CA2307748A1 - Aminomethyl-benzo[a]quinolizidine derivatives, preparation and therapeutic applications for neurodegenrative diseases - Google Patents

Abstract

The invention concerns 2-aminomethyl-benzo[a]quinolizidine derivatives, corresponding to general formula (I) in which: R¿1? represents either a hydrogen atom or a branched, linear or cyclic C¿1?-C¿4? alkyl group, a branched, linear or cyclic C¿1?-C¿4? hydroxy or alkoxy group, or a halogen atom such as F or Cl; R¿2? represents a hydrogen atom or a C¿1?-C¿6? alkyl group; R¿3? represents a hydrogen atom or can constitute a unit (C=X)-NR¿4?R¿5? and in that case constitutes a urea or thiourea with X = oxygen or sulphur; R¿4? and R¿5? can independently be a hydrogen atom or a linear, branched, cyclic C¿1?-C¿8? alkyl group, an aryl, aralkyl, aroyl group, said aryl groups capable of being substituted as well; R¿4? and R¿5? can be bound by a carbon chain optionally incorporating a heteroatom.

Description

Aminomethyl benzo derivatives [a) quinolizidine, their preparation and their application in therapy for neurodegenerative diseases The present invention relates to new derivatives of benzo (a] quinolizidine, and methods of preparing them.
It also relates to the use of these compounds as ~
of medicine, as well as for the preparation of a drug used as an a2 receptor antagonist adrënergiques and intended as such to treat neurodegenerative diseases. Are concerned. disease Parkinson's, Alzheimer's disease, chorea Huntington's, cognitive and memory impairment, attention and alertness deficits in the elderly, as well 1 ~ that ischemic and post ischemic disorders cerebral.
It has been shown that the locus coeruleus plays a role preponderant in the recovery of functions 20 dopaminergics altered by administration of MPTP in the monkey (Mavridis, Neuroscience (1991), 4î, 50î). Her destruction leads to a reduction in recovery.
Furthermore, compounds having an u2 action

2; antagonist are able to reduce symptoms Parkinsonian in monkeys (Colpaert, Brain Ris. Bull., (1991), 26, 627) or in the rat (Colpaert, Neuropharmacology (198'7), 25, 143), and this may be by increased dopamine release (Marry, 3n Naradrenergic Mechanisms in Parkinson's Disease, p.139, (1994), CRC Press, 3oca Raton. ; Marry and Colpaert, EfTec = of (+) - efaroxan on mouse striatal dooa: ~, ir. =
r. ~, etabolism in vivo. Dopamine 94 - Satellite ~!. = _ Jti; ~ g o.
tea KTTth Int. Corgr. Pharmacclogy, yuebec City, Ca: ~ ada, ~ 5 July 20-24, 199x).
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In addition, Idazoxan, a known antagonist compound a2, has shown to have a beneficial effect on the deleterious effects of cerebral ischemia (Gustafson, Exp. Brain. Res., (1991), 36, 555, and J. Cereb. Blocd Flow Metab., (1990), 10, 885), as well as in supranuclear palsy progressive, also a neurodegenerative disease (Ghika, Neurology, (1991), 41, 986). He was also shown that compounds with antagonist a2 activity cause an increase in the release of acetylcholine 10 at the level of the prefrontal cortex (Tellez, J. Neurochem.
(1997), 68, 778).
So a substance activating 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 dopaminergic, cholinergic, or this calls for the release of growth. These compounds are therefore useful in the case of Parkinson-type neurodegenerative diseases or Alzheimer's and their progression.
Many derivatives having antagonistic activity of noradrenergic a2 receptors are known, and more Particularly those described in patents US4855308, EP486385, W091 / 18886, US4497818, EP524G04, as well as in J. Med. Chem., 1991, ~ 4_, 705.
The compounds of the present invention are distinguished by the fact that it is ure benzo [aJ quinolizidine substituted in position 2 by an aminomethy group substituted for 7.' nitrogen court constitute ureas ~ u des amides. These new products have properties particularly interesting pharmacologicals which distinguish from other antagonist a2 compounds related. In particular they are endowed with an action at central and selective level on the noradrenergic target (a2 ;, as opposed to the target doaaminergi ~ w ° (D2j.

3 The classic treatment for Parkinson's disease is based on a dopaminergic agonist effect, to compensate too low levels of endogenous dopamine. Thus the 1-Dopa has been used for almost 30 years. However this treatment is not without side effects, both on the dopaminergic action itself (exhaustion of effect), only on dyskinesias and disorders unwanted peripheral cardiovascular. A compound having a dopamine agonist component may have a presynaptic effect on autoreceptors and at this account, behave unfavorably for a release sought increased dopamine.
It has been shown that agonists or agonists 1 ~ partial dopaminergics can have an effect unfavorable on the survival of neurons. Indeed, the dopaminergic neuron survival appears to be linked to increasing cyclic AMP formation at the level of the 2nd messenger (Michel P. Agid Y, J. Neurochem., (1996), 67, 1633). Now the D2 agonists will cause a decrease in cyclic AMP formation as it has been shown by Weiner and Molinoff (1994) (Catecholamines in Basic Neurochemistry. Molecular, Cellular and Medical aspects ; 5th Ed. GJ Siegal et al., Raven Press, PI '!. pp 261-281). The compounds of the present invention are devoid of dopaminergic effects and have the particularity to have an excellent passage to the central level, and a very long duration of action. A compound having selectively antagonistic activity on receptors 3o a2 adrenergic can by release of noradrenaline, reactivate the intrinsic functioning of others neurons, whether dopaminergic or cholinergic. So they can oppose the pathological degeneration and slow down the progression of the disease, or even stop it.
These compounds have a selectivity of action on the system central nervous system, and get rid of the effects secondaries of order c: ardiovasc ~.: peripheral area.
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WO 99 / 2185b PCT / FR98102281 .i The present invention particularly relates to compounds of general formula I.
R1 _ N ~~ '' R

in which .
R1 represents a hydrogen atom or an alkyl group of C1_6, linear, branched or cyclic, a group hydroxy or C1_6 alkoxy, branched, linear or cyclic, a halogen atom like F or C1.
R2 represents a hydrogen atom or an alkyl group in C1-6.
R3 represents a hydrogen atom or constitutes a motif (C = X) -NR4R5 and then constitutes a urea or thiourea as with X = oxygen or sulfur.
R4 and R5 can independently be a hydrogen atom or a linear, branched C ~ _g alkyl group, cyclic, an aryl, aralkyl, aroyl group. These aryl groups can also be substituted.
R4 e ~ R5 can be linked by a carbor chain. ~ E, incorporating. possibly a heteroato ~~ e.
R3 can also represent an alkylsulfonyl group or else optionally substituted arylsulfonyl.
3o R3 peLt consti ~ u ~ r un c ~ oti ~ acni no s ~.: Lronyl.

R3 represents an acyl or thioacyl group such that (C = X) -R6, where X represents an oxygen or sulfur atom.
R6 can represent hydrogen or an alkyl group or 5 linear, branched or cyclic C1-IO alkenyl, whether or not incorporating a heteroatom, such as oxygen or sulfur, incorporating a conjugated or unconjugated double bond with carbonyl C = X.
lo Rs can also represent a C1_g alkoxy group linear, branched or cyclic, an aralcoxy group possibly substituted.
R6 also represents an aryl or heteroaryl group, optionally substituted one or more times by a C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, C1, F, N02, CF3, CN, or a thiophene, furan, pyrrole, pyridine and their benzofused derivatives.
R6 represents an aralkyl group, aryloxyalkyl, the aryl part can be substituted and, whose chain alkyl can be linear, branched or cyclic.
R6 can have multiple cyclias systems aromatic or not, such as 2-indanyl or fluorenyl, coumarinyl, benzopyranyl.
R6 can also represent an aralkenyl group or aralcynyl. The aryl group conjugated with a double bond can be phenyl, naphthyl, polyaromatic like biphenyl or fluorenyl, heteroaromatic and its derivatives benzo merged. This aryl group can be optionally substituted one or more times by C 1-6 alkyls, hydroxy, alkoxy C1_g, halogens such as C1 or F, N02, CF3, CN, OCF3, OCH20 or form a bicyclic system with a saturated or unsaturated cycle with or without a hetereatome as O, t1 or S thus forming an indole, benzofuran or benzotiziophene. The alkeniy group can be possibly replaced by: -ialogèr ~ es, ~: i, alkyl, phenyl. The motif (C - X) -R6 thus forms a group cinnamoyl.
If, in particular, the group R3 forms a group (C = X) R6 3 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 Cl_4, methylenedioxy, alkylCl_6, OH, halogens like F, C1.

The term aryl represents a phenyl nucleus, or naphthyl, the aralkyl term meaning an aryl group attached to a alkyl chain of at least one carbon atom and capable of be linear, branched or cyclic.
The heteroaromatic group can be a cycle 5 or 6-link aromatic with one or more heteroatoms chosen from N, O or S, as well as their benzofused derivatives. They thus form a pyridine, a furan, a thiophene, an indole, a benzofuran, a benzothiophene, a benzoxazine, a quinoxaiine, a quinazolinè, a benzimidazole, a benzopyrazoie.
The invention also extends to the process, which is not exclusive, for the preparation of these compounds, characterized by the fact that we prepare a compound of formula I with the specifications R1 as indicated above and R2 = R3 = H
to form the intermediary of formula II
R, R, NHz O
FORM II FORM III

T
The benzo (a] quinolizidine-2-one of formula III is prepared ---- according to Brossi lHelv. Chim. Acta 1958, 41, 119).
According to the substituent in 9 of formula I, the process can be changed.
Thus, intermediary II (R1 = F) is prepared from 3-F phenetylamine by Pictet-Spengler reaction followed by acid hydrolysis to obtain 6-F
tetrahydroisoquinoline. Transformation into 3,4-di H
t0 isoquinoline is done by treatment with NBS followed by NaOH. In the case of intermediary II (R1 = Me) the 3,4-di-H-6-Me-isoquinoline is described (D. Pitea et al., Gazz-Chim. Ital., (1984), 114). Cyanation of the ketone in position 2 is carried out using tosylmethyl-isonitrile in the presence of potassium tert-butoxide according to the method described by Oldenziel (JOC (I977), 42, 3114). At this stage, the nitriles are separated axial and equatorial. Each of the nitriles is used in reduction with sodium borohydride in 2o presence of NiCl2 or else by aluminum hydride for lead to the aminomethyl derivative (II). The reaction of a chloride of Rô COC1 on this amine in the presence of base is done conventionally.
The intermediate of formula I- where 'R2 = alkyl, R3 = H, is obtained by reduction (LAH), of the amide compound corresponding, formed from I (RZ = CHO or COCH3).
The sulfurization of the amide obtained is done either by 3o presence of P2S5 in toluÄne or by the reagent Lawesson. The reaction of these amines with alkyl chlorofomiates provide carbamates corresponding.
The compounds for which R3 represents (C = X) -NR4R5 are ureas or thioureas are obtained by doing: ~ t react either an aryl isocyanate or isothiocyanate or aroyl or carba ~ royle chloride or thiocarbamoyl either with acid chlorides, aliphatic, aromatic or cinnamic on amine II
(R2 = H or alkyl, R3 = H).
It is also possible to conduct the synthesis up to the final compound I with the mixture of diastereoisomers, and to operate the separation only final stage (diastereoisomeric separation and enantiomeric).
The invention also relates to the preparation process of a diastereomerically pure compound by separation chromatographic or by crystallization of mixtures of diastereoisomers obtained during synthesis from the appearance of the chiral center in ~ position 2.
The enantiomerically pure compound thus obtained according to the claim 10 may be subject to separation over HPLC chiral column.
The basic compound obtained can then be treated by a stoichiometric amount of the acid agent.
Preferably, the substituent R1 is a hydrogen or methoxy, ethoxy, methyl, or fluorine and R2 = H, methyl, ethyl, R3 a group COCH3, CO-phenyl, CS-phenyl, cinnamoyl, optionally substituted with one or several methoxy, F, C1, as well as a furan group acryloyl, thienylacryloyl.
Also preferably, R3 represents, with nitrogen to which it is attached, a urea group or thiourea, di, tri or tetra substituted or not by alkyls or aryls.
The present invention also relates to their shape.
salified by mineral or organic acids.
The inventior. concerns different diastereoisomers obtained between the two: ~ asymmetric centers in position 2 el. Z ~ b.

