FR2770215A1 - New aminomethyl benzo(a) quinolizidine derivatives having alpha 2 adrenergic receptor antagonist activity - Google Patents

Abstract

Benzo(a)quinolizidine derivatives (I) which are 2-substituted by N-substituted aminomethyl are new. Aminomethyl benzo(a)quinolizidine derivatives of formula (I) are new. R1 = H, halo OH or 1-4C alkyl or 1-4C alkoxy (both optionally cyclized); R2 = H or 1-6C alkyl; R3 = H, alkyl sulfonyl or arylsulfonyl (both optionally substituted) or it forms (C=X)-NR4R5or (C=X)-R6; X = O or S; R4, R5 = H, 1-8C alkyl (optionally cyclized) or aryl, aralkyl, aroyl (all aryl groups optionally substituted) or R4 and R5 may be linked by a carbon chain, optionally containing a heteroatom; or R4 = aralkyl or aryloxyalkyl (the aryl part being optionally substituted and the alkyl part being optionally cyclized); R6 = H, 1-10C alkyl (optionally cyclized, optionally containing a heteroatom, optionally incorporating a double bond that may be conjugated with the C=X carbonyl), 1-8C alkoxy (optionally cyclized), optionally substituted aralkoxy or an aromatic or heteroaromatic group optionally substituted by 1-6C alkyl, 1-6C alkoxy, OH, halogens, nitro, CF3, CN, COCH3, thiophene, furan, pyrrole, pyridine and their benzo-fused derivatives, R6 may further contain aromatic cyclic systems such as 2-indanyl, fluorenyl, coumarinyl or benzopyranyl. aryl = phenyl or naphthyl; heteroaryl = 5- or 6-membered ring containing one or more N, O or S, as well as their benzofused derivatives forming pyridine, furan, thiophene, benzoxazine, quinoxaline, quinazoline, benzimidazole or benzopyrazole.

Description

Derivatives of aminomethylbenzo [a] quinolizidine,
their preparation and their application in therapeutics
for neurodegenerative diseases
The present invention relates to novel benzo [a] quinolizidine derivatives, and processes for their preparation.

It also relates to the use of these compounds as a medicament, as well as for the preparation of a medicament used as an α 2 adrenergic receptor antagonist and intended for this purpose to treat neurodegenerative diseases. They are: Parkinson's disease, Alzheimer's disease, Huntington's disease, cognitive and memory disorders, attention and vigilance deficits of the elderly, as well as ischemic and post-ischemic cerebral disorders.

The locus coeruleus has been shown to play a major role in the recovery of altered dopaminergic functions by MPTP administration in monkeys (Mavridis, Neuroscience (1991), 41, 507). Its destruction leads to a reduction in recovery.

Moreover, compounds having an antagonistic action are able to reduce parkinsonian symptoms in monkeys (Colpaert, Brain Res., Bull., (1991), 26,627) or in rats (Colpaert,
Neuropharmacology (1987), 26, 143), and this may be by elevation of dopamine release (Marien,
Noradrenergic Mechanisms in Parkinson's Disease, p.139, (1994), CRC Press, Boca Raton; Marien and Colpaert,
Effect of (+) - efaroxan on mouse striatal dopamine metabolism in vivo. Dopamine 94 - Satellite Meeting of the XIIth Int. Cong. Pharmacology, Quebec City, Canada,
July 20-24, 1994).

In addition, lXIdazoxan, a known α2-antagonist compound, has shown a beneficial effect on the deleterious effects of cerebral ischemia (Gustafson, Exp Brain, Res., (1991), 86, 555, and J. Cereb, Blood Flow Metab. (1990), 10, 885), as well as in progressive supranuclear palsy, also a neurodegenerative disease (Ghika, Neurology, (1991), 41, 986). Compounds with an antagonist activity have also been shown to cause elevation of acetylcholine release at the prefrontal cortex (Tellez, J. Neurochem.

(1997), 68, 778).

Thus a substance that activates the noradrenergic system may have the property of opposing the progression of the degeneration of the neurons involved, by reactivating the systems of the different cerebral localizations, whether they are dopaminergic, cholinergic, or that it calls for the release of growth factors. These compounds are therefore useful in the case of Parkinson-type neurodegenerative diseases or
Alzheimer's and their progression.

Numerous derivatives having α 2 noradrenergic receptor antagonist activity are known, and more particularly those described in patents US 4855308,
EP486385, WO91 / 18886, US4497818, EP524004, and in
J. Med. Chem., 1991, 34, 705.

The compounds of the present invention are distinguished by the fact that it is a benzo [a] quinolizidine substituted in the 2-position by an aminomethyl group substituted with nitrogen to form ureas or amides. These novel products have particularly interesting pharmacological properties which distinguish them from other related antagonists. In particular they are endowed with a central and selective action on the noradrenergic target
(a2), as opposed to the dopaminergic target (D2).

The classical treatment of Parkinson's disease is based on a dopaminergic agonist effect, to compensate for the low levels of endogenous dopamine. So the 1
Dopa has been used for almost 30 years. However, this treatment is not devoid of side effects, as much on the dopaminergic action itself (exhaustion of the effect), as on dyskinesias and peripheral cardiovascular disorders undesirable. A compound having a dopaminergic agonist component may have a presynaptic effect on autoreceptors and in this regard, behave adversely for a desired enhanced release of dopamine.

Dopamine agonists or partial agonists have been shown to have an adverse effect on neuronal survival. Indeed, the survival of dopaminergic neurons seems to be related to the increase of cyclic AMP formation at the level of the second messenger (Michel P. Agid Y, J. Neurochem., (1996), 67, 1633). However, D2 agonists will cause a decrease in cyclic AMP formation as shown by Weiner and Molinoff (1994) (Catecholamines in
Basic Neurochemistry: Molecular, Cellular and Medical Aspects; 5th Ed. GJ Siegal et al., Raven Press, NY. pp 261-281). The compounds of the present invention are devoid of dopaminergic effects and have the distinction of having an excellent passage at the central level, and a very long duration of action. A compound having selectively an α 2 -adrenergic receptor antagonist activity may, by release of norepinephrine, reactivate the intrinsic function of the other neurons, whether dopaminergic or cholinergic. Thus they can oppose the pathological degeneration and slow the progression of the disease, or even stop it.

These compounds have an action selectivity on the central nervous system, and overcome peripheral cardiovascular side effects.

dans laquelle
R1 représente un atome d'hydrogène ou un groupe alkyl
de C1-6 linéaire, ramifié ou cyclique, un groupe
hydroxy ou alcoxy en C1-6, ramifié, linéaire ou
cyclique, un atome d'halogène comme F ou Cl.The present invention particularly relates to the compounds of general formula I

in which
R1 represents a hydrogen atom or an alkyl group
of linear, branched or cyclic C1-6, a group
hydroxy or C1-6 alkoxy, branched, linear or
cyclic, a halogen atom such as F or Cl.

R2 represents a hydrogen atom or an alkyl group
in C1-6
R3 represents a hydrogen atom or constitutes a
(C = X) -NR4Rs and then constitutes a urea or
thiourea as with X = oxygen or sulfur.

R4 and R5 can be independently a hydrogen atom
or a branched linear C18 alkyl group,
cyclic, an aryl, aralkyl, aroyl group. These
aryl groups can be substituted as well.

R4 and R5 may be linked by a carbon chain, optionally incorporating a heteroatom.

R3 may also represent an optionally substituted alkylsulphonyl or arylsulphonyl group.

R3 may be an amino sulfonyl moiety.

R3 represents an acyl or thioacyl group such that (C = X)
R6, where X represents an oxygen or sulfur atom.

R6 may represent hydrogen or a linear or branched or cyclic C1-10 alkyl or alkenyl group, whether or not incorporating a heteroatom, such as oxygen or sulfur, incorporating a conjugated or non-conjugated double bond with the carbonyl C = X.

R6 may also be a linear, branched or cyclic C18 alkoxy group, an optionally substituted aralkoxy group.

R6 also represents an aryl or heteroaryl group, optionally substituted one or more times with a C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, Cl,
F, NO2, CF3, CN, or thiophene, furan, pyrrole, pyridine and their benzofused derivatives.

R6 represents an aralkyl, aryloxyalkyl group, the aryl portion of which may be substituted and wherein the alkyl chain may be linear, branched or cyclic.

R6 may comprise several aromatic or non-aromatic ring systems, such as a 2-indanyl or a fluorenyl, a coumarinyl, a benzopyranyl.

R6 may also represent an aralkenyl or aralkynyl group. The aryl group conjugated with a double bond can be phenyl, naphthyl, polyaromatic as biphenyl or fluorenyl, heteroaromatic and its benzo fused derivatives. This aryl group may be optionally substituted one or more times with C1-81 hydroxyalkyl, C1-8alkoxyalkyl, halogen such as Cl or F, NO2,
CF3, CN, OCF3, OCH2O or form a bicyclic system with a saturated or unsaturated ring, with or without a heteroatom such as O, N or S, thus forming an indole, benzofuran or benzothiophene. The alkenyl group may be optionally substituted with halogens, CN, alkyl, phenyl. The motif (C = X) -R6 thus forms a cinnamoyl group.

If, in particular, the group R3 forms a group (C = X) R6 and R6 represents an aralkenyl group, the group (C = X) R6 is chosen from the cinnamoyl or thiocinnamoyl groups substituted on the aromatic part by one or more alkoxy groups. C14, methylenedioxy, alkylCl6, OH, halogens such as F, Cl.

The term aryl represents a phenyl or naphthyl ring, the term aralkyl meaning an aryl group attached to an alkyl chain of at least one carbon atom and which may be linear, branched or cyclic.

The heteroaromatic group may be a 5- or 6-membered aromatic ring having one or more heteroatoms selected from N, O or S, as well as their benzofused derivatives. They thus form pyridine, furan, thiophene, indole, benzofuran, benzothiophene, benzoxazine, quinoxaline, quinazoline, benzimidazole, benzopyrazole.

The invention also extends to the non-exclusive process for the preparation of these compounds, characterized in that a compound of formula I is prepared with the specifications R1 as indicated above and R2 = R3 = H to form the intermediate of formula II

FORMULA II FORMULA III
Benzylquinolizidin-2-one of formula III is prepared according to Brossi (Helv Chim Acta 1958, 41, 119).

According to the 9-substituent of formula I, the process can be modified.

Thus, intermediate II (R1 = F) is prepared from 3-F phenethylamine by reaction of Pictet-Spengler followed by acid hydrolysis to give 6-tetrahydroisoquinoline. The conversion to 3,4-diisoquinoline is by NBS treatment followed by
NaOH. In the case of intermediate II (R1 = Me), 3,4di-H-6-Me-isoquinoline is described (D. Pitea et al.,
Gazz-Chim. Ital., (1984), 114). The cyanation of the ketone at position 2 is carried out using tosylmethylenonitrile in the presence of potassium tert-butoxide according to the method described by Oldenziel (JOC (1977), 42, 3114). At this stage the separation of the axial and equatorial nitriles is carried out. Each of the nitriles is used in the reduction with sodium borohydride in the presence of NiCl 2 or with aluminum hydride to yield the aminomethyl derivative (II). The reaction of an acid chloride R 6 COCl on this amine in the presence of base is done in a conventional manner.

The intermediate of formula I wherein R 2 = alkyl, R 3 = H, is obtained by reduction (LAH) of the corresponding amide compound formed from I (R 2 = CHO or COCH 3).

The sulphurization of the amide obtained is either in the presence of P2Ss in toluene or by the reagent of
Lawesson. The reaction of these amines with alkyl chlorofomiates provides the corresponding carbamates.

The compounds for which R3 represents (C = X) -NR4Rs are ureas or thioureas are obtained by reacting either an aryl or aroyl isocyanate or isothiocyanate or a carbamoyl or thiocarbamoyl chloride or with acid chlorides, aliphatic, aromatic or cinnamic on amine II (R2 = H or alkyl, R3 = H).

It is also possible to carry out the synthesis to the final compound I with the mixture of the diastereoisomers, and to operate the separation only at the final stage (diastereoisomeric and enantiomeric separation).

The invention also relates to the process for the preparation of a diastereomerically pure compound by chromatographic separation or by crystallization of the diastereoisomeric mixtures obtained during the synthesis at the onset of the chiral center in position 2.

The enantiomerically pure compound thus obtained according to claim 10 may be subjected to separation on a chiral HPLC column.

The basic compound obtained can then be treated with a stoichiometric amount of the acidic agent.

Preferably, the substituent R1 is a hydrogen or a methoxy, ethoxy, methyl, or fluorine and
R2 = H, methyl, ethyl, R3 a COCH3 group, CO-phenyl, CSphenyl, cinnamoyl, optionally substituted with one or more methoxy, F, Cl, and a furaneacryloyl, thienylacryloyl group.

Also preferentially, R3 represents, with the nitrogen to which it is attached, a urea or thiourea group, di, tri or tetra substituted or not by alkyls or aryls.

The present invention also relates to their salified form with inorganic or organic acids.

The invention relates to the different diastereoisomers obtained between the two asymmetric centers in position 2 and 11b.

The invention concerns their enantiomerically pure enigmatic and dextrorotatory form, as well as their addition salt, hydrochloride, sulphate, methanesulphonate, maleate, fumarate, oxalate, tartrate, succinate, citrate.

They correspond to the following compounds
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] propanamide.

 (RS), (SR) -N- [2- <1,3,4,6,7,11b-hexahydro-9-inethoxy-2H-benzo [a] quinolizinyl) methyl] -cyclohexylcarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolinyl) methyl] -isobutanamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -phenyl (&alpha;, &alpha; cyci opropyl) acetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -phenylacetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -9'H-fluorenyl-9 'carboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3-phenylpropanamide.

(RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-indanecarboxamide.)
(RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-chlorophenoxyacetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [a] quinolizin # 1) methyl] -2 ', 3' , 4 ', 5', 6'-pentafluorophenoxyacetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] phenoxyacetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methoxyacetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] acetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -thioacetamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -1'-methoxy-2-naphthalenecarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-pyridinecarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-thiophenecarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-furanecarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-naphthalenecarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -1'-naphthalenecarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-trifluoromethylbenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-methoxybenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-chlorobenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-chlorobenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-chlorobenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-trifluoromethylbenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] benzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -thiobenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] thio cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3-cyclohexylacrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3- (2'-furyl) - acrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-benzofurancarboxamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3- (1'-naphthyl) - acrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3- (2'-naphthyl) - acrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -9'H-fluorenyl-9'-methylenecarboxamide .

