imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the invention, activators of the 5HT ₂ receptor by allosteric modulation, in the combination are advantageously greater than that of the 5HT ₂ receptor antagonist so that the effect of the activator predominates on the effect of the antagonist throughout the sleep period.

Thus, in such a combination, the imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the invention and the 5HT ₂ receptor antagonist should have appropriate pharmacokinetic profiles in a suitable manner. that, administered at night, they produce concentration versus time curves similar to the concentration versus time curve of the VLT and 6-MH (Figure 2).

Thus, the pharmacokinetic parameters of the imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the invention and of the 5HT ₂ receptor antagonist must be in agreement, so that the concentration of imidazo [l, 5 ': l, 6] pyrido [3,4-b] indole according to the invention is prevalent during the nocturnal sleep period, and that, on the contrary, the concentration of the 5HT ₂ receptor antagonist in the body is higher than that of the imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the invention, during the diurnal period of activity, after awakening. Therefore, advantageously, the elimination of the imidazo [l ', 5': l, 6] pyrido [3,4-b] indole according to the invention must be faster than that of the 5HT receptor antagonist. ₂ (elimination half-life Ty ₂ z = 2.5 hours for 6-MH, Beagle dog), that is, the elimination half-life of imidazo [1 ', 5' : 1, 6] pyrido [3,4-b] indole according to the invention must be less than that of the 5HT ₂ receptor antagonist; this means that it is possible to combine, together with 6-MH, an imidazo [l, 5 ': l, 6] pyrido [3,4-b] indole according to the invention which has a half-life of elimination (T 1/2 z) less than 2 hours. It is also possible to administer an imidazo [l, 5 ': l, 6] pyrido [3,4-b] indole according to the invention having a elimination half-life greater than or equal to that of the antagonist of the 5HT ₂ receptor, ie the elimination of which is less rapid than that of the 5HT ₂ receptor antagonist, but for this it is also necessary to administer at awake a dose of 5HT ₂ receptor antagonist so that the effect of the 5HT ₂ receptor antagonist prevails over that of the imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the invention, until that imidazo [l ', 5': l, 6] pyrido [3,4-b] indole according to the invention is eliminated.

Advantageously, the imidazo [l, 5 ', l, 6] pyrido [3,4-b] indole according to the invention is present in the combination in an amount greater by weight than that of the antagonist.

Advantageously, the imidazo [1 ', 5', 1, 6] pyrido [3,4-b] indole according to the invention has a duration of elimination in the blood which is less than that of the receptor antagonist.

5HT ₂ , advantageously less than 2 hours. Advantageously, the 5HT ₂ receptor antagonist of general formula (VIII) or

(VlIIbis) is chosen from 6-methoxy-harmalan of the following formula:

ou l'analogue éthylé du 6-méthoxy-harmalan de formule suivante :

or the ethyl analogue of 6-methoxy-harmalan of the following formula:

ou leurs analogues hydrogénés, de formules

ou le composé de formule Ibis

or their hydrogenated analogues, of formulas

or the compound of formula Ibis

The present invention further relates to a pharmaceutical composition comprising the combination of the present invention and a 5HT ₂ receptor antagonist of general formulas (VIII) or (VHIbis):

VIII VI I I b 1 S in which

R 8 represents an alkyl group C1-C12alkyl, phenyl or phenyl (C ₁ -C _6), phenyl optionally substituted by alkoxy-C _6, 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 dashed line is absent as a combination product for a separate use in time for regulate the circadian sleep-wake cycle.

Advantageously, the combination according to the present invention is administered in the evening and the 5HT ₂ receptor antagonist of general formula VIII or VHIbis is administered in the morning. The present invention also relates to a pharmaceutical composition comprising an imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the present invention or a combination according to the invention and a pharmaceutically acceptable excipient. The pharmaceutical compositions according to the present invention can be formulated for administration to mammals, including humans. The dosage varies according to the treatment and the condition in question. These compositions are made so that they can be administered orally, topically, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally. In this case the active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals or humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration , topical, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.

When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient. A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

A syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant. The water dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.

For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible wetting agents are used. The active ingredient may also be formulated as microcapsules, optionally with one or more additive carriers.

Advantageously, the pharmaceutical composition according to the present invention is intended for oral or intravenous administration, advantageously orally.

The present invention further relates to a cosmetic composition comprising an imidazo [l ', 5': l, 6] pyrido [3,4-b] indole according to the invention and a cosmetically acceptable excipient. The pharmaceutical or cosmetic composition according to the invention may also be formulated for topical administration. It may be in the forms that are usually known for this type of administration, that is to say in particular lotions, mousses, gels, dispersions, sprays, shampoos, serums, masks, milks for example, with excipients allowing skin penetration in particular to improve the properties and accessibility of the active ingredient, this composition generally contains, in addition to the active ingredient according to the present invention, a physiologically acceptable medium, in general based on water or solvent, for example alcohols, ethers or glycols. It may also contain surfactants, preservatives, stabilizing agents, emulsifiers, thickeners, other active ingredients leading to a complementary or possibly synergistic effect, trace elements, essential oils, perfumes, dyes, collagen, chemical or mineral filters, moisturizers or thermal waters etc.

The present invention also relates to the combination according to the present invention or the composition according to the present invention containing the combination according to the present invention for its use as a medicament, advantageously intended to regulate the circadian sleep-wake cycle and / or to the treatment insomnia, mood disorders such as depression or anxiety, Parkinson's disease, Alzheimer's disease and diseases or disorders related to deregulation of the circadian sleep-wake cycle.

Another subject of the present invention is an imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to the invention or the composition according to the invention for its use as a medicament, advantageously as a drug having myorelaxant, hypnotic, sedative and / or analgesic activity, and / or for the treatment of diseases related to disorders of melatonin activity and / or the treatment of depression and psychiatric disorders, in particular stress, anxiety, insomnia, schizophrenia, psychosis or epilepsy, and / or the treatment of travel-related sleep disorders (jet lag) or neurodegenerative diseases of the central nervous system such as Parkinson's 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, mycoses, glaucoma and / or increased immune resistance and / or prevention of menopausal symptoms, premenstrual syndromes, effects of aging and sudden infant death.

Finally, the present invention relates to the use of imidazo [l ', 5': l, 6] pyrido [3,4-b] indole according to the invention as a contraceptive in humans or animals and / or to regulate births in ruminant animals. The examples of preparation of the compounds according to the present invention are given as an indication, not limiting. The raw materials and / or the different reagents used in these examples to synthesize the compounds according to the present invention are known products or prepared according to the invention. 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: Infrared, NMR and mass spectrometry.

EXAMPLE 1 2,3,5,6,11,1aα-HEXAHYDRO-1H-IMIDAZO [1 ', 5': 1,6] PYRIDO [3,4-b] INDOLE-1,3-DIONES (Compounds of Formula General II).

The compounds whose structure is indicated in the following Table I were synthesized: TABLE I

Example 1: 2-phenyl-2.3.5.6.11.11a-hexahydro-1H-imidazo IT .5 ': 1.61 pyridor3.4-b] indole-1,3-dione.

A solution of 1,2,3,4-tetrahydro-pyrido [3,4 b] indole-3-carboxylic acid (8 g, 34.7 mmol) and phenyl isocyanate (4.97 g) 7 mmol) in an anhydrous mixture of dimethylsulfoxide (34 ml) and acetone (170 ml) is heated at 16 H with stirring. After cooling, the precipitate is filtered off and the filtrate is concentrated to about 50 ml. 100 ml of water are added, the precipitate is filtered off and washed with petroleum ether. It is dried and recrystallized in ethyl acetate. White powder (9.2 g, 80%). M.p. 234 ° C. IR (KBr): 3362 (NH), 3055 (CH), 1775, 1716 (CO), 1648 (C = C). 1H NMR (DMSO): 11.07 (1H, NH), 7.50 (5H, C ₆ H ₅ ), 7.42 (1H, H10), 7.35 (1H, H7), 7.08 (1H, NH4); , H8), 7.01 (1H, H9), 4.98, 4.49 (2H, CH2-5), 4.55 (1H, H1a), 3.28, 2.94 (2H, CH2), 11). MS (m / z): 317 (M ⁺ ), 316. Example 2: 2-n-propyl-6-hydroxymethyl-2,3,5,6J; 1a-hexahydroimidazo [1,5] pyrido [3,4-b] indole-U-dione.

The procedure is as in the case of Example 1 by heating 16 H at 70 ^° C. of a solution of 1, 2,3,4-tetrahydro-9-hydroxymethyl-pyrido [3,4-b] indole- 3-carboxylic acid (2 g, 9.24 mmol) and n-propyl isocyanate (0.95 mL, 10.17 mol) in anhydrous dimethylsulfoxide (30 mL). White solid (0.99 g, 34%). F = 194 ° C. IR (KBr): 3408 (OH), 3050 (CH), 1761, 1703 (CO). 1H NMR (DMSO): 11.06 (1H, NH), 7.49 (2H, H7, H10), 7.15 (1H, H8), 7.03 (1H, H9), 6.38 (1H, OH), 5.45 (2H ₅ CH ₂ OH), 5.13, 4.47 (2H, CH2-5), 4.39 (IH ₅ Hl Ia), 3.23, 2.68 (2H, CH2 -11), 3.40, 1.57, 0.85 (7H, C3H7). MS (m / z): 313 (M ⁺ ), 284, 283.282.

Example 3: 2-n-butyl-6-hydroxymethyl-2,3,5,6-diol hexahydroimidazo [1,5] pyridazolindole-5-dione.

The procedure is as in the case of Example 1 by heating 16 H at 70 ^° C. of a solution of 1,2,3,4-tetrahydro-9-hydroxymethyl-pyrido [3,4-b] indole acid. 3-carboxylic acid (2 g, 9.24 mmol) and n-butyl isocyanate (1.15 mL, 10.17 mmol) in anhydrous dimethylsulfoxide (30 mL). White powder (1.15 g, 38%).

F = 188 ° C. IR (KBr): 3389 (OH), 2954 (CH), 1759, 1697 (CO), 1616 (C = C). NMR

1H (DMSO): 7.57 (2H, H7, H10), 7.22 (1H, H8), 7.11 (1H, H9), 6.44 (1H, OH), 5.51 (2H, CH2OH) ), 5.19, 4.53 (2H, CH2-5), 4.45 (IH ₅ Hl Ia), 3.29, 2.74 (2H, CH2-11),

3.48, 1.59, 1.35, 0.94 (9H, C4H9). MS (m / z): 327 (M ⁺ ), 298.297.

Example 4: 2-Cyclohexyl-6-hydroxymethyl-2,3,5,6J; 1a-hexahydroimidazo [1,5] pyridazole [3,4-b] indole-U-dione. The procedure is as in the case of Example 1 by heating 16 H at 60 ^° C. of a solution of 1, 2,3,4-tetrahydro-9-hydroxymethyl-pyrido [3,4-b] indole- 3-carboxylic acid 3 g, 11.49 mmol) and cyclohexyl isocyanate (1.58 g, 12.64 mmol) in anhydrous dimethylsulfoxide (35 ml). It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (98) and methanol (2). White powder (1.76 g, 41%). F = 220 ° C. IR (KBr): 3400 (OH), 2931 (CH), 1707 (CO), 1615 (C = C). 1H NMR (DMSO): 7.47 (1H, H1O), 7.42 (1H, H7), 7.10 (1H, H8), 7.01 (1H, H9), 6.48 (1H, OH), 5.41 (2H, CH2OH), 4.95, 4.42 (2H, CH2-5) , 4.27 (1H, H5), 3.28, 2.87 (2H, CH2-11), 3.36, 1.76, 1.24 (11H, C6H11). MS (m / z): 353 (M ⁺ ), 352.323.

Example 5: 2-Benzyl-6-hydroxymethyl-2,3,5,6-diol hexahydroimidazo [1,5-pyridazole] -2,4-indol-4-yl;

The procedure is as in the case of Example 1 by heating 4 H at 75 ° C of a solution of 6-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole- 3-carboxylic acid (1.5 g, 6.09 mmol) and benzyl isocyanate (0.974 g, 7.31 mmol) in anhydrous dimethylsulfoxide (25 ml). Beige solid (0.62 g, 30%) mp = 210 ° C. IR (KBr): 3349 (OH), 3043 (CH), 1763, 1697 (CO), 1629 (C = C). 1H NMR (CDCl3): 7.33 (1H, H10), 7.24 (1H, H7), 7.22 (5H, C6H5), 5.39 (2H ₅ CH ₂ OH), 5.08, 4, 28 (2H, CH2-5), 4.62 (2H ₅ CH ₂ C ₆ H _5), 3.95 (IH ₅ Hl Ia), 3.23, 2.58 (2H, CH2- 11). MS (m / z): 361 (M ⁺ ), 331.

Example 6: 2-Phenyl-6-hydroxymethyl-2,3,5,6J; 1α-hexahydroimidazo [1,5] pyrido [3,4-indol-5-ol-dione.

The procedure is as in the case of Example 1 by heating 3 H at 60 ^° C. of a solution of 1, 2,3,4-tetrahydro-9-hydroxymethyl-pyrido [3,4-b] indole- 3- carboxylic acid (2g, 8.13 mmol) and phenyl isocyanate (1.07 g, 8.94 mmol) in anhydrous dimethylsulfoxide (25 ml); Yellow powder (1.35 g, 48%). Mp 180 ° C. IR (KBr): 3384 (OH), 3051 (CH), 1771, 1716 (CO), 1638 (C = C). 1H NMR (DMSO): 7.51 (5H, C6H5), 7.44 (1H, H10), 7.26 (1H, H7), 7.05 (1H, H8), 6.98 (1H, H9); 5.40 (2H, CH ₂ OH), 5.37, 5.16 (2H, CH ₂ -5), 4.57 (1H, HCl), 3.36, 2.95 (2H, CH ₂ -11). ). MS (m / z): 347 (M ⁺ ), 346, 317, 316.

Example 7: 2-Cyclohexyl-9-methoxy-2,3,5,6Jl 1 Hexahydroimidazo | ^" 1 ', 5': 1,6] pyrido [3,4-b] indole, 3-dione.

The procedure is as in the case of Example 1 by heating at 60 ^° C. of a solution of 1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole-3- acid carboxylic acid (2 g,

8.13 mmol) and cyclohexyl isocyanate (1.1 g, 8.94 mmol) in the anhydrous dimethyl sulfoxide (25 ml). It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (98) and methanol (2). Beige powder (2.29 g, 80%). F = 204 ° C. IR (KBr): 3390 (NH), 2930 (CH), 1765, 1705 (CO). IH NMR (DMSO): 10.64 (1H, NH), 7.16 (1H, H7), 6.91 (IH HLO _5), 6.66 (1H, H8), 4.71, 4.34 ( 2H, CH2-5), 3.75 (3H, OCH3), 3 44 (1 H ₅ Hl Ia), 3,24,2,85 (2H, CH2-11), 3,55,1,77, 1.21 (11H, C6H11). MS (m / z): 353 (M ⁺ ), 352.

Example 8: 2-phenyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [5,1,6] pyrido [3,4-b] indole-1 3-dione. The procedure is as in the case of Example 1 by heating 3 H at 60 ^° C. of a solution of 1, 2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] indole- 3-carboxylic acid (2 g, 8.13 mmol) and phenyl isocyanate (1 g, 8.40 mmol) in anhydrous dimethylsulfoxide (35 ml). It is purified by chromatography on a silica column, eluting with a mixture of methanol (4.5) and dichloromethane (95.5). White powder (1.63 g, 58%). F = 244 ° C. IR (KBr): 3374 (NH), 2927 (CH), 1780, 1707 (CO), 1628 (C = C). 1H NMR (DMSO): 10.87 (1H, NH), 7.48, 7.42 (C6H5), 7.25 (1H, H7), 7.03 (1H, H10), 6.97 (1H, H8), 4.93, 4.45 (2H, CH2-5), 4.55 (1H, H1a), 3.75 (3H, OCH3), 3.28, 2.91 (2H, CH2-11). ). MS (m / z): 347 (M ⁺ ), 346.

Example 9 2- (2-Propenyl) -5-methyl-2,3,5,11,11a-hexahydro-1H-imidazo [1,5] pyrido [3,4-indol-4-olione.

The procedure is as in the case of Example 1 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (3 g, 13.03 mol) and 2-propenyl isocyanate (1.3 g, 15.63 mmol) in a mixture of dimethylsulfoxide (13 ml) and acetone (63 ml); White powder (2.2 g, 57%). F = 196 ° C. IR (KBr): 3285 (NH), 1767, 1709 (CO), 1643 C = C). 1H NMR (DMSO): 11.05 (1H, NH), 7.48 (1H, H10), 7.32 (1H, H7), 7.07 (1H, H8), 6.99 (1H, H9); 5.81 (1H, CH 2 CH = CH 2) 5.14 (2H, CH 2 CH = CH 2) 4.93 (1H, H 5), 4.41 (1H, H 1 Ia), 4.01 (2H, CH 2 CH = CH 2) 3.21, 2.71 (2H, CH2-11), 1.83 (3H, CH3-5). MS (m / z): 295 (M ⁺ ), 294.280. Example 10: 2 - (- Propenyl) -5,6-dimethyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1,5] pyridazole [3,4-blindole-U-dione].