WO 99121856 PCT / FIt98102281 l The invention relates to their enantiomerically pure form.
levogyre and dextrogyre, as well as their addition salt, hydrochloride, sulfate, methanesulfonate, maleate, fumarate, oxalate, tartrate, succinate, citrate.
They correspond to the following compounds (RS), (SR) -N- ¿2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-propanamide.
(RS), (SR) -N- j2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzofaJquinolizinyl) methyl J-cyclohexylcarboxamide.
(RS), (SR) -N- j2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzoja) quinolizinyl) methyl) -isobutanamide.
(RSJ, (SR) -N- j2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-l, i benzo òa] quinol i zinyl) mé thyl) -phenyl (a, a-cyclopropyl) acetamide.
(RS), (SR) -N- ò2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzoòaJquinolizinyl) methylJ-phenylacetamide.
(RS), (SR) -N- j2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methyl) -9'H-fluorenyl-9'-carboxamide.
(RS), (SR) -N- I2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methyl) -3-phenylpropanamide.
(RS), (SR) -N- ò2- (1, 3, 4, 6, 7, 31b-hexahydro-9-methoxy-ZH-benzojaJquinolizinyl) methyl] -2'-indanecarboxamide.) (RS), (SR) -N- j2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl) -4'-chlorophenoxyacétamiàe.
(RS), (SR) -N- ¿Z- (1, 3, 4, 6, 7, lIb-hexahydro-9-: nethoxy-2H-benzo (a] quinol i zinyl) m thyl) -2 ', 3', 4 ', 5', 6 '-pentafluorophenoxyacetamide.
(RS), (SR) -N- j2- (1, 3, 4, 6, 7, lIb-hexahydro-9-methoxy ~~ 2H-be. ~ zo ja] quinolizinyl) methyl) -phenoxyacetamic ~ e.
* rg (RS), (SR) -N- f2- (1, 3, 4, 6, 7, I1b-hexahydro-9-methoxy-2H-benzofa) quinolizinyl) methyl J-methoxyacetamide.
(RS), (SR) -N- f2- (I, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzofa) quinolizinyl) methyl) -acetamide.
S (RS), (SR) -N- f2- (I; 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzofa3quinolizinyl) methyl) -thioacetamide. .
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzola) quinolizinyl) methyl) -1'-methoxy-2'-naphthalenecarboxamide.
10 (RS), (SR) -N- f2- (I, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzofa] quinolizinyl) methyl) -4'-pyridinecarboxamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzola) quinolizinyl) methyl) -2'-thiophênecarboxamide.
(RS), (SR) -N- I2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzofaJquinolizinyl) methyl) -2'-furanecarboxamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo fa7 q ~ sinol izinyl) mé thyl J -2 '-naph taI ènecarboxamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzofalquinolizinyl) methyl J-I'-naphthalenecarboxamide.
(RS). (SRl -N- f2- (1, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl J-3'-trifluoromethylbenzamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methox} ~ -2H-benzofaJquinolizinyl) methyl) -2'-methoxybenzamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-.benzclalquinolizinyl) methyl] -2'-chlorobenzamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzofa] quinolizinyl) methyl) -3'-chlorobenzamide.
(RS), (SR) -N- f2- (1, 3, 4, ô, 7, Ilb-hexahydro-9-m thoxy-2H-benzo (aJquinolizinyl) methyl] -4'-chlorobenzamide.
(RS), (SR) -nl- f2- (1, 3, ç, 6, 7, Ilb-üexahydro-9-methoxy-2H-benzofaJquinolizinyl) methyl) -4'-trifluoromethylbenzamide.

WO 99 / Z1856 PC'TIFR98 / 02281 (RS), (SR) -N- (2- (I, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methylJ- benzamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methylJ-thiobenzamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methyl) -thio cinnamamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methylJ-3-cyclohexylacrylamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-10 benzolaJquinolizinyl) methyl J-3- (2'-furyl) -acrylamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzola) quinolizinyl) methyl J-2'-benzofuranecarboxamide.
(RS), (SR) -N- I2- (I, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H
benzolaJquinolizinyl) methyl J-3- (1'-naphthyl) -acrylamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzo (a J quinol izinyl) methyl J -3 - (2 '-naph tyl) -acrylamide.
(RS), (SR) -N- j2- (I, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl J-9'H-fluorenyl-9'-methylenecarboxamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl) -4'-phenylcinnamamide.
(RS), (SR) -N- l2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl J-3'-coumarinecarboxamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-2 ~ benzo (aJquinolizinyl) methylJ - (2'-thienyl) -3-acrylamide.
(RS), (SR) - ~ N- (2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methylJ- (3'-thienyl) -3-acrylamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, lIb-hexahydro-2H-benzo (aJquinolizinyl) methylJ-cinnamamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, llb-hexah.ydro-9.-fluoro-2H-benzolaJquinoliainyl) methylJ-cinnamamid ~~.

(RS), (SR) -N- (2- (I, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzo [aJ.quinolizinyl) methyl J -2 ', 3', 4 ', 5', 6 '-pentafluorocinnamamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl) -2,3-diphenylacrylamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methylJ-2-cyano-3-phenylacrylamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzo (αJquinolizinyl) methylJ-2-methyl-3-phenylacrylamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl J-2-fluoro-3-phenylacrylamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methylJ-3'-methoxybenzamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7,11b-hexahydro-9-methoxy-2H-benzolaJquinolizizyl) methylJ-4'-methoxybenzamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methylJ-4'-nitrobenzamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo (aJguinolizinyI) methylJ-3'-2o trifluoromethylcinnamamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2.H-benzo [aJquinolizinyl) methylJ-2'-chlorocinnamamide.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzo (aJ quinolizinyl) methyl) -3 ', 4', 5 '-trimethoxycinnamamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzo (aJquinolizinyl) methylJ-cinnamamide.
(RS), (SR) - ~~ 7- f2- (I, 3, 4, 6, 7, llb-hexahydro-9-métho: cy-2H-benzo (aJquinolizinyl) methylJ-2'-fluorocinnamamid =.
(RS), (SR) -lJ- (2 - (1, 3, 4, 6, 7, Ilb-hexahydro-9 -mé thoxy-2H-benzo (aJquinolizinyl) methylJ -2 '-chloro-6' -fioruocinnamamide.
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(RS), (SR) -N- f2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzo (a] quinolizinyl) methylJ-2 ', 4', 5'-trimethoxycinnamamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzofaJ9'uinolizinyl) methyl] -3 ', 4'-dimethoxycinnamamide.
(RS), (SR) -N- f2- (I, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzofaJquinolizinyl) methylJ-4'-methylcinnamamide.
(RS), (SR) -N- f2- (I, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzofaJquinolizinyl) methyl J-2 ', 3' ~ -dimethoxycinnamamide.
(RS), (SR) -N- f2- (I, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methyl] -2 ', 5'-dimethoxycinnamamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, 1Ib-hexahydro-9-methoxy-2H-benzofa] quinolizinyl) methyl J-2 ', 4'-dimethoxycinnamamide.
(RS), (SR) -N- f2- (I, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-I5 benzolaJquinolizinyl) methyl] -2'-methoxycinnamamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7,11b-hexahydro-9-methoxy-2H-benzo (a] quinolizinyl) methylJ-4'-fluarocinnamamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzofa] quinolizinyl) methyl J-3 ', 4'-methylenedioxycinnamamide.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzofa] quinolizinyl) methyl] -N'- (2-methoxyethyl) -thiourea.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-? 5 berzofa] quinolizinyl) methyl] -N'-ter-octylthiourea.
(RS), (SR) -N- f2- (I, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzofa] quinolizinyl) methyl] -N'-tertiobutylthiourée.
(RS), (SR) -N- f2- (1, 3, 9, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzofa) quinolizinyl) methyl J-N'-cyclohexylmethylthiourea.
.ü (RS), (SR) -N- f2- (I, 3, 4, 6, 7, IIb-hexahydro-9-méthcxy-2H-benzofaJquinolizinyl) methyl] -N'-butylthiourea.

(RS), (SR) -N- f2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzofa] quinolizinyl) methyl] -N'-2-phenylethylt. ~ iourée.
(RS), (SR) -N- f2- (1, 3, 4, 6, 7, I1b-hexahydro-9-methoxy-2H-benzo [a] quinolizinyl) methylJ-N'-benzylthiourea.
(RS), (SR) -N- [2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzo (a J quinol i zinyl) m thyl] -N ', N' -dimé thyl thiourée.
(RS), (SR) -N- [2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzoja] quinolizinyl) methyl) -N'-methylthiourea.
(RS), (SR) -N- (2- (1, 3, 4, 6, 7, I1b-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-N'-isobutylthiourea.
(RS), (SR) -N- [2 - (1, 3, 4, 6, 7, 1Ib-hexahydro-9 -mé thoxy-2H-benzo [aJquinolizinyl) methylJ-N'-cyclohexylthiourea.
(RS), (SR) -N- [2- (I, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzo [aJquinolizinyl) methylJ-N'-benzoylthiourea.
(RS), (SR) -N- j2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-N '- (2'-naphthyl) -thiourea.
(RS), (SR) -N- j2 - (1, 3, 4, 6, 7, I Ib-hexahydro- 9 -mê thoxy-2H-benzo [a] quinolizinyl) methylJ-N '- (l'-naphthyl) -thiourea.
(RS), (SR) -N- [2- (1, 3, 4, 6, 7, 1Ib-hexahydro-9-methoxy-3H-benzofa] auinolizinyl) methylJ-N'-phenylthiocrea.
(RS), (SR) -N- [2- (1, 3, 4, 6, 7, 1Ib-hexahydro-9-methoxy-2H-benzo [aJquinolizinyl) methyl] -N'-phenylurea.
(RS), (SR) -N- [2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzo [aJquinolizinyl) methylJ-N'-methylurea.
(RS), (SR) -N- [2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzo fa] quinolizinyl) methylJ-N ', N'-dimethylurea.
(RS), (SR) -N- [2 - (1, 3, 4, 6, 7, 11b-hexahydr o-2H-benzo (a J
quinolizinyl) methyl) -N'-methyl thiourea.
(RS), (SR) -N- (2 - (1, 3, 4, ô, 7, 1Ib-hexahydro- 9 -mé thoxy-2H-3U benzo ~ aJquinol i zinyl) methylJ-methyl -ber_zarnide.
(RS), (SR) -1 ~ Tj? .- (I, 3. 4, 6, 7, Il.i ~ -hexahydro-9-mét. '~ .Ory-2H-: cenzo (aJquinolizinyl) mers ~ ylJ-eth; rl-cinnamamiàe.