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-phenylcinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-coumarinecarboxamide.

(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] - (2'-thienyl) -3- acrylamide
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] - (3'-thienyl) -3- carylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl) methyl] -cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-fluoro-2H-benzo [a] quinolizinyl) methyl] -cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 3', 4 ', 5 ', 6'pentafluorocinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2,3-diphenylacrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2-cyano-3-phenylacrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2-methyl-3-phenylacrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2-fluoro-3-phenylacrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-methoxybenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-methoxybenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-nitrobenzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-trifluoromethylcinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-chlorocinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolinyl) methyl] -3 ', 4', 5'-trimethoxycinnamamide .

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-fluorocinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-chloro-6'-fluoro-cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 4', 5'-trimethoxycinnamamide .

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3 ', 4'-dimethoxycinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-methylcinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 3'-dimethoxycinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 5'-dimethoxycinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl-2 ', 4'-dimethoxycinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-methoxycinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-fluorocinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3 ', 4'-methylenedioxycinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N '- (2-methoxyethyl) thiourea .

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-ter-octylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-tert-butylthiourea.

(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-cyclohexylmethylthiourea
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-butylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-2-phenylethylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-benzylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N ', N'-dimethylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-methylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-isobutylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-cyclohexylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-benzoylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N '- (2'-naphthyl) thiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N '- (1'-naphthyl) thiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-phenylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-phenylurea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-methylurea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N ', N'-dimethylurea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl) methyl] -N'-methyl thiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methyl-benzamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -ethyl-cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methyl-cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methyl-N'-phenylurea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methyl, N'-methylthiourea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] formamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N'-benzoylurea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] -quinolizinyl) methyl] -benzylcarbamate.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N, N'-dimethylsulfonylurea.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] methylsulfonamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -phénylsulfonamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -méthyloxamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -2'H-benzopyran-3'carboxamide .

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] -quinolizinyl) methyl] -3,3-dimethylacrylamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -3'-phénylpropynamide.

 (SS), (RR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [quinolizinyl] methyl-4'-nitrocinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-ethoxy-2H-benzo [α-quinolizinyl) methyl-cinnamamide.

 (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methyl-N ', N'-dimethylthiourea.

The demonstration of the adrenergic 2-adrenergic activity of these compounds is made on the basis of 2-adrenergic receptor binding assays using tritiated 2-methoxy-Idazoxan, [3H] RX821002, as a radioactive ligand of these receptors ( NJ Mallard et al., Br J. Pharmacol (1991), 102, 221).

By way of example, the specific binding values are indicated in the table

<tb><SEP> COMPOUNDS <SEP> BINDING <SEP> a2
<tb> DES <SEP> EXAMPLES <SEP> N <SEP> [3H] <SEP> RX <SEP> 821002
<tb><SEP> IC50 <SEP> (nM) <SEP>
<tb><SEP> 90 <SEP> 1
<tb><SEP> 88 <SEP> 7
<tb><SEP> 78 <SEP> 3
<tb><SEP> 39 <SEP> 12
<tb><SEP> 1 <SEP> 9
<tb><SEP> 68 <SEP> 1,3
<tb><SEP> 18 <SEP> 6
<tb><SEP> 69 <SEP> 8.5
<Tb>
It is thus shown that the compounds of the invention according to general formula I have a strong affinity for adrenergic receptors.

The in vivo study of guanabenz-induced hypothermia reversion (2-agonist) was performed according to the test described by S. C. Dilsaver, Pharmacol. Biochem. Behav.

 (1993), 45 247. This test demonstrates the antagonistic effect of 2 adrenergic receptors of the compounds of the invention, as well as their activity at the central level. The inhibitory capacities are expressed in ED50 which represent the doses producing a significant inhibition against guanabenz induced hypothermia. These values are obtained using the method of J. T. Litchfield and F. Wilcoxon (J. Pharmacol.

Exp. Ther. (1949), 96, 99) calculated only when inhibition occurs in more than 60 k of the animals tested.

The table below reproduces the values obtained intraperitoneally for the products of the present invention.

<tb> COMPOUNDS <SEP><SEP> HYPOTHERMIA <SEP> INDUCED <SEP> BY <SEP> LE
<tb> EXAMPLES <SEP> N <SEP> GUANABENZ <SEP> DE50 <SEP> MG / KG <SEP> (IP)
<tb><SEP> 39 <SEP> 0.47
<tb><SEP> 88 <SEP> 0.34
<tb><SEP> 78 <SEP> 0.91
<tb><SEP> 1 <SEP> 0.56
<tb><SEP> 70 <SEP> 0.63
<tb><SEP> 55 <SEP> 0.53
<tb><SEP> 18 <SEP> 0.98
<tb><SEP> 31 <SEP> 0.71
<Tb>
The compounds of the invention according to the general formula I are thus shown as 2 adrenergic receptor antagonist agents and thereby cause noradrenaline release. They can be used in human therapy and are of interest for the treatment of neurodegenerative diseases and their progression such as Parkinson's disease, Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, cognitive disorders related to age, disorders of attention and memorization, brain damage due to central ischemic accidents.

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula
I and a suitable excipient. The pharmaceutical compositions may conveniently be presented for oral, injectable or parenteral administration, in the form of capsules, capsules, tablets, or injectable preparations, at a dose of 0.1 to 200 mg per day.

The examples which follow illustrate the invention without, however, limiting its scope.

EXAMPLE 1
(PS), (SP) -9-methoxy-1, 3,4,6,7, 1H-hexahydro-2H-benzo
[a] quinoizin-2-nethana'nine
This compound is synthesized in 6 stages
Stage 1
N-formyl-2- [3'-methoxyphenyl] ethylamine
A solution containing 31.2 g of 3-methoxyphenethylamine
(0.206 mol), 35.2 g of ethyl formate (38.3 ml, 0.475 mol, 2.3 eq) in 125 ml of toluene was heated at 800 ° C for 7 h. After evaporation of the solvent, 37 g of an orange oil, which is used as such for the rest of the synthesis (quantitative yield), are isolated.

Rf (CH2Cl2 / MeOH 9/1) = 0.63
1 H NMR (400 MHz, CDCl 3): 8.06 ppm (br s, 1H, NH) 8.00 ppm (s, 1H, CHO); 7.20 ppm (m; 1H; H5 '); 6.77 ppm (m, 3H, H 2, H 4, H 6); 3.74 ppm (s, 3H, OCH 3); 3.35 ppm (m; 2H; CH2N); 2.70 ppm (m, 2H, Ar-CH 2).

Stage 2
6-Methoxy-3,4-dihydroisoquinoline hydrochloride
To a solution of 48.12 g PCl5 (0.23 mol, 1.12 eq) in 160 ml of CH2Cl2 maintained at 0 ° C. in an ice-bath, a solution of 37 g is added dropwise over a period of 2 hours. N-formyl-2- [3'-methoxyphenyl ethyl amine (0.206 mole) in 20 ml of CH 2 Cl 2.
1 H NMR (400 MHz, CDCl 3): 13.76 ppm (br s, 1H, NH) 9.08 ppm (s, 1H, H 1); 7.91 ppm (d, J = 8.5 Hz; 1H)
H8); 7.10 ppm (m, 2H, H5, H7); 3.92 ppm (s; 3H)
OCH3); 3.86 ppm (m; 2H; H3); 3.12 ppm (m; 2H; H4)
Stage 3 9-Ethoxy-1, 3,4,6,7, 1H-hexahydro-2H-benzofluoroquinizin-2-one
A mixture containing 35.3 g of 6-methoxy-3,4-dihydroisoquinoline hydrochloride (0.178 mole) and 44.6 ml of methyl vinyl ketone (37.5 g, 0.535 mole, 3 eq) is heated at 600 ° C. for 3 hours. The reaction medium which takes up in mass is taken up in acetone and then filtered.

The pink-salmon crystals obtained are dried in a desiccator at 550 ° C. (m = 37.18 g, yield = 78 W).

The transition to the free base is done by treatment with
1N NaOH of a solution of the salt in CH2Cl2.

Rf (CH2Cl2 / MeOH 95/5): 0.40
1 H NMR (400 MHz, CDCl 3) (base): 6.98 ppm (d, J = 8.6).
Hz; 1H; H11); 6.74 ppm (dd, J = 8.6 Hz and 2.4 Hz 1H, H10); 6.66 ppm (d, J = 2.4 Hz, 1H, H8); 3.78 ppm (s, 3H, OCH3); 3.49 ppm (m; 1H; H11b); 3.25 ppm (m; 1H; H4eq); 3.20-3.08 ppm (m; 2H; H6 eq,
H7ax); 2.91 ppm (m; 1H; Hleq); 2.56-2.82 ppm (m; 4H; H3ax, H4ax, 6ax, H7eq); 2.48-2.39 ppm (m; 2H H1ax, H3eq).

Stage 4
(RS), (SR) -9-methoxy-1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolin-2-carbonitrile
A solution containing 30.18 g of ketone base (0.13 mol); 25.5 g of tosylmethylisonitrile (0.13 mol of 1 eq); 7.6 ml of ethanol (6.01 g, 0.13 mol, 1 eq) in 600 ml of DME is cooled to 0 ° C. in an ice bath.

After addition of 29.3 g of tBuOK (0.26 mol, 2 eq), the reaction mixture is kept at 0 ° C. for 1 h 30 and then at ambient temperature for 1 h. The solution is then heated at 900 ° C. for 2 hours and then left at room temperature overnight.

The solid residues are removed by filtration and the solution is evaporated to dryness. The brown oil obtained is separated by chromatography on a silica column (eluent petroleum ether / AcOEt 5/5).

13 g of the diastereoisomer A (CN
equatorial): rdt = 41%
2.8 g of a mixture fraction of the two
diastereoisomers: rdt = 9%
6.16 g of diastereoisomer B (axial CN)
rdt = 19.5 k, ie an overall yield of 69.5 W cyanine derivatives. diastereoisomer A ((RS), (SR))
Rf (AcOEt / MeOH 95/5): 0.71
1 H NMR (200 MHz, CDCl 3): 7 ppm (d, J = 8.5 Hz, 1H)
H11); 6.70 ppm (dd, J = 8.5 and 2.4 Hz, 1H, H10) 6.60 ppm (d, J = 2.4 Hz, 1H, H8); 3.75 ppm (s; 3H)
OCH3); 3.18-2.86 ppm (m; 4H; 4a, 6a, 7a, 11b); 2,732.22 ppm (m, 4H, H1a, H2, H7b, H6b), 2.11-1.88 ppm (m 2H, H3a, H3b); 2.65 ppm (m; 1H; H1b).

13 C NMR (50.32 MHz, CDCl 3); 125.7 ppm (C11); 113.5 ppm
(C8); 112.2 ppm (C10) 61.5 ppm (ClIb); 55.2 ppm (OCH3 and C4); 54.8 ppm (C6); 34.4 ppm (C1); 29.6 ppm (C7) 28.7 ppm (C3); 27.4 ppm (C2). diastereoisomer B ((RR), (SS))
Rf (AcOEt / MeOH 95/5) 0.49 Rt4NH (200 MHz CDCl3): 7.07 ppm (d, J = 8.5Hz 1H, H11); 6.74 ppm (dd; J = 8.5 Hz and 2.4 Hz; 1H
H10); 6.64 ppm (d, J = 2.4 Hz, 1H, H8); 3.77 ppm
(s; 3H; OCH3); 3.54 ppm (d; J = 11.5 Hz; 1H)
Hllb); 3.28-2.91 ppm (m, 4H, H2, H4a, H6a, H7a) 2.80-2.45 ppm (m; 4; H1a, H4b, H6b, H7b); 2.00 ppm
(m; 2H; H3a, H3b); 1.70 ppm (m; 1H; H1b).

13 C NMR (50.32 MHz, CDCl 3): 125.7 ppm (C 11); 113.5 ppm
(C8); 112.2 ppm (C10); 58.8 ppm (Cllb); 55.2 ppm
(OCH3); 52.2 ppm (C4 and C6); 33.4 ppm (C1); 29.7 ppm
(C7); 27.6 ppm (C3); 26.3 ppm (C2)
Stage 5
(RS), (SR) -9-methoxy-1, 3,4,6,7, 1H-hexahydro-2H-benzofluoroquinoline-2-methanamine
A solution containing 9 g of the diastereoisomeric nitrile A of the previous stage (37 mmol) in 300 ml MeOH is cooled to OOC. 44.14 g NiCl 2, 6H 2 O (186 mmol, 5 eq) are added and the mixture is stirred for 15 mm at 0 ° C. before the slow addition of 11.24 g NaBH 4 (300 mmol, 8 eq). The rate of addition of NaBH4 must be such that the temperature of the reaction mixture is kept below 5 C.

Stirring is maintained at 0 ° C. at room temperature for 2 h 30 minutes. The mixture is then evaporated to dryness and then the black residue is taken up in CH 2 Cl 2 / 1N NaOH. Both phases are filtered on cellite. After abundant rinsing with CH 2 Cl 2, the organic phase is separated by decantation and then dried over MgSO 4.

After evaporation, 9 g of a yellow oil are obtained (yield = 87 k)
1 H NMR (400 MHz, CDCl 3): 7.20 ppm (d, J = 8.4 Hz 1H, H 11); 6.71 ppm (d, JJ = 8.4 Hz, 1H, H10); 6.62 ppm (s, 1H, H8); 3.77 ppm (s, 3H, OCH3); 3.20-2.92 ppm (m; 4H; H4a, H6a, H7a, H11b); 2.72-2.62 ppm (m 3H, H7b, CH2NH2); 2.51 ppm (m; 1H; Hla); 2.42-2.30 ppm (m; 2H; H4b, H6b); 1.80 ppm (m; 1H; H3a); 1.59 ppm (m; 1H; H2); 1.33 ppm (m; 1H; H3b); 1.08 ppm
(m; 1H; H1b).

Stage 6
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -benzamide
113 μl of benzoyl chloride (137 mg, 0.97 mmol, 1.2 eq) are added to a solution of 200 mg of the diastereoisomeric amine A of the previous stage (0.81 mmol) and 166 l of pyridine (162 mg 2.05 mmol, 2.5 eq) in 5 ml of THF. After 24 hours of reaction at room temperature, the solvent is evaporated. The residue is taken up in CH 2 Cl 2 and then washed with 1N NaOH. The organic phase is dried on
MgSO4, filtered and then evaporated to dryness. After purification by chromatography on a silica column (eluent CHCl 3 / MeOH / NH 4 OH 95/5/1), 150 mg of pure compound are isolated.