The procedure is as in the case of Example 12 starting from 2- (2-propenyl) -5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5' 1, 6] pyrido [3,4-b] indole-1,3-dione (Ig, 3.39 mmol), iodomethane (1.92 g, 13.55 mmol) and benzyltrimethylammonium bromide (0.361). g, 1.02 mmol) in a mixture of dichloromethane (110 ml) and 50% aqueous sodium hydroxide (40 ml). It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane (99.8) and methanol (0.2). Yellow solid (0, 89 g, 85%). Mp 120 ° C. IR (KBr): 3051 (CH), 1771, 1711 (CO). 1H NMR (CDCl3): 7.40 (1H, H10), 7.23 (1H, H7), 7.17 (1H, H8), 7.06 (1H, H9), 5.80 (1H, CH2 CH = CH2), 5.33 (1H, H5), 5.21, 5.15 (2H, CH2CH = CH2), 4.30 (1H, H1Ia), 4.10 (3H, CH3N), 4.07 ( 2H, CH 2 CH = CH 2), 3.35, 2.77 (2H, CH 2 - 11), 1.53 (3H, CH 3 - 5). MS (m / z): 309 (M ⁺ ), 308, 294.

Example 11: 2-n-propyl-5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1,5] pyridazole [3,4-b] indole-1,3-dione.

A solution of 2- (2-propenyl) -5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5: 1,6] pyrido [3,4-b] ] Indole-1,3-dione (1 g, 3.39 mmol) in 100 ml of methanol is hydrogenated under atmospheric pressure at 20 ^° C. in the presence of 10% palladium on charcoal. After filtration, the filtrate is concentrated to a small volume and the crystals are collected. White powder (0.89 g, 89%). F = 220 ° C. IR (KBr): 3321 (NH), 2970 (CH), 1764, 1703 (CO), 1624 (C = C). 1H NMR (DMSO): 11.10 (1H, NH), 7.46 (1H, H10), 7.33 (1H, H7), 7.07 (1H, H8), 6.98 (1H, H9) 5.13 (1H, H5), 4.53 (1H, H1a1a), 3.21, 26.6 (2H, CH2-11), 1.50 (3H, CH3-5), 3.38, 1, 52.0, 84 (7H, C3H7). MS (m / z): 297 (M ⁺ ), 296.282.281.

Example 12: 2-n-propyl-5,6-dimethyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1.5] pyrido [3.4-blindole-1.3-dione] A solution of 2-n-propyl-5-methyl-2,3,5,6,11,1-la-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole-1,3-dione (0.9 g, 3.03 mmol), iodomethane (1.72 g, 12.11 mmol) and benzyltrimethylammonium bromide (0.323 g, 0.91 mmol), in a mixture of dichloromethane (98 ml) and 50% aqueous sodium hydroxide (36 ml) is stirred for 1 h 30 ^min. Then 3H at 25 ° C. The organic phase is decanted, dried over magnesium sulphate and evaporated to dryness. The residual oil is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). Yellow powder (0.70 g, 75%). F = 114 ° C. IR (KBr): 3053 (CH), 1766, 1704 (CO), 1615 (C = C). 1H NMR (CDCl3): 7.41 (1H, H1O), 7.22 (1H, H7), 7.16 (1H, H8), 7.16 (1H, H9), 5.31 (1H, H5). 4.26 (1H, H1a1), 3.62 (3H, NCH3), 3.34, 2.75 (2H, CH2-11), 3.47, 1.62, 0.89 (7H, C3H7). ), 1.48 (3H, CH3-5). MS (m / z): 311 (M ⁺ ), 296.281.

Example 13: 2-n-propyl-5-methyl-6-ethyl-2,3,5,6,11,1-la-hexahydro-1H-imidazo [5]: 1,61 pyrido [3,4-diol] bl indole-1,3-dione.

The procedure is as in the case of Example 12 starting from 2-n-propyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1', 5 ': l , 6] pyrido [3,4-b] indole-1,3-dione (0.9 g, 3.03 mmol), iodoethane (1.89 g, 12.11 mmol), and benzyltrimethylammonium bromide ( 0.323, 0.91 mmol) in a mixture of dichloromethane (98 ml) and 50% aqueous sodium hydroxide (36 ml). It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99.8 / 0.2). Yellow powder (0.43 g, 44%). F = 100 ^° C. IR (KBr): 2925 (CH), 1766, 1704 (CO). 1H NMR (CDCl3): 7.42 (1H, H1O), 7.26 (1H, H7), 7.15 (1H, H8), 7.16 (1H, H9), 5.31 (1H, H5). , 4.27 (1H, Hl la), 4.07 (2H, NCH 2 CH 3), 3.22, 2.76 (2H, CH 2 -11), 3.46, 1, 40.0, 86 (7H, C3H7), 1.51 (3H, CH3-5), 1.33 (3H, NCH2CH3). MS (m / z): 325 (M ⁺ ), 310.296.

Example 14: 2-n-butyl-5-methyl-2.3.5.6.11.11a-hexahydro-1H-imidazo [5,5]: 1.61 pyrido [3,4-b] indole-1,3-dione.

The procedure is as in the case of Example 1 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (3.18 g, 13.8 mmol) and n-butyl isocyanate (1.64 g, 16.57 mmol) in an anhydrous mixture of dimethylsulfoxide (13.4 ml) and acetone (66.5 g). ml). Powder white (3.2 g, 74%) mp = 172 ° C. IR (KBr): 3347 (NH), 2953 (CH), 1765, 1698 (CO), 1624 (C = C). IH NMR (DMSO): 11.07 (1H, NH) 7.47 (IH HLO _5), 7.31 (1H, H7) 7 O7 (1H, H8), 6.98 (1H, H9) 4, 92 (1H, H5), 4.34 (1H, H1a1a), 3, 15.2.67 (2H, CH2-1 1), 3.34, 1. 52, 1.29, 0.90 (9H). , C4H9) 1.82 (3H, CH3-5). MS (m / z): 311 (M ⁺ ), 310, 297, 296.

Example 15: 2-Cyclohexyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1,5] pyridazole [3,4-b] indole-U-dione.

The procedure is as in the case of Example 1 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2 g, 8.69 mmol) and cyclohexyl isocyanate (1.3 g, 10.42 mol) in an anhydrous mixture of dimethylsulfoxide (8.5 ml) and acetone (41.9 ml). Yellow solid (2 g, 68

%). F = 232 ° C. IR (KBr): 3301 (NH), 3061 (CH), 1765, 1698 (CO), 1621 (C = C).

IH NMR (DMSO): 11.01 (1H, NH), 7.54 (IH HLO _5), 7.39 (1H, H7), 7.14 (1H, H8), 7.05 (1H, H9) , 4.97 (1H, H5), 3.87 (1H ₅ HCl), 3.22, 299 (2H, CH2-11), 1.85 (3H, CH3-5), 2.73, 2.13, 1.82, 1.23 (11H, C6H11). MS (m / z): 337 (M ⁺ ), 336.322.

Example 16: 2-Benzyl-5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole l, 3-dione. The operation is carried out as in the case of Example 1 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole acid. carboxylic acid (2 g, 8.7 mmol) and benzyl isocyanate (1.39 g, 10.4 mmol) in an anhydrous mixture of dimethylsulfoxide (8.5 ml) and acetone (42 ml). White powder (2.50 g, 83%). Mp 170 ° C. IR (KBr): 3342 (NH), 2925 (CH), 1767, 1703 (CO), 1626 (C = C). 1H NMR (DMSO): 11.08 (1H, NH), 7.48 (1H, H10), 7.31 (5H, C6H5), 7.28 (1H, H7), 7.07 (1H, H8); , 6.99 (1H, H9), 4.95 (1H, H5), 4,6O (2H, CH2C6H5), 4.46 (IH ₅ Hl Ia) 3,18,2,72 (2H, CH2-11 ), 1.84 (3HCH3-5). MS (m / z): 345 (M ⁺ ), 344.330.

Example 17: 2- (2-Tolyl) -5-methyl-2,3,6,11,1a-tetrahydro-1H-imidazo [1,5-pyrido [3,4-bl indole-U-dione] The procedure is as in the case of Example 1 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2 g, 8.69 mmol) and 2-tolyl isocyanate (1.39 g, 10.42 mmol) in an anhydrous mixture of dimethylsulfoxide (10 ml) and acetone (42 ml). Purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/5). White powder (2.04 g, 68%). M.p. 232 ° C. IR (KBr): 3354 (NH), 3067 (C = C), 1770, 1712 (CO) 1621 C = C). IH NMR (DMSO): 11.09 (1H, NH), 7.51 (IH HLO _5), 7.39 (1H, H7), 7.30, 7.11 (4H, C6H4CH3), 7.03 ( 1H, H8), 6.99 (1H, H9), 5.05 (1H, H5), 4.57 (1H, H1a), 3.31, 2.82 (2H, CH2-11), 2, 44 (3H, C6H4CH3), 1.83 (3H, CH3-5). MS (m / z): 345 (M ⁺ ), 344.330.

EXAMPLE 18 2- (4-Tolyl-5-methyl-23,5Al) -1,4-tetrahydro-1H-imidazo [1,5-pyrido [3,4-indole-U-dione]

The procedure is as in the case of Example 1 by heating for 16 hours under reflux of a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2g, 8.69 mmol) and 4-tolyl isocyanate (1.39 g, 10.42 mmol) in an anhydrous mixture of dimethylsulfoxide (8.5 ml) and acetone (41.8 ml) .

Yellow powder (1.8 g, 60%). F> 260 ° C. IR (KBr): 3365 (NH), 2975 (CH), 1773, 1708

(CO). 1H NMR (DMSO): 11.04 (1H, NH), 7.51 (1H, H10), 7.31 (1H, H7), 7.10 (4H, C6H4CH3), 7.02 (1H, H8) , 6.99 (1H, H9), 5, O1 (1H, H5), 4.51 (IH ₅ Hl Ia),

3.23.2.87 (2H, CH2611), 2.35 (3H, C6H4CH3), 1.85 (3H, CH3-5). MS (m / z): 345

(M ⁺ ), 344,331,330.

Example 19: 2- (4-anisyl) -5-methyl-2,3,6,11,1-la-tetrahydro-1H-imidazo [1,5-pyrido [3,4-b] indole-U-dione] .

The procedure is as in the case of Example 1 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2 g, 8.7 mmol) and 4-anisyl isocyanate (1.55 g, 10.4 mmol) in an anhydrous mixture of dimethylsulfoxide (8.5 ml) and acetone (42 ml). White powder (2 g, 60%); F> 260 ° C. IR (KBr): 3333 (NH), 2923 (CH), 1770, 1709 (CO), 1633 (C = C) 1H NMR (DMSO) 11.1 O (1H, NH), 7.51 (1H, H, O); 7.31 (4H, C6H4OCH3), 7, O9 (1H, H7), 7, O1 (1H, H8), 6.81 (1H, H9), 5.00 (1H, H5), 4.51 (1H ₅ Hl Ia), 3.75 ( 3H, OCH3), 3.31,2.86 (2H, CH2-11), 1.87 (3H, CH3-5). MS (m / z): 361 (M ⁺ ), 360.346.345.

EXAMPLE 20 2- (4-Fluorophenyl) -5-methyl-2,3,5,6,11,1-la-hexahydro-1H-imidazolinium, 5 ': 1,61 pyrido [3,4-bl indole- l, 3-dione.

The procedure is as in the case of Example 1 by refluxing 18 H with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole -3- carboxylic acid (2 g, 8.68 mmol) and 4-fluorophenyl isocyanate (1.6 g, 10.42 mmol) in an anhydrous mixture of dimethylsulfoxide (9 ml) and acetone (42 ml). Yellow powder (1.96 g, 65%); F = 252 ° C. IR (KBr): 3312 (NH), 1774, 1710 (CO), 1644 (C = C). 1 H NMR (DMSO): 11.10 (NH), 7.47 (1H ₅ H10), 7.41 (1H, H7), 7.29 (4H, C6H4F), 7.03 (1H, H8), 6 , 98 (1H, H9), 4.97 (1H, H5), 4.47 (1H, H18a), 3.27.2.85 (2H, CH2-11), 1.84 (3H, CH3), -5); MS (m / z): 349 (M ⁺ ), 348.334.

Example 21: 2- (2-trifluoromethylphenyl) -5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-diol] b] indole-1,3-dione.

The procedure is as in the case of Example 1 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2 g, 8.68 mmol) and 2-trifluoromethylphenyl isocyanate (1.95 g, 10.42 mmol) in an anhydrous mixture of dimethylsulfoxide (8.5 ml) and acetone (42 ml). It is purified by chromatography on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (75/25). Yellow powder (1.83 g, 83%). F = 190 ^° C IR (KBr): 3368 (NH), 3065 (CH), 1777, 1721 (CO), 1640 C = C). 1H NMR (DMSO): 11.14 (1H, NH), 7.91.7.77 (4H, C6H4CF3), 7.53 (1H, H10), 7.34 (1H, H7), 7.10 ( 1H, H8), 6.99 (1H, H9), 5.03 (1H, H5), 4.58 (1H, H1a), 3.26, 2.88 (2H, CH2-11), 1, 85 (3H, CH3-5). MS (m / z): 399 (M ⁺ ), 398.384.

Example 22: 2- (4-Trifluoromethylphenyl) -5-methyl-2,3,5,11,1-hexahydro-1H-imidazo [1 ', 5': 1,61 pyrido [3,4-bl indole- 1,3-dione. The procedure is as in the case of Example 1 by refluxing 18 H with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2 g, 8.68 mmol) and 4-trifluoromethylphenyl isocyanate (1.95 g, 10.42 mmol) in an anhydrous mixture of dimethylsulfoxide (8.5 ml) and acetone (41.8 ml) ). Purify by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (75/25). White powder (2.08 g, 60%). F = 250 ^° C. IR (KBr): 3360 (NH), 2932 (CH), 1779, 1718 (CO), 1643 (C = C). 1H NMR (DMSO): 11.12 (1H, NH), 7.89.7.7O (4H, C ₆ H ₄ CF ₃ ), 7.51 (1H, H, O), 7.34 (1H, H) , 7.07 (1H, H8), 6.99 (1H, H9), 5.01 (1H, H5), 4.54, (1H, H1a), 3.23, 299 (2H, CH2), - 11), 1.88 (3H, CH3-5). MS (m / z): 399 (M ⁺ ), 398.384.

Example 23: 2-Propyl-5-methyl-9-methoxy-2,3,5,6-hexa-1-hydroxahydro-1H-imidazo [1-5] pyridinol [3,4-bl indole-1.3] -dione.

The procedure is as in the case of Example 1 by heating 16 H at 70 ^° C. of a solution of acidel-methyl-6-methoxy-1,2,3,4-tetrahydro-pyrido [3,4-b] ] Indole-3-carboxylic acid (2g, 7.69 mmol) and n-propyl isocyanate (0.87 ml, 9.23 mmol) in 40 ml of anhydrous dimethylsulfoxide. Beige solid (1.5 g, 60%). Mp 190 ° C.

IR (KBr): 3346 (NH), 2970 (CH), 1767, 1702 (CO). 1H NMR (CDCl3): 7.93

(1H, NH), 7.22 (1H, H7), 6.94 (1H, H1O), 6.85 (1H, H8), 4.94 (1H, H5) 4, 15.3, 49 (2H). , CH2-11), 3.87 (3H, OCH3), 2.77 (1H, 1 an), 3.49, 2.60, 0.02 (7H, C3H7), 1.90

(3H, CH3-5). MS (m / z): 327 (M ⁺ ), 326,313,312.

Example 24: 2-n-butyl-5-methyl-9-methoxy-2,3,5,6J; 1a-hexahydro-1H-imidazo [1 ', 5': 1,61 pyrido [3,4-b] ] indole-1,3-dione. The procedure is as in the case of Example 1 by heating 16 H at 70 ^° C. of a solution of acidel-methyl-6-methoxy-1,2,3,4-tetrahydro-pyrido [3,4-b] ] Indole-3-carboxylic acid (5 g, 19.2 mmol) and n-butyl isocyanate (2.6 ml) in anhydrous dimethylsulfoxide (100 ml). IR (KBr): 3334 (NH), 2931 (CH), 1766, 1696 (CO). 1H NMR (CDCl3): 7.89 (1H, NH), 7.27 (1H, H7), 6.97 (1H, H1O), 6.87 (1H, H8), 4.96 (1H, H5) , 4, 17,3,34 (2H, CH2-11), 3.86 (3H, CH3O), 2.80 (IH ₅ Hl Ia), 3,56,1,63, l, 37, 0, 95 (9H, C4H9), 1.93 (3H, CH3). MS (m / z): 341 (M ^+), 340,327,326. Example 25: 2-Cyclohexyl-5-methyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo], 5 ': 1,6] pyrido [3,4-b] ] indole-1,3 dione.

The procedure is as in the case of Example 1 by heating 16 H at 70 ^° C. of a solution of 1-methyl-9-methoxy-1,2,3,4-tetrahydro-pyrido acid [3,4- b] Indole-3-carboxylic acid (2 g, 7.69 mmol) and cyclohexyl isocyanate (1.18 mL, 9.23 mmol) in anhydrous dimethylsulfoxide (40 mL). Light yellow solid (1.13 g, 40%).

F = 210 ° C. IR (KBr): 3385 (NH), 2939 (CH), 1764, 1692 (CO), 1590 (C = C). RMN IH

(Cdc13): 7.85 (1H, NH), 7.23 (1H, H7), 6.94 (IH HLO _5), 6.84 (1H, H8), 4, 92 (1H, H5), 4 , 08, 3.31 (2H, CH2-11), 3.83 (3H, CH3O), 2.75 (IH Hl Ia _5), 3.89, 2.17, 1.83, 1.61,

1.25 (HH, C6H11), 1.89 (3H, CH3-5). MS (m / z): 367 (M ⁺ ), 366.353.352.