(RS), (SR) -N-j2- (I, 3, 4, 6, 7, 1Lb-hexahydro-9-methoxy-2H-benzojaJquinoliz.inyl) methylJ-methyl-cinnamamide.
(RS), (SR) -N-j2- (I, 3, 4, 6, 7, 3Ib-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-methyl-N'-phenylurea:
S (RS), (SR) -N-j2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzojaJquinol i zinyl) th thylJ-mé thyl, N '-mé thyl thi urée.
(RS), (SR) -N-j2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-formamide.
(RS), (SR) -N-j2- (I, 3, 4, 6, 7, IZb-hexahydro-9-methoxy-2H-t0 benzojaJquinolizinyl) methylJ-N'-benzoylurea.
(RS), (SR) -N-j2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzojaJ-quinolizinyl) methyl) -benzylcarbamate.
(RS), (SR) -N-j2- (1, 3, 4, 6, 7, I1b-hexah ~ idro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-N ', N' dimethylsulfonylurea.
15 (RS), (SR) -N-j2- (I, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-methylsulfonamide.
(RS), (SR) -N-j2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-21 ~ -benzojaJquinolizinyl) methylj-phenylsulfonamide.
(RS), (SR) -N- j2 - (I, 3, 4, 6, 7, I Ib-hexahydro - 9 -mé thoxy-2H-2o benzojaJquinolizinyl) methylJ-methyloxamamide.
(RS), (SR) -N-j2- (~, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-2'H-benzopyrane-3'-carboxar ~ i's.
(RS), (SR) -N-j2- (1, 3, 4, 6, 7, IIb-hexahydro- ~ -methoxy-2H-2 ~ benzojaJ-quinolizinyl) methylJ-3,3-di. ~ Nethylacrylamide.
(RS), (SR) -N-j2- (Z, 3, 4, 6, 7, 1Ib-hexahydro-9-methoxy-2H-benzojaJquinolizinyl) methylJ-3'-phenylpropynanide.
(SS), (RR) - ~ 'V- (2- (ï, 3, ç, 6, 7, lIb-r ~: cahydro-9-m ~ tho: cy-2H-benza (a) cruinol i zinyl) methyl) -cir_namamide.

(RS), (SR) -N- (2- (I, 3, 4, 6, 7, 1Ib-hexahydro-9-methoxy-2H-benzo ~ a quinolizinyl) methyl -4'-nitrocinnamamide.
(RS), (SR) -N- (2- (I, 3, 4, 6, 7, IIb-hexahydro-9-ethoxy-2H-benzo (a -quinolizinyl) methyl -cinnamamide.
(RS), (SR) -N- [2- (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzo [a] quinol i ziny.I) mé thyl] -mé thyl -N ', N' -dimethylthiourea.
lU The demonstration of antagonistic activity 2 adrenergic of these compounds is made on the basis of binding tests on the adrenergic receptor 2 in using tritiated 2-methoxy-Idazoxan, (3H] RX821002, as a radioactive ligand for these receptors (NJ Mallard 1 ~ et al., Br. J. Pharmacol. (1991), 102, 221).
For example, the specific binding values are shown in the table.
BINDING COMPOUNDS a.2 EXAMPLES N [3g] RX 821002 - IC50 (nM) 68 1.3 69 8.5 WO 99/21856 PCTlFR98102281 I1 is thus shown that the compounds of the invention according to.
the general formula I have a powerful affinity on 2 adrenergic receptors.
The in vivo study of the reversal of induced hypothermia by guanabenz (2 agonist) is performed according to the test described by SC Dilsaver, Pharmacol. Biochem..Behav.
(1993), 45, 247. This test highlights the effect 2 adrenergic receptor antagonist of the compounds of the invention, as well as their activity at the level central. The inhibitory capacities are expressed in ED50 which represent the doses producing an inhibition significant against hypothermia induced by guanabenz. These values are obtained using the method of JT Litchfield and F. Wilcoxon (J. Pharmacol.
Exp. Ther. (1949), 96, 99) calculated only - when inhibition occurs in more than 60% of animals tested.
The table below reproduces the values obtained by intraperitoneally for the products of this invention.
COMPOUNDS OF HYPOTHERMIA INDUCED BY

EXAMPLES N GUANABENZ DE50 MGfKG (I.
P.) 39 0.47 88 0.34 78 0, 91 1 0.56 70 0.63 55 0.53 18 0.9 31 0, 71 ls The compounds of the invention according to general formula I
are thus shown as antagonistic agents of 2 adrenergic receptors and thus cause release of noradrenaline. They can be used in human therapy and have an interest in treatment of neurodegenerative diseases and their progression such as Parkinson's disease, Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, disorders age-related cognitive, attention deficit and memorization, brain damage due to central ischemic attacks.
The present invention also relates to the compositions pharmaceuticals comprising at least one compound of formula I and a suitable excipient. The essays pharmaceuticals can be presented, so suitable, for oral administration, injectable or parenteral, in the form of capsules, capsules, tablets, or injections, at dose 0.1 at 200 mg per day.
The following examples illustrate the invention without however limit its scope.
Example 1.
(RS), (SR) -9-methoxy-I, 3,4,6,7,11b-hexahydro-2H-benzo (aJquinolizine-2-methanamine This compound is synthesized in 6 stages.
Stage 1 N-formyl-2- ~ 3'-methoxyphenyl) ethylamine A solution containing 31.2 g of 3-methoxyphenethylamine (G, 20 mole), 35.2 g of for ~:, ethyl iate (38.3 ml;

0.475 mole; 2.3 eq) in 125 ml of toluene is heated at 80 ° C for 7 h. After evaporation of the solvent, isolates 37 g of an orange oil used as it is for following the synthesis (quantitative rdt).
Rf (CH2C12 / MeOH 9/1) - 0.63 1 H NMR (400 MHz, CDC13). 8.06 ppm (broad s; 1H; NH);
8.00 ppm (s; 1H; CHO); 7.20 ppm (m; 1H; H5 '); 6.77 ppm (m; 3 H; H2 ', H4', H6 '); 3.74 ppm (s; 3H; OCH3) 3.35 ppm (m; 2H; CH2N); 2.70 ppm (m; 2H; Ar-CH2).
Stage 2 6-methoxy-3,4-dihydro-isoquinoline hydrochloride To a solution of 48.12 g PC15 (0.23 mole; 1.12 eq) in 160 ml of CH2Cl2 maintained at 0 ° C. in an ice bath, a solution of 37 g N-formyl-2- (3'-methoxyphenyl ethylamine (0.206 mole) in 20 ml of CH2Cl2. The reaction is maintained another 2 h at 0 ° C but the solvent is evaporated. The residue crude is taken up in petroleum ether and then treated with precaution with ice water., After extraction and decantation, the aqueous phase is basified with NaOH and then extracted with CH2C12. The sentence organic is then dried over MgS04, filtered and then evaporated to dryness.
The crude oil (32.9 g) is taken up in ether. We add 72.4 ml of a solution :: C1 / iPrOH 3.31 (0.22 mole).
The crystals obtained are filtered and washed with ether.
After drying in a desiccator at 55 ° C., 35.3 g of yellow crystals (yield = 87%).
Pf (CH2C12 / MeOH 95/5). 0.15 WO 99/21856 PCT / FR98 / 0228i 1 H NMR (400 MHz, CDC13). 13.76 ppm (broad s; 1H; NH);
9.08 ppm (s; 1H; H1); 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-methoxy-Z, 3, 4, 6, 7, .Ilb-hexahydro-2H-benzo ~ aJquinolizine-2-one A mixture containing 35.3 g of 6-methoxy hydrochloride 3,4-dihydroisoquinoline (0.178 mole) and 44.6 ml of methylvinylketone (37.5 g; 0.535 mole; 3 eq) is heated at 60 ° C for 3 h 30. The reaction medium which solidifies is taken up in acetone and then filtered.
The pink-salmon crystals obtained are dried with desiccator at 55 ° C (m = 37.18 g; rdt = 7B%).
The transition to the free base is done by treatment with 1N NaOH of a salt solution in CH2C12.
Rf (CH2C12 / MeOH 95/5). 0.40 1 H NMR {400 MHz; CDC13) (bases. 6.88 ppm (d; J = 8.6 Hz; 1H; H11); 6.74 ppm (dd; D - 8.6 Hz and 2.4 Hz;
1H; H10); 6.66 ppm (d; D - 2.4 Hz; 1H; H8); 3, 78 ppm (s; 3H; OCH3); 3.49 ppm (m; 1H; H 11b); 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, H7ëq); 2.48-2.39 ppm (m; 2H;
Hla ~ c, H3ëq).
Stage 4 (RSi, (SR) -9-métho.cy-1, 3, 4, 6, 7, 1Lb-heaahydro-2 :: - b ~~ nzo (a) auinolizine-2-curry ~ oni ~ rile A solution containing 30.18 g of ketone base (0.13 mole); 25.5 g tosylmethylisonitrile (0.13 mole; 1 eq); 7.6 ml of ethanol (6.10 g; 0.13 mole; 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 mole; 2 eq), Ie reaction mixture is maintained at 0 ° C for 1 h 30 then at room temperature for 1 h. The solution is then heated at 90 ° C for 2 h and then abandoned at room temperature overnight.
Solid residues are removed by filtration and 1a 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 diastereoisomer A (CN) are isolated equatorial). rdt = 41 2, B g of a mixture mixture of the two diastereoisomers. rdt = 9 6.16 g of diastereoisomer B (axial CN).
rdt = 19.5%
or an overall yield of cyan derivatives of G9.5%.
diastereoisomer A ((RS), (SR)) 2 ~
Rf (AcOEt / MeOH 95/5). 0.71 1 H NMR (200 MHz; CDC13). 7 ppm (d; J = 8.5 Hz; 1H;
H11); 6.70 ppm (dd; J - 8.5 and 2.4 Hz; 1H; H10);
~ 0 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, 73-2.22 ppm (m; 4H; Hla, H2, H7b, H6b); 2.11-I, 88 ppm (m;
2H; H3a, H3b); 2.65 ppm (n; 1H; Hib).
NMR 13C (50.32 MHz; CDC13). 125.7 ppm (Cïl), 113.5 ppm 35 (C8); 112.2 ppm (C10); 61.5 ppm (Cllb); 55.2 ppm (OCH3 and C4); 54.8 ppm (Co); 34.4 ppm (C1); 29.6 ppm (C7);
28.7 ppm (C3); 27.4 ppm (C2).
àiastsrëoisor "era ° ((RR), (SS)) Rf (AcOEt / MeOH 95/5). 0.49 RIrIN 1H (200 MHz; CDC13). 7.07 ppm (d; D - 8.5 Hz;
1H; H11); 6.74 ppm (dd; D - 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; Hla, H4b, H6b, H7b); 2.00 ppm (m; 2H; H3a, H3b); 1.70 ppm (m; 1H; Hlb).
13C NMR (50.32 MHz; CDC13). 125.7 ppm (C11); 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 (Cl); 29.7 ppm (C7); 27.6 ppm (C3); 26.3 ppm (C2) Stage S
t5 (RSJ, (SR) -9-methoxy-1, 3, 4, 6, 7, IIb-hexahydro-2H-benzo ~ a) quinolizine-2-methanamine A solution containing 9 g of the diastereoisomeric nitrile A
from the previous stage (37 mmol) in 300 ml MeOH is cooled to 0 ° C. 44.14 g NiCl2, 6H20 are added (186 mmoles; 5 eq) and let stir 15 mm at 0 ° C before the slow addition of 11.24 g NaBH4 (300 mmol; 8 eq). The NaBH4 addition rate should be such that the temperature of the reaction mixture is maintained 2 ~ below S ° C.
Stirring is maintained at 0 ° C at room temperature for 2 h 30 min. The mixture is then evaporated to dryness and then the black residue is taken up in CH2Cl2 / 1N NaOH. Both phases are filtered on cellite. After abundant rinsing with CH2C12, the organic phase is separated by settling then dried on MgS04.
After evaporation, 9 g of a yellow oil are obtained (~ dt - 87%) e NMR 1 :: (4 0 0 MHz; CDCl 3). 7.20 ppm (d; D - 8.4 1H; X11); 6.71 ppm (d; D - 8.4 H'z; l ~ l; H10); 5.52 ppm (s'1H;; 3, ppm (s;; OCH3) 3, 20-2, ; H8) 77 3H; 92 ppm (m 4H; H4a, H6a, H7a, Hllb) 2.72-2, ppm (m ; ; 62;