Yld = 53 k
Rf (CH 2 Cl 2 / MeOH / NH 4 OH 90/102): 0.53 tof (oxalate): 112 C
1 H NMR (200 MHz, DMSO d 6) (oxalate) 8.61 ppm (t;
NH): 7.87 ppm (m, 2H, H₂, H6); 7.42-7.58 ppm (m 3H; H3 ', H4', H5 '); 7.25 ppm (d, J = 8.6 Hz, 1H H11); 6.75-6.89 ppm (m; 2H; H8, H10); 4.13 ppm (d
J = 10 Hz; 1H; Hllb); 3.75 ppm (s, 3H, OCH 3); 3,582.87 ppm (m, 8H, H1a, H3a, H4a, H4b, H6a, H6b, H7a,
H7b); 2.55 ppm (m; 1H; H2); 1.88 ppm (m; 1H; H3b) 1.45 ppm (m; 1H; H1b).

Elemental analysis:
Theoretical: C (65.44), H (6.41), N (6.36)
Experimental: C (64.89), H (6.21), N (6.18)
In a similar manner to Example 1, but using the corresponding reagents, the compounds of formula 1 are obtained and are listed by the examples in table 1 following TABLE 1

<tb> Example <SEP> Ri <SEP> R2 <SEP> R3 <SEP> T0Fusion <SEP> Analysis <SEP> leinerair.
<Tb>

<SEP> N0 <SEP><J \ <SEP> O \ <SEP> 0 \ <SEP> Salt
<tb><SEP> 0a <SEP> 1680C <SEP> Theoretical <SEP>: <SEP> C <SEP> (60,70), <SEP> H <SEP> read <SEP> N (5,90)
<tb><SEP> 2 <SEP> OCH3 <SEP> H <SEP> ffi <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP><60,28),<SEP> H <SEP> (5.56), <SEP> N <SEP> (5.68)
<tb><SEP> 3
<tb><SEP> O / \ o <SEP> 1200C <SEP> Theoretical <SEP> C <SEP> In <SEP> H <SEP> (5,73), <SEP> N (5,90)
<tb><SEP> 4 <SEP> OCH3 <SEP> H <SEP> - <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (61,10), <SEP> H <SEP > (5.84), <SEP> N <SEP> (5.4e)
<tb><SEP>OoCH><SEP> l400C <SEP> Theoretical <SEP>: <SEP> C <SEP> (66,26), <SEP> H <SEP> L <SEP> U <SEP> m <SEP> N <SEP> (6.72)
<tb><SEP> s <SEP> OCH3 <SEP> H <SEP>''<SEP> Hydrochloride <SEP> Experimental <SEP>: <SEP> C <SEP> (66,99), <SEP> H <SEP> (7.34), <SEP> N <SEP> Y <SEP> V
<tb><SEP> oCH, <SEQ> 1120C <SEP> Theoretical <SEP>: <SEP> C <SEP> rd <SEP> (63,82), <SEP> rd <SEP> raw <SEP> H <SEP> (6.43), <SEP> rd <SEP> N (5.95)
<tb><SEP> 6 <SEP> OCH3 <SEP> H <SEP> o <SE> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (63,13), <SEP> H <SEP> (6,21), <SEP> N <SEP> (5,84)
<tb><SEP> H0, <SE> 1280C <SEP> Theoretical <SEP>: <SEP> C <SEP> (63,82), <SEP> H <SEP> (6,43), <SEP> N (5.95)
<tb><SEP> 7 <SEP> OCH3 <SEP> c <SEP> Oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (63,35), <SEP> H <SEP> (6, 50), <SEP> N <SEP> (5.37)
<tb><SEP> 2i00C <SEP> Theoretical <SEP>: <SEP> C <SEP> (59,05), <SEP> H <SEP>(5,35>,<SE> N <SEP> (5 , 51)
<tb><SEP> s <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> cr <SEP> C <SEP> (59,03), <SEP> H <SEP > (5.25), <SEP> N <SEP> (5.48)
<tb><SEP> 1380C <SEP> Theoretical <SEP>: <SEP> rl <SEP> C <SEP> (59,05), <SEP> H <SEP> (5,35), <SEP> N ( 5,5l)
<tb><SEP> 9 <SEP> OCH3 <SEP> H <SEP> a <SEP> r (<SEP> Experimental <SEP>: <SEP> C <SEP> (59,34), <SEP> H <SEP> (5.43), <SEP> N <SEP> (5.31)
<Tb>

<SEP> 1430C <SEP> Theoretical <SEP> C <SEP> (68,56), <SEP> H <SEP> (6,16), <SEP> N (5,71)
<tb><SEP> 10 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (68,02), <SEP> H <SEP> (6, 10), <SEP> N <SEP> (5.31)
<tb><SEP> o <SEP>, <SEP>'<SEP> 1290C <SEP> Theoretical <SEP>: <SEP> C <SEP> (68,56), <SEP> H <SEP> read <SEP > N (5.71)
<tb><SEP> It <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (68,04), <SEP> H <SEP> (5, 80), <SEP> N <SEP> (5.03)
<tb><SEP> 1670C <SEP> Theoretical <SEP>: <SEP> C <SEP> (66.91), <SEP> H <SEP> read <SEP> N (5.38)
<tb> 12 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (67,12), <SEP> H <SEP> (6,15), <SEP> N <SEP> ZZ
<tb> 0, 'N <SEP> 1000C <SEP> Theoretical <SEP> C <SEP> (56,49), <SEP> H <SEP> Hz <SEP> N (7,91)
<tb> 13 <SEP> OCH3 <SEP> H <SEP> - <SEP> dioxalate <SEP> Experimental <SEP>: <SEP> Ln4 <SEP> C <SEP> (56,52), <SEP> H <SEP> (5.67), <SEP> N <SEP> (7.52)
<tb> 0, <SEP> 1600C <SEP> Theoretical <SEP> C <SEP> (61,13), <SEP> H <SEP> h <SEP> (6,41), <SEP> C5 <SEP> X <SEP> h
<tb><SEP> 14 <SEP> 0 <SEP> OCH3 <SEP> Hs1 <SEP> Hydrochloride <SEP> Experimental <SEP>: <SEP> C <SEP> (61,10), <SEP> H <SEP > (6.90), <SEP> N <SEP> (6.86)
<tb> 15 <SEP> OCH3 <SEP> H <SEP> 0 / d <SEP> 1650C <SEP> Theoretical <SEP>: <SEP> C <SEP> ut <SEP> H <SEP> ut <SEP> N (7.43)
<tb>u><SEP> Experimental <SEP>: <SEP> C <SEP> (63.63), <SEP> H <SEP> (6.1?), <SEP> N <SEP> U
<tb> 16 <SEP> OCH3 <SEP> H <SEP> 1430C <SEP> Theoretical <SEP> C <SEP> (64.99), <SEP> H <SEP> (S, 87), <SEP> N (5.83)
<tb><SEP> o <SEP> rd <SEP> oxalate <SEP> rd <SEP> Experimental <SEP> C <SEP> (64,57), <SEP> rd <SEP><SEP> H <SEP > (5.59), <SEP> N <SEP> (5.85)
<tb> 17 <SEP> OCH3 <SEP> H <SEP> c, ffi '<SEP> 1980C <SEP> Theoretical <SEP>: <SEP> C <SEP> (63,77), <SEP> H <SEP > E <SEP> N (5.51)
<tb><SEP> VU <SEP> oxalate <SEP> Experimental <SEP> C <SEP> (63,46), <SEP> H <SEP> (5,60), <SEP> N <SEP> (5 , 52)
<tb><SEP> o <SEP> 1320C <SEP> Theoretical <SEP>: <SEP> C <SEP> (66.94), <SEP> H <SEP> Ec <SEP> 6 <SEP> X
<tb><SEP> 18 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP> C <SEP> (67,23), <SEP> H <SEP> (6,37), <SEP> N <SEP> (5.90)
<tb> m <SEP> 1420C <SEP> Theoretical <SEP> C <SEP> (67,48), <SEP> H <SEP> r <SEP> ao <SEP> N <SEP> (5,83)
<tb><SEP> 19 <SEP> OC2H5 <SEP> H <SEP> I, oxalateExperimental <SEP> C <SEP> (7.93), <SEP> H <SEP> (6.66), <SEP> N <SEP> (5.87)
<Tb>

<SEP> o, ffi'c <SEP> 1320C <SEP> Theoretical <SEP>: <SEP> C <SEP> (67,48), <SEP> H <SEP> (6,71), <SEP> N (5.83)
<tb><SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP>(67,55>,<SEP> H <SEP> (6,? 8), <SEP> N <SEP> ( 5.85)
<tb><SEP> Oxalate <SEP> Experimental <SEP> C <SEP> (64.90), <SEP> H <SEP> (6.40), <SEP> N <SEP> (5.15)
<tb><SEP> 1280C <SEP> Theoretical <SEP>: <SEP> C <SEP><63,87),<SEP> H <SEP><6,51),<SEP> N (5,32)
<tb> 22 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP><64,17),<SEP> H <SEP> (6,42), <SEP> N <SEP> (5.37)
<tb><SEP> 1300C <SEP> Theoretical <SEP>: <SEP> C <SEP><63.87),<SEP> H <SEP><6.51),<SEP> N <5.32)
<tb><SEP> os) "<SEP>2070'C<SEP> Theoretical <SEP> C <SEP> (63,87), <SEP> H <SEP> (6,51), <SEP> N ( 5.32)
<tb> 25 <SEP> OCH3 <SEP> H <SEP> 0CM <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (63,40), <SEP> H <SEP> (6 , 20), <SEP> N <SEP> (5,17)
<tb><SEP>o> 5 <SEP> 1560C <SEP> Theoretical <SEP>: <SEP> C <SEP> (62,58), <SEP> H <SEP> (6,52), <SEP> N (5.03)
<tb> 26 <SEP> OCH3 <SEP> H <SEP> -. <SEP> Oxalate <SEP> Experimental <SEP> C <SEP> (62.69), <SEP> H <SEP> (6.44), <SEP> N <SEP> (5.07)
<tb><SEP> l400C <SEP> Theoretical <SEP>: <SEP> C <SEP><62.58),<SEP> H <SEP> (6.52), <SEP> N <5.03)
<tb> 27 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (62,34), <SEP> H <SEP> (6,45), <SEP> N <SEP> (4.91)
<tb> 28 <SEP> OCH3 <SEP> H <SEP> o <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP><67.10),<SEP> H <SEP> (5 , 95), <SEP> N <SEP> (5.41)
<tb><SEP> oxalate <SEP> Experimental <SEP> C <SEP> (62,42), <SEP> H <SEP> (5,73), <SEP> N <SEP> (5,50)
<Tb>

<SEP> 1420C <SEP> Theoretical <SEP>. <SEP> C <SEP> (64.45), <SEP> H <SEP> (6.03), <SEP> N (5.78)
<tb><SEP> 30 <SEP> OaI3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP> C <SEP> (64,34), <SEP> H <SEP> (5,90), <SEP> N <SEP> (5.70)
<tb><SEP> 31 <SEP> OCH3 <SEP> H <SEP> 1300C <SEP> Theoretical <SEP>: <SEP> C <SEP> (64,45), <SEP> H <SEP> (6, 03), <SEP> N (5.79)
<tb><SEP> oxalate <SEP> Ln <SEP> Experimental <SEP>: <SEP> C <SEP> (64,79), <SEP> H <SEP> (6,06), <SEP> N <SEP> read
<tb><SEP> 1880C <SEP> Theoretical <SEP> C <SEP><56,12),<SEP> H <SEP> (4,53), <SEP>, <SEP>, <SEP>, <SEP>,
<tb><SEP> 32 <SEP> CH3 <SEP> H <SEP> 0, F <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (56,30), <SEP> H <SEP> (4.49), <SEP> N <SEP> (5.11)
<tb> 33 <SEP> OCH3 <SEP> H <SEP> 1260C <SEP> Theoretical <SEP> C <SEP> (60,17), <SEP> H <SEP> (5,44), <SEP> N (5.40)
<tb> oxalate <SEP> Experimental <SEP> C <SEP> (59,37), <SEP> H (5,31), <SEP> N (5,21), Cl
<tb> (6.68)
<tb><SEP> 1480C <SEP> Theoretical <SEP>: <SEP> C <SEP> (61,05), <SEP> H <SEP>F;<SEP> N (8.21)
<tb><SEP> 34 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SE> C <SEP> (61,64), <SEP> H <SEP> (5, 52), <SEP> N <SEP> ut
<tb> 1260C <SEP> Theoretical <SEP> C <SEP> (60,67), <SEP> H <SEP> (5,47), <SEP> N (5,24)
<tb><SEP> 35 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> rd <SEP> Experimental <SEP> C <SEP> (60,72), <SEP> H <SEP> (5, 12), <SEP> N <SEP> (5,17)
<tb> 1330C <SEP> Theoretical <SEP>: <SEP> a, <SEP> C <SEP> (70,83), <SEP> H <SEP> (6,32), <SEP> N (5, 16)
<tb><SEP> -rl <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (70,98), <SEP> H <SEP> (6,27), <SEP> N <SEP> (5.22)
<tb> o <SEP> 138 <SEP> O <SEP> \ Q) <SEP> p, <SEP>: <SEP> C <SEP><69.75),<SEP> H <SEP><6, 24), <SEP> N (5.42)
<tb> 37 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP> C <SEP> cx <SEP> cc <SEP> H <SEP> (6,20), <SEP> N <SEP><5,37)
<tb><SEP> 1520C <SEP> Theoretical <SEP>: <SEP> C <SEP> Q, <SEP> a, <SEP> H <SEP><6,24),<SEP> a, <SEP> Q,
<tb> 38 <SEP> OCH3 <SEP> H <SEP> R <SEP> cO <SEP> R <SEP>U><SEP>:<SEP> C <SEP> (69,53), <SEP> H <SEP> (6.39), <SEP> N <SEP> r (
<Tb>