Example 26: 2-N-benzyl-5-methyl-9-methoxy-1,2,3,4-hexahydro-1H-imidazo [1,5] pyridazole [3,4-indol-4-ol] -dione. The procedure is as in the case of Example 1 by heating 16 H at 70 ^° C. of a solution of 1-methyl-6-methoxy-1,2,3,4-tetrahydro-pyrido acid [3,4- b] Indole-3-carboxylic acid (2 g, 7.69 mmol) and benzyl isocyanate (1.23 g, 9.23 mmol) in anhydrous dimethylsulfoxide (40 ml). Beige solid (2.01 g, 70%). F = 208 ° C.

IR (KBr): 3326 (NH), 3029 (CH), 1772, 1710 (CO), 1625 (C = C). 1H NMR (CDCl3): 7.91 (1H, NH), 7.42 (1H, H7), 7.41, 7.3 (5H, C6H5), 6.93 (1H, H1O), 6.83 (1H). , H8),

4.90 (1H, H5), 4.69 (2H, CH2C6H5), 4.16 (1H, H61a), 3.83, (3H, OCH3), 3.32, 2.78

(2H, CH2-11). MS (m / z): 375 (M ⁺ ), 374,361,360.

Example 27: 2-Phenyl-5-methyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [5,5]: 1.61 pyrido [3,4-blindole-1,3-dione] .

One operates as in the case of Example 1 by heating 16 H 70 ⁰ C to a solution of l-methyl-6-methoxy-l, 2,3,4-tetrahydro-pyrido [3,4- b] Indole-3-carboxylic acid (3 g, 11.5 mmol) and phenyl isocyanate (1.5 mL, 13.8 mmol) in dry dimethylsulfoxide (60 mL). Solid beige (2.95, 70%). F> 26o ° C. IR (KBr): 3337 (NH), 3067 (CH), 1770, 1708 (CO), 1626 (C = C). 1H NMR (DMSO): 10.95 (1H, NH), 7.49.7.43 (5H, C6H5), 7.24 (1H, H7), 7.04 (1H, H1O) 6.95 (1H , H8), 5.19 (1H, H5), 3.75 (3H, OCH3), 3.38 (1H, 1H, H1a), 3.28, 288 (2H, CH2-11) 1.91 (3H). , CH3-5). MS (m / z): 361 (M ⁺ ), 347.346.

Example 28: 2- (4-Chlorophenyl) -5-methyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo [5, 1,6] pyrido [3, 4-b] indole-1,3-dione.

The procedure is as in the case of Example 1 by heating 4 H at 70 ^° C. of a solution of 1-methyl-6-methoxy-1,2,3,4-tetrahydro-pyrido [3,4 b] Indole-3-carboxylic acid (5.2 g, 20 mmol) and 4-chlorophenyl isocyanate (3.7 g, 24 mmol) in dry dimethylsulfoxide (100 ml). Yellow solid (4.19 g, 53%). Mp = 252 ° CIR (KBr): 3340 (NH), 3062 (CH), 1772, 1713 (CO), 1631 (C = C). 1H NMR (CDCl3): 7.81 (1H, NH), 3062 (1H, CH), 7.37 (4H, C ₆ H ₄ Cl), 7.18 (1H, H10), 6.90 (1H, H7), 6.82 (1H, H8), 4.96 (1H, H5), 3.79 (3H, OCH3), 3.39 (1H, H1a), 3.29, 287 (2H, CH2-11) 1.89 (3H, CH3-5). MS (m / z): 395 (M ⁺ ), 380.

Example 29: 2- (4-anisyl) -5-methyl-9-methoxy-2,3,5,6,11,11a-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole-1 , 3-dione.

The operation is carried out as in the case of Example 1 by heating at 75 ° C. for 4 hours with a solution of 1-methyl-6-methoxy-1,2,3,4-tetrahydro-pyrido acid [3,4- b] Indole-3-carboxylic acid (5 g, 19.2 mmol) and 4-anisyl isocyanate (3.44 g, 23 mmol) in anhydrous dimethylsulfoxide (100 ml). White solid (3.75 g, 50%). F = 238 ° C. IR (KBr): 3336 (NH), 3069 (CH), 1770, 1713, (CO), 1610 (C = C). 1H NMR (DMSO): 10.93 (1H, NH), 7.3O, 7.14 (4H, C6H4OCH3), 7.21 (1H, H10), 6.83 (1H, H7), 6.71 ( 1H, H8), 4.96 (1H, H5), 3.78, 3.75 (6H, OCH3), 4.29 (1H, H1a), 3.22, 2.79 (2H, H11) 1 , 85 (3H, CH3-5). MS (m / z): 391 (M ⁺ ), 376.

Example 30: 2-n-propyl-5-hydroxymethyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1,5] pyridazole [3,4-b] indole-1,3-dione.

The procedure is as in the case of Example 1 by heating at reflux for 16 hours with an acid-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3-carboxylic acid solution. (2g, 8.13 mmol) and n-propyl isocyanate (0.824 g, 9.75 mmol) in an anhydrous mixture of dimethylsulfoxide (7.9 ml) and acetone (39.1 ml). White solid (1.14g, 45%). F = 174 ° C. IR (KBr): 3435 (OH), 3325 (NH), 2978 (CH), 1758, 1702 (CO). 1H NMR (DMSO): 11.09 (1H, NH), 7.52 (1H, H10), 7.31 (1H, H7), 7.11 (1H, H8), 6.99 (1H, H9) 4.94 (1H, H5), 4.35.4, O4 (2H, CH2OH) 4.29 (1H H1a), 3.21.2.73 (2H, CH2-11). MS (m / z): 313 (M ⁺ ), 312.283.

Example 31: 2 n -butyl-5-hydroxymethyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1-5] pyridinol [3,4-indol-4-dione].

The operation is carried out as in the case of Example 1 by refluxing for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2 g, 8.13 mmol) and n-butyl isocyanate (0.967 g, 9.75 mmol) in an anhydrous mixture of dimethyl sulfoxide (7.9 ml) and acetone (39.1 ml). White solid (1.06g, 40%). IR (KBr): 3417 (OH), 3332 (NH), 2959 (CH), 1753, 1693 (CO), 1624 (C = C). 1H NMR (DMSO): 10.99 (1H, NH), 7.48 (1H, H10), 7.34 (1H, H7), 7.07 (1H, H8), 6.98 (1H, H8) , 4.91 (1H, H5), 4.38.4.01 (2H, 2H, CH ₂ OH) 4.34 (1H, H11) 3,18,2,66 (2H, CH2-11), 3 , 40.1, 53, 1.9, 0.99 (9H, C4H9). MS (m / z): 327 (M ⁺ ), 326,297,296.

Example 32: 2-Cyclohexyl-5-hydroxymethyl-2,3,5,6,11 la-hexahydro-1H-imidazo | ^" 1 ', 5': 1,6] pyrido [3,4-b] indole-1,3-dione The procedure is as in the case of Example 1, by refluxing for 16 hours a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3-carboxylic acid (1.6 g, 6.5 mmol) and cyclohexyl isocyanate (ImI, 7.8 mmol) ) in an anhydrous mixture of dimethylsulfoxide (32 ml) and acetone (32 ml) White powder (0.87 g, 38%) mp = 248 ° C. IR (KBr): 3326 (OH), 3269 (NH) ), 2935 (CH), 1758, 1687 (CO), 1626 (C = C) .1H NMR (CDCl3): 8.85 (1H, NH), 7.43 (1H, H10), 7.35 (7H NMR (CDCl3):? , 30, H7), 7.14 (1H, H8), 7.10 (1H, H9), 5.57 (1H, H5), 4.97 (1H, OH), 4.13 (2H, CH2OH) , 4.08 (1H, H1a1), 3.32, 2.75 (2H, CH2-11), 3.91, 2.10, 1.68, 8.59, 1, 22 (11H, C6H11) MS (m / z): 353 (M ⁺ ), 335.332.

Example 33: 2-Benzyl-5-hydroxymethyl-2,3,5,6,11 H -hexahydro-1H-imidazo [1,5] pyridazole [3,4-b] indole-U-dione. The operation is carried out as in the case of Example 1 by refluxing for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (3g, 12.2mmol) and benzyl isocyanate (1.74ml, 13.3mmol) in an anhydrous mixture of dimethylsulfoxide (12ml) and acetone (60ml). It is purified by chromatography on a silica column, eluting with a mixture of chloroform and methanol (99/1). Beige solid (1.36g, 31%). Mp 190 ° C. IR (KBr): 3346 (OH), 3248 (NH), 1771, 1709 (CO). 1H NMR (CDCl3): 8.94 (1H, NH), 7.49 (1H, H10), 7.44 (5H, C6H5), 7.33 (1H, H7), 7.19 (1H, H8) , 7, O1 (1H, H9), 5.59 (1H, H5) 4.63 (2H, CH2C6H5), 4.37 (2H, CH2OH) 4.11 (IH ₅ Hl Ia) 3,29,2, 81 (2H, CH2-11). MS (m / z): 361 (M ⁺ ), 360.331.

Example 34: 2-Phenyl-5-hydroxymethyl-2,3,5,6,11 1,1-hexahydro-1H-imidazo [br], 5 ': 1,61 pyrido [3,4-bl indole-1, 3-dione.

The operation is carried out as in the case of Example 1 by refluxing for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2 g, 8.13 mmol) and phenyl isocyanate (1 ml, 9.76 mmol) in an anhydrous mixture of acetone (39 ml) and dimethyl sulfoxide (7.9 ml). Beige solid (1.8g, 63%). F = 240 ° C. IR (KBr): 3401 (OH), 2963 (CH), 1710, 1698 (CO), 1625 (C = C). 1H NMR (DMSO): 11.06 (1H, NH), 7.41 (1H, H10), 7.37 (1H, H7), 7.88 (1H, H8), 7.0O (1H, H9); , 7.5O, 743 (5H, C6H5), 4.96 (1H, H5), 4.53 (2H, CH2OH), 4.02 (1H, H1a), 3.25, 2.84 (2H, CH2-11). MS (m / z): 347 (M ⁺ ), 329.

Example 35: 2- (4-Tolyl) -5-hydroxymethyl-2,3,5,11,11a-hexahydro-1H-imidazolyl, 5 ': 1: 61 pyrido [3,4-bl indole -l, 3-dione. The procedure is as in the case of Example 1 by heating 12 H at reflux of a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3-carboxylic acid (4 g, 16.3 mmol) and 4-tolyl isocyanate (2.9 g, 22 mmol) in an anhydrous mixture of dimethyl sulfoxide (15 ml) and acetone. Beige solid (3.45g, 66%). F = 234 ° C. IR (KBr): 3296 (OH), 3088 (CH), 1770, 1697 (CO), 1640 (C = C). 1H NMR (CDCl3): 7.46 (1H, H1O), 7.28 (1H, H7), 7.18 (1H, H8), 7.17 (1H, H9), 7.22. (4H, C6H4CH3), 5, 14,5,03 (2H, CH ₂ OH), 4.19 (1H, H5), 4.34 (lH, Hl), 3,43,2,93 (2H, CH2-11), 1.58 (3H, C6H4CH3). MS (m / z) 361 (M ⁺ ), 360.343.

Example 36: 2- (4-Trifluoromethylphenyl) -5-hydroxymethyl-2,3,5,6,11,1-hexahydro-1H-imidazo], 5 ': 1,6] pyrido [3,4-b] ] indole-1,3-dione.

The procedure is as in the case of Example 1 by refluxing 18 H with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (2g, 8.13mmol) and 4-trifluoromethylphenyl isocyanate (1.4ml, 9.75mmol) in an anhydrous mixture of dimethylsulfoxide (40ml) and acetone (40ml). Brown powder (2.09g, 62%). F = 142 ° C. IR (KBr): 3400 (OH), 2928 (CH), 1775, 1715 (CO), 1616 (C = C). 1 H NMR (DMSO): 11.08 (1H, NH), 7.90, 733 (4H ₅ C ₆ H ₄ CF ₃ ), 7.49 (1H, H 10), 7.35 (1H, H 7), 7 11 (1H, H8), 7.14 (1H, H9), 5.17 (1H, H5), 4.71 (1H, H1a), 3.86 (2H, CH2OH), 3.33.2 , 98 (2H, CH2-11). MS (m / z): 415 (M ⁺ ), 397.386.385.384.

Example 37: 2-N-propyl-5-hydroxymethyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo [5]: 1.61 pyrido [3.4-bl indole -1.3-dione.

The procedure is as in the case of Example 1 by heating at reflux for 18 hours with a solution of 1-hydroxymethyl-6-methoxy-1,2,3,4-tetrahydro-pyrido [3,4-b] acid. indole-3-carboxylic acid (3g, l, 09mmol) and n-propyl isocyanate (1.2ml, 12.8mmol) in an anhydrous mixture of dimethylsulfoxide (11ml) and acetone (52ml). Beige solid (1.75g, 47%). Mp 140 ° C. IR (KBr): 3465 (OH), 3315 (NH), 1762, 1708 (CO). 1H NMR (DMSO): 11.16 (1H, NH), 7.35 (1H, H7), 7.14 (1H, H10), 6.96 (1H, H8), 5.07 (1H, H5). 4.41.4.11 (2H, CH 2 OH), 4.29 (1H, hi), 3.77 (3H, OCH 3), 3.28, 2.81 (2H, CH 2 -11). MS (m / z): 343 (M ⁺ ), 342,313,312.

Example 38: 2-Benzyl-5-hydroxymethyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-h] blindole-1,3-dione. The operation is carried out as in the case of Example 1 by heating at reflux for 18 hours with a solution of 1-hydroxymethyl-6-methoxy-1,2,3,4-tetrahydro-pyrido [3,4- b] indole-3-carboxylic acid (3g, 10.9 mmol) and benzyl isocyanate (1.73 g, 13 mmol) in a mixture of dimethylsulfoxide (11 ml) and acetone (52 ml). White solid (1.61g, 38%). F = 188 ° C. IR (KBr): 3479 (OH), 3322 (CH), 1774, 1717 (CO). 1H NMR (DMSO): 10.93 (1H, NH), 7.29 (1H, H7), 7.02 (1H, H10), 6.99 (1H, H8), 5.11 (1H, H5) , 4.58 (2H, CH2C6H5), 4.08 (2H, CH ₂ OH), 4.33 (lH, Hl), 3.79 (3H, OCH3), 3,31,2,84 (2H, CH2-11). MS (m / z): 390 (M ^+), 361.360.

Example 39: cis-2-n-butyl-5-phenyl-2, 3,5,6,11,1a-hexahydro-1H-imidazo WS: 1.61 pyrido [3,4-indol-1,3-dione. A solution of ethyl cis-1-phenyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3-carboxylate (1,5g, 4,69mmol) and n-butyl isocyanate (0.43 g, 5.15 mmol) in 2-butanone (40 ml) is heated under reflux for 3 hours under nitrogen. After cooling, the precipitate formed is drained, rinsed with diisopropyl ether and dried. White powder (1.28g, 70%). F = 235 ° C. IR (KBr): 3435 (NH), 2948 (CH), 1768, 1704 (CO), 1624 (C = C). 1H NMR (CDCl3): 7.53 (1H, H10), 7.48 (1H, H7), 7.25 (5H, C6H5), 7.13 (1H, H8), 7.88 (1H, H9) 5.71 (1H, H5), 4.28 (1H, H1a1a), 3.40, 2.97 (2H, CH2-11) 3.47, 1.56, 1.28, 8.88 (9H). , C4H9). MS (m / z): 373 (M ⁺ ), 372.296.

Example 40: cis-2-Cyclohexyl-5-phenyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1,5] pyridazolindole-1,3-dione.

The procedure is as in the case of Example 39 by heating under reflux for 3 hours under nitrogen with a solution of cis-phenyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- ethyl carboxylate (1.65 g, 4.69 mmol) and cyclohexyl isocyanate (0.65 g, 5.16 mmol) in 2-butanone (40 ml). White powder (1.44 g, 77%) mp> 260 ° C. IR (KBr): 3463 (NH), 2933 (CH), 1767, 1703 (CO). 1H NMR (CDCl3): 7.50 (1H, H1O), 7.3O (1H, H7), 7.22 (5H, C6H5), 7.11 (1H, H8), 7.08 (1H, H9) 5.71 (1H, H5), 4.23 (IH Hl Ia _5), 3.41, 2.98 (2H, CH2-11), 3,79,2,07,1,73,1,45 ( 11H, C6H11). MS (m / z): 399 (M ⁺ ), 322.

Example 41: 2-Benzyl-5- (sodium phenyl-2-sulfonate) -2,3,5,6,11,1 Hexahydro-1H-imidazo IT, 5 ': 1, 61 pyrido [3,4- bi indole-1,3-dione. The procedure is as in the case of Example 1 by heating at 60 ^° C. to 60 ^° C. of a solution of 1- (2-phenyl-2-sulphonate sodium) - 1,2,3,4-tetrahydro-pyrido [3, 4- b) Indole-3-carboxylic acid (2g, 5.1 mmol) and benzyl isocyanate (0.66ml, 5.35mmol) in anhydrous dimethylsulfoxide (40ml). Yellow powder (2.2g, 85%). F> 250 ° C. IR (KBr): 3365 (NH), 3060 (CH), 1769, 1711 (CO), 1634 (C = C). 1H NMR (DMSO): 10.16 (1H, NH), 7.47 (1H, H10), 7.28 (1H, H7), 7.37 (4H, C6H4SO3Na), 7.07 (1H, H8) , 6.99 (1H, H9), 5.42 (1H, H5), 4.58 (1H, H1a1), 4.49 (2H, CH2C6H5), 3.33, 3.27 (2H, CH2), 11). MS (m / z): 509 (M ⁺ ), 486.458.