3H; H7b; H2NH2): 2, ppm (m;; Hla) 2, 42-2, 51 1H; 30 ppm (m 2H; H4b, H6b) 1.80 ppm; 1H; at) ;
; ; (m H3 1.59 ppm (m 1H; H2); 1.33 ppm (m;; H3b) 1.08 ; 1H; ppm (m; 1H Hlb).
;

Stage 6 (RS), (SR) -N- ~ 2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methylJ-benzamide 113 ~ 1 benzoyl chloride (137 mg; 0.97) mmol; 1.2 eq) to a solution of 200 mg of amine diastereoisomer A of the previous stage (0.81 mmol) and 166 ~ tl 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 by CH2C12 then washed with 1N NaOH. The organic phase is dried over MgS04, filtered and then evaporated to dryness. After purification by chromatography on a silica column (eluent CH2C12 / MeOH / NH40H 95/5/1), 150 mg of compound are isolated pure.
Yid = 53 Rf (CH2C12 / MeOH / N '~ i40H 90/102). 0.53 t ° f (oxalate). 112 ° C
1 H NMR (200 MHz; DMSO d6) (oxalate). 1H
8.51;
ppm (t ;

3o NH). 7.87 ppm (m; 2H; H2 ';H6'); (m 7.42-7.58;
ppm 3H; H3 ', H4', H5 '); 7.25 ppm (d;. 8.6 Hz 1H
J; ;
-H11); 6.75-6.89 ppm (m; 2H; H10); 4, 13 ( H8, ppm;

J = 10 Hz; 1H; Hllb); 3.75 ppm; ; OCH3) 3.58-(s 3H;

2.87 ppm (m; SH; Hla; H3a, H4a, H4b, H6a, H6b, H7a, H7b); 2.55 ppm (m; 1H; H2); 1.88ppm (m; 1H 3b) ; H;

1.45 ppm (m; 1H; Hlb).

Elementary analysis.
Theoretical. C (65.44), H (6.41), N (6.36);
Experimental: C (64.89), H (6.21), N (6.18) Analogously 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 .

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Example 46.
(SS), (RR) -N- [2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzo [a I quinol i zinyl) m th thyl) - cinnamami de This compound is synthesized in 2 stages.
Stage 1 10 (SS), (RR) -9-methoxy-1, 3, 4, 6, 7, IIb-hexahydro-2H-benzo [a) quinolizinyl-2-methananine 220 μl ~ H2SO4 (405 mg; 4.13 mmol; 1 eq) are added.
drop by drop to a mixture containing 8.25 ml of IS solution LiAlH4 / Et20 1M (8.25 mmol; 2 eq) and 10 ml of THF. There is a white precipitate and gassing. The solution is stirred at temperature ambient for ~ h then cooled to 0 ° C in a ice. Then add a solution of 1 g cyano axial 20 obtained as diastereoisomer B at stage 4 of Example 1. (4.13 mmol) in 2 ml of THF, dropwise drop. After addition, the reaction continues at t °
room for 1 h. Hydrolysis of the reaction mixture is done by Na2S04 / H20. The precipitate formed is eliminated 25 by filtration the filtrate is then evaporated to dryness. We isolates 925 mg of a yellow oil (yield = 91%).
Stage 2 30 (SS), (RR) -N- [2- (1, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzola) auinolizinyl) methyl) -cinnamamide Addition of 689 mg cinnamoyl chloride (4.1 c mmoles; 1.1 eq) to a solution of 925 mg of amine from previous stage (3.76 ramoles) and 577 ~ tl of methylamine (419 mg; 4.14 mmol; 1.1 eq) in 10 ml CH? C12. The reac = io: ~ is e; cothermic. After / has the mixture _, 1 reaction is treated with 1N NaOH. The organic phase is dried over Na2SO4, filtered and then evaporated to dryness. We isolates 865 mg of pure compound after chromatography on silica column (eluent. CH2C12 / MeOH / NH40H
98 / 1.7 / 0.3).
Rf (CH2C12 / MeOH / NH40H 95/5 / 0.5). 0.31 t ° f (hydrochloride). 161 ° C
t0 1 H NMR (400 MHz; CDC13) (base). 7.65 ppm (d; D - 15.6 Hz; 1H; CH = ÇH-Ar); 7.52 ppm; (m; 2H; H2 'and H6');
7.38 ppm (m; 3H; H3 ', H4' and H5 '}; 7.06 ppm (d; J =
8.6 Hz; 1H; H11); 6.71 ppm (dd; J = 8.6 and 2.6 Hz;
1H; H10); 6.6 L ppm (d; J = 2.6 Hz; 1H; H8); 6, 42 35 ppm (d; J - 15.6 Hz; 1H; CH = ÇH-Ar); 5.30 ppm (m;
1H; NH}; 3.77 ppm (s; 3H; OCH3); 3.62-3.50 ppm (m;
3H; H11b and C H 2 N); 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; H2);
1.993 ppm (m; 1H; H3a); 1.83 ppm (m; 1H; H3b); 1, 61 ppm (Hlb).
Elementary analysis.
Theoretical. C (69.80), H (7.08}, N (6.78);
25 Experimental. C (69.75), H (7, p4), N (6.76) Example 47 (RS), (SR) -N- ~ 2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-30 benzolaJquinolizinyl) methylJ-acetamide 139 μl of acetic acid ~ .ze (151 mg; 1.48 are added.
mmoles; 1.2 eq) to a solution of 300 mg of amine obtained in Stage S of Example 1 (1.21 mmol) and 0.25 ml of pyridine (3 mmol; 2.5 eq) in 8 ml of T ~ iF. around 3 a.m.
stirring at room temperature, the solvent is evaporated and the residue is taken up in CH2Cl2 / 1N NaOH.
After decantation, the phase o ~ ganiq ~ ae is dried su.
MgSOç, 'filtered then evaporated to dryness. The prOQul ~ rut 2S ~

purified by chromatography on a silica column (eluent CH2C12 / MeOH / NH40H 90/9/1). 230 mg of an oil are isolated yellow (rdt = 6 5%).
Rf (CH2C12 / MeOH / NH40H 90/10/2). 0.50 t ° f (oxalate). 98 ° C
1 H NMR. 7, ppm (t wide (200 96;
MHz ;
DMSO
d6) (based) 1H; NH). 7.23 ppm (d; J = Hz;; H11); 6, 8, 7 1H 82 ppm (dd J = 8, 7 Hz and 2, S Hz 1H; 0); 6, 77 ; ,; H1 ppm (d; J 2.5 Hz; 1H; H8); ppm (d; J = 12 Hz = 4, 10;

1H; Hllb) OCH3) 3.52-3.33 ppm ; ;
3.74 ppm (s ;

;

(m; 2H) and 3.18-2.88 ppm (m; (Hla, H3a, H4a, H4b, 6H) H6a, H6b, H7a, H7b); 2.40 ppm; 1H H2); 1.78 (m; ppm IS (m 1H H3b); 1.32 ppm (m; Hlb).
; ; 1H;

Elementary analysis.
Theoretical. C (60.31), H (6.92), N (7.40);
Experimental. C (60, 19), H (6, 62), N (7, 09) Analogously 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 .

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Example 64 (RS), (SR) -N-j2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2N-benzojaJquinolizinyl) methylJphënylsulfonamide Addition of 0.19 ml of phenylsulfonyl chloride (263 mg; 1.49 mmol; 1.2 eq) to a 300 mg solution amine obtained in Stage S of Example 1 (1.21 mmol) and 0.25 ml pyridine (3 mmol; 2, S eq) in 10 ml THF.
The reaction is maintained at room temperature for 10 days. After adding 0.19 ml of chloride additional phenylsulfonyl and reaction for another 10 days, the solution is evaporated to dryness. The residue is purified by chromatography on a silica column (eluent CH2C12 / MeOH 95/5). 166 mg of an oil are isolated which crystallizes at rest (rdt = 35%).
Rf (CH2C12 / MeOH 95/5). 0.26 t ° f (oxalate). 130-135 ° C
1 H NMR (200 MHz; CDC13) (base). 7, B7 ppm (dd; J = 6.2 Hz and 1.7 Hz; 2H; H2 'and H6'); 7.60-7.46 ppm (m; 3H;
H3 ', H4', H5 '); 7.10 ppm (d;, J = 8.5 Hz; 1 H; H11);
6.68 ppm (dd; J = 8.6 Hz and 2.5 Hz; 1H; H10); 6.60 ppm (d; J - 2, S Hz; 1H; H8); 4.81 ppm (broad t; 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; Hlb).
Elementary analysis 3 ~
Theoretical. C (57.97), H (5.92), N (5.88);
Experimental. C (57.47), H (5.92), N (5, B1) i - WO 99/21856 PCT / FR98l02281 Example 65 (RS), (SR) -N- ~ 2- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzo ~ aJquinol i ziny.I) mé thylJ-mé thyl sut fonami de Analogously to Example 64, but using the methane sulfonyl chloride, the title compound is got .
10 t ° f (oxalate). 156 ° C
Elementary analysis.
Theoretical. C (52.16), H (6.32), N (6.76);
Experimental. C (52.73), H (6.25), N (6.85) t5 Example 66 (RS), (SR) -N- ~ 2- (I, 3, 4, 6, 7, I1b-hexahydro-9-methoxy-2H
benzofaJquinolizinyl) methyl J-N ', N' dimethylsulfonylurea Analogously to Example 64, but using the N, N-dimethylsulfamoyl chloride, the title compound is obtained.
t ° f (oxalate). 110 ° C
Elementary analysis Theoretical. C (51.45), H (6.59), ~ 1 (9.47);
Experimental. C (51.27), H (6.61), N (9.24) Example 67 (RS), (SR) -N- ~ 2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo ~ aJquinolizinyl) methyl-Jbenzylcarbamate 0.18 ml dropwise addition of chloroformate benzyl (215 mg; 1.26 mmol; 1.05 eq) diluted in 1 ml EMR to a solution of 300 mg of amine obtained in stage 5 of example 1 (1.22 mmol) in 5 ml of water added a little DME. After 4 days of reaction at 100 ° C., the reaction mixture is evaporated to dryness, taken up by CH2C12 then washed with 1N NaOH. After purification by chromatography on a silica column, 118 mg of carbamate, composed of the title (rdt = 36 's).
ts Rf (CH2C12 / MeOH / NH40H 90/9/1). 0.54 t ° f (oxalate). 104 ° C
1 H NMR (CDCl3; 400 MHz) (base). 7.28 ppm (m; 5H;
Ph). J - 8, H11); 6, ppm 7.6 Hz; 66 03 1H;
ppm (d ;

(dd; 8.6 Hz and, 4 Hz;; H10) 6.53 ppm;
J 2 1H; (d J
=

- 2, 4; 1H; H8) 5.03 ppm (s; 2H Ph H_20) 3.71 Hz; ; ;

ppm (s 3H; OCH3) 3.14-2.88 ppm (m 6H; CH2N, llb, ; ; ; H

H7a, H6a, H4a); 2.4 ppm (m 1H; ~; 2.45 ppm (m 62; Hla);
~

1H H7b); 2.26 ppm (m; 2H; H4b H6b); 1, ppm ; and 71 (m; 2H H2 and H3a) 1.35 ppm (m; 1H H3b); l, ppm ; ; ; OB

(m; 1H Hlb).
;