<SEP> 1600C <SEP> Theoretical <SEP>. <SEP> C <SEP> (63,15), <SEP> H <SEP> (6,18), <SEP> N (6,14)
<tb><SEP> c <SEP> Experimental <SEP>: <SEP> C <SEP> (62.90), <SEP> H <SEP> (6.05), <SEP> N <SEP> (6) , 10)
<tb><SEP> 1240C <SEP> Theoretical <SEP>: <SEP> C <SEP> (64,45), <SEP> H <SEP> (6,03), <SEP> N <5,78)
<tb> oxalate <SEP> Experimental <SEP> C <SEP> (64,46), <SEP> H <SEP> (6,03), <SEP> N <SEP> read
<tb><SEP> 1500C <SEP> Theoretical <SEP>: <SEP> C <SEP> (65.98), <SEP> H <SEP> (5.95), <SEP> N (8.55)
<tb> 41 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP> C <SEP> (65,52), <SEP> H <SEP><5,93>,<SEP> N <SEP><8.51)
<tb> 890C <SEP> Theoretical <SEP>: <SEP> C <SEP> (67,48), <SEP> H <SEP> (6,71), <SEP> N (5,83)
<tb><SEP> -42 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (67,03), <SEP> H <SEP> (6 , 42), <SEP> N <SEP> (5,68)
<tb><SEP> 2100C <SEP> Theoretical <SEP> C <SEP> (71.09), <SEP> H <SEP> (5.97), <SEP> N <SEP> (5.18)
<tb><SEP> 43 <SEP> OCH3 <SEP> H <SEP> o <SEP> xalate <SEP> Experimental <SEP>: <SEP> C <SEP><70.68),<SEP> H <SEP > (6.15), <SEP> N <SEP> (5.09)
<tb> 1460C <SEP> Theoretical <SEP>: <SEP> C <SEP> (70,83), <SEP> u, <SEP> H <SEP> (6,32), <SEP> N (5, 16)
<tb> 44 <SEP> OCH3 <SEP> H <SEP>u><SEP> Experimental <SEP>: <SEP> C <SEP> (70,57), <SEP> H <SEP> (6,25) , <SEP> N <SEP> U <SEP> (5.04)
<tb><SEP> 1340C <SEP> Theoretical <SEP> rd <SEP> (67,23), <SEP> (d <SEP> H <SEP> (6,08), <SE> N <SEP> (6.03)
<tb><SEP> 45 <SEP> OCH3 <SEP> H <SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (67,58) <SEP>;<SEP> H <SEP> (6.03), <SEP> N <SEP> (5.97)
<Tb>
Example 46
(SS), (RR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -cinnamamide
This compound is synthesized in 2 stages
Stage 1 (SS), (RR) -9-methoxy-1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl-2-methananine
220 H 2 SO 4 (405 mg, 4.13 mmol, 1 eq) is added dropwise to a mixture containing 8.25 ml of LiAlH 4 / Et 2 O 1M solution (8.25 mmol, 2 eq) and 10 ml of THF. . There is a white precipitate and gassing. The solution is stirred at ambient temperature for 1 h and then cooled to 0 ° C. in an ice bath. A solution of 1 g cyano axial obtained as diastereoisomer B in Step 4 of Example 1 (4.13 mmol) in 2 ml of THF is then added dropwise. After addition, the reaction is continued at room temperature for 1 hour. The hydrolysis of the reaction mixture is carried out with Na 2 SO 4 / H 2 O. The precipitate formed is filtered off and the filtrate is then evaporated to dryness. 925 mg of a yellow oil are isolated (yield = 91%).

Stage 2
(SS), (RR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -cinnamamide
Addition of 689 mg of cinnamoyl chloride (4.14 mmol, 1.1 eq) to a solution of 925 mg amine of the previous stage (3.76 mmol) and 577 μl of methylamine
(419 mg, 4.14 mmol, 1.1 eq) in 10 ml CH2Cl2. The reaction is exothermic. After 1/4 h the reaction mixture is treated with 1N NaOH. The organic phase is dried over Na 2 SO 4, filtered and then evaporated to dryness. 865 mg of pure compound are isolated after chromatography on a silica column (eluent CH 2 Cl 2 / MeOH / NH 4 OH 98 / 1.7 / 0.3).

Rf (CH2Cl2 / MeOH / NH4OH 95/5 / 0.5): 0.31 tof (hydrochloride): 1610C
1 H NMR (400 MHz, CDCl 3) (base) 7.65 ppm (d, J = 15.6)
Hz; 1H; CH = CH-Ar); 7.52 ppm; (m; 2H; H 2 'and H 6') 7.38 ppm (m; 3H; H 3 ', H 4' and H 5 '); 7.06 ppm (d, J, 8.6 Hz, 1H, H11); 6.71 ppm (dd, J = 8.6 and 2.6 Hz 1H, H10); 6.61 ppm (d, J = 2.6 Hz, 1H, H8); 6.42 ppm (d, J = 15.6 Hz, 1H, CH = CH-Ar); 5.30 ppm (m H, NH); 3.77 ppm (s, 3H, OCH3); 3.62-3.50 ppm (m 3H, H11b and CH2N); 3.14 ppm (m; 1H; 7Ha); 3.00 ppm
(m; 1H; H6a); 2.92-2.57 ppm (m; 4H; H4a, H4b, H6b,
H7a); 2.12 ppm (m; 1H; Hla); 2.05 ppm (m; 1H; H 2) 1.93 ppm (m; 1H; H 3 a); 1.83 ppm (m; 1H; H3b); 1.61 ppm (Hlb).

Elemental analysis:
Theoretical: C (69.80), H (7.08), N (6.78)
Experimental: C (69.75), H (7.04), N (6.76)
EXAMPLE 47
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -acetamide
139 l of acetic anhydride (151 mg, 1.48 mmol, 1.2 eq) are added to a solution of 300 mg of amine obtained in Step 5 of Example 1 (1.21 mmol) and 0.25 g. ml of pyridine (3 mmol, 2.5 eq) in 8 ml of THF. After stirring for 3 h at room temperature, the solvent is evaporated and the residue is taken up in CH 2 Cl 2 / 1N NaOH.

After decantation, the organic phase is dried over
MgSO4, filtered and then evaporated to dryness. The crude product is purified by chromatography on a silica column (eluent
90/9/1 CH2Cl2 / MeOH / NH4OH). 230 mg of a yellow oil are isolated (yield = 65 W).

Rf (CH 2 Cl 2 / MeOH / NH 4 OH 90/10/2: 0.50 tof (oxalate): 980C
1 H NMR (200 MHz, DMSO d6) (base): 7.96 ppm (tmax 1H, NH): 7.23 ppm (d, J = 8.7 Hz, 1H, H11); 6.82 ppm (dd, J = 8.7 Hz and 2.5 Hz, 1H, H10); 6.77 ppm
(d, J = 2.5 Hz, 1H, H8); 4.10 ppm (d, J = 12 Hz, 1H, H11b); 3.74 ppm (s, 3H, OCH 3); 3.52-3.33 ppm
(m; 2H) and 3.18-2.88 ppm (m; 6H) (H1a, H3a, H4a, H4b,
H6a, H6b, H7a, H7b); 2.40 ppm (m; 1H; H 2); 1.78 ppm
(m; 1H; H3b); 1.32 ppm (m; 1H; H1b).

Elemental analysis:
Theoretical: C (60.31), H (6.92), N (7.40)
Experimental: C (60.19), H (6.62), N (7.09)
In a similar manner to Example 1, but using the corresponding reagents, the compounds of formula 1 are obtained and are listed by the examples in table 2 following TABLE 2

<tb> Examples <SEP> T0 <SEP> Merge
<tb><SEP> N0 <SEP> R2 <SEP> R3 <SEP> Sel <SEP> Elementary <SEP> Analysis
<tb><SEP> 48 <SEP> OCH3H <SEP> 1020C <SEP> Theoretical <SEP>: <SEP> C <SEP><61,21),<SEP> H <SEP><7,19>,<SEP> N <SEP><, 14)
<tb><SEP> L) <SEP> Experimental <SEP>: <SEP> C <SEP> (61,21), <SEP> H <SEP><7,09),<SEP> N <SEP> V
<tb><SEP> 49 <SEP> OCH3 <SEP> H <SEP> 1420C <SEP> Theoretical <SEP>: <SEP> C <SEP>(64.67>,<SEP> H <SEP><8, 28), <SEP> N <SEP><7.94)
<tb><SEP> cQ) <SEP> Experimental <SEP>: <SEP> C <SEP> u, <SEP> r- <SEP> H <SEP><7.81),<SEP> N <SEP> ut
<tb><SEP> 50 <SEP> OCH3 <SEP> H <SEP> 1600C <SEP> Theoretical <SEP>: <SEP> C <SEP><67,24),<SEP> H <SEP><8, 46), <SEP> N <SEP><7,13)
<tb><SEP>,<SEP> Experimental <SEP>: <SEP> C <SEP><66.99),<SEP> H <SEP> (8,16), <SEP> N <SEP><6 , 88)
<tb><SEP> 51 <SEP> OCH3 <SEP> H <SEP> 1500C <SEP> Theoretical <SEP>: <SEP> C <SEP><64.85)<SEP>;<SEP> H <SEP><7,16)<SEP>;<SEP> N <SEP><6.30)
<tb><SEP> oxalate <SEP> rd <SEP> Experimental <SEP>: <SEP> C <SEP> ca <SEP><64,35);<SEP> H <SEP><7.55)<SEP>;<SEP> N <SEP> rd <SEP><5.89)
<tb><SEP> 52 <SEP> OCH3 <SEP> H <SEP> 980C <SEP> Theoretical <SEP>: <SEP> C <SEP> (66,06), <SEP> H <SEP> -r ( <SEP> N <SEP><6,16)
<tb><SEP> \ a, <SEP> H <SEP> \ a, <SEP> a <SEP> Experimental <SEP>: <SEP> C <SEP><66,45),<SEP> H <SEP ><6.67),<SEP> N <SEP> (5.84)
<tb><SEP> 54 <SEP> OCH3 <SEP> H <SEP> 1330C <SEP> Theoretical <SEP> C <SEP> (65,83), <SEP> H <SEP><8,01>,<SEP> N <SEP> cl
<tb><SEP> Hydrochloride <SEP> Experimental <SEP> C <SEP><65.75),<SEP> H <SEP><7.74),<SEP> N <SEP> o
<tb><SEP> 55 <SEP> OCH3 <SEP> H <SEP> O <SEP> 1250C <SEP> Theoretical <SEP>: <SEP> C <SEP> (60.92), <SEP> H <SEP ><7.67),<SEP> N <SEP> (7.89)
<tb><SEP> OMO <SEP> Chlorydrate <SEP> Experimental <SEP>: <SEP> C <SEP><60.62),<SEP> H <SEP> (7.80), <SEP> N <SEP><7.41)
<Tb>

<tb> 56 <SEP> OCH3 <SEP> H <SEP> 920C <SEP> Theoretical <SEP>: <SEP> C <SEP> (63,82), <SEP> H <SEP> (6,43), <SEP> N <SEP><5.95)
<tb><SEP> I <SEP> OI <SEP> Experimental <SEP> C <SEP> \ D <SEP><SEP> Ln <SEP> H <SEP><6.31),<SEP> N <SEP><5.85)
<tb> 57 <SEP> OCH3 <SEP> H <SEP> 1250C <SEP> Theoretical <SEP>: <SEP> C <SEP> (53,58), <SEP> H <SEP><4,50),<SEP> N <SEP><5.00)
<tb><SEP> m <SEP> Experimental <SEP>: <SEP> \ 05 <SEP> C <SEP> Ln <SEP> Z <SEP> \ O <SEP> H <SEP><4.46),<SEP> N <SEP><4.93)
<tb> 58 <SEP> OCH3 <SEP> H <SEP> hON <SEP> 710C <SEP> Theoretical <SEP>: <SEP> C <SEP><59,46),<SEP> H <SEP><5 , 79), <SEP> N <SEP><5.55)
<tb><SEP> oxalate <SEP> Experimental <SEP> C <SEP> (59.88), <SEP> H <SEP><5.56),<SEP> N <SEP><5.41)
<tb> 59 <SEP> OCH3 <SEP> H <SEP> 940C <SEP> Theoretical <SEP> C <SEP> (67,48), <SEP> H <SEP><6,71),<SEP> N <SEP><5.83)
<tb><SEP> Oxalate <SEP> Cr <SEP> C <SEP><67.87),<SEP> H <SEP><6.28),<SEP> N <SEP><5.64)
<tb> 60 <SEP> OCH3 <SEP> H <SEP> 1200C <SEP> Theoretical <SEP> C <SEP><67.48),<SEP> H <SEP><6.71),<SEP> N <SEP><5.83)
<tb><SEP> u <SEP> Experimental <SEP> C <SEP> (66.99), <SEP> H <SEP><6.53),<SEP> N <SEP> u
<tb> 61 <SEP> OCH3 <SEP> H <SEP> 1600C <SEP> Theoretical <SEP> C <SEP><56.87),<SEP> H <SEP><6.20),<SEP> N <SEP> (6.63)
<tb><SEP> rl <SEP> Experimental <SEP>: <SEP> C <SEP> (56.99), <SEP> H <SEP><5.96),<SEP> N <SEP><6 , 32)
<tb> 62 <SEP> 0CM <SEP> 1320C <SEP> Theoretical <SEP>: <SEP> C <SEP><65,58),<SEP> H <SEP><6,11),<SEP> N <SEP><5.66)
<tb> 63 <SEP> uU <SEP> Oxalate <SEP> Experimental <SEP>: <SEP> \ Q) <SEP> C <SEP><65.35),<SEP> H <SEP><6.23 ), <SEP> N <SEP><5.51)
<tb><SEP> OCH <SEP> 1150C <SEP> Theoretical <SEP> C <SEP><56.87),<SEP> H <SEP><6.20),<SEP> N <SEP> (6 , 63)
<tb><SEP> o <SEP> Oxalate <SEP> e <SEP>: <SEP> C <SEP> (56.99), <SEP> H <SEP><5.96),<SEP> N <SEP><6.32)
<Tb>
EXAMPLE 64
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] phenylsulfonamide
Addition of 0.19 ml of phenylsulfonyl chloride (263 mg, 1.49 mmol, 1.2 eq) to a solution of 300 mg of amine obtained in Step 5 of Example 1 (1.21 mmol) and 0 25 ml pyridine (3 mmol, 2.5 eq) in 10 ml THF.

The reaction is kept at room temperature for 10 days. After addition of 0.19 ml of additional phenylsulfonyl chloride and reaction for a further 10 days, the solution is evaporated to dryness. The residue is purified by chromatography on a silica column (eluent
CH2Cl2 / MeOH 95/5). 166 mg of an oil which crystallizes at rest (rdt = 35 W) are isolated.