Example 42: 2-Phenyl-5- (sodium phenyl-2-sulfonate) -2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1.61 pyrido [3.4-bl indole -1.3-dione.

The procedure is as in the case of Example 1 by heating 16 H at 60 ^° C. of a solution of 1-acid (2-phenyl-2-sulfonate sodium) - 1,2,3,4-tetrahydro-pyrido [3 4- (b) indole-3-carboxylic acid 2g, 5.1 mmol) and phenyl isocyanate (0.66ml, 6.12mmol) in anhydrous dimethylsulfoxide (40ml). Yellow powder (1.7 g, 67%). F> 250 ° C. IR (KBr): 3392 (NH), 3058 (C = C), 1772, 1718 (CO), 1649 (C = C). 1H NMR (DMSO): 10.83 (1H, NH), 7.42 (1H, H10), 7.35 (4H, C6H4SO3Na), 7.28 (1H, H7), 7.17 (1H, H8) , 6.99 (1H, H9), 5.6O (1H, H5), 4.75 (1H, H1a), 3.32, 288 (2H, CH2-11). MS (m / z): 495 (M ⁺ ), 494,472.444.

Example 43: 2- (4-Chlorophenyl) -5- (sodium phenyl-2-sulfonate) -2,3,5,6,11,11a-hexahydro-1H-imidazo [1 ', 5': 1.61 pyrido [3] , 4-b] indole-1,3-dione. The procedure is as in the case of Example 1 by heating 16 H at 70 ^° C. of a solution of 1-acid (sodium phenyl-2-sulfonate) - 1,2,3,4-tetrahydro-pyrido [3 4-chloro-4-chlorophenyl isocyanate (0.6 g, 4 mmol) in anhydrous dimethylsulfoxide (30 ml). Yellow powder (1.27 g, 72%). F> 250 ° C. IR (KBR): 3369 (NH), 3060 (CH), 1776, 1719 (CO), 1633 (C = C). 1H NMR (DMSO): 10.86 (1H, NH), 7.84 (1H, H10), 7.70 (1H, H7), 7.50, 7.33 (1H, 4H, C6H4Cl), 7, 23 (1H, H8), 7.02 (1H, H9), 5.15 (1H, H5), 4.78 (1H, H1a), 3.36.303 (2H, CH2-11). MS (m / z): 529 (M ⁺ ), 528.506. EXAMPLE 2 1-HYDROXY-I ₉ S O ₉ S _{9 9 9} It IIa-hexahydro-IH-imidazo [l ', 5': 1,6] pyrido [3,4-b] indole-3-ones (compounds of general formula III).

The compounds whose structure is indicated in the following Table II were synthesized: TABLE II

Example 44: 1-Hydroxy-2-n-propyl-5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [5,1,6] pyrido [3,4] -b] indole-3-one.

A mixture of 2-n-propyl-5-methyl-2,3,5,6,11,1-la-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole-1,3-dione (2g, 6,73mmol) and sodium borohydride (1,01g, 26,9mmol) in 40 ml of methanol is heated under reflux for 3 hours with stirring. After evaporation to dryness under vacuum, the residue is taken up in 150 ml of water and the suspension is stirred for 15 minutes. The mixture is filtered off and the solid is washed successively twice with diethyl ether, 1 time with tetrahydrofuran and 1 time with diethyl ether. White solid (0.684g, 68%). F> 260 ° C. IR (KBr): 3401 (OH), 3285 (NH), 2965 (CH), 1681 (CO). 1H NMR (DMSO) 10.86 (1H, NH), 7.41 (1H, H10), 7.29 (1H, H7), 7.14 (1H, H8), 6.96 (1H, H9), 5.18 (1H, H1), 4,8O (1H, H5), 3.82 (Hl ₅ Hl la), 2,92,2,68 (2H, CH2-11), 1.35 (3H, CH3 -5), 3.20, 1.52, 0.86 (7H, C3H7). MS (m / z): 299 (M ⁺ ), 284, 281, 266.

Example 45: 1-Hydroxy-2-n-butyl-5-methyl-2,3,5,6,11,1 hexahydro-1H-imidazo | ^" 1 ', 5': 1,6] pyrido [3Ab] indol-3-one.

The procedure is as in the case of Example 44 starting from 2-n-butyl-5-methyl-2,3,5,6,11,1 la, -hexahydro-1H-imidazo [1', 5 ' : 1, 6] pyrido [3,4-b] indolel, 3-dione (1.6 g, 5.14 mmol) and sodium borohydride (1.55 g, 41.1 mmol) in 35 ml of methanol with heating at reflux 2 H 30. White powder (0.96 g, 60%). F = 198 ° C. IR (KBr): 3494 (OH), 3233 (NH), 2968 (CH), 1682 (CO). IH NMR (DMSO): 10.93 (1H, NH), 7.41 (IH HLO _5), 7.29 (1H, H7), 7 O4 (1 H, H8), 6.96 (1H, H9) , 5.16 (1H, H1), 4.78 (1H, H5) 3.80 (1H ₅ H1a), 2.86, 2.62 (2H, CH211), 34, 3.07, 1.52. 0.84 (9H ₅ C ₄ H ₉ ), 1.32 (3H, CH 3 -C). MS (m / z): 313 (M ⁺ ), 298, 295, 280.

Example 46: 1-Hydroxy-2-cyclohexyl-5-methyl-2,3,6,11,1-la-hexahydro-1H-imidazo [1 ', 5': 1,61 pyrido [3,4-b]] indole-3-one. A solution of 2-cyclohexyl-5-methyl-2,3,5,6,11,1-la-hexahydro-1H-imidazo [1, 5: 1,6] pyrido [3,4-b] indole-1 3-dione (1.4 g, 5.04 mmol) in 30 ml of tetrahydrofuran is added dropwise with stirring at -5 ^° C. to a solution of lithium aluminum hydride (1.53 g, 40.3 mmol) in 25 ml. ml of tetrahydrofuran. It is then stirred at 20 ^° C. for 3 h. After cooling to between 0 ° and 5 ° C., 1.6 ml of aqueous sodium hydroxide and 6.5 ml of water are added and the mixture is then stirred for 15 minutes and filtered through celite. The solution is dried over magnesium sulfate and evaporated to dryness. Purify by chromatography on a silica column eluting with a mixture of diethyl ether and petroleum ether (80/20) and then with diethyl ether. Yellow solid (1.10g, 65%). F = 134 ° C. IR (KBr): 3393 (OH), 3341 (NH), 1677 (CO). 1 H NMR (CDCl3): 8.01 (1H, NH), 7.40 (1H, H10), 7.23 (1H, H7), 7.09 (1H, H8), 7.14 (1H, H9), 4.95 (1H, H1), 4.54 (1H, H5), 3.6O (1H, H1a), 3.20.3.04 (2H, CH2-11), 3.49, 1.21 1.24 (1H, C6H11), 1.27 (3H, CH3-5). MS (m / z): 339 (M ⁺ ), 321.

Example 47: 1-Hydroxy-2-benzyl-5-methyl-2,3,5,6,11,1a, -hexahydro-1H-imidazo [1 ', 1,5': 1,61 pyrido [3,4], b] indole-3-one.

The procedure is as in the case of Example 46 by stirring 5 H at 20 ^° C. of a solution of 2-benzyl-5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1α, 5 ', 1,6] pyrido [3,4-b] indole-1,3 diones (2g, 5,8mmol) and lithium aluminum hydride (1.76 g, 46.5 mmol) in 100 ml of tetrahydrofuran. It is purified by crystallization from a mixture of methanol and dichloromethane. White powder (0.93g, 45%). F = 230 ° C. IR (KBr): 3416 (OH), 3257 (NH), 3055 (CH), 1667 (CO). RMN IH (DMSO): 10.96 (1H, NH), 7.42 (1H, H10), 7.3O (5H, C6H5), 7.26 (1H, H7), 7.14 (1H, H8), 6 , 94 (1H, H9), 6.48 (1H, OH), 4.76 (1H, H1), 4.66 (1H, H5), 4.47, 4.18 (2H ₅ CH ₂ C ₆ H _5), 3.37 (IH ₅ Hl Ia), 3,02,2,89 (2H, CH2-11), 1.73 (3H, CH3-5). MS (m / z): 347 (M ⁺ ), 332.329.

Example 48: 1-Hydroxy-2-phenyl-5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1,5] pyridazole [3,4-blindole-U-one] .

The procedure is as in the case of Example 44 from 2-phenyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indolel, 3-dione (Ig; 3mmol) and sodium borohydride (0.46 g, 12 mmol) in 20 ml of methanol with heating at reflux for 3 hours. White solid (0.72g, 70%). F> 250 ° C. IR (KBr): 3417 (OH), 3248 (NH), 3055 (CH), 1666 (CO). 1 H NMR (DMSO): 11.03 (1H, NH), 7.66.7, O7.7, O3 (5H, C6H5), 7.31 (1H, H10), 7.66 (1H, H7), 7.02 (1H, H8), 6.95 (1H, H9), 6.74 (1H, OH), 5.52 (1H, H1), 5.05 (1H, H5), 3.75 (1H, H9), ₅ H1 Ia), 3.04.2, 57 (2H, CH2-11), 1.49 (3H, CH3-5). MS (m / z): 333 (M ⁺ ), 318.315.

Example 49: 1-Hydroxy-2- (2-tolyl-5-methyl-23α) -1-hexahydro-1H-imidazo [1α, 5 ': 1,61-pyrido [3,4-b] indol-3-one.

The procedure is as in the case of Example 46 by stirring for 3 h. at 20 ^° C. of a solution of 2- (2-tolyl) -5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole-1,3-dione (1,2g; 3,47mmol) and lithium aluminohydride (1,05g; 27,76mmol) in 130 ml of tetrahydrofuran. Purify by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (90/10). Yellow solid (0.42g, 35%). F = 216 ° C. IR (KBr): 3400 (OH), 3303 (NH), 3056 (CH), 1689 (CO). 1H NMR (DMSO): 11.02 (1H, NH), 7.46 (1H, H10), 7.3O (1H, H7, O4 (1H, H8), 6.97 (1H, H9), 7, 26,7,2O (4H, C6H4CH3), 5.26 (1H, H1), 4.74 (1H, H5), 3.98 (IH Hl Ia _5), 3.12, 2.85 (2H, CH2 -11), 2.21 (3H ₅ C ₆ H ₄ CH ₃ ), 1.73 (3H, CH ₃ -C), MS (m / z): 347 (M ⁺ ), 332.329.

Example 50: 1-Hydroxy-2-n-propyl-5-phenyl-2, 3,5,6,11,1a-hexahydro-1H-imidazo], 5 ': 1.61 pyrido [3.4- indole-3-one bl. The procedure is as in the case of Example 44 starting from 2-n-propyl-5-phenyl-2,3,5,6,11,1-hexahydro-1H-imidazo [r, 5 ': l , 6] pyrido [3,4-b] indole-1,3-dione (0.74 g, 2 mmol) and sodium borohydride (0.30 g, 7.82 mmol) in 20 ml of ethanol with 3 H heating. reflux. White powder (0.53 g, 70%). F = 250 ° C. IR (KBr): 3435 (OH), 3256 (NH), 3086 (CH), 1674 (CO). 1H NMR (DMSO): 10.28 (1H, NH), 7.53 (2H, H7, H10), 7.23 (7H, C6H5, H8, H9), 5.70 (1H, H5), 5, 40 (1H, H1), 3.43 (lH, Hl), 2,84,2,64 (2H, CH2-5), 2,56,1,98, 0.90 (7H ₅ C ₃ H ₇ ). MS (m / z): 361 (M ⁺ ), 346.343.

Example 51: 1-Hydroxy-2-cyclohexyl-5-phenyl-2,3,5,6J; 1H-hexahydro-1H-imidazo | ^" 1 ', 5': 1,6] pyrido [3,4-b] indole-3-one

The procedure is as in the case of Example 44 from 2-cyclohexyl-5-phenyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole 1,3-dione (1.1 g, 2.75 mmol) and sodium borohydride (0.42 g, 11.1 mmol) in 20 ml of ethanol with reflux heating for 6 minutes. H. White powder (0.60 g, 55%). F = 225 ° C. IR (KBr): 3371 (OH), 3240 (NH), 2933 (CH), 1673 (CO). 1H NMR (CDCl3): 7.53 (1H, H1O), 7.28 (1H, H7), 7.25 (5H, C6H5), 7.20 (1H, H8), 7.16 (1H, H9) 6.15 (1H, OH), 5.69 (1H, H5), 5.22 (1H, H1), 3.86 (1H, H1a), 3.07.2.95 (2H, CH2-11). ), 3.11, 1.76, 1.24 (11H, C6H11). MS (m / z): 401 (M ⁺ ), 386,383,368.

Example 52: 1-Hydroxy-2-n-propyl-5-methyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [5], 5 ': 1.61 pyrido [3, 4-b] indole-3-one. The procedure is as in the case of Example 44 starting from 2-n-propyl-5-methyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [1 '] 5 ': 1, 6] indole-1,3-dione (3g; 9,17mmol) and sodium borohydride (1,4g; 36,7mmol) in 90 ml of ethanol with heating at reflux for 3 h. White solid (1.35g, 45%). F> 260 ° C. IR (KBr): 3245 (OH), 2962 (CH), 1678 (CO). 1H NMR (DMSO): 10.74 (1H, NH), 7.17 (1H, H7), 6.93 (1H, H1O), 6.67 (1H, H8), 6.10 (1H, OH) , 5.16 (1H, H1), 4.76 (1H, H5), 3.76 (3H, OCH3), 3.73 (1H, H1a), 3.20, 2.99 (2H, CH2), 11), 2.6, 1.47, 0.85 (7H, C3H7), 1.31 (3H, CH3-5). MS (m / z): 329 (M ⁺ ), 314, 311,296. Example 53: 1-Hydroxy-2-n-butyl-5-methyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo [1 ', 5': 1,61 pyrido] [3,4-b] indole-3-one.

The procedure is as in the case of Example 44 starting from 2-n-butyl-5-methyl-9-methoxy-2,3,5,6,11,1 hexahydro-1H-imidazo [1 '] 5 ': 1, 6] pyrido [3,4-b] indole-1,3-dione (4.5 g; 13.2 mmol) and sodium borohydride (2 g; 53 mmol) in 100 ml of ethanol with reflux heating for 3 h. White solid (2.7g, 60%).

F = 260 ° C. IR (KBr): 3254 (OH), 2954 (CH), 1678 (CO). 1H NMR (DMSO): 10.73

(1H, NH), 7.17 (1H, H7), 6.92 (1H, H10), 6.68 (1H, H8), 6.08 (1H, OH) 5.16 (1H, H1),

4.77 (1H, H5), 3.76 (3H, OCH3), 3.73 (1H, H61a), 3.28, 2.85 (2H, CH2-11), 3.02, 1.46 , 1.33, 0.89 (9H, C4H9), 1.32 (3H, CH3-5). MS (m / z): 343 (M ⁺ ), 328.325;

Example 54: 1-Hydroxy-2-cyclohexyl-5-methyl-9-methoxy 2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1,61 pyrido [3, 4-b] indole-3-one.

The procedure is as in the case of Example 44 starting from 2-cyclohexyl-5-methyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [1, 5]. 1: 6] pyrido [3,4-b] indole-1,3-dione (2 g; 5.45 mmol) and sodium borohydride (0.82 g; 21.8 mmol) in 40 ml of ethanol with reflux heating for 4 hours. White solid (1.3g, 65%). F> 260 ° C. IR (KBr): 3393 (OH), 3297 (NH), 2921 (CH), 1678 (CO). 1H NMR (DMSO): 10.73 (1H, NH), 7.17 (1H, H7), 6.92 (1H, H1O), 6.67 (1H, H8), 5.92 (1H, OH) , 5.22 (1H, H1), 4.75 (1H, H5), 3.73 (3H, OCH _3), 3.70 (IH ₅ Hl Ia), 2.85 (2H, CH2-11), 3.33, 1.68 (1 H ₅ C ₆ H n), 1.30 (3H, CH3-5). MS (m / z): 369 (M ⁺ ), 354, 351, 336.

Example 55: 1-Hydroxy-2-benzyl-5-methyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo [1 ', 5': 1.61 pyrido [3.4-b] indole-3-one.

The procedure is as in the case of Example 44 starting from 2-benzyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [1, 5]. 1: 6] pyrido [3,4-b] indole-1,3-dione (4g, 10.6 mmol) and sodium borohydride (1.6 g, 42.4 mmol) in 80 ml of ethanol with heating for 3 h.30. White solid (1.6g, 40%). F = 198 ° C. IR (KBr): 3279 (OH), 3028 (CH), 1671 (CO). IH NMR (DMSO): 10.77 (1H, 1H, NH), 7,34,7,24 (5H, C6H5), 7.19 (1H, H7), 6.93 (IH ₅ HLO) 6.68 (1H, H8), 6.28 (1H, OH), 5.05 (1H, H1), 4.84 (1H, H5), 4,6O, 4.13 (2H, CH ₂ C ₆ H _5), 3.86 (IH, Hl Ia ), 3.73 (3H, OCH ₃ ), 2.87.2.65 (2H, CH 2 - 11), 1.37 (3H, CH 3 - 5). MS (m / z): 377 (M ⁺ ), 362, 359.344.