Elementary analysis.
Theoretical. C (63.82), H (6.43), N (5.95);
Experimental. C (53.82), H (6.83), N (5.92) Fxemnle 68 (RS), (SR) -N-j2- (I, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2N-benzo (aJquinol i zinyl) m thylJ- thi obenzami de To a solution of 305 mg (0.79 mmol) of N- [2-(1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo (aj quinolizinyl) methyl] benzamide previously obtained according to Example 1 in 100 ml of toluene is added 322 mg (0.80 mmol) of [2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-dithio] (Lawesson reagent). The medium is heated to reflux and left without agitation for 2 days. After evaporation of the solvent, the residue is filtered through alumina eluted with dichloromethane. The filtrate is evaporated to give 250 mg (85%) of an oil yellow which is treated with oxalic acid to give 239 mg (77%) of pale yellow oxalate crystals.
Rf (CH2Ci2 / MeOH 90/9/1). 0.58 z0 t ° f (oxalate). 165 ° C
1 H NMR (200 MHz; CDC13} (base). 7.81 ppm (s Large;
1H; NH); 7.76 ppm (dd; J = 7.6 Hz and 1.3 H2; 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); 3.28-2.97 ppm (m; 4H; H4a, H6a, H7a, Hllb); 2.77-2.38 ppm (m; 4H; Hla, 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; Hlb}.
Elementary analysis.
Theoretical. C (63.14), H (6.18), N (6.13);
Experimental. C (63.38), H ~ (6.16), N (6.07) Example 69 (RS), (SR) -N- (2- (Z, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzo ~ aJquinolizinyl) methylJ-thioacetamide Analogously to Example 68 but using the corresponding reagents, the title compound is obtained.
t ° f (oxalate). 113 ° C
Elementary 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, IIb-hexahydro-9-methoxy-2H-benzo ~ aJquinolizinyl) methylJ-thiocinnamamide Analogously to Example 68 but using the corresponding reagents, the title compound is obtained.
t ° f (oxalate). 128 ° C
Elementary analysis.
Theoretical. C (64.71), Fi (6.2?), N (5.80);
Experimental. C (64.94), H (6.29), N (5.62) Example 71 (RS), (SR) -PJ- ~ 2 ~ - (1, 3, 4, 6, 7, Ilb-hexahydro-9-methoxy-2H-benzo ~ aJquinolizü: yl) methylJ-N'-phenyl ~ ré.e Addition of a 90 μl solution dropwise phenylisocyanate (98 mg; 0.82 mmol; 1 eq) in S ml CH ~ C1 ~ to a solu: .ion of 200 mg of amine obtained at the stage ..> 5 5 of 1 ~ example 1 (0.82 mmol) in S ml C: ~ 2C12. After 15 '. ~. ~ e reaction at room temperature, SO1'TaIlt eS:

evaporated then the oily residue is purified by chromatography on a silica column (eluent CH2C12 / MeOH
95/5). 160 mg of a yellow oil which crystallizes are isolated at rest (rdt = 54%).

Rf (CH2C12 / MeOH 90/10). 0.35 t ° f (hydrochloride). 185 ° C
1 H NMR (200 MHz; DMSO d6) (hydrochloride). 7.45-7.10 ppm IO (m; 5H; H2 ', H3', H5 ', H6' ,, H11); 6.81-6.95 ppm (m;
3H; H4 ', H8, H10); 4.42 ppm (d; D - 11.3 Hz; 1H;
Hllb); 3.74 ppm (s; 3H; OCH3); 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, IS Hlb, 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, 11b-hexahydro-9-methoxy-2H-benzo (aJçnlinol i zinyl) mé thyl JN '-mé thyl urë e Analogously to Example 71 but using the corresponding reagents, the title compound is obtained.
t ° f (hydrochloride). 160 ° C
Elementary analysis Theoretical. C (60.08), H (7.71), N (12.36);
Experimental. C (60.24), H (8.00), ~ i (11.86) Example 73 (RS), (SR) -N- ~ 2- (3, 3, 4, 6, 7, lob-hexahydro-9-methoxy-2H-benzolaJquinolizinyl) methylJ-N'-benzoylurea Analogously to Example 71 but using the corresponding reagents, the title compound is obtained.
t ° f (oxalate). 210 ° C
Elementary analysis Theoretical. C (62.10), H (6.04), N (8.69);
Experimental. C (62.00), H (5.87), D1 (8.37) t5 Example 74 (RS), (SR) -N- (2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzo ~ aJquinoliziny3) methylJ-N ', N'-dimethy3urée 20 A solution of 0.24 ml of dimethylcarbamoyl chloride (280 mg; 2.6 mmol; 1.2 eq) in 2 ml THF to a solution of 530 mg of amine obtained in stage 5 of example 1 (2.15 mmol) and 0.44 ml pyridine (425 mg; 5.4 mmol; 2.5 eq) in 30 ml 25 THF. The reaction is maintained at room temperature for 2 days then heated to 80 ° C for 5 days after addition of a DMAP spatula tip.
The reaction mixture is taken up in 1N NaOH j CH2Cl2.
30 The organic phase is dried over MgS04, filtered and then dry evaDOrE. The crude oil is aurified by chromatography on a silica column. We isolate 390 mg of product (ràt - 57%) s5 Rf (CH2C12 ~ Me0H 955) - 0.17 t ° f (oxalate). 122 ° C

1 H NMR (400 MHz; CDC13) (base). 7.11 ppm (d; J = 8.7 Hz; 1H; H11); 6.72 ppm (dd; J = 6.7 and 2.6 Hz; 1H;
H10); 6.61 ppm (d; D - 2.6 Hz; 1H; HS); 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 (CH3) 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; H2); 1.78 ppm (m; 1H; H3a); 1.41 ppm (m; 1H; H3b); 1.12 ppm (m; 1H; Hlb) Elementary analysis Theoretical. C (58.95), H (7.17), N (10.31);
Experimental. C (59.26), H (6.96), N (9.83) IS
Example 75 (RS), (SR) -N- ~ 2- (1, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzo ~ aJquinolizinyl) méthyZJ-N'-phenylthioc ~ rée 230 bel (260 mg; 1.92 mmol;
1.2 eq) of phenylisothiocyanate in a 400 mg solution amine (1.6 mmol) in 20 ml CH2Cl2. The reaction is maintained at room temperature for 4 h. The mixture 2 ~ reaction is treated with 1N NaOH. The organic phase is washed with sat. NaCl, dried over MgS04, filtered and then evaporated to dryness. The oily residue is purified by chromatography on a silica column (eluent CH2C12 / MeOH / NH40H 98 / 1.7 / 0.3).
Yid = 53 Rf (CH2C12 / NIeOH / NH40H 90/9/1). 0.38 t ° f (oxalate). 146 ° C
NMR .. (400 MHz; CDC13) (base). î, 63 ppm (s broad;
li-I; D1H); 7.49 ppm (m; 2H; H3 'and H5'); 7.35 ppm (t .;
D - 7.4 Hz; 1H; H4 '); 7.23 p: .m (d; J = 7.8 Hz; 2: ~;
H2 ', Hô'); 7.05 ppm (d; J = 2.5 Hz; 1H;: T11); 6, 72 ppm (dd; J = 8.6 2.6 Hz and; 1H
; H10) ; 6.61 ppm (d ; J

- 2.6 Hz; 6.18 ppm (broad s; 1H; NH); 3.77 1H; H8).

ppm (s; 3H; OCH3); 3.64 ppm (m ; 1H
; Hp, (CH2N)) ;

3.53 ppm (m; 1H;; 3.22-3.10 ppm (m;
Hg (CH2N) 2H;
) H11b, H7a) 3.07-2; 2H; H7a and H4a); 2, ; 95 ppm 68 (m ppm (m; 1H; H7b) 2.54 (m; 1H; H6b); 2, 36 ; ppm ppm (m; 1H) and 2.27 (m; 1H) (Hla and H4b); 2.05 ppm ppm (m 1H; H2); 1.7 ppm (m; 1H H3a); 1.42 ppm (m; 1H
; ;

H3b); 1.12 ppm (m 1H; .Hlb).
;

Elementary analysis.
Theoretical. C (61.13), H (6.20), N (8.91);
Experimental. C (61.31), H (6.14), N (8.68) Analogously to Example 75, but using the corresponding reagents the compounds of formula 1 are obtained by the examples in the following table 3.

co 0, rm .-.... O 01 O rl lf) M _ M
l ~ M.

N ~ -1t- ~ Q1 rfCO rl01 Cp00 O COtl1OD lp01 M ... M .r M .r N. ~ CO ~ .tf1..r ~ '~.
OO

z ~ z ~ z ~ z ~ z ~ z ~ z zzz - ~ z - ~ z .. z 'z.; z ~ z . . . ui. NN. NM. u ~ wo TIS, -Ih hhhhh ~ 'a0 01h O1h O l0 l0l0 M ~ M '-'M v, .. ~ .r M

~ x ~ x ~ x ~ ~ '' xhxhx ~ ox , .. ~ ... .. .r .r, ..

xx - ~ x -; x -: x -. ~ x.; x. ~ x .. ~
, v ... h tp M OD ~ G1 l0 . . h. ~. . o. ~. ~. o. co MN.-1c0 rlN rl01 riri tf1O o0ri rlV ' h. tl1LC1tf1lf1Lf1U1 lf7tD M lDO l0 01t0 ... ._. .. ~
.

~ ~ .. ..., ..
lf1lf7COU WU CO rl O riU _ ~ U
_ ~ n _u1 _m _u1U _ ~ U _ ~ U _tO
U ~~ ~ .. ~~

UUUUUU ~~ U ~ U
. .

y ~ ~
v ~ v ~ v ~ v ~ ~ ~ a ~~ v ~ v N
~ N ~ ~ ~ v ~ v ~ ~ ~

'E tTE b "E O'E crE iTE t3'E tTE
h ~ ~ N

wovovowovovovow awawavawawaw r. ~ w .ck. ~ k. ~ k. ~ k. ~ k ~ x ~ kcx H w H wrw H w H w. w H w. w HH

v U. U r. ~. ~ U ~ U. U ~ U. U ~ U, ~
COr1 o fd o rtfo td o ~ o t1io (~ o rteo b ~ ~ D.-1D r-1lDrl M ri c ~ rl M rlO ri O k CstU7 d '(~ ~ f'lI ~ rlf N fI $ C'f0 lf1 (atD; 0 MO
k ~ k ~, k ~ k ~ k. ~ k ~ k ~. ~

0 0 0 0 0 0 o NE
H v x __ '_.' ~ ..
- ~

___ _-_ _-_ _-_ _ - ~ _ -_ _ H

xxxx - ~ xxx . -M ~ MMMM c '~ f ~ d c D l ~ 00 Q1 O ri NM
lhrhh oo ao m ao z k w

4 ~
NOT
ra00 lG O lD ~ rfN
I ~ I ~ CO
d'v O v O ~ 'cr z ~ z ~ z ~ z z ~ z ~ z ~ z N ~ DI ~ lf1 t0p a1 O ~ Lf1 1D ~ f1 Lf7 L! ~
~ O ~ Q1 ~ 01 '-' 00 x ~ x ~ x ~ x x ~ x ~ x ~ x u WE . N t ~ OO
NC ~ d ~ d ~
Lf1l0 ~ lDtrla ri ~ O
~ vv NC ~ cr O
~ oU ~ U ~ U ~ U

UU ~~ U. U
ri ri ri rl ~ OOO y G ~ ~ G
~ ~ b 'U "' ~
.,.,., ~. ~.,. i., ~., a ~ .tS. ~ lr i. ~ Sa ~ SaSa O ~ O ~ n ~ O ~ a ~ O
~~ f.1 ~ N Glu ~ NLb ~ rJO, ~ k ~ k ~ k ~ k EnW E- ~ WE ~ W EnW

v ~ N
U ~ U ~ .. ~ U ~ U
o ~ o rtio t ~ o (t3 ov ~ ~ ~ av ~ to rl (13ln fUN fIf ~ 'x x ~ k ~ x ~

..
..