Rf (CH2Cl2 / MeOH 95/5): 0.26 tof (oxalate): 130-1350 ° C
1 H NMR (200 MHz, CDCl 3) (base): 7.87 ppm (dd, J = 6.2
Hz and 1.7 Hz; 2H; H2 'and H6'); 7.60-7.46 ppm (m; 3H)
H3 ', H4', H5 '); 7.01 ppm (d, J = 8.6 Hz, 1H, H11) 6.68 ppm (dd, J = 8.6 Hz and 2.5 Hz, 1H, H10); 6.60 ppm
(d, J = 2.5 Hz, 1H, H8); 4.81 ppm (t wide; 1H
NH); 3.77 ppm (s, 3H, OCH3); 3.22-2.86 ppm (m; 6H)
CH2N; H4a, H6a, H7a, H11b); 2.65 ppm (m; 1H; H7b) 2.48 ppm (m; 1H; H6b); 2.36-2.18 ppm (m; 2H; H4b and
Hla); 1.88 ppm (m; 1H; H2); 1.70 ppm (m; 1H; H3a) 1.30 ppm (m; 1H; H3b); 1.00 ppm (m; 1H; H1b).

Elemental analysis:
Theoretical: C (57.97), H (5.92), N (5.88)
Experimental: C (57.47), H (5.92), N (5.81)
Example 65
(RS), (SR) -N- [2- (1,3,4,6,7,11b) hexahydro-9-methoxy-2H-benzo [ajquinolinyl) methylmethylsulfonamide
In a similar manner to Example 64, but using methane sulphonyl chloride, the title compound is obtained (oxalate): 1560C
Elemental analysis:
Theoretical: C (52.16), H (6.32), N (6.76)
Experimental: C (52.73), H (6.25), N (6.85)
Example 66 (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [ajquinolizinyl) methyl] -N ', N'-dimethylsulfonylurea
In a similar manner to Example 64, but using N, N-dimethylsulfamoyl chloride, the title compound is obtained tf (oxalate): 1100C
Elemental analysis
Theoretical: C (51.45), H (6.59), N (9.475)
Experimental: C (51,27), H (6,61), N (9,24)
Example 67
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] benzylcarbamate
Addition dropwise of 0.18 ml of benzyl chloroformate (215 mg, 1.26 mmol, 1.05 eq) diluted in 1 ml
DME to a solution of 300 mg of amine obtained in Step 5 of Example 1 (1.22 mmol) in 5 ml of water supplemented with a little DME. After 4 days of reaction at 1000C, the reaction mixture is evaporated to dryness, taken up in CH2Cl2 and then washed with 1N NaOH. After purification by chromatography on a silica column, 118 mg of carbamate, the title compound (yield = 36%), are isolated.

Rf (CH2Cl2 / MeOH / NH4OH 90/9/1): 0.54 tf (oxalate): 1040C
1H NMR <CDCl3; 400 MHz) (base): 7.28 ppm (m; 5H)
Ph): 7.03 ppm (d, J = 8.6 Hz, 1H, H11); 6.66 ppm
(dd, J = 8.6 Hz and 2.4 Hz, 1H, H10); 6.53 ppm (d, J = 2.4 Hz, 1H, H8); 5.03 ppm <R
Example 68
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -thiobenzamide
To a solution of 305 mg (0.79 mmol) of N- [2]
(1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] benzamide previously obtained according to example 1 in 100 ml of toluene is added 322 mg
(0.80 mmol) [2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-dithio] (Lawesson's reagent). The medium is refluxed and left stirring for 2 days. After evaporation of the solvent, the residue is filtered over alumina eluted with dichloromethane. The filtrate is evaporated to give 250 mg (85%) of a yellow oil which is treated with oxalic acid to give 239 mg (77%) of pale yellow oxalate crystals.

Rf (CH 2 Cl 2 / MeOH 90/9/1): 0.58 tf (oxalate): 165 ° C
1 H NMR (200 MHz, CDCl 3) (base): 7.81 ppm (brH, NH); 7.76 ppm (dd, J = 7.6 Hz and 1.3 Hz, 2H, H2 'and H6'); 7.42 ppm (m; 3H; H3 ', H4', H5 '); 7.10 ppm
(d, J = 8.6 Hz, 1H, H11); 6.72 ppm (dd, J = 8.6 Hz and 2.7 Hz, 1H, H10); 6.61 ppm (d, J = 2.7 Hz, 1H, H8) 3.82 ppm (m, 2H, CH2N); 3.77 (s; 3H; OCH3); 3.282.97 ppm (m; 4H; H4a, H6a, H7a, H11b1; 2.77-2.38 ppm;
(m; 4H; H1a, H4b, H6b, H7b); 2.25 ppm (m; 1H
H3a); 1.88 ppm (m; 1H; H2); 1.68 ppm (m; 1H; H3b) 1.33 ppm (m; 1H; H1b).

Elemental analysis:
Theoretical: C (63,14), H (6,18), N (6,13)
Experimental: C (63.38), H (6.16), N (5.07)
Example 69
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -thioacétamide
In a similar manner to Example 68 but using the corresponding reagents, the title compound is obtained tof (oxalate): 1130C
Elemental analysis:
Theoretical: C (57.85), H (6.64), N (7.10)
Experimental: C (58.01), H (6.36), N (6.75)
Example 70
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -thiocinnamamide
In a similar manner to Example 68 but using the corresponding reagents, the title compound is obtained tof (oxalate): 1280C
Elemental analysis:
Theoretical: C (64.71), H (6.27), N (5.80)
Experimental: C (64.94), H (6.29), N (5.62)
Example 71
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N'-phenylurea
Add dropwise of a solution of 90 μl of phenylisocyanate (98 mg, 0.82 mmol, 1 eq) in 5 ml
CH 2 Cl 2 to a solution of 200 mg of amine obtained in Step 5 of Example 1 (0.82 mmol) in 5 ml CH 2 Cl 2. After reaction for 16 hours at room temperature, the solvent is evaporated and the oily residue is purified by chromatography on a silica column (eluent CH 2 Cl 2 / MeOH 95/5). 160 mg of a yellow oil which crystallizes at rest (rdt = 54 W) are isolated.

Rf (CH2Cl2 / MeOH 90/10): 0.35 tof (hydrochloride): 1850C
1H NMR (200MHz, DMSO d6) (hydrochloride): 7.45-7.10 ppm
(m; 5H; H 2 ', H 3', H 5 ', H 6', H 11); 6.81-6.95 ppm (m 3H; H4 ', H8, H10); 4.42 ppm (d; J = 11.3 Hz; 1H;
Hllb); 3.74 ppm (s, 3H, OCH 3); 3.62-2.92 ppm (m, 6H, CH2N, H4a, H6a, H6b, H7a, H7b); 2.92 ppm (m; 1H
H2); 1.95 ppm (m; 2H) and 1.70-1.30 ppm (m; 2H) (Hla,
H1b, H3a, H3b).

Elementary analysis
Theoretical: C (65.74), H @ (7.02), N (10.45)
Experimental: C (65.32), H (6.97), N (10.19)
Example 72
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N'-methylurea
In a similar manner to Example 71 but using the corresponding reagents, the title compound is obtained tf (hydrochloride): 1600C
Elemental analysis
Theoretical: C (60.08), H (7.71), N (12.36)
Experimental: C (60,24), H (8,00), N (11,86)
EXAMPLE 73
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N'-benzoylurea
In a similar manner to Example 71 but using the corresponding reagents, the title compound is obtained tof (oxalate): 2100C
Elemental analysis
Theoretical: C (62.10R, H (6.04), N (8.69)
Experimental: C (62.00), H (5.87), N (8.37)
Example 74
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N ', N'-dimethylurea
A solution of 0.24 ml of dimethylcarbamoyl chloride (280 mg, 2.6 mmol, 1.2 eq) in 2 ml THF is added dropwise to a solution of 530 mg of amine obtained in Step 5 of Example 1 (2.15 mmol) and 0.44 ml pyridine (425 mg, 5.4 mmol, 2.5 eq) in 30 ml.
THF. The reaction is maintained at ambient temperature for 2 days and then heated at 80 ° C. for 5 days after addition of a spatula tip of DMAP.

The reaction mixture is taken up in 1N NaOH / CH2Cl2.

The organic phase is dried over MgSO 4, filtered and then evaporated to dryness. The crude oil is purified by chromatography on a silica column. 390 mg of product are isolated (yield = 57%)
Rf (CH 2 Cl 2 / MeOH 95/5) - 0.17 tof (oxalate): 1220C.

1 H NMR (400 MHz, CDCl 3) (base) 7.11 ppm (d, J = 8.7
Hz; 1H; H11); 6.72 ppm (dd; J = 8.7 and 2.6 Hz; 1H
H10); 6.61 ppm (d, J = 2.6 Hz, 1H, H8); 4.55 ppm
(t, J = 5.2 Hz, 1H, NH); 3.77 ppm (s; 3H; OCH3) 3.28-3.08 ppm (m; 4H H11b, H7a and CH2N); 3.03 ppm
(m; 1H; H4a); 2.96 ppm (m; 1H; H6a); 2.91 ppm (s, 6H, N (CH 3) 2); 2.68 ppm (m; 1H; Hla); 2.50 ppm (m 1H; H7b); 2.38-2.29 ppm (m; 2H; H6b and H4b); 1.83 ppm (m; 1H; H 2); 1.78 ppm (m; 1H; H3a); 1.41 ppm
(m; 1H; H3b); 1.12 ppm (m; 1H; Hlb)
Elemental analysis
Theoretical: C (58,95), H (7,17), N (10,31)
Experimental: C (59,26), H (6,96), N (9,83)
Example 75
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N'-phenylthiourea
230 l (260 mg, 1.92 mmol, 1.2 eq) of phenyl isothiocyanate are added dropwise to a solution of 400 mg of amine (1.6 mmol) in 20 ml CH 2 Cl 2. The reaction is kept at room temperature for 4 hours. The reaction mixture is treated with 1N NaOH. The organic phase is washed with sat. NaCl, dried over MgSO 4, filtered and then evaporated to dryness. The oily residue is purified by chromatography on a silica column (eluent CH 2 Cl 2 / MeOH / NH 4 OH 98 / 1.7 / 0.3).

Yld = 53
Rf (CH2Cl2 / MeOH / NH4OH 90/9/1): 0.38 tf (oxalate): 1460C
1 H NMR (400 MHz, CDCl 3) (base): 7.63 ppm (1H; 7.49 ppm (m; 2H; H3 'and H5'); 7.35 ppm (t
J = 7.4 Hz; 1H; H4 '); 7.23 ppm (d, J = 7.8 Hz, 2H)
H2 ', H6'); 7.05 ppm (d, J = 8.6 Hz, 1H, H11); 6.72 ppm (dd, J = 8.6 and 2.6 Hz, 1H, H10); 6.61 ppm (d, J = 2.6 Hz, 1H, H8): 6.18 ppm (broad, 1H, NH); 3.77 ppm (s, 3H, OCH3); 3.64 ppm (m, 1H, HA (CH2N)) 3.53 ppm (m, 1H, HB (CH2N)); 3.22-3.10 ppm (m; 2H)
H11b, H7a); 3.07-2.95 ppm (m; 2H; H7a and H4a); 2.68 ppm (m; 1H; H7b); 2.54 ppm (m; 1H; H6b); 2.36 ppm
(m; 1H) and 2.27 ppm (m; 1H) (H1a and H4b); 2.05 ppm (m; 1H; H2); 1.7 ppm (m; 1H; H3a); 1.42 ppm (m; 1H
H3b); 1.12 ppm (m; 1H; H1b).

Elemental analysis:
Theoretical: C (61.13), H (6.20), N (8.91)
Experimental: C (61.31), H (6.14), N (8.68)
In a similar manner to Example 75, but using the corresponding reagents, the compounds of formula 1 are obtained by the examples in Table 3 following TABLE 3

<tb> Examples <SEP> T0 <SEP>Q><SEP> r (<SEP> u \ <SEP> 00 <SEP> cO <SEP> O <SEP> CO <SEP> Ln <SEP> cO <SEP>U>
<tb><SEP> N0 <SEP> Ri <SEP> R2 <SEP> R3 <SEP> Sel <SEP> Analysis <SEP>
<tb><SEP> 76 <SEP> OCH3 <SEP> H <SEP> 1460C <SEP> Theoretical <SEP> C <SEP><55.73),<SEP> H <SEP><6.65),<SEP> N <SEP><10.26)
<tb><SEP> HNi <SEP> c0 <SEP> Experimental <SEP> C <SEP> C15 <SEP> H <6.61), <SEP> N <SEP> DS <SEP> = 6
<tb><SEP> t <SEP> Experimental <SEP>: <SEP> C <SEP> (58.76), <SEP> H <SEP> c <SEP> u, <SEP> o <SEP> N <SEP><8.98)
<tb><SEP> 79 <SEP> OCH3 <SEP> H <SEP> 1530C <SEP> Theoretical <SEP>: <SEP> C <SEP><58.51),<SEP> H <SEP> \ O <SEP> U <SEP> U) <SEP> N <SEP><9.31)
<tb><SEP> O <SEP> Experimental <SEP> C <SEP> (59,03), <SEP> H <SEP><7,26),<SEP> N <SEP> U <SEP> U <SEP> U
<tb><SEP> 80 <SEP> OCH3 <SEP> H <SE> 1440C <SEP> rd <SEP> Theoretical <SEP>: <SEP> C <SEP> (II <SEP> (61,51), <SEP> H <SEP><8.14)<SEP>,<SEP> N <SEP><8.28)
<tb><SEP> N <SEP> EE <SEP> Experimental <SEP> C <SEP><61.58),<SEP> H <SEP><8.23),<SEP> N <SEP><8 , 17)
<tb><SEP> O <SEP> Experimental <SEP>: <SEP> C <SEP><61.09),<SEP> H <SEP><7.51),<SEP> N <SEP> a,
<tb><SEP> 83 <SEP> o <SEP> m <SEP> o <SEP> rd <SEP> o <SEP> 2300C <SEP> Theoretical <SEP>: <SEP> C <SEP><64.91 ), <SEP> H <SEP><6.90),<SEP> N <SEP><9.46)
<tb><SEP> or <SEP> Experimental <SEP>: <SEP> C <SEP> cd <SEP> u, <SEP> m <SEP> H <SEP><6.65),<SEP> N <SEP><9.31)
<Tb>

<tb> 84 <SEP> OCM3 <SEP> H <SEP> 1190C <SEP> Theoretical <SEP>: <SEP> C <SEP> (62,50), <SEP> M <SEP><6,66),<SEP> N <SEP><8.41)
<tb><SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP> (62,20), <SEP> H <SEP><6,62),<SEP> N <SEP><8 , 16)
<tb> 85 <SEP> OCH3 <SEP> H <SEP> 1560U <SEP> Theoretical <SEP>: <SEP> C <SEP> (64,47), <SEP> H <SEP><5,99),<SEP> N <SEP><8.06)
<tb><SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP><64,36),<SEP> M <SEP><5,98),<SEP> N <SEP><7 , 86)
<tb> 86 <SEP> OCH3 <SEP> Hz (j <SEP> H
<tb><SEP> oxalate <SEP> Experimental <SEP>: <SEP> C <SEP><64,14),<SEP> M <SEP><5,97),<SEP> N <SEP><7 , 92)
<tb> 87 <SEP> OCM3 <SEP> H
<Tb>
Example 88
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N ', N'-dimethylthiourea
Addition of 238 mg dimethyl thiocarbamoyl chloride
(2.11 mmol, 1.2 eq) dissolved in 5 ml of THF to a solution of the amine obtained in Step 5 of Example 1
(392 mg, 1.6 mmol), 0.32 ml of pyridine (2.5 eq) and 233 mg of 4-dimethylaminopyridine (1.2 eq) in 50 ml of
THF. After refluxing for 48 h, the reaction mixture is evaporated to dryness, taken up in CH 2 Cl 2 and then treated with 1N NaOH. The organic phase is dried over MgSO 4, filtered and then evaporated to dryness. The brown oil obtained is purified by chromatography on a silica column.