Example 56: 1-Hydroxy-2-phenyl-5-methyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo], 5 ': 1.61 pyrido [3, 4-b] indole-3-one.

The procedure is as in the case of Example 44 starting from 2-phenyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [1, 5]. 1, 6] pyrido [3,4-b] indole-1,3-dione (2.5 g, 6.92 mmol) and sodium borohydride (1.05 g, 27.7 mmol) in 50 ml of ethanol with reflux heating for 2 h. White solid (1.26g, 50%). Mp 190 ° C. IR (KBr): 3371 (OH), 3311 (NH), 2927 (CH), 1683 (CO). IH NMR (DMSO): 10.81 (1H, NH), 7,69,7,33,7, O5 (5H, C6H5), 7.20 (1H, H7), 6.97 (IH ₅ HLO) 6.70 (1H, H8), 6.54 (1H, OH), 5.80 (1H, H1), 4.90 (1H, H5), 4.03 (1H, H18a), 3.74 ( 3H ₅ OCH ₃ ), 2.96, 2.74 (2H, CH 2? 11), 1.41 (3H, CH 3?). MS (m / z): 363 (M ^+), 348, 345, 330.

Example 57: 1-Hydroxy-2- (4-anisyl) -5-methyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1, 61 pyrido [3,4-b] indol-3-one.

The procedure is as in the case of Example 44 starting from 2- (4-anisyl) -5-methyl-9-methoxy-2,3,5,6,11,1-laimidazo [1, 5]. 1,6] pyrido [3,4-b] indole-1,3-dione (2.1 g, 5.37 mmol) and sodium borohydride (0.812 g, 21.48 mmol) in 40 ml of ethanol with refluxing for 3 h. White solid (1.6g, 75%). F = 200 ° C. IR (KBr): 3398 (OH), 3280 (NH), 2967 (CH), 1689 (CO). 1H NMR (DMSO): 10.82 (1H, NH), 7.49, 7, 32.7, 20 (4H, C ₆ H ₄ OCH ₃ ), 6.95 (1H, H 7), 6.85 ( 1H, H1), 6.69 (1H, H8), 6.63 (1H, OH), 5.37 (1H, H1), 5, O1 (1H, H5), 3.75 (IH ₅ Hl Ia) , 3.73, 3.72 (6H, 20CH ₃ ), 2.99, 251 (2H, CH2-11), 1.46 (3H, CH3-5). MS (m / z): 393 (M ⁺ ), 378.375.360.

Example 58: 1-Hydroxy-2- (4-chlorophenyl) -5-methyl-9-methoxy-2,3,5,6,1,1-hexahydro-1H-imidazo], 5 ': 1, Pyrido [3,4-indol-3-one. The procedure is as in the case of Example 44 starting from 2- (4-chlorophenyl) -5-methyl-9-methoxy-2,3,5,6,11,1-la-hexahydro-1H-imidazo [ 5 ', 1, 6] pyrido [3,4-b] indole-1,3-dione (2.2 g, 5.56 mmol) and sodium borohydride (0.84 g, 2 mol) in 40 ml. of ethanol with reflux heating for 3 h 30. White solid (1.65g, 75%). F = 212 ° C. IR (KBr): 3405 (OH), 3297 (NH), 2992 (CH), 1687 (CO). IH NMR (DMSO): 10.86 (1H, NH), 7,7O, 7,4O (4H, C6H4C1), 7.21 (1H, H7), 6.89 (IH HLO _5), 6.80 ( 1H, OH), 6.69 (1H, H8), 5.51 (1H, H1), 5.02 (1H, H5), 3.74 (1H, H17a), 2.99.2, 53 ( 2H, CH2-11), 1.47 (3H, CH3). MS (m / z): 397 (M ⁺ ), 382,379,364.

EXAMPLE 3 2,3,5,6,11,1aα-HEXAHYDRO-1H-IMIDAZO [1 ', 5': 1,6] PYRIDO [3,4-b] INDOLE-3-ONES (compounds of general formula IV ).

The compounds whose structure is indicated in the following Table III have been synthesized: TABLE III

Exemple 59 : cis-2-methyl-5-phenyl-2,3,5,6J l,l la-hexahydro-lH-imidazo WS :1.61 pyridor3.4-blindole-3-one.

Example 59: cis-2-methyl-5-phenyl-2,3,5,6,11,1-hexahydro-1H-imidazo WS: 1.61 pyridor3.4-blindol-3-one.

A solution of cis- (1-phenyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indol-3-yl) -N-methylmethanamine (2 g, 6.87 mmol) and triphosgene (Ig; 4 mmol) in 60 ml of chloroform is stirred for 16 hours at 0 ^° C. 100 ml of ice water are added and the aqueous phase is decanted, which is extracted twice with 40 ml of chloroform. The combined organic phases are dried over magnesium sulphate and concentrated until the beginning of the crystallization. Yellow powder (1.52g, 70%). F> 260 ° C. IR (KBr): 3232 (NH), 2892.2843 (CH), 1688 CO). 1H NMR (CDCl3): 7.43 (1H, H7), 7.31 (1H, H1O), 7.26 (1H, H6), 7.16.70 (H, C6H5), 7.13 ( H, H9,5,46 (1H, H5), 3.86 (IH ₅ Hl Ia), 3,52,3,15 (2H, CH 2 l), 3,10,2,84 (2H, CH2- 11), 2.72 (3H, CH3-2) MS (m / z): 317 (M ⁺ ), 316.302.

Example 60: cis-2-benzyl-5-phenyl-2,3,5,6J; 1a-hexahydro-1H-imidazo [1,5] pyridor3,4-blindol-3-one.

The operation is carried out as in the case of Example 59 by stirring 18 H at 0 ^° C. of a solution of cis- (1-phenyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indol-3-yl) -N-methyl benzylamine (2 g, 5.94 mmol) and triphosgene (0.87 g, 47 mmol) in 70 ml of chloroform. White solid (1.13 g, 3%). F> 260 ° C. IR (KBr): 3240 (NH), 2932, 2860 (CH), 1689 (CO). 1H NMR (CDCl3): 7.46 (1H, H1O), 7.26 (1H, H7), 7.21 (1H, H8), 7.21.7.12 (10H, 2C6H5), 7.04 (1H, H9), 5.51 (1H, H5), 4.54.4, OO (2H, CH2C6H5), 3.88 (1H, H1a), 3.40, 3.38 (2H, CH2- 1), 2.9, 2.80 (2H, CH 2 -11). MS (m / z): 393 (M ⁺ ), 392.

Example 61: cis-2,6-dimethyl-5-phenyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1-5'-1,6] pyridor-3,4-blindol-3-one.

A solution of cis-2-methyl-5-phenyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [r, 5 '] was stirred for 3 hours at a temperature of 25 ^° C. , 6] pyrido [3,4-b] indol-3-one (2g, 6.30mmol), benzyltrimethylammonium bromide (0.437g, 1.9mmol) and iodomethane (3.55g, 25.2mmol) in a mixture of dichloromethane (80 ml) and 50% aqueous sodium hydroxide solution (30 ml). The organic phase is decanted and washed 3 times with 50 ml of water. It is dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). Yellow solid (0.99g, 48%). Mp = 248 ° C. IR (KBr) = 3430 (NH), 2921.2846 (CH), 1698 (CO). 1H NMR (CDCl3): 7.48 (1H, H10), 7.28 (1H, H7), 7.2O (1H, H8), 7.18.7.11) (5H, C ₆ H ₅ ), 7.04 (1H, H9), 5.64 (1H, H5), 3.87 (1H, H1a), 3.43.3,15 (2H, CH2-1), 3.21 (3H, CH3). -6), 3.07, 2.86 (2H, CH2-11), 2.67 (3H, CH3-2). MS (m / z): 331 (M ⁺ ), 316.301.

Example 62: cis-2-benzyl-5-phenyl-6-methyl-2, 3,5,6,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-armol] -3-one.

The procedure is as in the case of Example 61 by stirring 4 H at 25 ° C of a solution of cis-2-benzyl-5-phenyl-2,3,5,6, 1,1,1-la-hexahydro- 1H-imidazo [1α, 5 ': 1,6] pyrido [3,4-b] indol-3-one (2.40 g, 6.30 mmol) benzyltrimethylammonium bromide (0.437 g, 1.9 mol) and iodomethane (3.55 g, 25.2 mmol) in a mixture of dichloromethane (80 ml) and 50% aqueous sodium hydroxide (30 ml). It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). Yellow solid (1.59g, 64%). F = 179 ° C. IR (KBr): 3230 (NH), 2929.2845 (CH), 1698 (CO). 1H NMR (CDCl3): 7.45 (1H, H1O), 7.23 (1H, H7), 7.09 (1H, H8), 7.03 (1H, H9), 7.21.7, 0 ( 10H, 2C6H5), 5.72 (1H, H5), 4.58.3.93 (2H, CH2C6H5), 3.82 (1H, H1a1), 3.34, 3, 10 (2H, CH2-1. 3.25 (3H, CH3-6), 2.98.2.85 (2H, CH2-11). MS (m / z): 407 (M ⁺ ), 392.

EXAMPLE 4 2,3,5,6,11,1aα-HEXAHYDRO-1H-IMIDAZO [1α, 5 ': 1,6] PYRIDO [3,4-b] INDOLES (compounds of the general formula V).

The compounds whose structure is indicated in the following Table IV were synthesized: TABLE IV

(a) monomethane sulfonate

(b) dimethane sulfonate

Example 63: 2-n-propyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [a], 5 ': 1,61pyridor3,4-blastole.

A solution of 2-n-propyl-5-methyl-2,3,5,6,11,1-la-hexahydro-1H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole-1,3-dione (2g, 6,73mmol) in 55 ml of tetrahydrofuran is added dropwise with stirring at 0 ^° C. to a suspension of lithium aluminum hydride (2.02 g, 53.8 mmol) in 55 ml. of anhydrous tetrahydrofuran and then stirred for 3 hours at 20 ^° C. 2.02 ml of water, 2.02 ml of aqueous 2N sodium hydroxide solution and 6.06 ml of water are hydrolyzed by successive additions. The mixture is stirred for 30 minutes, the suspension is filtered through Bchner and the precipitate is washed with tetrahydrofuran. The filtrates are combined and evaporated to dryness under vacuum. Purify by chromatography on a silica column eluting with ethyl acetate. Yellow powder (Ig, 55%). Mp 140 ° C. IR (KBr): 3132 (NH), 3035, 2960 (CH). NMR (CDCl3): 7.78 (1H, NH), 7.44 (1H, H10), 7.3O (1H, H7), 7.13 (1H, H8), 7.07 (1H, H9), 4.06.3.52 (2H, CH2-3), 3.67 (1H, H5), 3.27 (1H, H61a), 3.19, 2.83 (2H, CH2-1), 2 , 75, 2.64 (2H, CH 2 -11), 2.62, 1. 55.0.93 (7H ₅ C ₃ H ₇ ), 1.45 (3H, CH 3 -C). MS (m / z): 269 (M ⁺ ), 254. Example 64; 2-butyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [r, 5 '; 1,1pyrido [3,4-ethanol.

The procedure is as in the case of Example 63 starting from 2-n-butyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole-1,3-dione (1.5 g, 4.8 mol) and lithium aluminum hydride (1.46 g, 38.5 mmol) in 80 ml of tetrahydrofuran with stirring 3 H at 20 ⁰ C. Purified by chromatography on a column of silica eluting with a mixture of chloroform and methanol (90/10). Yellow powder (0.54g, 40%). F = 100 ^° C. IR (KBr): 3248 (NH), 3042, 2960 (CH), 1620 (C = C). 1H NMR (CDCl3): 7.68 (1H, NH), 7.39 (1H, H10), 7.25 (1H, H7), 7.14 (1H, H8), 7.11 (1H, H9). , 3.98 (1H, H5), 3,16,2,82 (2H, CH2-1), 2.96 (1H, H1a), 2.68, 2.57 (CH 2 -11), 2.56, 1.44, 1.27.0.86 (9H, C 4 H 9) 1.05 (3H, CH 3 O). MS (m / z): 283 (M ⁺ ), 268.

Example 65: 2-Cyclohexyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazole, 5 ': 1,61pyridor3,4-blastole.

The procedure is as in the case of Example 63 from 2-n-cyclohexyl-5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole-1,3-dione (0.8 g, 2.37 mmol) and lithium aluminum hydride (0.75 g, 19.8 mmol) in 30 ml of tetrahydrofuran with refluxing 2H. Purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2 and 95/5). Beige solid (0.33g, 45%). F = 166 ° C. IR (KBr): 3221 (NH), 2925 (CH), 1620 (C = C). 1H NMR (CDCl3): 7.99 (1H, NH), 7.37 (1H, H10), 7.2O (1H, H7), 7.12H, H8), 6.98 (1H, H9) , 4.10, 4.39 (2H, CH2-3), 3.67 (1H, H5), 3.39 (1H, H1a), 3.02, 2.73, (2H, CH2-1) , 2.73, 2.55 (2H, CH2-11), 3.12, 2.19, 1.77 (1H, C6H11), 1.35 (3H, CH3-5). MS (m / z): 309 (M ⁺ ), 294.

Example 66: 2-Phenyl-5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1,61 pyrido [3,4-blindole. A) BASE. The procedure is as in the case of Example 63 starting from 2-phenyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole-1,3-dione (Ig, 3.02mmol) and lithium aluminum hydride (0.91g, 24.14mmol) in 50ml of tetrahydrofuran with stirring 2H at 20 ⁰ C. is purified by chromatography on a silica column eluting with ethyl acetate. Yellow solid (0.5g, 55%). F = 216 ° C. IR (KBr): 3408 (NH), 3048 (CH), 2970 (CH), 1612 (C = C). 1H NMR (CDCl3) 7.73 (1H, NH), 7.42 (1H, H10), 7.28 (1H, H7), 7.23 (5H, C6H5), 7.09 (1H, H8), 7.04 (1H, H9), 4.68.3.86 (2H, CH2-3), 3.82 (1H, H5), 3.82.3.64 (2H, CH2-1), 3, 31 (IH ₅ Hl Ia), 2,99,2,73 (2H, CH2-11) 1.53 (3H, CH3-5). MS (m / z): 303 (M ⁺ ), 288.211. B) MONOMETHANESULFONA TE

A basic solution (015 g, 0.49 mmol) and methanesulfonic acid (47.5 mg, 0.49 mmol) in 5 ml of ethanol is stirred for 5 hours at 20 ^° C. The mixture is filtered off with suction, washed with diethyl ether and dried. Orange powder. Mp: 240 ° C, IR (KBr): 3429 (NH), 3181 (NH), 3061 (CH), 1601 (C = C). C) DIMETHANESULFONATE.

A basic solution (50 mg, 0.16 mmol) and methanesulfonic acid (47.5 mg, 0.49 mmol) in 5 ml of ethanol is stirred for 5 hours at 20 ^° C. The mixture is filtered off with suction, washed with diethyl ether and dried. Solid orange. F> 260 ° C. IR (KBr): 3430.3181 (NH), 1601 (C = C).

Example 67: 2- (4-Tolyl) -5-methyl-2,3,5,6,1-la-hexahydro-1H-imidazo [1,5] 1,6-pyridor-4-blindole.

The procedure is as in the case of Example 63 from 2- (4-tolyl) -5-methyl-

2,3,5,6,11,1a-hexahydro-1H-imidazo [r, 5 ': 1,6] pyrido [3,4-b) indole-1,3-dione (1,2g, 3, 47 mmol) and lithium aluminum hydride (1.05 g, 27.76 mmol) in 130 ml of tetrahydrofuran with stirring for 3 h at 20 ^° C. is purified by chromatography on a silica column eluting with a mixture of cyclohexane and acetate of ethyl (90/10). Yellow solid (0.41g, 38%). F = 216 ° C. IR (KBr): 3435 (NH), 2962.2920 (CH), 1615 (C = C). 1H NMR (CDCl3): 7.71 (1H, NH), 7.43 (1H, H10), 7.27 (1H, H7), 7.1O (1H, H8), 7.16 (1H, H9) , 6.91, 6, 41 (4H, C6H4CH3), 4.64, 3.84 (2H, CH2- 3), 3.78 (1H, H5), 3.62.3,31 (2H, CH2-1), 2.98, 2.73 (2H, CH2-11), 2.19 (3H, C6H4CH3) , 1.49 (3H, CH3-5). MS (m / s): 317 (M ⁺ ), 316.302.

Example 68: 2- (4-anisyl) -5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo

The procedure is as in the case of Example 63 from 2- (4-anisyl) -5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1, 5]. 1: 6] pyrido [3,4-b] indole-1,3-dione (2.2 g, 7.7 mmol) and lithium aluminum hydride (2 g, 52.9 mmol) in 240 ml of tetrahydrofuran with stirring for 4 h at 20 ^° C. is purified by chromatography on a column of silica eluting with a mixture of cyclohexane and ethyl acetate (75/25). White powder (0.40g, 20%). F = 242 ° C. IR (KBr): 3411, NH), 2961, 2919 (CH), 1615 (C = C). IH NMR (DMSO): 10.94 (1H, NH), 7.45 (IH HLO ₅₎ 7.37 (1H, H7), 7,1O (1H, H8), 7, O1 (1H, H9) 6 , 90, 6.57 (4H, C6H4OCH3), 4.65, 3.86 (2H, CH2-3), 3.73 (3H, OCH3), 3.82 (1H, H5), 3.67, 3 , 27 (2H, CH2-1), 3.37 (1H, H1a), 3.01.2.66 (2H, CH2-11), 1.56 (3H, CH3-5). MS (m / z): 333 (M ⁺ ), 332.318.