'"" C "y"' ( xxxx MMMM
xxx UVUU
OOOO

r imom WO 99/21856 PCf / FR98 / 02281 .l6 Example 88 (RS), (SR) -N- (2- (1, 3, 4, 6, 7, 11b-hexahydro-9-méthcxy-2H-benzo ~ aJquinolizinyl) methylJ-N ', N'-dimethylthiourëe Addition of 238 mg of dimethyl thiocarbamoyl chloride (2.11 mmol; 1.2 eq) dissolved in 5 ml of THF 'at one solution of the amine obtained in stage 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 heating at reflux for 48 h, the mixture reaction is evaporated to dryness, taken up in CH2C12 then treated with 1N NaOH. The organic phase is dried over MgS04, filtered and then evaporated to dryness. The brown oil obtained is purified by chromatography on a silica column.
81 mg of pure thiourea of the title are isolated (rdt = 23%).
Rf (CH2C12 / MeOH / NH40H 90/9/1). 0.48 t ° f (oxalate). 105 ° C
1 H NMR (200 MHz; CDC13). 7.08 ppm (d; J - 8.6 Hz ;

1H; H11); 6.69 2.4 Hz; 1H
ppm (dd;
; D - 8.6 and H10); 6.58 ppm (d; J - 2.4 Hz; 1H HS); 5.55 ppm ;

(mla rge; 1H OCH3); 3, 6 ; NH); ppm 3.75 ppm , (s; 3H
;

(m 2H; CH2H); 3.27 ppm (5.6H; NMe2); 3.14-2.89 ; ppm (m; 4H; H4a H6a; H7a; H11b); 2.6 ppm (m; 1H
; 6;

H7b); 2.48 ppm (m; 1H; H6b); 2.33 (m; 2H; Hla ppm;

H4b); 2.04 ppm (m; 1H; H2); i, 78 (m; 1H; H3a) ppm;

1.46 ppm (m;; H3b); 1.12 ppm (: n 1H; 1H; Hlb).

., 0 Elementary analysis.
Thêcrique. C (56, 72), H (6, 90), ~ i (9, 92);
Experimental. C (55.93), H (6.39), N (9.52) WO 99r11856 PCf / FR98 / 02281 .lï
Example 89 Stage 1 (RS), (SR) -N- ~ 2- (I, 3, 4, 6, 7, lIb-hexahydro-9-methoxy-2H-benzo (aJquinol i ziny.I) mé thylJ-formamide 193 mg (2.27 mmol; 1 eq) of 0-formyl- are added hydroxyacetonitrile (prepared according to J. Prakt Chem, 1996, 338, 488-90) to a solution of 560 mg of amine obtained at Stage S of Example 1 (2.27 mmol) in 10 ml CH2C12 kept in an ice bath.
The reaction is maintained at room temperature for 8 p.m. The reaction mixture is then washed with 1N NaOH, dried over MgS04, filtered and then evaporated to dryness. The solid crude obtained is purified by column chromatography silica (eluent CH2C12 / MeOH 92/8). We isolate 422 mg of formamide (yield = 68%).
Rf (CH2C12 / MeOH 9/1). 0.38 1 H NMR (400 MHz; 8.22 ppm (s;; CHO) 7.10 CDC13) 1H;
.

ppm (d; - Hz; H11); 6.1 ppm (dd; =
J 8.6; J 8.6 Hz 1H H10); 6.62 ppm (d J - 2, Hz and 2,; ; 5;
S Hz ;

1H; H8) 5, ppm (s rge; 1H; NH) 3.78 (s ; 69 la; ppm;

3H; OCH3; ; 2H; H2N); 3.15 (m ) 3 ppm;
, ppm (m 1H; H7a) 3.10 ppm (m 1H; H11b); 3.05ppm (m 1H
; ; ; ;

li4a); 2, (m;; H6a); 2.70 pm (m 1H
98 1H p; ;
ppm H7a); 2.52 ppm (m 1H H6b); 2.48-2.30 ppm (m; 2H
; ; ;

Hla, H4b) 1, ppm (m 1H; H2); 1, ppm (m 1H
; 85; 77; ;

H3a); 1.44 ppm (m 1H H3b); 1.17 ppm Hlb).
; ; (m .; 1H;

WO 99/21856 PCT / P'R98 / 02281 4b Stage 2 (RS), (SR) -N- (2- (I, 3, 4, 6, 7, I1b-hexahydro-9-methoxy-2H-benzo (aJquinol izinyl) mé thylJ-mé thy.I amine To a solution of 2.2 g of formamide from the previous stage (8.02 mmol) in 50 ml THF at 0 ° C, 640 mg is added LiAlH4 ground (16 mmol; 2 eq) in small fractions.
After heating at 45-50 ° C for 48 h, the mixture l0 reaction is hydrolyzed with Na2SO4 / H2O. The solid formed is removed by filtration. The filtrate is evaporated to dryness then purified by chromatography on a silica column (eluent CH2C12 / MeOH / NH40H 90/9/1).
Rf (CH2C12 / MeOH / NH40H 80/18/2). 0.56 1 H NMR (400 MHz; CDC13) base. J 8.7 7.14 -ppm (d ;

Hz; 1H; H11) 6.70 ppm (dd; 8.7 and 2.6 Hz 1H
; J; ;
=

H10); 6.61 ppm (d; J 2.6 Hz 1H; H8) 3.77 ppm -; ;

(s 3H; OCH3) 3.15 ppm (m 1H; H7a); ppm (d ; ; ; 3.08;

J = 11.2 Hz; ; Hllb) 3.02ppm (m; 1H; a) 2.96 1H; H4;

ppm (m; 1H; ppm (m 1H; H7a) 2.56-2.48 H6a); 2.68; ;

ppm (m; 3H;) ppm (s;; e) H2N ~ and H6b; 3H NM;
2.46 2.42 -2.30 ppm; 2H; a H4b); 1.81-1.70 ppm (m (m Hl and;
, 2H H2 and H3a) I, 39 ppm (m IH; H3b); ppm (m ; ; ; 1.11;

1H; Hlb).

13C (100.63.MHz; CDC13). 157.7 ppm (C9); 135.8 ppm and 130.6 ppm (C7a and Clla); 125.8 ppm (C11) 113.3 ; ppm and 111.8 ppm (C8 and C10) 62.4 ppm (OCH3) 58.5 ppm ; ;

(CH2N); 56.3 ppm (C4) 55.1 ppm (Clib) 52.4 ppm ; ;

(C6); 35.83 pnm and 35.80 ppm (NCH3 and C2) 36.2 ; pm

5 (Cl); 30.2 ppm and 29.9 ppm (C3 and C7).

WO 99/2185

6 PCTIFR98 / 02281 .19 Example 90 (RS), (SR) -N- ~ 2- (Z, 3, 4, 6, 7, ZZb-hexahydro-9-methoxy-2H-benzo ~ aJquinolizinyl) methylJ-methyl, N'-methylthiourea Addition of 345 mg (4.7 mmol; I, 2 eq) of isothiocyanate of methyl to a solution of 1 g of amine obtained at Example 89 (3.8 mmol) in 20 ml CH2C12. After 5 p.m.
reaction at room temperature, the mixture reaction is washed with 1N NaOH, dried over MgS04, then evaporated to dryness. The crude oil obtained is purified by chromatography on a silica column (eluent CH2C12 / MeOH / NH40H 95 / 4.5 / 0.5). We isolate pure thiourea with a yield of 37%.
IS
Rf (CH2C12 / MeOH 90/10). 0.40 t ° f (oxalate). 105 ° C
1 H NMR (400 MHz; CDC13) (base). 7.10 ppm (d; J = 8.7 Hz; 1H; H11); 6.72 ppm (dd; u - 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; ÇH2N); 3.22 ppm (s; 3H; Lv'Me); 3.17 ppm (d; J =
4.4 rice; 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; Hlb).
Elementary analysis.
Théo = '_ çue. C (56.72), H (6.90), N (9.92);
Experiential; C (56.64), H (5.71), N (9.68) Example 91 (RS), (SR) -N- (2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2N-benzolaJquinolizinyl) methylJ-methyl-N'-phenylurea Analogously to Example 90 but using the corresponding reagents, the title compound is obtained.
t ° f (oxalate). 117 ° C
l0 Elementary 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- (I, 3, 4, 6, 7, IIb-hexahydro-9-methoxy-2H-benzofaJquinol izinyl) mé thylJ-mé thyl - cinnamamide Analogously to Example 1 but using the corresponding reagents, the title compound is obtained.
t ° f (oxalate). 124 ° C
Elementary analysis.
Theoretical. C (67.48), H {6.71) I, N (5.83);
Experimental. C (67.44), H (6.44), N (5.82) Example 93 (RS), (SR) -N- ~ 2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-3U benzo ~ aJçruinclizinyl) methylJ-ethyl-cinnamamide Ana7.ogue in example 1 but using the reacti fs correspondar_t where the (RS), (SR) -N- (2- (1, 3, 4, 5,

7, llb-hexahydro-9-methoxy-2H-b ~ nzo [a] quinolizinyi) methylJ

ethylamine is obtained analogously to the amine of example 89 but using the compound from example 47, the title compound is obtained.
t ° f (oxalate). 120 ° C
Elementary analysis.
Theoretical. C (68.00), H (6.93), N (5.66);
Experimental. C (67.72), H (6.76), N (5.60) t0 Example 94 (RS), (SR) -N- (2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo ~ aJquinol i zinyl J th thyl J-th thyl -benzami from Analogously to Example 1 but using the corresponding reagents, the title compound is obtained.
t ° f (oxalate). 150 ° C
Elementary 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- I2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzofaJquinolizinylJmethyl) -3-cyc.Iohexy3acrylamide.
Stage 1 Ethyl 3-circlohexyl acrylate To a solution of S g of cycl ol-.exylcarboxal dehyde (44.6 mmol) in 100 ml CH2C12, 17.1 ç of carbox_rméthyiêretriphén ~, rlnhosphorane (49, _ ~~; ~ oles;

1.1 eq). After 72 hours of reaction at room temperature, the solvent is evaporated and the residue taken up in ether oil. The insolubles are separated by filtration, then the filtrate is evaporated to dryness. 5.25 g of an oil are isolated light yellow (rdt = 65%).
1 H NMR (400 MHz; CDC13). 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; CH3ÇH20); 2.15 ppm (m; 1H; H1 '); 1.73-1.59 ppm (m; 5H; Equatorial H);
1.33 - 1.06 ppm (m; 8H; axial H and CH3CH20).
Stage 2 3-cyclohexyl-acrylic acid A solution containing 5.25 g (28.8 mmol) of 3-ethyl cyclohexyl-acrylayte, 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 HC1, then extracted with CH2C12. The organic phase is dried- with MgSOa_, filtered then evaporated to dryness. We isolate 4, 4 g of a creamy soil (rdt -99%).
2 ~, 1 H NMR (400 MHz; CDC13). 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; H
equatorial); 1.32-1.04 ppm (m; SH; H axial).
Stage 3 3-cyclohexyl-acryol chloride A solution containing 1 g of 3-cyclohexyl-acrylic acid (6.5 mmol) and 2.83 g SOC12 (4.63 g; 39 mmol; 6 eq) is heated at 75 ° C. for 4 h. The residue is taken up by toluene and then evaporated to dryness. 1.1 g of a brown oil (yield = 98%).
1 H NMR (400 MHz; CDC13). 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; 5H; H
equatorial); 1.32-1.03 ppm (m; 5H; H axial).
Stage 4 t0 (RS), (SR) -N- (2- (I, 3, 4, 6, 7, 1Ib-hexahydro-9-methoxy-2H-benzola] qu.inolizinyl) methyl] -3-cyclohexylacrylamide Dropwise addition of 320 mg of acid chloride (1.8 mmol; 1.2 eq) to a solution of 380 mg of amine obtained in stage 5 of example 1, (1.5 mmol) in 15 ml THF. The reaction is maintained at room temperature for 48 h. The reaction mixture is then evaporated.
dry and the residue is taken up in CH2C12 and then washed with NaOH
1N. The organic phase is dried over MgS04, filtered and then evaporated to dryness. The crude oil obtained is purified by chromatography on a silica column (eluent CH2C12 / MeOH / NH40H 98 / 1.7 / 0.3). 184 mg of solid are isolated brown (rdt = 31%).
2 ~ ' Rf (CH2C12 / MeOH / NH40H 90/9/1) - 0.47 t ° f (oxalate). 140 ° C
RM.N 1H (400 MHz; CDC13) (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 - 8.5 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 = ÇH-CO); 5, 65 ppm (m; 1H; NH); 3.77 ppm (s; 3H; OCH3); 3.29 ppm (m; 2 ~ i; 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 (; ~; 1H; Hla); 2.54 ppm (m; 1H; H7b); 2, 41-2, 30 ppm (~~; 2H; H4b and H6b); 2.10 ppm (~;; l :?; CH