81 mg of thiourea of the pure title are isolated (yield = 23).

Rf (CH2Cl2 / MeOH / NH4OH 90/9/1): 0.48 tof (oxalate): 1050C NMR H (200 MHz, CDCl3): 7.08 ppm (d, J = 8.6Hz, 1H, H11); 6.69 ppm (dd; J = 8.6 and 2.4 Hz; 1H)
H10); 6.58 ppm (d, J = 2.4 Hz, 1H, H8); 5.55 ppm
(mgr; 1H; NH); 3.75 ppm (s, 3H, OCH 3); 3.6 ppm
(m; 2H; CH 2 H); 3.27 ppm (5.6H NMe2); 3.14-2.89 ppm
(m, 4H, H4a, H6a, H7a, H11b); 2.66 ppm (m; 1H
H7b); 2.48 ppm (m; 1H; M6b); 2.33 ppm (m; 2H; Hla;
H4b); 2.04 ppm (m; 1H; H2); 1.78 ppm (m, 1H, H3a) 1.46 ppm (m, 1H, H3b); 1.12 ppm (m; 1H; H1b).

Elemental analysis:
Theoretical: C (56.72), H (6.90), N (9.92)
Experimental: C (56.93), H (6.39), N (9.52)
Example 89
Stage 1
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] formamide
193 mg (2.27 mmol, 1 eq) of 0-formylhydroxyacetonitrile (prepared according to J. Prakt Chem, 1996, 338, 488-90) is added to a solution of 560 mg of amine obtained in Step 5 of Example 1 (2.27 mmol) in 10 ml CH2Cl2 maintained in an ice bath.

The reaction is kept at room temperature for 20 hours. The reaction mixture is then washed with 1N NaOH, dried over MgSO 4, filtered and then evaporated to dryness. The crude solid obtained is purified by chromatography on a silica column (eluent CH2Cl2 / MeOH 92/8). 422 mg of formamide are isolated (yield = 68 W).

Rf (CH2Cl2 / MeOH 9/1): 0.38
NMR M (400 MHz, CDCl 3) 8.22 ppm (s, 1H, CHO); 7.10 ppm (d, J = 8.5 Hz, 1H, H11); 6.71 ppm <dd; J = 8.6 Hz and 2.5 Hz; 1H; H10); 6.62 ppm (d 3 J = 2.5 Hz 1H, H8); 5.69 ppm (brs; 1H; NH); 3.78 ppm (s, 3H, OCH3); 3.27 ppm (m; 2H; CH2N); 3.15 ppm (m H, H7a); 3.10 ppm (m; 1H; H11b); 3.05 ppm (m; 1H
H4a); 2.98 ppm (m; 1H; H6a); 2.70 ppm (m; 1H
H7a); 2.52 ppm (m; 1H; H6b); 2.48-2.30 ppm (m; 2H)
Hla, H4b); 1.85 ppm (m; 1H; H 2); 1.77 ppm (m; 1H
H3a); 1.44 ppm (m; 1H; H3b); 1.17 ppm (m; 1H; H1b).

Stage 2
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methylamine
To a solution of 2.2 g of formamide of the previous stage
(8.02 mmol) in 50 ml of THF at 0 ° C., 640 mg is added
LiAlH4 ground (16 mmol, 2 eq) in small fractions.

After heating at 45-500C for 48 h, the reaction mixture is hydrolysed with Na2SO4 / H2O. The solid formed is removed by filtration. The filtrate is evaporated to dryness and then purified by chromatography on a silica column
(eluent CH 2 Cl 2 / MeOH / NH 4 OH 90/9/1).

Rf (CH 2 Cl 2 / MeOH / NH 4 OH 80/18/2): 0.56
1 H NMR (400 MHz, CDCl 3) base: 7.14 ppm (d, J = 8.7
Hz; 1H; H11); 6.70 ppm (dd; J = 8.7 and 2.6 Hz; 1H
H10); 6.61 ppm (d, J = 2.6 Hz, 1H, H8); 3.77 ppm
(s; 3H; OCH3); 3.15 ppm (m; 1H; H7a); 3.08 ppm (d
J = 11.2 Hz; 1H; Hllb); 3.02 ppm (m; 1H; H4a); 2.96 ppm (m; 1H; H6a); 2.68 ppm (m; 1H; H7a); 2.56-2.48 ppm (m; 3H; CH2N and H6b); 2.46 ppm (s, 3H, NMe) 2.42-2.30 ppm (m, 2H, Hla and H4b); 1.81-1.70 ppm (m 2H, H2 and H3a); 1.39 ppm (m; 1H; H3b); 1.11 ppm (m 1H, Hlb).

13 C NMR (100.63 MHz, CDCl 3): 157.7 ppm (C 9); 135.8 ppm and 130.6 ppm (C7a and Clla); 125.8 ppm (Cll); 113.3 ppm and 111.8 ppm (Cb and C10); 62.4 ppm (OCH3); 58.5 ppm <CH2N); 56.3 ppm (C4); 55.1 ppm (Cllb); 52.4 ppm (C6); 36.83 ppm and 36.80 ppm (NCH3 and C2); 36.2 ppm
(C1); 30.2 ppm and 29.9 ppm (C3 and C7).

Example 90
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methyl, N'-methylthiourea
Addition of 345 mg (4.7 mmol, 1.2 eq) of methyl isothiocyanate to a solution of 1 g of amine obtained in Example 89 (3.8 mmol) in 20 ml CH2Cl2. After 17 hours of reaction at ambient temperature, the reaction mixture is washed with 1N NaOH, dried over MgSO4 and then evaporated to dryness. The crude oil obtained is purified by chromatography on a silica column (eluent CH 2 Cl 2 / MeOH / NH 4 OH 95 / 4.5 / 0.5). The pure thiourea is isolated in a yield of 37 W.

Rf (CH2Cl2 / MeOH 90/10): 0.40 tof (oxalate): 1050C
1 H NMR (400 MHz, CDCl 3) (base): 7.10 ppm (d, J = 8.7
Hz; 1H; H11); 6.72 ppm (dd; J = 8.7 and 2.6 Hz; 1H
H10); 6.62 ppm (d, J = 2.6 Hz, 1H, H8); 5.50 ppm
(m; 1H; NH); 3.78 ppm (s, 3H, OCH3); 3.68 ppm (m 2H; CH 2 N); 3.22 ppm (s, 3H, NMe); 3.17 ppm (d, J = 4.4 Hz, 3H, NHMe); 3.27-3.14 ppm (m; 2H; H7a,
Hllb); 3.11-2.98 ppm (m; 2H; H6a and H4a); 2.72 ppm
(m; 1H; H7a); 2.56 ppm (m; 1H; Hla); 2.40 ppm (m 1H, H6b); 2.32-2.18 ppm (m, 2H, H4b and H2); 1.76 ppm (m; 1H; H3a); 1.56 ppm (m; 1H; H3b); 1.24 ppm (m; 1H; H1b).

Elemental analysis:
Theoretical: C (56.72), H (6.90), N (9.92)
Experimental: C (56.64), H (6.71), N (9.68)
Example 91
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methyl-N'-phenylurea
In a similar manner to Example 90 but using the corresponding reagents, the title compound is obtained tof (oxalate): 1170C
Elemental analysis:
Theoretical: C (63.95), H (6.65), N (8.95)
Experimental: C (64.29), H (6.54), N (8.49)
Example 92
(RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzofluoro-zinyl) -methyl-methyl cinnamine
In a similar manner to Example 1 but using the corresponding reagents, the title compound is obtained tf (oxalate !: 1240C
Elemental analysis Theoretical: C (67.48), H (6.71), N (5.83)
Experimental: C (67.44), H (6.44), N (5.82)
Example 93
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -ethyl-cinnamamide
In a similar manner to Example 1 but using the corresponding reagents where the (RS), (SR) -N- [2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H) benzo [a] quinolizinyl) methyl] ethylamine is obtained analogously to the amine of Example 89 but using the compound of Example 47, the title compound is obtained tof (oxalate): 1200C
Elemental analysis:
Theoretical: C (68.00), H (6.93), N <5.66)
Experimental: C (67.72), H (6.76), N (5.60)
Example 94
(RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methyl-benzamide
In a similar manner to Example 1 but using the corresponding reagents, the title compound is obtained tof (oxalate): 1500C
Elemental analysis
Theoretical: C (66.06), H (6.65), N (6.16)
Experimental: C (65.47), H (6.24), N (5.82)
Example 95
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3-cyclohexylacrylamide.

Stage 1 3-cyclohexyl ethyl acrylate
To a solution of 5 g of cyclohexylcarboxaldehyde
(44.6 mmol) in 100 ml CH 2 Cl 2, 17.1 g carboxymethylenetriphenylphosphorane (49.1 mmol 1.1 eq) was added. After 72 hours of reaction at ambient temperature, the solvent is evaporated and the residue is taken up in petroleum ether. The insolubles are separated by filtration, and the filtrate is evaporated to dryness. 5.25 g of a light yellow oil are isolated (yield = 65%).

1 H NMR (400 MHz, CDCl 3): 6.82 ppm (dd, J = 15.8 and 6.8
Hz; 1H; H3); 5.77 ppm (dd; J = 15.8 and 1.3 Hz; 1H;
H2); 4.11 ppm (q, J = 7.1 Hz, 2H, CH 3 CH 2 O); 2.15 ppm (m; 1H; H1 '); 1, 1.73-1.59 ppm (m; 5H; equatorial H) 1.33-1.06 ppm (m; 8H; H axial and CH3CH2O).

Stage 2
3-cyclohexyl-acrylic acid
A solution containing 5.25 g (28.8 mmol) of 3-cyclohexyl-ethyl acrylate, 50 ml 1N NaOH and 50 ml THF is stirred at room temperature for 50 h. After decantation, the aqueous phase is washed with ether, acidified with concentrated H 2, and then extracted with CH 2 Cl 2. The organic phase is dried with MgSO4, filtered and then evaporated to dryness. 4.4 g of a cream solid (.rdt = 99%) are isolated.

1 H NMR (400 MHz, CDCl 3): 6.75 ppm (dd, J = 15.7 and 6.7
Hz; 1H; H3); 5.68 ppm (dd; J = 15.7 and 0.7 Hz; 1H)
H2); 2.12 ppm (m; 1H; H1 '); 1.75-1.58 ppm (m; 5H; equatorial H); 1.32-1.04 ppm (m; 5H; H axial).

Stage 3
3-cyclohexyl-acryl chloride
A solution containing 1 g of 3-cyclohexyl-acrylic acid
(6.5 mmol) and 2.83 g SOCl2 (4.63 g, 39 mmol, 6 eq) was heated at 750 ° C. for 4 hours. The residue is taken up in toluene and then evaporated to dryness. 1.1 g of a brown oil are obtained (yield = 98%).

1 H NMR (400 MHz, CDCl 3): 6.76 ppm (dd, J = 15.7 and 6.8
Hz; 1H; H3); 5.70 ppm (dd; J = 15.7 and 1.3 Hz; 1H;
H2); 2.15 ppm (m; 1H; H1 '); 1.80-1.58 ppm (m; SH; Equatorial H); 1.32-1.03 ppm (m; 5H; H axial).

Step 4 (PS), (SP) -N- [2- (1,3,4,6,7, 1H-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3-cyclohexylacrylamide
Addition dropwise of 320 mg of acid chloride
(1.8 mmol, 1.2 eq) to a solution of 380 mg of amine obtained in Step 5 of Example 1 (1.5 mmol) in 15 ml THF. The reaction is kept at room temperature for 48 hours. The reaction mixture is then evaporated to dryness and the residue is taken up in CH 2 Cl 2 and then washed with 1N NaOH. The organic phase is dried over MgSO 4, filtered and then evaporated to dryness. The crude oil obtained is purified by chromatography on a silica column (eluent
CH 2 Cl 2 / MeOH / NH 4 OH 98 / 1.7 / 0.3). 184 mg of brown solid are isolated (yield = 31%).

Rf (CH2Cl2 / MeOH / NH4OH 90/9/1) = 0.47 tof (oxalate): 1400C
1 H NMR (400 MHz, CDCl 3) (base): 7.11 ppm (d, J = 8.6).
Hz; 1H; H11); 6.81 ppm (dd, J = 15.4 and 6.7 Hz, 1H cyclohex-CH = C); 6.72 ppm (dd, J = 8.6 and 2.6 Hz 1H, H10); 6.61 ppm (d, J = 2.6 Hz, 1H, H8); 5.71 ppm (dd, J = 15.4 and 1.0 Hz, 1H, -CH = CH-CO); 5.65 ppm (m; 1H; NH); 3.77 ppm (s, 3H, OCH3); 3.29 ppm
(m; 2H; CH2N); 3.23-3.10 ppm (m; 2H; H7a, H11b) 3.07 ppm (m; 1H; H4a); 3.01 ppm (m; 1H; H6a); 2.70 ppm (m; 1H; Hla); 2.54 ppm (m; 1H; H7b); 2.41-2.30 ppm (m; 2H; H4b and H6b); 2.10 ppm (m; 1H; cyclohexyl CH); 1.94-1.70 ppm (m; 6H; H2 and equatorial cyclohexyl); 1.65 ppm (m; 1H, H3a); 1.48 ppm (m 1H, H3b); 1.35-1.08 ppm (m; 6H; Hla, axial cyclohexyl H).