Example 69: 2- (4-Fluorophenyl) -5-methyl-2,3,5,6,1-laa-hexahydro-1H-imidazo [1,5] pyridor3,4-blindole. The procedure is as in the case of Example 63 starting from 2- (4-fluorophenyl) -5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [1, 5 1: 6] pyrido [3,4-b] indole-1,3-dione (1.5 g, 4.3 mol) and lithium aluminum hydride (1.3 g, 34.4 mmol) in 100 ml of tetrahydrofuran with stirring 4 h at 20 ⁰ C. It is purified by chromatography on a silica column eluting with a mixture of petroleum ether and ethyl acetate (85/15). White powder (0.35g, 25%); F = 262 ° C. IR (KBr): 3407 (NH), 3049, 2922 (CH), 1613 (C = C). 1H NMR (CDCl3): 7.73 (1H, NH), 7.44 (1H, H10), 7.27 (1H, H7), 7.12 (1H, H8), 7.05 (1H, H9) , 6.90, ₆ , 41 (4H, C ₆ H ₄ F), 4.63, 3.85 (2H, CH 2 -3), 3.79 (1H, H 5), 3.62, 3.35 ( 2H, CH2-1), 3.31 (1H, H1a1), 2.99.2, 72 (2H, CH2-11), 1.17 (3H, CH3-5). MS (m / z): 321 (M ⁺ ), 320.306. Example 70: 2-Phenyl-5-hydroxymethyl-2, 3,5,6,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-armol.

The procedure is as in the case of Example 63 starting from 2-phenyl-5-hydroxymethyl-2,3,5,6,11,11a-hexahydro-1H-imidazo [1 ', 5': 1 6] pyrido [3,4-b] indole-1,3-dione (0.8 g, 2.3 mmol) and lithium aluminum hydride (0.77 g, 20 mmol) in 40 ml of tetrahydrofuran with 2 H heating. at reflux. Beige powder (0.242g, 33%). Mp 180 ° C. IR (KBr): 3384 (OH), 2900 (CH), 1602 (C = C). 1H NMR (DMSO): 10.65 (1H, NH), 7.41 (1H, H10), 7.33 (1H, H7), 7.02 (1H, H8), 6.95 (1H, H9) , 7.22, 6.71 (5H, C6H5), 5.52 (1H, OH), 5.10, 4.81 (2H, CH2OH), 4.38 (1H, H5), 3.95, 3 , 86 (2H, CH2-3), 3.69, 3.42 (2H, CH2-1), 3.36 (1H, H1a), 2.96.2, 70 (2H, CH2-11), MS (m / z): 319 (M ⁺ ), 318, 302, 301, 242.

Example 71: 2 N -propyl-5-methyl-9-methoxy-2,3,5,6,11,11a-hexahydro-1H-imidazo [r, 5 ': 1,61pyrido [3,4-bluene. The procedure is as in the case of Example 63 starting from 2-n-propyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [r, 5 ': 1,6] pyrido [3,4-b] indole-1,3-dione (0.90, 2.75 mmol), and lithium aluminum hydride (0.84 g, 22mol) in 40 ml of tetrahydrofuran with heating 3 H30 at reflux. Yellow solid (0.29g, 35%). Mp 160 ° C. IR (KBr): 3342.3195 (NH), 2909 (CH), 1627 (C = C). 1H NMR (CDCl3): 7.74 (1H, NH), 7.25 (1H, H7), 6.96 (1H, H10), 6.84 (1H, H8), 4, 11.3, 54 ( 2H, CH3-3), 3.89 (3H, OCH _3), 3,73,3,29 (2H, CH2-1), 3.71 (1H, H5), 3, O7 (IH ₅ Hl Ia) 2.94, 2.80 (2H, CH 2 -11), 2.68, 1.74.0.99 (7H ₅ C ₃ H ₇ ), 1.50 (3H, CH 3 -C). MS (m / z): 299 (M ⁺ ), 298, 284.241.

Example 72: 2-n-butyl-5-methyl-9-methoxy-2.3.5.6.11.11a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-blindole.

The procedure is as in the case of Example 63 starting from 2-n-butyl-5-methyl-9-methoxy-2,3,5,6,11,11a-hexahydro-1H-imidazo [1 ']. , 5 ', 1,6] pyrido [3,4-b] indol-1,3-dione (Ig, 2.93 mmol) and lithium aluminum hydride (0.89 g, 23.4 mmol) in 40 ml of tetrahydrofuran with heating 3 H30 at reflux. Solid orange (0.37g, 40%). F = 146 ° C. IR (KBr): 3192 (NH), 3065, 2930 (CH), 1625 (C = C). RMN IH (CDCl3): 7.66 (1H, NH), 7.17 (1H, H7), 6.89 (1H, H1O), 6.77 (1H, H8), 4.33.37 (2H, CH2-3), 3.82 (3H, OCH _3), 3,66,3,22 (2H, CH2-1), 3.62 (1H, H5), 3.21 (IH ₅ Hl Ia), 3 , 01, 2.84 (2H, CH2-11), 2,72,2,59,1,65, 0.91 (9H ₅ C ₄ H _9), 1.42 (3H, CH3-5). MS (m / z): 313 (M ⁺ ), 312,298,255.

Example 73: 2-Cyclohexyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-armol.

The procedure is as in the case of Example 63 starting from 2-cyclohexyl-5-methyl-

9-Methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [r, 5 ': 1,6] pyrido3,4-b] indole-1,3-dione (0.90 g, 2 45 mmol) and lithium aluminum hydride (0.75 g, 19.6 mmol) in 40 ml of tetrahydrofuran with heating at reflux for 4 hours. Yellow solid (0.38g, 46%). Mp 190 ° C. IR (KBr): 3190 (NH), 3066.2932 (CH), 1625 (C = C). 1H NMR (CDCl3): 7.76 (1H, NH), 7.25 (1H, H7), 6.97 (1H, H1O), 6.84 (1H, H8), 4.21.32 ( 2H, CH 2 - 3), 3.90 (3H, OCH ₃ ), 3.72, 3.37 (2H, CH 2-1) 3.72 (1H, H 5), 3.08 (1H, H 1a), 2,91,2,83 (2H, CH2-11), 2,68,2,41,1,72,1,34 (1 1H, C ₆ H _II), 1, 50 (3H, CH3-5) . MS (m / z): 339 (M ⁺ ), 338,324,256.

Example 74: 2-Benzyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-armol. The procedure is as in the case of Example 63 starting from 2-benzyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [r, 5 ' 1, 6] pyrido [3,4-b] indole-1,3-dione (Ig, 2,66 mmol) and lithium aluminum hydride (0.81 g, 21.3 mmol) in 40 ml of tetrahydrofuran with heating 4 H at reflux. Beige solid (0.48g, 52%). F = 124 ° C. IR (KBr): 3410 (NH), 3027.2923 (CH), 1625 (C = C). 1H NMR (CDCl3): 7.55 (1H, NH), 7.22 (1H, H7), 6.83 (1H, H10), 6.72 (1H, H8), 7.32, 7.27, 7.14 (5H, CH 2 C 6 H 5), 4.03, 457 (2H, CH 2 3), 3.83 (1H, H 5), 3.77 (3H, OCH 3), 3.73, 3.42 ( 2H, CH2-1), 3.40 (2H, CH2C6H5), 3.18 (1H, H1a1), 2.97,2.77 (2H CH2-11), 1.52 (3H, CH3-5) . MS (m / z): 347 (M ⁺ ), 346.332.356.

Example 75: 2-Phenyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazor, 5 ': 1,61pyridor3,4-blastole. The procedure is as in the case of Example 63 starting from 2-phenyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [r, 5 ' 1: 6] pyrido [3,4-b] indole-1,3-dione (Ig, 2.77 mmol) and lithium aluminohydride (0.84, 22.1 mmol) in 40 ml of tetrahydrofuran with heating 1H30 to reflux. Solid brown (0.50g, 55%). F = 206 ° C. IR (KBr): 3246 (NH), 2922 (CH), 1620 (C = C), 1H NMR (CDCl3): 7.62 (1H, NH), 7.21, 6.67, 7.68 (5H); , C6H5), 7.26 (1H, H7), 6.88 (IH HLO ₅₎ 6.75 (1H, H8) 4,67,3,85 (2H, CH2-3), 3.79 (3H, OCH ₃ ), 3.71 (1H, H5), 3.67.3.33 (2H, CH2-1), 3.16 (1H, H17a), 2.97,2.73 (2H, CH2- 11), 1.48 (3H, CH3-5). MS (m / z): 333 (M ⁺ ), 332,318,241.

Example 76: 2- (4-anisyl) -5-methyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4] -blindole.

The procedure is as in the case of Example 63 starting from 2- (4-anisyl) -5-methyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [ 5 ', 1, 6] pyrido [3,4-b] indole-1,3-dione (Ig, 25.5mmol) and lithium aluminum hydride (0.78g, 20mmol) in 40ml of tetrahydrofuran with heating 3H30 at reflux. Beige solid (0.29 g, 32%) mp = 226 ° C. IR (KBr): 3415, (NH), 2959.2994 (CH), 1623 (C = C). 1H NMR (CDCl3): 7.67 (1H, NH), 7.2O (1H, H7), 6.92 (1H, H1O), 6.8O (1H, H8), 6.85.6, 48 ( 4H, C6H4OCH3), 4.66.3.89 (2H, CH2-3) 3.81 (1H, H5), 3.84 (3H, OCH3), 3.75 (3H, OCH3), 3.67, 3.36 (2H, CH2-1) 3.26 (1H, H1a), 2.99.2.74 (2H, CH2-11), 1.25 (3H, CH3-5). MS (m / z): 363 (M ⁺ ), 362.348.241.

Example 77: 2- (4-Chlorophenyl) -5-methyl-9-methoxy-2,3,5,11,11a-hexahydro-1H-imidazo [r, 5 ': 1,61pyrido]; ^"3,4-b" | indole. The procedure is as in the case of Example 63 starting from 2- (4-chlorophenyl) -5-methyl-9-methoxy-2,3,5,6,11,1-la-1H-imidazo [1 ']. , 5 ': 1,6] pyrido [3,4-b] indole-1,3-dione (5g, 12.6 mmol) and lithium aluminum hydride (1.92 g, 50.5 mmol) in 150 ml of tetrahydrofuran with heating at reflux for 4 hours. Beige solid (1.39 g, 30%) F = 100 ^° C. IR (KBr): 3413 (NH), 2945.2969 (CH), 1624 (C = C). 1H NMR (CDCl3): 7.61 (1H, NH), 7.18 (1H, H7), 6.87 (1H, H10), 6.75 (1H, H8), 7.12, 6.38 ( 4H, C6H4Cl), 4.62,3.82 (2H, CH2-3), 3.80 (3H, OCH3), 3.75 (1H, H5), 3.61, 3.29 (2H, CH2- 1), 3.17 (IH ₅ Hl Ia), 2,97,2,69 (2H, CH2-11), 1.48 (3H.CH3-5). MS (m / z): 367 (M ⁺ ), 366,352,241.

EXAMPLE 5 2,3,6,11-TETRAHYDRO-5H-IMIDAZO [1 ', 5': 1,6] PYRIDO [3,4-b] INDOLE-3-ONES (compounds of general formula VI).

The compounds whose structure is indicated in the following Table V were synthesized: TABLE V

Example 78: 2-n-propyl-5-methyl-2,3,6J-1-tetrahydro-5H-imidazo [5 ', 1,6] pyrido [3,4-b ^] indol-3-one.

A solution of 1-hydroxy-2-n-propyl-5-methyl-2, 3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1,2] pyrido [3, 4-b] indol-3-one (6.62 g, 22.1 mmol) and 4-toluenesulphonic acid (2.41 g, 44.2 mmol) in 460 ml of toluene is heated under reflux at 3 H in an apparatus of Dean-Stark. After evaporation of the solvent in vacuo, an oily residue is obtained which is dissolved in dichloromethane. It is washed with an aqueous solution of sodium monosodium carbonate and then with water. It is dried over magnesium sulphate and evaporated to dryness under reduced pressure. It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). Yellow powder (3g, 50%). F = 180 ^° C. IR (KBr): 3241 (NH), 2961 (CH), 1669 (CO). IH NMR (Cdc13): 7.44 (IH HLO _5), 7.32 (1H, H7), 7.16 (1H, H8), 7, O7 (1H, H9), 6, O7 (IH, Hl) , 5.27 (1H, H5), 3.87 (2H, CH2-11), 3.55, 1.61, 0.90 (7H, C3H7), 1.70 (3H, CH3-5). MS (m / z): 281 (M ⁺ ), 266, 238, 210.

Example 79: 2 n -butyl-5-methyl-2,3,6,11-tetrahydro-5H-imidazo [4,5]: 1: 61 pyridol-3,4-blindol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2-n-butyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5 ': 1; 6] pyrido [3,4-b] indole-3-one

(5g, 15.95mmol) and 4-toluenesulphonic acid (6.07g, 31.9mmol) in 350ml of toluene. It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). Beige powder (2.6 g, 55%); Mp 190 ° C. IR (KBr): 3188 (NH), 2957 (CH), 1669 (CO). 1H NMR (CDCl3): 8.77 (1H, NH), 7.43 (1H, H10), 7.14 (1H, H7), 7.11 (2H, H8H9), 6.06 (1H, H1) , 5.24 (1H, H5), 3.61 (2H, CH2-11), 3.81, 1.32.1, 13 (9H, C4H9), 1; 75 (3H, CH3-5). MS (m / z): 295 (M +), 280,238,210.

Example 80: 2-Cyclohexyl-5-methyl-23Al 1-tetrahedro-5H-imidazo [5,5]: 1.61 pyrido [3,4-b] indol-3-one. The procedure is as in the case of Example 78 starting from 1-hydroxy-2-cyclohexyl-5-methyl 2,3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5' 1: 6] pyrido [3,4-b] indole-1,3-dione (0.8 g, 3.35 mmol) and 4-toluenesulfonic acid (0.9 g, 4.7 mmol) in 55 ml of toluene. Purified by chromatography on a silica column eluting with diethyl ether and then with the mixture of diethyl ether and methanol (98/2). Solid orange (0.25g, 22%). Mp 140 ° C. IR (KBr): 3206 (NH), 2927 (CH), 1664 (CO). 1H NMR (CDCl3): 8.91 (1H, NH), 7.43 (1H, H10), 7.32 (1H, H7), 7.15 (1H, H8), 7.16 (1H, H9). , 6.11 (1H, H1), 5.31 (1H, H5) 3.84 (2H, CH2-11), 1.65 (3H, CH3-5). MS (m / z): 321 (M ⁺ ), 306, 239, 238.

Example 81: 2-Benzyl-5-methyl-23Al 1-tetrahedro-5H-imidazo [5,5]: 1.61 pyrido [3,4-b] indol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2-benzyl-5-methyl-2,3,5,6,11,1a-hexahydro-1H-imidazo [r, 5 ' 1, 6] pyrido [3,4-b] indole-1,3-dione (0.80 g, 2.3 mmol) and 4-toluenesulfonic acid (0.9 g, 4.7 mmol) in 60 ml of toluene. It is purified by chromatography on a silica column, eluting successively with the mixtures of dichloromethane and methanol in the proportions of (98/2), (95/5) and (90/10). Solid brown (0.28g, 30%). F = 164 ° C. IR (KBr): 3405 (NH), 2921 (CH), 1690 (CO). IH NMR (Cdc13): 12.85 (1H, NH), 7.87 (2H, H7, H10), 7.58 (1H, H8), 7.39 (5H, C ₆ H _5), 7.17 (1H, H9), 5.22 (1H, H1), 4.86 (2H, CH ₂ C ₆ H _5), 4.70 (1H, H5), 3, O6 (2H, CH2-11), 2 , 32 (3H, CH3-5). MS (m / z): 329 (M ⁺ ). Example 82: 2-n-propyl-5,6-dimethyl-2,3,5,6-tetrahydro-5H-imidazo [r, 5 ': 1,6] pyrido [3,4-b] indole-3 one.

To a solution of 2-n-propyl-5-methyl-2,3,5,6-tetrahydro-5H-imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole-3 One (Ig, 3.56 mmol) in 115 ml of dichloromethane is successively added with vigorous stirring, 45 ml of 50% aqueous sodium hydroxide solution, benzyl tributyl ammonium bromide (0.38 g, 1.07 mmol) and iodomethane ( 2 g, 14.2 mmol). 1H30 is stirred at 0 ^° C. and then 4 H at 20 ^° C. 100 ml of water are added and decanted after stirring. The organic phase is washed 3 times with water and dried over magnesium sulfate. It is evaporated to dryness under reduced pressure and the residue is chromatographed on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). Yellow powder (0.62g, 60%). F = 100 ^° C. IR (KBr): 2962 (CH), 1674 (CO). 1H NMR (CDCl3): 7.44 (1H, H10), 7.29 (1H, H7), 7.19 (1H, H8), 7.14 (1H, H9), 6.14 (1H, H1) 5.25 (1H, H5), 3.79 (2H, CH2-11), 3.62 (3H, NCH3), 3.54, 1.63.0.93 (7H, C3H7), 1.56 ( 3H, CH3-5). MS (m / z): 295 (M ⁺ ), 294.280, 252.237.