5. ~
cyclohexyl); 1.94-1.70 ppm (m; 6H; H2 and cyclohexyl equatorial); 1.65 ppm (m; 1H, H3a); 1.48 ppm (m;
1H; H3b); 1.35-1.08 ppm (m; 6H; Hla, cyclohexyl H
axial).
Elementary 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- (I, 3, 4, 6, 7, Ilb-hexahydro-2H-benzolaJquinolizinyl) methylJ-cinnamamide Stage 1 3,4-dihydroisoquinoline hydrochloride 20m1 (150mmol) of 1,2,3,4-tetrahydroisoquinoline dissolved in 350m1 of CH2C12, and 29.5 g (l, leq) of NBS. The reaction mixture is stirred for 4 hours at room temperature and then overnight after addition of 100m1 of concentrated NaOH. The sentence organic is recovered after decantation, washed with water then extracted with HC1 1N. The aqueous phase is basified with concentrated NH40H then extracted with CH2C12. The new organic phase is then washed with a saturated NaCl solution, dried over MgS04, filtered and then evaporated to dryness. A brown oil is recovered. m = 16.58.
Salt comes in the form of a yellow solid, it is obtained by adding 44.6m1 of solid solution HC1 / it? ROH at 3.1M. The overall yield is 73.4%.
RMNli: (400MHz, DMSOd6). 13.99 ppm (s, 1H, NH); 9.23ppm (s, 1H, H1); 7.92 ppm (m, 1H, H3); 7.79 ppm (m, 1H, H5);
7.52ppm (m, 2H, H6, H7); 3.94ppm (t, J = BHz, 2H, H3);
3.15 ppm (t, J = BHz, 2H, H4).

Stage 2 3.3, ç, 6.7, I1b-hexahydro-2H-benzo [aJquino3izine-2-one 5 In a flask, 10g (60mmo1) of stage 1 hydrochloride previous and 15 ml (3eq) of methylvinylketone are heated at 60 ° C for 4h. After addition of acetone, a solid brown is recovered by filtration. The solid is taken up in CH2C12 and then extracted with 1N HCl. After 10 basification, the aqueous phase is extracted with CH2Cl2.
The organic phase is filtered, dried over MgS04 and then evaporated to dryness. 9.52 g of a brown solid are obtained. The yield is 67%.
1 H NMR (400MHz, CDC13). 7.17 ppm (m, 3H, aromatic H);
7.08 ppm (m, 1H, aromatic H); 3.58ppm (dd, J = 12Hz and 2.4Hz, 1H, Hlib); 3.28 ppm (m, 1H, H4eq); 3.16ppm (m, 2H, H7ax and H6eq); 2.95ppm (dm, J = 14.4Hz, 1H, Hleq);
2.83ppm (m, 1H, H7eq); 2.74-2.62ppm (m, 3H, H3eq, H4ax 20 and H6ax); 2.52-2.42ppm (m, 2H, Hlax and H3ax).
Stage 3 (RS), (SR) -1, 3, 4, 6, 7, 11b-hexahydro-2H-benzo [aJ quinolizine-25 2-carbonitrile 8.52 g are introduced into a 500 ml flask (42.3mmo1) of the previous stage 2 ketone, 150m1 of DME, 8.268 (leq) of TosMIC and 2.5m1 (leq) of ethanol. The 30 reaction mixture is stirred for 30 min; 9.5g (2eq) of tBuOK are added and agitation continues 30 min more at 0 ° C. After return to temperature ambient, the reaction mixture is heated to 90 ° C.
pendar: t 4h, filtered and then evaporated to dryness. A
35 flash chromatography (petroleum ether / acetate ethyl. 8/2) allows the two isomers to be separated.
Three fractions are recovered. 1st fraction, P
diast_ ~~ isomer h, 3.2 g of yellow solid ta = 36 ~); 2nd fraction, 0.738 of mixture of diastereoisomers A and B
(R = 8.1%); 3rd fraction, diastereoisomer B, 1.178 yellow solid (R = 13%).
1 H NMR (400 MHz, CDC13).
diastereoisomer A. (RR), (SS) -7.20-7.09ppm (m, 4H, H
aromatic); 3.18ppm (d, J = 10.4Hz, 1H, H11b);
3.06 ppm (m, 1H, H7ax); 3.03ppm (dm, J = 12Hz, 1H, H4eq);
2.94ppm (m, 1H, H6eq); 2.74-2.63ppm (m, 3H, Hlax, H2, to H7eq); 2.55ppm (dt, J = 11.6Hz, J = 3.6Hz, 1H, H6ax);
2.34ppm (dt, J = 12Hz, J = 2Hz, 1H, H4ax); 2.08-1.92ppm (m, 2H, H3ax and H3eq); 1.74ppm (q, J = 12.4Hz, 1H, Hleq).
diastereoisomer B. (RR), (SS) -7.19-7.09ppm (m, 4H, H
aromatic); 3.58 ppm (d, J = 11.2 Hz, 1 H, H11b); 3.18-3.07 ppm (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); 1.17ppm. (dt, 1H, Hlax).
2o Stage 4 2- (1, 3, 4, 6, 7, 13b-hexahydro-2H-benzo (a) quinolizinyl) me thy.I friend do Dissolve lg (4.7mmo1) of diastereoisomeric nitrile A
in 80m1 of methanol. Cool to 0 ° C and then add 5.2g (5eq) of nickel chloride. Borohydride sodium (8eq) is slowly added. The mixture reaction mixture is stirred at 0 ° C. for 1 h and then at temperature 3o ambient for 30min. The solvent is evaporated. The salts nickel are suspended, with 1N NaOH and the amine is extracted by CH2C12. The nickel complexes are eliminated by filtration on celite. After several successive washes with CH2C12, the filtrate is evaporated at dry. A brown oil of mass 0.9 g is obtained, with a 86% yield.

WO 99! 21856 PCTIFR98 / 02281 1 H NMR (400 MHz, DMSOd6). 7.26ppm (m, 1H, aromatic H);
7.14-7.05ppm (solid, 3H, aromatic H); 3.30ppm (s broad, 1H, NH2); 3.03 ppm (d, J = 10.8 Hz, 1H, H11b); 2.95-2.88ppm (solid, 2H, H7ax and H4eq); 2.66-2.34ppm (solid, 6H, CH2NH2, H7eq, H6eq, H4ax and Hleq); 2.22ppm (m, 1H, H6ax); 1.68ppm (d, J = 12.8Hz, 1H, H3eq); 1.46ppm (m, 1H, H2); 1.17 ppm (m, 1H, H3ax); 0.88ppm (q, J = 12Hz, 1H, Hlax).
IO Stage 5 (RS), (SR) -N- [2- (I, 3, 4, 6, 7, IIb-hexahydro-2X-benzo [a) quinolizinyl) methyl J-cinnamamide We introduce into a 100m1 flask, 450mg (2mmo1) of the aminomethyl obtained in the preceding stage 4, 15 ml of THF
and 0.4m1 (2.5eq) of pyridine. We add drop to drop 416mg (l, 2eq) dissolved cinnamoyl chloride in lOml of THF. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated, a brown solid is recovered. After extraction 1N CH2C12 / NaOH and purification by chromatography clair (eluent: CH2C12 / MeOH / NH40H: 98 / 1.7 / 0.3), one obtains 279 mg of an orange solid (R = 39%). At this dissolved base in a minimum of MeOH, is added 4lmg (leq) of oxalic acid dissolved in a minimum of acetone. This makes it possible to form the oxalate salt of the title compound, yellow solid with a melting point of 188 ° C.
1 H NMR (400 MHz, CDC13) of the base. 7.64ppm (d, J = 15.6HZ, 1H, Ph-ÇH = CH), 7.50ppm (d, J = 6Hz, 2H, orthocinnamic H), 7.34 ppm (m, 3H, H meta and H paracinnamic); 7.21-7, O8ppm (solid, 4H, HB, H9, H10, H11); 6.40ppm (d, J = 15.6Hz, 1H, CH = CHCO); 5.79 ppm (broad s, 1H, NH); 3.37ppm (m, 2H, CH2NH); 3.18 ppm (d, J = 12 Hz, 1H, H11b); 3.16 ppm (m, 1H, H7ax); 3, Olppm (d, J = 11.6Hz, 1H, H4eq); 2.97pm (m, 1H, H6eq); 2.71ppm (d, J = 16Hz, 1H, H7eq); 2.53ppm (dt, J = 11.5 and 3.6Hz, 1 ::, H6ax); 2, 41-2, 33pp ~~ (r ~, 2, H4ax and Hleq);
* rB

SR
1.92ppm (m, 1H, H2); 1.80ppm (d, J = 12.4Hz, 1H, H3eq);
1.47 ppm (dq, J = 12.4 and 4 Hz, 1H, H3ax); 1.22ppm (q, J = 12Hz, 1H, Hlax).
Rf (CH2CL2 / MeOH / NH4C1 90/9/1) = 0.49 Elementary 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- (3, 3, 4, 6, 7, .Ilb-hexahydro-2H-benzo ja) quinolizinyl) methyl) -N'-methylththourea To a solution of 450mg (2mmo1) of the amine obtained at stage 4 of example 96 dissolved in 25m1 of CH2C12, we drip 183mg (l, 2eq) of isothiocyanate of methyl dissolved in 20m1 of CH2Cl2. Agitation is kept at room temperature overnight. An oil 2o brown is obtained after evaporation of the solvent. This is purified on a silica column (eluent:
CH2C12 / MeOH / NH40H: 97 / 2.5 / 0.5).
Rf (CH2C12 / MeOH / NH4CH 90/9/1) - 0.37 t ° f (oxalate). 194 ° C
1 H NMR (400 MHz, CDC13). 7.26-7.09ppm (solid, 4H, H
aromatic); 4.74 ppm (broad, 2H, NH); 3.42ppm (m, 2H, CH2NH); 3.17 ppm (d, J = 12 Hz, 1H, H11b); 3.15ppm (m, 1H, H7ax); 3.03 ppm (s, 3H, CH3N); 3.12-2.96ppm (m, 2H, H6eq, H4eq); 2.71ppm (d, J = 16Hz, 1: ~, H7eq); 2.53ppm (dt, J = 11.6 and 3.6 Hz m, 1H, H6ax); 2.40-2.33ppm (solid, 2H, H4ax and Hlax); 1.98 ppm (m, 1H, H2); 1.80ppm (d, J = 12.8Hz, 1H, H3eq); 1.45ppm (dq, J = 12.4 and 4Hz, 1H, H3ax);
1.18 ppm (q, J = 12 Hz 1H, Hlax).