Elemental analysis:
Theoretical: C (66.08), H (7.68), N (5.93)
Experimental: C (65.70), H (7.26), N (5.67)
Example 96
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-2H-benzo] quinolinyl) methyl] cinnamami
Stage 1 3,4-dihydroisoquinoline hydrochloride
In a flask of 11 are introduced 20 ml (150 mmol) of 1,2,3,4-tetrahydroisoquinoline dissolved in 350 ml of CH2Cl2, and 29.5 g (l, leq) of NBS. The reaction mixture is stirred for 4 hours at room temperature and then overnight after the addition of 100 ml of concentrated NaOH. The organic phase is recovered after decantation, washed with water and extracted with 1N HCl. The aqueous phase is basified with concentrated NH 4 OH and extracted with CH 2 Cl 2. The new organic phase is then washed with a saturated solution of NaCl, dried over MgSO 4, filtered and then evaporated to dryness. We recover a brown oil: m = 16.5g
The salt is in the form of a yellow solid, it is obtained by adding 44.6 ml of a solution
3.1M HCl / iPrOH. The overall yield is 73.4%.

1 H NMR (400 MHz, DMSOd 6): 13.99 ppm (s, 1H, NH); 9,23ppm
(s, 1H, H1); 7.92 ppm (m, 1H, H8); 7.79 ppm (m, 1H, H5) 7.52 ppm (m, 2H, H6, H7); 3.94ppm (t, J = 8Hz, 2H, H3); 3.15ppm (t, J = 8Hz, 2H, H4).

Stage 2 1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-2-one
In a flask, 10 g (60 mmol) of the hydrochloride of the preceding stage 1 and 15 ml (3eq) of methyl vinyl ketone are heated at 60 ° C. for 4 hours. After addition of acetone, a brown solid is recovered by filtration. The solid is taken up in CH 2 Cl 2 and then extracted with 1N HCl. After basification, the aqueous phase is extracted with CH 2 Cl 2.

The organic phase is filtered, dried over MgSO 4 and then evaporated to dryness to give 9.52 g of a brown solid. The yield is 67%.

1 H NMR (400 MHz, CDCl 3): 7.17 ppm (m, 3H, aromatic H) 7.08 ppm (m, 1H, aromatic H); 3.58ppm (dd, J = 12Hz and 2.4Hz, 1H, H11b); 3.28 ppm (m, 1H, H4eq); 3.16 ppm (m, 2H, H7ax and H6eq); 2.95 ppm (dm, J = 14.4Hz, 1H, Hleq) 2.83ppm (m, 1H, H7eq) 2.74-2.62ppm (m, 3H, H3eq, H4ax and H6ax); 2.52-2.42ppm (m, 2H, H1ax and H3ax)
Stage 3
(RS), (SR) -1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizine 2-carbonitrile
In a 500ml flask, introduced at 0 C 8.52g
(42.3mmol) of the previous stage 2 ketone, 150ml of
DME, 8.26g (leq) of TosMIC and 2.5ml (leq) of ethanol. The reaction mixture is stirred for 30 minutes; 9.5 g (2eq) of tBuOK are added and stirring is continued for another 30 min at OOC. After returning to ambient temperature, the reaction mixture is heated at 900 ° C. for 4 h, filtered and then evaporated to dryness. Flash chromatography (petroleum ether / ethyl acetate: 8/2) separates the two isomers.

Three fractions are recovered: 1st fraction, diastereoisomer A, 3.2 g of yellow solid (R = 36%); 2nd fraction, 0.73 g of mixture of diastereoisomers A and B
th yellow solid (R = 13%).

1 H NMR (400 MHz, CDCl 3) diastereoisomer A: (RR), (SS) -7.20-7.09 ppm (m, 4H, aromatic H); 3.18 ppm (d, J = 10.4 Hz, 1H, H11b) 3, O6ppm (m, 1H, H7ax); 3.03ppm (dm, J = 12Hz, 1H, H4eq) 2.94ppm (m, 1H, H6eq) 2.74-2.63ppm (m, 3H, H1ax, H2,
H7eq); 2.55ppm (dt, J = 11.6Hz, J = 3.6Hz, 1H, H6ax) 2.34ppm (dt, J = 12Hz, J = 2Hz, 1H, H4ax) 2 2.08-1.92ppm (m , 2H, H3ax and H3eq); 1.74 ppm (q, J = 12.4 Hz, 1H, Hleq). diastereoisomer B: (RR), (SS) -7.19-7.09ppm (m, 4H, aromatic H); 3.58 ppm (d, J = 11.2 Hz, 1H, H11b); 3,183.07ppm (m, 2H, H7ax and H2); 2.98-2.94ppm (m, 2H, H6eq and H6ax) 2.76-2.60ppm (m, 3H, Hleq, H4eq and H7ax) 2.53ppm (d, J = 13.6Hz, 1H, H4ax ); 2.19 ppm (m, 2H, H3ax and
H3eq); 1.17 ppm (dt, 1H, H1ax).

Step 4 2- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl) methylamine
Lg (4.7 mmol) of diastereoisomeric nitrile A was dissolved in 80 ml of methanol. It is cooled to 0 ° C. and then 5.2 g (5 eq) of nickel chloride are added. Sodium borohydride (ss) is slowly added. The reaction mixture is stirred at 0 ° C. for 1 hour and then at room temperature for 30 minutes. The solvent is evaporated. The nickel salts are suspended with 1N NaOH and the amine is extracted with CH 2 Cl 2. The nickel complexes are removed by filtration on celite. After several successive washings with CH 2 Cl 2, the filtrate is evaporated to dryness. A brown oil with a mass of 0.9 g is obtained, with a yield of 86%.

1 H NMR (400 MHz, DMSOD 6) 7.26 ppm (m, 1H, aromatic H) 7.14-7.0 Opp (solid, 3H, aromatic H); 3.30 ppm (bs, 1H, NH 2); 3.03 ppm (d, J = 10.8 Hz, 1H, H11b); 2.952.88 ppm (solid, 2H, H7ax and H4eq); 2,66-2,34ppm
(solid, 6H, CH2NH2, H7eq, H6eq, H4ax and Hleq); 2,22ppm
(m, 1H, H6ax); 1.68 ppm (d, J = 12.8 Hz, 1H, H3eq); 1,46ppm
(m, 1H, K2); 1.7 ppm (m, 1H, H3ax); 0.88ppm (q, J = 12Hz, 1H, H1ax).

Step 5 (PS), (SP) -N- [2- (1,3,4,6,7, 1H-hexahydro-2H-benzo [a] quinolizinyl) methyl] -cinnamamide
Into a 100 ml flask, 450 mg (2 mmol) of the aminomethyl obtained in Step 4 above, 15 ml of THF and 0.4 ml (2.5 eq) of pyridine. 416 mg (1.2 eq) of cinnamoyl chloride dissolved in 10 ml of THF are added dropwise. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated, a brown solid is recovered. After extraction
CH 2 Cl 2 / 1N NaOH and purification by flash chromatography (eluent: CH 2 Cl 2 / MeOH / NH 4 OH: 98 / 1.7 / 0.3) gives 279 mg of an orange solid (R = 39%). To this base dissolved in a minimum of MeOH is added 41 mg (lq) of oxalic acid dissolved in a minimum of acetone. This makes it possible to form the oxalate salt of the
1.92ppm (m, 1H, H2); 1.80ppm (d, J = 12.4Hz, 1H, H3eq)
1.47ppm (dq, J = 12.4 and 4Hz, 1H, H3ax); 1.22ppm (q,
J = 12Hz, 1H, H1ax).

Rf (CH 2 Cl 2 / MeOH / NH 4 Cl 90/9/1) = 0.49
Elemental analysis:
Theoretical: C (68.79), H (6.47), N (6.42)
Experimental: C (69.24), H (6.42), N (6.39)
Example 97
(RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl) methyl] -N'-methylthiourea
To a solution of 450 mg (2 mmol) of the amine obtained in Step 4 of Example 96 dissolved in 25 ml of CH 2 Cl 2, 183 mg (1.2 eq) of methyl isothiocyanate dissolved in 20 ml of CH 2 Cl 2 are introduced dropwise. Stirring is maintained at room temperature overnight. A brown oil is obtained after evaporation of the solvent. This is purified on a silica column (eluent:
CH 2 Cl 2 / MeOH / NH 4 OH: 97 / 2.5 / 0.5).

Rf (CH2Cl2 / MeOH / NH4CH 90/9/1) = 9.37 tf (oxalate): 1940C
1 H NMR (400 MHz, CDCl 3): 7.26-7.09 ppm (solid, 4H, aromatic H); 4.74ppm (ss, 2H, NH); 3.42ppm (m, 2H,
CH2NH); 3.17 ppm (d, J = 12Hz, 1H, H11b); 3.15 ppm (m, 1H,
H7ax); 3.03 ppm (s, 3H, CH 3 N); 3.12-2.96ppm (m, 2H,
H6eq, H4eq); 2.71ppm (d, J = 16Hz, 1H, H7eq); 2.53ppm (dt,
J = 11.6 and 3.6 Hz m, 1H, H max); 2.40-2.33ppm (massive, 2H,
H4ax and H1ax); 1.98 ppm (m, 1H, H2); 1.80 ppm (d, J = 12.8 Hz, 1H, H3eq); 1.45ppm (dq, J = 12.4 and 4Hz, 1H, H3ax); 1.18 ppm (q, J = 12Hz 1H, H1ax).

Elemental analysis:
Theoretical: C (56.97), H (6.64), N (11.07)
Experimental: C (56.90), H (6.84), N (10.40)
Example 98
(PS), (SP) -N- [2- (1,3,4,6,7, 1H-hexahydro-9-fluoro-2H-benzo [a] quinolizinyl) methyl] -cinnamamide
Stage 1 6-fluoro-1,2,3,4-tetrahydroisoquinoline.

9 ml (69 mmol) of 3-fluorophenylethylamine, 90 ml of concentrated HCl and 41 ml of formaldehyde are introduced. The reaction mixture is heated at 1000C for 6h and then thrown into water. The aqueous phase is washed with ether, basified with concentrated NaOH and extracted with CH 2 Cl 2. The organic phase is washed with a saturated solution of
NaCl, dried over MgSO4, filtered and then evaporated to dryness. N, N'-bis- (6-fluoro-1,2,3,4-tetrahydroisoquinoline) methylene is obtained in the form of a yellow paste.

This amine is hydrolyzed in 1N HCl for 4 hours at 750C.

The aqueous phase is neutralized with NaOH and then extracted in CH2Cl2. After purification by flash chromatography in a mixture of CH 2 Cl 2 / MeOH / NH 4 OH: 95/4/1, 1.835 g of the title compound is recovered in the form of a yellow oil with a yield of 17.5.

1H NMR (400MHz, DMSOd6): 7.02ppm (m, 1H, H8); 6.90 ppm (m, 2H, H5, H7); 3.78ppm (s, 2H, H1); 2.90ppm (t,
J = 5.8 Hz, 2H, H4); 2.67ppm (d, J = 5.8Hz, 2H, H3).

13 C NMR (100.6 MHz, CDCl 3): 161.09 ppm (d, 1 ° C-F = 243 Hz,
C6); 136.76 ppm (t, JCCJ-F = 7 Hz, C4); 131.28 ppm (C8a); 127.61 ppm (d, 3 ° C-F = 7.9 Hz, C8); 115.44ppm (d, 2JC-F = 20.4Hz, C5 or C7); 112.85ppm (d, 2JC-F = 21.4Hz, C5 or
C7); 47.70 ppm (C1); 43.42 ppm (C3); 29.22 ppm (C4).

Stage 2 6-fluoro-3,4-dihydroisoquinoline
350mg (2.3mmol) of the saturated compound of the preceding stage, 5ml of CH2Cl2 and 451mg are introduced into a 100ml flask.
(1,1eq) NBS. The same procedure as that of the compound obtained in Example 96 Stage 1 is applied, 230 mg of a yellow oil is obtained (R = 66.8%).

1 H NMR (400MHz, DMSOd6): 8.32 ppm (s, 1H, H1); 7,46ppm
(dd, 1H, H8); 7.12 ppm (m, 2H, H7, H5); 3.62ppm (t, 2H,
H3); 2.70ppm (t, 2H, H4).

Stage 3 9-fluoro-1,3,4,6,7,11b-hexahydro (2H) benzo [a] quinolizine2-one
2.03 g (10.9 mmol) of the hydrochloride of the compound obtained in the preceding stage and 2.7 ml (3eq) of methyl vinyl ketone are introduced. It is heated at 600C for 3h. 1.39 g of the salt of the title compound are obtained. After acid-base extraction, 1.15 g of a brown oil is recovered with a yield of 48%.

1 H NMR (400MHz, CDCl 3): 7.03ppm (dd, J = 8.611Hz, J = 5.6Hz, 1H, H11); 6.87 ppm (m, 2H, H8, H10); 3.54ppm (d,
J = 11.6 Hz, 1H, H11b); 3.28 ppm (m, 1H, H4eq); 3.14 ppm (m, 2H, H7ax and H6eq); 2.92ppm (dm, J = 14.4Hz, 1H, Hleq) 2.83ppm (m, 1H, H7eq) 2.73-2.6lppm (m, 3H, H3eq, H4ax and H6ax); 2.50-2.42ppm (solid, 2H, Hlax and H3ax).

Stage 4
(RS), (SR) -9-fluoro-1,3,4,6,7,11b-hexahydro (2H) benzo [a] quinolizine-2-carbonitrile
The procedure is identical to that of stage 3 of compound 96. The amounts involved are 1.15 g (5 mmol) of ketone of the stage. above, 20 ml dimethoxy ether, 1.0 g (1 eq) tosylmethylisonitrile, 0.3 ml (1 eq) ethanol and 1.18 g tBuOK. The overall yield of the reaction after flash chromatography in a mixture: petroleum ether / ethyl acetate: 5/5, is 68.4 8. 40.8 k of the diastereoisomer A and 23.3% of the diastereoisomer B are isolated. .