Example 83: 2-n-butyl-5,6-dimethyl-2,3,5,6-tetrahedro-5H-imidazo [1 '] 5': 1.61 pyrido [3,4-armol-3-one. The procedure is as in the case of Example 82, using a solution of 2-n-butyl-5-methyl-2,3,5,6-tetrahydro-5H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] -dol-3-one (Ig, 3.39 mmol) in 110 ml of dichloromethane, 50% aqueous sodium hydroxide solution (41 ml), benzyl tributyl ammonium bromide (0.36 g, , 01mmol) and iodoethane (1.92g, 13.5mmol). Purified by chromatography on a silica column, eluting with dichloromethane and then with a mixture of dichloromethane and methanol (99/1). Yellow powder (0.57 g, 55%) mp = 90 ° C. IR (KBr): 2959 (CH), 1676 (CO). 1H NMR (CDCl3): 7.42 (1H, H10), 7.27 (1H, H7), 7.19 (1H, H8), 7.07 (1H, H9), 6.04 (1H, H1). , 5.29 (1H, H5), 3.77 (2H, CH2-11), 3.65 (3H, NCH3), 3.56, 1.59, 1.35.0.95 (9H, C4H9) 1.55 (3H, CH3-5). MS (m / z): 309 (M ⁺ ), 308, 280.221. Example 84: 2-n-propyl-5-methyl-9-methoxy-2,3,6,11-tetrahydro-5H-imidazo [1,5] pyridor-3,4-indol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2-n-propyl-5-methyl-9-methoxy-2,3,5,6,11,1-la-hexahydro-1H- imidazo [r, 5 ': 1, 6] pyrido [3,4-b] indol-3-one (Ig, 3.04 mmol) and 4-toluenesulfonic acid (1.02 g, 6.07 mmol) in 70 ml of toluene. Purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/5). Brown solid (0.34g, 36%). F = 98 ° C. IR (KBr): 3392 (NH), 2962 (CH), 1667 (CO). 1H NMR (CDCl3): 8.74 (1H, NH), 7.2O (1H, H7), 6.88 (1H, H10), 6.77 (1H, H8), 6.66 (1H, H1) , 5.22 (1H, H5), 3.79 (3H, OCH3) 3.76 (2H, CH2-11), 3.55, 1.14, 0.88 (7H, C3H7), 1.64 ( 3H, CH3-5). MS (m / z): 311 (M ⁺ ), 296.

Example 85: 2-n-butyl-5-methyl-9-methoxy-2,3,6,11-tetrahydro-5H-imidazo [1,5] pyridor3,4-blindol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2-n-butyl-5-methyl-9-methoxy-2,3,5,6,11,1 hexahydro-1H- imidazo [r, 5 ': 1,6] pyrido [3,4-b] indol-3-one (2.3 g, 6.7 mmol) and 4-toluenesulfonic acid (0.13 g, 6.7 mmol) in 140 ml of toluene. Purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (98/2) and then (95/5). Solid brown (1,1g, 50%). F = 90 ° C. IR (KBr): 3211 (NH), 2931 (CH), 1667 (CO). 1H NMR (CDCl3): 8.88 (1H, NH), 7.19 (1H, H7), 6.88 (1H, H10), 6.78 (1H, H8), 6.06 (1H, H1) , 5.25 (1H, H5), 3.70 (3H, OCH3), 3.60, 1.61, 1.31, 0.88 (9H, C4H9), 1.65 (3H, CH3-5) . MS (m / z): 325 (M ⁺ ), 310,296,268.

Example 86: 2-Cyclohexyl-5-methyl-9-methoxy-2,3,6,11-tetrahydro-5H-imidazo [1-5]: 1.61 pyridor3.4-blindol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2-cyclohexyl-5-methyl-9-methoxy-2,3,5,6,11,11a-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indol-3-one (Ig, 2.71 mmol), and 4-toluenesulfonic acid (1.03 g, 5.42 mmol) in 70 ml of toluene. Purified by column chromatography silica eluting with a mixture of dichloromethane and methanol (95/5). Brown solid (0.33g, 35%). IR (KBr): 3208 (NH), 2931 (CH), 1664 (CO). 1 H NMR (CDCl3): 8.36 (1H, NH), 7.21 (1H, H7), 6.88 (1H, H10), 6.79 (1H, H8), 6.10 (1H, H1), 5.23 (1H, H5), 4.00.3.85 (2H, CH2-11), 3.79 (3H, OCH3), 3.42, 1.75, 1.35, 1.12 ( 1H, C6H11), 1.62 (3H, CH3-5). MS (m / z): 351 (M ⁺ ), 336, 268, 253.

Example 87: 2-Benzyl-5-methyl-9-methoxy-2,3,6,11-tetrahydro-5H-imidazo [1,5] pyridor3,4-blindol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2-benzyl-5-methyl-9-methoxy-2,3,5,6,1 1,1-la-hexahydrolH-imidazo [l ', 5': 1,6] pyrido [3,4-b] indole-1,3-dione (0.9g, 2.35 mmol) and 4-tolenesulfonic acid (45.4mg, 0.24mmol) in 70 ml of toluene. Purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2). Solid brown (310mg, 34%). F = 78 ° C. IR (KBr): 3213 (NH), 2926 (CH), 1667 (CO). IH NMR (Cdc13): 8.66 (1H, NH), 7.24 (1H, H7), 7.21 (IH HLO _5), 7.18 (5H, C6H5), 7.15 (1H, H8) , 5.98 (1H, H1), 5.21 (1H, H5), 4.80 (2H, CH2C6H5), 4.29 (2H, CH2-1, 3.88 (3H, OCH3), 1, 60 (3H, CH3-5) MS (m / z): 359 (M ⁺ ), 344.

Example 88: 2-Phenyl-5-methyl-9-methoxy-2,3,61-tetrahydro-5H-imidazo [1,5] 1,6-pyridor-3,4-blindol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2-phenyl-5-methyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [ 5 ', 1, 6] pyrido [3,4-b] indol-3-one (Ig, 2.75 mmol) and 4-toluenesulfonic acid (52.4 mg, 0.275 mmol) in 70 ml of toluene. It is purified by chromatography on a silica column, eluting with dichloromethane then with dichloromethane and methanol (95/5). Solid brown (275mg, 29%). F = 128 ° C. IR (KBr): 3245 (NH), 2976 (CH), 1674 (CO). 1H NMR (CDCl3): 8.65 (1H, NH), 7.59, 7.38, 7.18 (5H, C6H5), 7.12 (1H, H7), 6.9O (1H, H10), 6.79 (1H, H8), 6.4651H, H1) 5.35 (1H, H5), 3.91 (2H, CH2-11), 3.89 (3H, OCH3), 1.67 (3H, CH3-5). MS (m / z): 345 (M ⁺ ), 330. Example 89: 2- (4-Chlorophenyl) -5-methyl-9-methoxy-2,3,6,11-tetrahydro-5H-imidazo | ^"R, 5 ': l, 61pyrido [3,4-b] indol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2- (4-chlorophenyl) -5-methyl-9-methoxy-2,3,5,6,11,11a-hexahydro- 1 H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indol-3-one (1,1g, 2,76mmol) and 4-toluenesulfonic acid (53mg, 0.276mmol) in 70 ml of toluene. Purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2). Yellow solid (430mg, 41%). F = 138 ° C. IR (KBr): 3384 (NH), 2929 (CH), 1678 (CO). 1H NMR (CDCl3): 8.40 (1H, NH), 7.55, 7.32 (4H, C6H4Cl), 7.12 (1H, H7), 6.90 (1H, H10), 6.80 ( 1H, H8), 6.43 (1H, H1), 5.26 (1H, H5), 3.86 (2H, CH2-11), 3.80 (3H, OCH3), 1.65 (3H, CH3 -5). MS (m / z): 379 (M ⁺ ), 354.350.

Example 90: 2- (4-anisyl) -5-methyl-9-methoxy-2,3,6,11-tetrahydro-5H-imidazo [1,5] 1,6-pyridor-4-blindol-3-one.

The procedure is as in the case of Example 78 starting from 1-hydroxy-2- (4-anisyl) -5-methyl-9-methoxy-2,3,5,5,11,11a-hexahydro- 1 H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indol-3-one (Ig, 2.54 mmol) and 4-toluenesulfonic acid (48.3 mg, 0.254 mmol) ) in 70ml of toluene. Purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2). Yellow solid (362mg, 38%). F = 128 ° C. IR (KBr): 3247 (NH), 2931 (CH), 1672 (CO). 1H NMR (CDCl3): 8O (1H, NH), 7.44.7.05 (4H, C6H4OCH3), 6.87 (2H, H7, H10), 6.76 (1H, H8), 6.35 ( 1H, H1), 5.31 (1H, H5), 3.86 (2H, CH2-11), 3.79.3.74 (6H, 2 OCH3), 1.65 (3H, CH3-5). MS (m / z): 375 (M ⁺ ), 360.346.

EXAMPLE 6 1-OXO-2,3,5,6,11,1a-HEXAHYDRO-1H-IMIDAZO [1 ', 5': 1, 6] PYRIDO [3,4-b] INDOLE-3-THIONES (compounds of general formula VIl).

The compounds whose structure is indicated in the following Table VI were synthesized:

Exemple 91 : l-oxo-2-cyclohexyl-5-methyl-2, 3,5,6, 11,1 la-hexahydro-lH- imidazo[r,5':l,61pyrido[3,4-blindole-3-thione.

Example 91: 1-Oxo-2-cyclohexyl-5-methyl-2,3,6,6,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-armol-3] -thione.

A solution of acid-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3-carboxylic acid (2 g, 8.69 mmol) and cyclohexyl isothiocyanate (1.3 g, 9.56 mmol) in an anhydrous mixture of dimethylsulfoxide (8 ml) and acetone (40 ml) is heated for 16 hours under reflux with stirring. After evaporation of the solvents under vacuum, 40 ml of water are added to the residue and the mixture is stirred for 30 minutes. The precipitate is filtered off and recrystallized in ethyl acetate. Yellow solid (1.81 g, 59%) mp = 238 ° C. IR (KBr): 3329 (NH), 2931 (CH), 1713 (CO), 1623 (C = C). 1 H NMR (CDCl 3): 7.94 (1H, NH), 7.47 (1H, H10), 7.35 (1H, H7), 7.18 (1H, H8), 7.14 (1H, H9), 4.62 (1H, H5), 4.27 (1H, H18a), 3.37, 2.75 (2H, CH2611), 2.24, 1.70, 1.3611H, C6H11), 1.62. (3H, CH3-5). MS (m / z): 353 (M ⁺ ), 352.338.

Example 92: 1-Oxo-2- (3-trifluoromethylphenyl) -5-methyl-2,3,5,6,11,1-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4] -blindole-3-thione.

The operation is carried out as in the case of Example 91 by heating at reflux for 16 hours with a solution of 1-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (Ig, 4.35 mmol) and 3-trifluoromethylphenyl isothiocyanate (0.97 g, 4.8 mmol) in an anhydrous mixture of dimethylsulfoxide (6 ml) and acetone (30 ml). Yellow powder (1.15g, 64%). F> 260 ° C. IR (KBr): 3355 (NH), 1732 (CO). 1H NMR (DMSO): 10.91 (1H, NH), 7.91.7.78 (4H, C6H4CF3), 7.56 (1H, H10), 7.31 (1H, H7), 7.14 ( 1H, H8), 9.98 (1H, H9), 5.51 (1H, H5), 4.86 (1H, H11a), 3.24, 2.91 (2H, CH2-11), 1, 87 (3H, CH3-5). MS (m / z): 415 (M ⁺ ), 414.400.

Example 93: 1-Oxo-2-methyl-5-hydroxymethyl-2, 3,5,6,11,1a-hexahydro-1H-imidazo [1 ', 5': 1,61pyrido [3,4-armol] 3-thione.

The operation is carried out as in the case of Example 91 by heating at reflux for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] -carboxylic acid (1H). , 5g, 6, 1mmol) and methyl isothiocyanate (0.5ml, 7.3mmol) in an anhydrous mixture of dimethylsulfoxide (6ml) and acetone (30ml). Yellow solid (0.7 g, 38%) mp = 120 ° C. IR (KBr): 3367 (NH), 2932 (CH), 1740 (CO), 1621 (C = C). RMN IH (CDCl3): 8.68 (1H, NH), 7.49 (1H, H10), 7.36 (1H, H7), 7.23 (1H, H8), 7.13 (1H, H9), , 85 (IH, H5), 4.43 (IH ₅ Hl Ia), 4,26,3,91 (2H, CH2OH), 3.33 (3H, CH3-2), 3.47, 2.79 ( 2H, CH211). MS (m / z): 301 (M ⁺ ), 383.270.

Example 94: 1-Oxo-2-cyclohexyl-5-hydroxymethyl-2,3,5,11,11a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-armol-3] -thione.

The operation is carried out as in the case of Example 91 by heating at reflux for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] -3-carboxylic acid. (1.5 g, 6 mmol) and cyclohexylisothiocyanate (ImI, 7.02 mmol) in an anhydrous mixture of dimethylsulfoxide (6 ml) and acetone (30 ml). Beige solid (1.49, 66%). F = 122 ° C. IR (KBr): 3359 (OH), 3199 (NH), 2929 (CH), 1732 (CO). 1H NMR (CDCl3): 8.55 (1H, NH), 7.51 (1H, H10), 7.38 (1H, H7), 7.16 (1H, H8), 7.11 (1H, H9) 5.83 (1H, H5), 4.61 (1H, H1a), 4.33, (2H, CH2OH), 3.44, 2.87 (2H, CH2-11), 2.35, 1.84, 1.38, 0.89 (11H, C6H11). MS (m / z): 369 (M ⁺ ), 351.

Example 95: 1-Oxo-2-benzyl-5-hydroxymethyl-2,3,5,11,11a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-armol-3] -thione.

The procedure is as in the case of Example 91 by refluxing 16 H of a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (3g, 12.2mmol) and benzyl isothiocyanate (1.86ml, 14.04mol) in an anhydrous mixture of dimethylsulfoxide (12ml) and acetone (60ml).

Yellow solid (2.02 g, 44%) F = 100 ^° C. IR (KBr): 3390 (OH), 3226 (NH),

3084 (CH), 1745 (CO). 1H NMR (CDCl3): 8.80 (1H, NH), 7.52 (1H, H10), 7.38 (1H, H7), 7.32 (5H, C6H5), 7.23 (1H, H8) 7.16 (1H, H9), 5.94 (1H, H5), 4.67, 4.04

(2H ₅ CH ₂ OH) 4 ₅ 34 (1H ₅ HCl) ₅ 4 ₅ 16 (2H ₅ CH ₂ C ₆ H ₅ ) ₅ 3.55 ₅ 3 ₅ 01 (2H ₅ CH ₂ -11). SM

(m / z): 377 (M ⁺ ), 359.268.

Example 96: 1-Oxo-2-phenyl-5-hydroxymethyl-2,3,5,11,11a-hexahydro-1H-imidazolor 5 ': 1,61pyridor3,4-b ^" indole-3 -thione. The operation is carried out as in the case of Example 91 by heating at reflux for 16 hours with an acid-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3-carboxylic acid solution. (3g, 12.2mmol) and phenylisothiocyanate (1.55ml, 12.9mmol) in an anhydrous mixture of dimethylsulfoxide (12ml) and acetone (60ml). Yellow solid (2.87g, 67%). F> 260 ° C. IR (KBr): 3419 (OH), 3364 (NH), 3057 (CH), 1748 (CO), 1595 (C = C). 1H NMR (CDCl3): 8.42 (1H, NH), 7.26 (1H, H10), 7.24 (1H, H7), 7.21 (5H, C6H5), 6.92 (1H, H8) , 6.86 (1H, H9), 5.58 (1H, H5), 4.91 (1H ₅ Hl Ia), 4,19,4,04 (2H, CH2OH), 3,19,2,85 ( 2H, CH 2 -11). MS (m / z): 363 (M ⁺ ), 345.254.

Example 97: 1-Oxo-2-benzoyl-5-hydroxymethyl-2, 3,5,6,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4-blindole] 3-thione

The operation is carried out as in the case of Example 91 by heating at reflux for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-pyrido [3,4-b] indole-3- acid. carboxylic acid (3g, 1.2mmol) and benzoyl isothiocyanate (1.86ml, 13.8mmol) in an anhydrous mixture of dimethylsulfoxide (12ml) and acetone (60ml). It is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). Yellow solid. IR (KBr): 3430 (OH), 1742, 1696 (CO). IH NMR (Cdc13): 8.47 (1H, NH), 7.55 (IH HLO _5), 7.39 (1H, H7), 7.45 (5H, C6H5), 7.18 (1H, H8) , 7.06 (1H, H9), 5.35 (1H, H5), 5.15, 4.96 (2H, CH2OH), 4.42 (1H, H1a), 3.76, 2.56 ( 2H, CH 2 -I 1). MS (m / z): 391 (M ⁺ ), 373.268.

Example 98: 1-Oxo-2-methyl-5-hydroxymethyl-9-methoxy-2,3,5,6,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4] -blindole-3-thione.

The operation is carried out as in the case of Example 91 by heating at reflux for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-9-methoxy-pyrido [3,4-b] acid. indole-3-carboxylic acid (3g, 10.9mmol) and methyl isothiocyanate (0.9ml, 12.53mmol) in an anhydrous mixture of dimethylsulfoxide (10.5ml) and acetone (52ml). Yellow solid (1.98g, 55%). F = 134 ° C. IR (KBr): 3368 (OH), 2935 (CH), 1739 (CO), 1627 (C = C). IH NMR (CDCl _3): 8.41 (1H, NH), 7.17 (1H, H7), 6.85 (IH HLO _5), 6.79 (1H H8 _{5) 5} 5 ₅ 74 (1H H5 ₅ ), 4.37 (IH Hl Ia _5), 4.18, 3.86 (2 H ₅ CH ₂ OH), 3.33, 2.75 (2H, CH2-11), 3.26 (3H, NCH _3), 3,33,2,75 (2H, CH2-11). MS (m / z): 331 (M ⁺ ), 313.300.

Example 99: 1-Oxo-2-cyclohexyl-5-hydroxymethyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole-3-thione.

The operation is carried out as in the case of Example 91 by refluxing for 18 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] acid. indole-3-carboxylic acid (2g, 7.06mmol) and cyclohexyl isocyanate (1.17g, 8.33mmol) in an anhydrous mixture of dimethylsulfoxide (8ml) and acetone (40ml). Solid orange (1.89g, 65%). F = 124 ° C. IR (KBr): 3391 (OH), 3931 (CH), 1741 (CO), 1626 (C = C). 1H NMR (CDCl3): 8.42 (1H, NH), 7.24 (1H, H7), 6.9O (1H, H10), 6.88 (1H, H8), 5.81 (1H, H5) , 4.61 (1H, HCl), 4.34, 4.27 (2H, CH ₂ OH), 3.89 (3H, OCH ₃ ), 3.38, 2.77 (2H, CH 2 -11) , 2.25, 1.70, 1.26, 0.88 (1 H ₅ C ₆ H n). MS (m / z): 399 (M ⁺ ), 381.298.

Example 100: 1-Oxo-2-benzyl-5-hydroxymethyl-9-methoxy-2,3,5,6,11,1-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4] -blindole-3-thione

The operation is carried out as in the case of Example 91 by heating at reflux for 16 hours with a solution of 1-hydroxymethyl-1,2,3,4-tetrahydro-6-methoxy-pyrido [3,4-b] acid. indole-3-carboxylic acid (3g, 10.9 mmol) and benzyl isocyanate (1.66ml, 12.5mmol) in an anhydrous mixture of dimethylsulfoxide (10ml) and acetone (52ml). Beige solid (2.08g, 49%). Mp 140 ° C. IR (KBr): 3390 (OH), 3226 (NH), 1746 (CO), 1622 (C = C). 1 H NMR (DMSO): 98 (1H, NH), 7.37 (5H, C6H5), 7.33 (1H, H7), 6.81 (1H, H10), 6.79 (1H, H8). , 5.70 (1H, H5), 5.24, 4.89 (2 H ₅ CH ₂ C ₆ H _5), 5.05 (IH Hl _5), 4 ₅ 06 (2 H ₅ CH ₂ OH) 3 _{5 5} Order 81 (3 H ₅ OCH _3), 3.23 ₅ 2 ₅ 83 (2H CH2-11 _5). MS (m / z): 407 (M ⁺ ), 389.298.

Example 101: 1-Oxo-2-phenyl-5-hydroxymethyl-9-methoxy-2,3,5,11,1a-hexahydro-1H-imidazo [a, 5 ': 1,61pyrido [3,4] -blindole-3-thione The procedure is as in the case of Example 91 by heating under reflux 18 H of a 1-hydroxymethyl-1,2,3,4-tetrahydro-6-methoxy-pyrido acid solution [ 3, 4-b] indole-3-carboxylic acid (2g, 7.25 mmol) and phenyl isothiocyanate (ImI, 8.33 mmol) in a mixture of dimethylsulfoxide (7 ml) and acetone (35 ml). Yellow solid (1.76g, 62%). F> 260 ° C. IR (KBr): 3557 (OH), 3333 (NH), 2953 (CH), 1738 (CO), 1626 (C = C). 1 H NMR (DMSO): 93 (1H, NH), 7.45 (5H ₅ C ₆ H ₅ ), 7.31 (1H, H 7), 7.03 (1H, H, O), 6.75 (1H). , H8), 5.69 (1H, OH), 5.2O (1H, H5), 4.08, 4.04 (2H, CH ₂ OH), 3.76 (3H, OCH ₃ ), 3.02 , 3.32 (2H, CH2-11). MS (m / z): 393 (M ⁺ ), 375.

EXAMPLE 7 TESTS OF HYPNOTIC ACTIVITY IN CHICKS

The effect on the state of alertness of Valentonine, 6-methoxy-harmalan and certain Valentonergic compounds according to the present invention was tested in flesh-type JA657 strain chicks, aged from 10 to 14 days. The animals are subjected to alternating illumination programs comprising 12 hours of darkness (20h to 8h) and 12h of illumination (8h to 20h). The ambient temperature is 25 ° C during the first week of chick rearing and 22 ° C from the second week. During the day, the illumination is provided by a halogen lamp (300 W) placed 30 cm above the floor of the vivarium.

During the tests, the live weight of the chicks ranged between 85 and 120 g. The tests are carried out between 14 and 15h. The chicks are allotted in groups of 3, in identical vivariums of 30 cm x 50 cm x 30 cm. The products tested are administered intramuscularly (IM) in the major pectoralis muscle, either in aqueous solution (for the water-soluble reference compound CF 054 MS), or 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 live weight. The doses administered for the products tested (Valentonergic and reference substances) range from 0.25 μMoles to 5 μMoles per 100 g body weight. The placebo corresponds to 0.2 ml of the solution per 100 g body weight. When ethanol is used in the solvent, its effect was compared beforehand with that of physiological saline (NaCl solution 0.9%) or distilled water. The solutions of the products tested were prepared extemporaneously by successive dilution of a stock solution, obtained from 2.5 to 50 μM of product. exactly weighed, added either of 2 ml for injection (for the compound CF 054-MS), or successively of 0.5 ml of pure ethanol then 1 ml of PEG 400, ultrasonically agitated and then supplemented to 2 ml with 0 5 ml of distilled water for injection (for all the compounds tested and the reference compounds, Ethyl.carbo 7 and CF 019 MS) In tables II to V below are presented the results obtained after IM administration of doses included between 0.25 and 5 μMoles of test products, dissolved in 0.2 ml of distilled water or of ethanol / PEG 400 / water, per 100 g of live weight. For each chick, the injected volume is adjusted, according to real live weight, to 0.2 ml per 100 g live weight, which corresponds to doses of between 1 and 10 mg / kg body weight. The observed parameters are the locomotor activity and the waking state of the chicks during 2 hours, 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 time of adaptation to the device. Five stages of vigilance have been defined:

- stage 1: active watch;

Stage 2: animal lying down, maintaining the head with tonicity, open eye;

Stage 3: light sleep, sleeping animal; closed eye with intermittent opening, motionless posture unmodified by stimulation; - stage 4: deep sleep recumbent: relaxation of the neck, characteristic posture head under the wing or back;

Stage 5: sleep standing: closed eye, motionless, drooping head (catatonic). These five stages roughly correspond to the vigilance and sleep stages defined when examining the electroencephalographic plots in this species. The correspondence is as follows:

• Deep sleep lying down: Stage 4 = "slow wave sleep" (SWS)

• Sleep standing = "sleep-like state I" (SLSI).

Stage 3, asleep, could correspond to phases of REM sleep, with head shaking, for example. Chicks are observed by a trained observer with continuous video monitoring for at least one hour after the animals wake up. Two stimuli were used to confirm observations of chick behavior at regular intervals:

- the noise caused by the impact of a plastic object on the window of the vivarium, comparable to that of the beak of a chick on the glass, corresponds to a moderate stimulus. It is practiced at each observation period (every 5 minutes);

- and the presentation of a metal feeder filled with the usual food, left 2 minutes in the vivarium. It is a powerful stimulus involving vision, hearing and smell. It is practiced every 15 minutes, that is to say 6 times, at least, with each test. Awakening is defined by the appearance of elaborate conscious behavior of research and consumption of food or drink. Sleep Time (TS) is defined as the sum of the duration of the phases of light sleep (stage 3), deep sleep (stage 4) and sleep (stage 5). The Sedation Time, after waking, corresponds to stage 2. The Dulling Time (TA) is equal (within 1 minute) to the time required for the transition from the active sleep state (stage 1) to a non-state. vigil (stages 3, 4 and 5). Sleep Time (TS) is equal to the duration of the sleep period from sleep to wake up. It is expressed in minutes and in difference (minutes) compared to placebo (Δ TS vs placebo). The total sedation time over the period is expressed in% of the period (Sed).

Reference products are the following valentonergic compounds: Ethyl carbo 7 (water insoluble product), CF 054 MS (water soluble mesylate) and CF 019 MS (water soluble mesylate).

Ethyl carto7 CF05ΦMS CF019-MS

For each product tested, several series of measurements were carried out on batches of 3 animals, each indicated value is the average in each batch of 3 chicks. When the number of lots is greater than or equal to 2, the figures given are the average values observed. TABLE VII

Legend: NA: Not Applicable. The animals remain vigilant throughout the observation period

TA: Sleep Time is equal to the time it takes to go from active standby to a non-watchful state.

TS: Sleep time is equal to the duration of the sleep period from sleep to waking.

Results:

In chicks of this age, the duration of a sleep-wake cycle is 20 to

30 minutes during the day. It appears therefore, from the dose of 1 mg / kg that 11 compounds out of 13 tested induce a very strong decrease in locomotor activity attested by a duration of the first sleep greater than 20 minutes. Animals do not sleep after placebo. The number of products tested in this case, at higher doses, increases to 13/13 at doses of 3 and 10 mg / kg, respectively, as evidenced by the examination of the results collected in Tables VIII to X.

There is a positive net dose-response relationship for most tested compounds, with a reduction in the drowsiness period as the dose increases.

Over 90 minutes, the difference in sedation time, expressed as a percentage of the observation period, with that observed after the placebo, is greater 50

% for 10 compounds out of 13 from the dose of 1 mg / kg, for 13 compounds out of 13 to 3 mg / kg and for 13 compounds out of 13 to 10 mg / kg.

The compounds tested are in base form, with the exception of Examples 1 and 2 which are methanesulphonates.

TABLE VIII (Dose: 1 mg / kg)

Claims

1. Imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole of the following general formula (I):

in which : Rl represents a hydrogen atom or an alkoxy group-C _6; R2 represents a hydrogen atom or an alkyl group Ci-C _6, optionally substituted by hydroxy; R3 represents a hydrogen atom, an alkyl group Ci-C _{6 alkyl} optionally substituted by hydroxy, or an aryl group substituted by a sulfonic group; the dotted line is absent and ring ^^ ^ ^{R 6} is ⁰ or ^{R 6} wherein R 6 represents a hydrogen atom, a hydroxy group or an alkyl group Ci-C _6; or the dotted line ring represents a bond and ^{R 6} represents ^{R 6} wherein ^{R 6} represents a hydrogen atom, a hydroxy group or a C ₁ -C ₆ alkyl group; ^{R 4} represents ^ ^x wherein X represents an oxygen or sulfur atom or - ^{R 4} wherein R 4 represents a hydrogen atom or an alkyl group Ci-C _6; R5 represents an alkyl group Ci-C ₆ alkenyl, C ₂ -C _6, cycloalkyl C ₃ -C ₁₂ an aryl group, an arylcarbonyl group or an aralkyl group, the aryl group being optionally substituted by a halogen atom, an alkoxy group or Ci-C ₆ alkyl, Ci-C _{6 alkyl} optionally substituted by one or more halogen atoms; or their mixtures, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof, for its use as a medicament. 2. Imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to claim 1, characterized in that it is chosen from the compounds of general formulas (II) to (VII) below:

wherein R1 to R3 and R5 are as defined in claim 1, or mixtures thereof, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof. 3. Imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to claim 1 or 2, characterized in that it is chosen from the following compounds of formulas 1 to 101:

8

10

11 12

13 14

15 16

17 18

19 20

21 22

23 24

25 26

27 28

29 30

31 32

33 34

35 36

41 42

43 44

45 46

47 48

49 52

53 54

55 56

57 58

63 64

65 66

67 68

69 70

71 72

73 74

75 76

77 78

79 80

81 82

83 84

85 86

87 88

89 90

91 92

93 94

95 96

97 98

99 100

101 4. Imidazo [1α, 5 ': 1,6] pyrido [3,4-b] indole as defined in any one of claims 1 to 3 or compound of formula

39 40

50 51

59 60

61 62 for use as a medicament having myorelaxant, hypnotic, sedative and / or analgesic activity and / or for the treatment of diseases related to disorders of melatonin activity and / or the treatment of depression and psychiatric disorders, particularly stress, anxiety, insomnia, schizophrenia, psychosis or epilepsy, and / or the treatment of travel-related sleep disorders ("jet lag") or neurodegenerative diseases of the system 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, mycoses, glaucoma and / or increased immune resistance and / or prevention of menopausal symptoms, Premenstrual syndromes, effects of aging and sudden infant death. 5. Association of an imidazo [l, 5 ': l, 6] pyrido [3,4-b] indole as defined in any one of claims 1 to 3 or a compound of formula

39 40

50 51

59 60

61 62 and a 5HT ₂ receptor antagonist of the following general formulas (VIII) or (VHIbis)

V I I I V I I I b: in which R 8 represents an alkyl group C1-C12alkyl, phenyl or phenyl (C ₁ -C _6), phenyl optionally substituted by alkoxy-C _6, 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 dashed line is absent. 6. Combination according to claim 5, characterized in that imidazo [l ', 5': l, 6] pyrido [3,4-b] indole or the compound of formula

39 40

50 51

59 60

61 is present in an amount by weight greater than that of the antagonist. 7. Combination according to claim 5 or 6, characterized in that imidazo [l ', 5': l, 6] pyrido [3,4-b] indole or the compound of formula

39 40

50 51

59 60

61 62 has a duration of elimination in the blood less than that of the 5HT ₂ receptor antagonist, advantageously less than 2 hours. 8. Combination according to any one of claims 5 to 7, characterized in that R18 represents a methyl or ethyl group, advantageously the 5HT ₂ receptor antagonist of general formula (VIII) or (VHIbis) is chosen from 6 methoxy-harmalan of the following formula:

or the ethyl analogue of 6-methoxy-harmalan of the following formula:

or their hydrogenated analogues, of formulas

or the compound of formula Ibis

9. A pharmaceutical composition comprising the combination according to any one of claims 5 to 8 and a 5HT ₂ receptor antagonist of general formula (VIII) or (VHIbis):

V I I I V I I I b 1 S in which R 8 represents an alkyl group C1-C12alkyl, phenyl or phenyl (C ₁ -C _6), phenyl optionally substituted by alkoxy-C _6, 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 dashed line is absent as a combination product for a separate use in time for regulate the circadian sleep-wake cycle. 10. Association according to any one of claims 5 to 8 for its use as a medicament. The combination of any one of claims 5 to 8 for use as a medicament for regulating the circadian sleep-wake cycle and / or for the treatment of insomnia, mood disorders such as depression, or anxiety, Parkinson's disease, Alzheimer's disease and diseases or disorders related to deregulation of the circadian sleep-wake cycle. 12. Use of imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole as defined in any one of claims 1 to 3 or the compound of formula

39 40

50 51

59 60

61 62 as a contraceptive in humans or animals and / or to regulate births in ruminant animals. 13. Cosmetic composition comprising an imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole as defined in any one of claims 1 to 3 and a cosmetically acceptable excipient. 14. Imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole of the following general formula III to VI:

wherein R1 to R3 and R5 are as defined in claim 1, or mixtures thereof, or their pharmaceutically acceptable addition salts, or their isomers, enantiomers, diastereoisomers or mixtures thereof. 15. Imidazo [1 ', 5': 1,6] pyrido [3,4-b] indole of formula 2 to 101 below

8

10

12 13

15 16

17 18

19 20

21 22

23 24

25 26

27 28

29 30

31 32

33 34

35 36

37 38

41 42

43 44

45 46

47 48

49 52

53 54

55 56

57 58

63 64

65 66

67 68

69 70

71 72

73 74

75 76

77 78

79 80

81 82

83 84

85 86

87 88

89 90

91 92

93 94

95 96

97 98

99 100

101 16. A process for preparing a compound of general formula (III) according to claim 2 by partial reduction of the compound of formula (II) according to claim 2, preferably by heating with NaBH ₄ or LiAlH _4. 17. Process for the preparation of a compound of general formula (IV) according to claim 2 by cyclization of the compound of general formula (XII) below:

in which R1 to R5 are as defined in claim 1 with phosgene, advantageously triphosgene in chloroform. 18. Process for preparing a compound of general formula (V) according to claim 2 by total reduction of the compound of formula (II) according to claim 2, advantageously using NaBH ₄ or LiAlH ₄ . 19. Process for the preparation of a compound of general formula (VI) according to claim 2, by dehydration of the compound of formula (III) according to Claim 2, advantageously by refluxing in toluene in the presence of 4-toluenesulfonic acid. 20. A pharmaceutical composition comprising an imidazo [1 ', 5': 1, 6] pyrido [3,4-b] indole according to any one of claims 14 or 15 or a combination according to any one of claims 5 to 8 or a compound of formula

11

14 and a pharmaceutically acceptable excipient. 21. Composition according to any one of claims 9 or 20, characterized in that it is intended for oral or intravenous administration, advantageously orally.