1 H NMR (400 MHz, CDCl 3) diastereoisomer A: (RS), (SR) -7.10 ppm (dd, JmF = 5.6 Hz and
JoH = 8.6 Hz, 1H, H11); 6.87 ppm (ddd, JoF = 8.5 Hz, JmH = 2.5 Hz, 1H, H8); 6.80 ppm (dd, JoF = 9.3 Hz, JmH = 2.5 Hz, 1H, H10); 3.13 ppm (d, J = 10.8 Hz, 1H H11b); 3.10 ppm (m, 1H, H7ax); 3.02 ppm (dm, J = 12Hz, 1H, H4eq); 2.94 ppm (m, 1H, H6eq) 2.74-2.65 ppm (m, 2H, H2, H6ax); 2.61 ppm (dm, J = 12.8 Hz, 1H, H7eq); 2.51 ppm (m, 1H, Hleq); 2.34ppm (td, J = 12Hz,
J = 2.8Hz, 1H, H4ax); 2.07 ppm (m, 1H, H3eq); 1.99 ppm (m, 1H, H3ax); 1.72ppm (q, J = 11.6Hz, 1H, H1ax). diastereoisomer B (RR), (SS) -7.10 ppm (dd, JmF = 5.6 Hz,
JoH = 8.6 Hz, 1H, H11); 6.88ppm (ddd, JoF = 8.4Hz, JoH = 8.6Hz,
JmH = 2.5Hz, 1H, H8); 6.80 ppm (dd, JoF = 9.3, JmH = 2.5 Hz, 1H, H10); 3.53ppm (d, J = 11.2Hz, 1H, H11b); 3,18-3,07ppm
(m, 2H, H7ax and H2); 2.98-2.94ppm (m, 2H, H6eq and
H6ax); 2.76-2.60ppm (m, 3H, H1eq, H4eq and H7ax) 2.49ppm (d, J = 13.2Hz, 111, H4ax); 1.98ppm (m, 2H, H3ax and
H3eq); 1.70ppm (ddd, 1H, H1ax).

Stage 5
(RS), (SR) -2- (9-fluoro-1,3,4,6,7,11b-hexahydro (2H) benzo [a] quinolizinyl) methylamine
The procedure is identical to that of Stage 4 of Example 96. The quantities involved are 494 mg (2.7 mmol) of the nitrile A of the previous stage, 3.16 g (5 eq) of nickel chloride, 649 mg (8 eq) of NaBH4, 40ml of methanol. A brown oil is obtained with a yield of 97.8%. The amine is directly engaged in the next step.

Step 6 (RS), (SR) -N- [2- (9-fluoro-1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl) methyl] -cinnamamide
The procedure is identical to that of Step 5 of Example 96. The quantities involved are 498 mg (Smmol, 1 eq) of the amine of the previous stage, 15 ml of THF, 0.4 ml (2.5 eq) of pyridine, 425 mg (1,2eq) cinnamoyl chloride. Purification on a silica column makes it possible to recover 304 mg of the title compound.

Rf (CH2Cl2 / MeOH / NH4CH 95/5 / 0.5) = 0.43 tf (oxalate) = 1640C
H NMR (400MHz, CDCl3): 7.65ppm (d, J = 15.6Hz, 1H, Ph)
CH = CH); 7.50ppm (dd, J = 7.7 and 2.7Hz, 2,
Horthocinnamic); 7.36ppm (m, 3H, Hmeta and
Hparacinnamic); 7.15 ppm (dd, JmF = 5Hz, 7Hz, JoH = 8.6Hz 1H,
H11); 6.83ppm (dt, JoF = 8.5Hz, JmH = 2, GHz, 1H, H10) 6.76ppm dd, JoF = 9.4Hz, JmH = 2.3Hz, 1H, H8); 6.41 ppm (d, J = 1F, 6Hz, 1H, CH = CHCO); 5.83ppm (bs, 1H, NH) 3.36ppm (m, 2H, CH 2 NH 3; 11ppm (d, J = 11.6Hz, 1H, m.p.
H11b); 3.10 ppm (m, 1H, H7ax); 3.03ppm (dm, J = 11.6Hz, 1H, H4eq); 2.96 pm (m, 1H, H6eq); 2.69ppm (d, J = 16.8Hz, 1H, H7eq); 2.50pm (dt, J = 11.6 and 4Hz, 1H, H6ax); 2,372.31 ppm (m, 2H, H4ax, H1eq); 1.91ppm (m, 1H, H2) 1.80ppm (d, J = 12.8Hz, 1H, H3eq); 1.45ppm (ddd, J = 12.4 and 4Hz, 1H, H3ax); 1.18 ppm (q, J = 14.2 Hz, 1H, H1ax).

Elemental analysis:
Theoretical: C (66.07), H (5.99), N (6.16)
Experimental: C (65.72) H (6.02), N (6.13)

Claims (15)

 cyclic, a halogen atom such as F or Cl.  hydroxy or C1-C4 alkoxy, branched, linear or  Ci-4, linear, branched or cyclic, a group  in which in particular R 1 represents a hydrogen atom or an alkyl group of

 CLAIMS 1 - A compound of formula I R2 represents a hydrogen atom or a C1-C6 alkyl group.  or sulfur.  then a urea or thiourea as with X = oxygen  constitute a pattern (C = X) -NR4Rs and constitutes R3 represents a hydrogen atom or can  substituted.  aroyl, these aryl groups can also be  branched, cyclic, an aryl group, araikyl,  or a linear C1-8 alkyl group, R4 and R5 can be independently a hydrogen atom R4 and R5 may be linked by a carbon chain optionally incorporating a heteroatom. R3 may also represent an optionally substituted alkylsulphonyl or arylsulphonyl group. R3 represents a hydrogen or an acyl or thioacyl group such that (C = X) -R6, where X represents an oxygen or sulfur atom. R6 may represent a hydrogen or a C1-10 linear, branched or cyclic alkyl group, incorporating or not a heteroatom, such as oxygen or sulfur, incorporating a double bond conjugated or not conjugated with the carbonyl C = X. R6 may also be a linear, branched or cyclic C18 alkoxy group, an optionally substituted aralkoxy group. CF3, CN, COCH3, or thiophene, furan, pyrrole, pyridine and their benzofused derivatives. R6 also represents an aromatic or heteroaromatic group, such as a phenyl or naphthyl optionally substituted one or more times with a C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, NO 2, R4 represents an aralkyl, aryloxyalkyl group, the aryl portion of which may be substituted and wherein the alkyl chain may be linear, branched or cyclic. R6 may include several aromatic ring systems such as 2-indanyl, fluorenyl, coumarinyl or benzopyranyl. R6 may also represent an aralkenyl group. The aryl group conjugated with a double bond may be phenyl, naphthyl, polyaromatic as biphenyl or fluorenyl, heteroaromatic and its benzofused derivatives. This aryl group may be optionally substituted one or more times with C1-8alkyl, C1-8alkoxyhalogenyl, NO2, CF3, CN, OCF3, OCH2O, or form a bicyclic ring with a saturated or unsaturated ring, with or without a ring. a heteroatom such as O, N or S thus forming an indole, benzofuran or benzothiophene. The alkenyl group may be optionally substituted with halogens, CN, alkyl, phenyl. The motif (C = X) -R6 thus forms a cinnamoyl group. The term aryl represents a phenyl or naphthyl ring, the term aralkyl meaning an aryl group attached to an alkyl chain of at least one carbon atom and which may be linear, branched or cyclic. The heteroaromatic group may be a 5- or 6-membered aromatic ring having one or more heteroatoms selected from N, O or S, as well as their benzofused derivatives. They thus form pyridine, furan, thiophene, indole, benzofuran, benzothiophene, benzoxazine, quinoxaline, quinazoline, benzimidazole, benzopyrazole. 2 - A compound according to claim 1, characterized in that R1 represents a hydrogen, a methoxy group, a methyl or a fluorine. 3 - Compound according to claim 1 and 2, characterized in that R2 represents a hydrogen, a methyl or an ethyl. 4 - Compound according to claim 1, 2 and 3 characterized in that R3 represents a group (C = X) NR4Rs and thus forms a urea or a thiourea, X = O or S. 5 - Compound according to claims 1, 2 and 3, characterized in that R3 forms a group (C = X) R6 and R6 represents an alkyl or aryl group. 6 - Compound according to claims 1, 2 and 3, characterized in that R3 forms a group (C = X) R6 and R6 represents an aralkenyl group. The group (C = X) R 6 and selected from cinnamoyl or thiocinnamoyl groups substituted on the aromatic part by one or more C1-4 alkoxy, methylenedioxy, alkylC1-6, OH, halogen such as F, Cl. 7 - Compound according to claims 1 to 6, characterized in that it is selected from the following compounds (PS), (SP) -N- [2 (1,3,4,6, 7, 11b-hexahydro-9 -methoxy-2H-benzo [a] quinolizinyl) methyl] propanamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b) hexahydro-9-methoxy-2H-benzo] quinolizinyl) methyl] -cyclohexylcarboxamide.  (PS), (SP) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] isobutanamide.  (PS), (SP) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -phenyl (&alpha;, &alpha; cyclopropyl) acetamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -phenylacetamide.  (PS), (SP) -N- [2- (1,3,4,6,7,7-Hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -9'H-fluorenyl-9 'carboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3-phenylpropanamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-indanecarboxamide. (PS) (SP) -N- [2- (1,3,4,6,7,11b) hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-chlorophenoxyacetamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 3', 4 ', 5 ', 6'pentafluorophénoxyacétamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -phenoxyacetamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methoxyacetamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] acetamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -thioacetamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -1'-methoxy-2-naphthalenecarboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-pyridinecaboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-thiophenecarboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-furanecaboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-naphthalenecarboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -1'-naphthalenecarboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-trifluoromethylbenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-methoxybenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-chlorobenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-chlorobenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-chlorobenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-trifluoromethylbenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] benzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -thiobenzamide.  (PS), (SP) -N- [2- (1,3,4,6,7,16-Hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] thio cinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3-cyclohexylacrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -cyclohexenylcarboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3- (2'-furyl) acrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-benzofurancarboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3- (1'-naphthyl) - acrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3- (2'-naphthyl) acrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -9'H-fluorenyl-9'-methylenecarboxamide .  (PS), (SP) -N- [2 (1,3,4,6,7, 1H-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-phenylcinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-coumarinecarboxamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] - (2'-thienyl) - 3-acrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] - (3'-thienyl) -3- acrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl) methyl] -cinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-fluoro-2H-benzo [a] quinolizinyl) methyl] -cinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 3', 4 ', 5', 6'-pentafluorocinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2,3-diphenylacrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2-cyano-3-phenylacrylamide .  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2-methyl-3-phenylacrylamide .  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2-fluoro-3-phenylacrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-methoxybenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-methoxybenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-nitrobenzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3'-trifluoromethylcinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-chlorocinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3 ', 4', 5'- triméthoxycinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] cinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-fluorocinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-chloro-6 ' -fluorocinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 4', 5 '-triméthoxycinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3 ', 4'-dimethoxycinnamamide .  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-methylcinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 3'-dimethoxycinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2 ', 5'-dimethoxycinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolinyl) methyl] -2 ', 4'-dimethoxycinnamainide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -2'-methoxycinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -4'-fluorocinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -3 ', 4'-methylenedioxycinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolinizinyl) methyl] -N '- (2-methoxyethyl) thiourea .  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-ter-octylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-1H-benzo [a] quinolizinyl) methyl] -N'-tert-butylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-cyclohexylmethylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-butylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-2-phenylethylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-benzylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N ', N'-dimethylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-methylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-isobutylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-cyclohexylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-benzoylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N '- (2'-naphthyl) thiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N '- (1'-naphthyl) thiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-phenylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-phenylurea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N'-methylurea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N ', N'-dimethylurea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizinyl) methyl] -N'-methylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methyl-benzamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -ethyl-cinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methyl-cinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -methyl-N'-phenylurea.  (RS), (SR) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methyl, N'-methylthiourea.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] formamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -N'-benzoylurea.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] -quinolizinyl) methyl] benzylcarbamate.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -N, N'-dimethylsulfonylurea.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] methylsulfonamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -phénylsulfonamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -méthyloxamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -2'H-benzopyran-3'carboxamide .  (RS), (SP) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] -quinolizinyl) methyl] -3,3-dimethylacrylamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b) -hexahydro-9-methoxy-2H-benzo [alquinolizinylmethyl] -3'-phenylpropynamide.  (SS), (RR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] -cinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11-hexahydro-9-methoxy-2Hbenzo [a] quinolizinyl) methyl] -4'-nitrocinnamamide.  (RS), (SR) -N- [2- (1,3,4,6,7,11b-hexahydro-9-ethoxy-2H-benzo [a] -quinolizinyl) methyl] -cinnamamide.  (PS), (SP) -N- [2- (1,3,4,6,7,11b -hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methyl] methyl-N ', N' dimethyl thiourea. 8 - Compound according to claims 1 to 7 characterized in that it is in a diastereoisomerically pure and enantiomerically pure form, forming a salt with inorganic or organic acids such as hydrochloride, sulfate, methanesulfonate, maleate, fumarate, citrate, succinate , tartrate. 9 - Process for the preparation of a compound according to one of claims 1 to 8, characterized in that a compound of formula II is reacted with tosylméthylisonitrile in basic medium, which separates the diastereoisomers, that the the nitrile is reduced to the primary amine, and this amine is reacted with isocyanates, alkyl or aryl isothiocyanates, carbanoyl or thiocarbanoyl chlorides, or with aliphatic acid chlorides, aromatic or cinnamic. 10 - Process for the preparation of a diastereomerically pure compound by chromatographic separation or by crystallization of the diastereoisomeric mixtures obtained during the synthesis according to claim 9 as soon as the chiral center in position 2 appears. 11 - Process for preparing an enantiomerically pure compound from a compound obtained according to claim 10 by chiral column separation HPLC. 12 - Process for preparing the salt of a compound obtained according to claim 11, characterized in that the basic compound is treated with a stoichiometric amount of the acidic agent. 13 - As a medicament, the compound according to one of claims 1 to 8. 14 - Pharmaceutical composition characterized in that it comprises at least one compound of formula I according to claims 1 to 8 and a suitable excipient. 15 - Use of a compound of formula I according to one of claims 1 to 8, for the preparation of a medicament for the treatment of neurodegenerative diseases, in particular the disease of Parkinson's disease, Alzheimer's disease, Parkinson's disease Huntington, cognitive and memory disorders, attention deficit and vigilance deficits of the elderly, ischemic and post-ischemic cerebral disorders, as well as the progression of neurodegenerative diseases.