Elementary analysis.
Theoretical. C (56.97), H (6.64), N (11.07);
Experimental. C (56.90), H (6.84), N (10.40) Example 98 (RS), (SR) -N- (2- (3, 3, 4, 6, 7, ZIb-hexahydro-9-fluoro-2H-benzola) quinoliziny3) methyl) -cinnamamide Stage 1 6-f3uoro-3,2,3,4-tetrahydroisoquinoline.
9m1 (69mmo1) of 3-fluorophenylethylamine are introduced, 90m1 of concentrated HC1 and 41m1 of formaldehyde. The mixture reaction is heated at 100 ° C for 6 h and then thrown into the water. The aqueous phase is washed with ether, basified with concentrated NaOH and extracted with CH2C12.
organic phase is washed with a saturated solution of NaCl, dried over MgS04, filtered and then evaporated to dryness. We obtains N, N'-bis- (6-fluoro-1,2,3,4-tetrahydroiso-quinoline) methylene in the form of a yellow paste.
This aminal is hydrolyzed. in-HC1 1N for 4 h at 75 ° C.
The aqueous phase is neutralized with NaOH and then extracted in CH2C12, After purification by chromatography flash in a mixture CH2C12 / MeOH / NH40H: 95/4/1, on ' recovers 1.8358 of the title compound as uae yellow oil with a yield of 17.5%.
1 H NMR (400 MHz, DMSOd6). 7.02ppm (m, 1H, H8); 6.90ppm (m, 2H, H5, H7); 3.78ppm (s, 2H, H1); 2.90ppm '(t, J = S, SHz, 2H, H4); 2.67ppm (d, J = 5.8Hz, 2H, H3).
RMN13C (100.6MHz, CDC13). 161.09ppm (d, 1JC_ ~ = 243Hz, C6); 136.76ppm (t, 3JC-F = 7Hz, C4); 131.28 ppm (C8a);
127, âlppm (â, 3JC_g = 7.9Hz, C9); 115.44ppn (â, 2JC-ç
* rB

= 20, 4Hz, C5 or C7); 112, 85ppm (d, 2JC-g = 21, 4Hz, C5 or C7); 47.70 ppm (C1); 43.42 ppm (C3); 29.22 ppm (C4).
Stage 2 6-f3uoro-3,4-dihydroisoquinoline We introduce into a 100m1 350mg (2.3mmo1) flask saturated compound from the previous stage, 5m1 of CH2C12 and 451mg lo (l, leq) from NBS. We apply the same procedure as that of the compound obtained in Example 96 stage l, we obtains 230 mg of a yellow oil (R = 66.8%).
1 H NMR (400 MHz, DMSOd6). 8.32ppm (s, 1H, Hl); 7.46ppm 15 (dd, 1H, H8); 7.12ppm (m, 2H, H7, H5); 3.62ppm (t, 2H, H3); 2.70ppm (t, 2H, H4).
Stage 3 20 9-fluoro-1, 3, 4, 6, 7, 11b-hexahydro (2Hibenzo jaJquinoli2ine-2-one 2.038 (10.9mmo1) of the hydrochloride of the compound are introduced obtained at the previous stage 'and 2.7m1 (3eq) of Methyl vinyl ketone. It is heated at 60 ° C for 3 h. We obtains 1.398 from the salt of the title compound. After acid-base extraction, 1.15 g of an oil are recovered brown with a yield of 48%.
1 H NMR (400MHz, CDC13). 7.03ppm (dd, J = 8.6Hz, J = 5.6Hz, 1H, H11) '; 6.87ppm (m, 2H, H8, H10); 3.54ppm (d, J = 11.5 Hz, 1F-I, H11b); 3.28 ppm (m, 1H, H4eq); 3.14ppm (m, 2H, H7ax and: -i5eq); 2.92ppm (dm, J = 14.4Hz, 1: ~, Hleq);
2.83ppm (m, 1H, H7eq); 2.73-2.61ppm (m, 3H, H3eq, H4ax 35 and Hôax); 2.50-2.42ppm (massiL, 2H, Hlax and H3ax).

Stage 4 (RS), (SR) - 9 -f1 uoro-1, 3, 4, 6, 7, 11b-hexahydro (2: ~) benzo (a J
quinolizine-2-carbonitrile The operating mode is identical to that of stage 3 of the compound 96. The quantities entered are 1.15 g (5mmo1) of ketone from the previous stage, 20m1 of dimethoxyether, 1.038 (leq) of tosylmethylisonitrile, 0.3 ml (leq) of ethanol and 1.18 g of tBuOK. The overall yield of the reaction after flash chromatography in. a mix . ether of petroleum / ethyl acetate. 5/5, is 68.4%. We isolate 40.8% of diastereoisomer A and 23.3% of diastereoisomer B.
IS
1 H NMR (400 MHz, CDC13).
diastereoisomer A. (RS), (SR) -7, lOppm (dd, JmF = 5.6Hz and JoH = 8.6 Hz, 1H, H11); 6.87ppm (ddd, Jog = 8.5Hz, J ~ = 2.5Hz, 1H, H8); 6.80ppm (dd, Jog = 9.3Hz, J ~ = 2.5Hz, 1H, H10);
3.13 ppm (d, J = 10.8 Hz, 1H Hllb); 3.1Oppm (m, 1H, H7ax);
3.02ppm (dm, J = 12Hz, 1H, H4eq); 2.94ppm (m, 1H, H6eq);
2.74-2.65 ppm (m, 2H, H2, H6ax); 2.61ppm (dm, J = 12.8Hz, 1H, H7eq); 2.51 ppm (m, 1H, Hleq); 2.34ppm (td, J = 12Hz, J = 2.8Hz, 1H, H4ax); 2.07ppm (m, 1H, H3eq); 1.99ppm (m, 1H, H3ax); 1.72ppm (q, J = 11.6Hz, 1H, Hlax).
diastereoisomer B. (RR), (SS) -7, lOppm (dd, Jmg = 5.6Hz, JoH = 8.6 Hz, 1H, HI); 6.88ppm (ddd, Jog = 8.4Hz, JoH = 8.6Hz, J ~ = 2.5Hz, 1H, H8); 6, BOppm (dd, Jog = 9, 3, J ~ .r = 2.5Hz, 1H, H10); 3.53 ppm (d, J = 11.2 Hz, 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, Hleq, H4eq and H7ax);
2.49ppm (d, J = 13.2Hz, 1H, H4ax); 1.98ppm (m, 2: I, H3ax and H3eq); 1.70ppm (ddd, 1H, Hlax).

Stage 5 (RS), (SR) -2- (9-fluoro-1, 3, 4, 6, 7, lIb-hexahydro (2H) benzo fa) quinolizinyl) methylamine The procedure is identical to that of stage 4 of Example 96. The quantities involved are 494 mg (2.7 mmol) of nitrite A from the previous stage, 3.168 (5eq) of nickel chloride, 649mg (8eq) of NaBH4, 40m1 of 10 methanol. A brown oil is obtained with a yield of 97.8 ° x. The amine is directly engaged in the step next.
Stage 6 (RS), (SR) -N- (2- (9-fluoro-1, 3, 4, 6, 7, 11b-hexahydro-2H-benzo (aJquinolizinyl) methyl] -cinnamamide The procedure is identical to that of stage 5 of z0 example 96. The quantities used are 498 mg (5mmol, leq) from the previous stage amine, 15m1 of THF, 0.4m1 (2.5 eq) of pyridine, 425 mg (1.2 eq of chloride cinnamoyle. Purification on a silica column allows recovering 304 mg of the title compound.
Rf (CH2C12 / MeCH / NH4CH 95/5 / 0.5) - 0.43 t ° f (oxalate) - 164 ° C
1 H NMR (400 MHz, CDC13). 7.65ppm (d, J = 15.6Hz, 1H, Ph-3G CH = CH); 7.50ppm (dd, J = 7.7 and 2.7Hz, 2H, Horthocinnamic); 7.36ppm (m, 3H, Hmeta and Hparacinnamique); 7.15ppm (dd, JmF = 5.7Hz, ~ oH = 8.6Hz 1H, H11); 6.83ppm (dt, JoF = 8.5Hz, JmH = 2.6Hz, 1H, H10);
6.76ppm dd, JoF = 9.4Hz, J ~ = 2.3Hz, 1H, H8); 6.41ppm (d, J = 15.6 Hz, 1H, CH = CHCO); 5.83ppm (broad s, 1H, NH), 3.36 ppm (m, 2H, CH2NH); 3, llppm (â, J = 11.6Hz, 1H, H? lb); 3, Oppm (m, 1: ~, H7ax); 3.03ppm (m, J = 11.6Hz, 1H r.4eq); 2.96pm (r ~, 1H, H6eq); 2.69gpm (d, J = 16, BHz, * rB

1H, H7eq); 2.50pm (dt, J = 11.6 and 4Hz, 1H, H6ax); 2, 37-2.31 ppm (m, 2H, H4ax, Hleq); 1.91 ppm (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, 1 H, Hlax).
Elementary analysis.
Theoretical. C (66.07}, H (5.99), N (6.16);
Experimental. C (65.72) H (6.02), N (6.13)

Claims (15)

1 - A compound of formula I:
in which in particular:
R1 represents a C1-4 alkyl group, linear, branched or cyclic, hydroxy or C1-4 alkoxy, branched, linear or cyclic, a halogen atom such as F or Cl.

R2 represents a hydrogen atom or a C1-6 alkyl group.

R3 represents a hydrogen atom or may constitute a motif (C=X)-NR4R5 and then constitutes a urea or thiourea as with X=oxygen or sulphur.

R4 and R5 may independently be hydrogen or or a linear, branched C1-8 alkyl group, cyclic, aryl, aralkyl, aroyl, these groups aryl which can also be substituted by groups C1-4 alkoxy, halogen or nitro or cyano.

R4 and R5 can be linked by a carbon chain incorporating possibly a heteroatom.

R3 represents hydrogen or an acyl or thioacyl group such as (C=X)-R6, where X represents an oxygen or sulfur atom.
R6 can represent hydrogen or a C1-10 alkyl group linear, branched or cyclic, whether or not incorporating a heteroatom, such as an oxygen or a sulfur provided that it does not is not directly related to the cx group, incorporating a double bond conjugated or not with carbonyl C=X.
R6 also represents an aromatic group or heteroaromatic, especially a phenyl or naphthyl optionally substituted one or more times by an alkyl in C 1-6, C 1-6 alkoxy, hydroxy, halogen, NO2, CF3, CN, COCH3, or a thiophene, furan, pyrrole, pyridine and their derivatives benzofused.
R6 represents an aralkyl, aryloxyalkyl group, the part of which aryl can be substituted by halogen, alkoxy, nitro or cyano R6 can have several aromatic ring systems, in particular a 2-indanyl, a fluorenyl, a coumarinyl or a benzopyranyl.
R6 can also represent an aralkenyl group. The group aryl conjugated with a double bond can be phenyl, naphthyl, polyaromatic, in particular biphenyl or fluorenyl, heteroaromatic and its benzofused derivatives.
This aryl group can be optionally substituted one or several times with C1-8 alkyls, hydroxy, C1-8 alkoxy, halogens, NO2, CF3, CN, OCF3, OCH2O, or form a system bicyclic with a saturated ring or not possessing or not a O, N or S heteroatom thus forming an indole, benzofuran or benzothiophene. The alkenyl group can optionally be substituted by halogens, CN, alkyl, phenyl. The pattern (C =
X)-R6 thus forms a cinnamoyl group.
The term aryl represents a phenyl ring, or naphthyl, 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 being able to be an aromatic ring with 5 or 6 members having one or more selected heteroatoms from N, O or S, as well as their benzofused derivatives. They thus form a pyridine, a furan, a thiophene, an indole, a benzofuran, a benzothiophene. 2 - Compound according to claim 1, characterized in that R1 represents a methoxy group, a methyl or a fluorine. 3 - Compound according to claim 1 and 2, characterized in that R2 represents hydrogen, methyl or ethyl. 4 - Compound according to claim 1, 2 and 3 characterized in that that R3 represents a group (C = X)NR4R5 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 a group alkyl or aryl. 6 - Compound according to claims 1, 2 and 3, characterized in that R3 forms a group (C=X) R6 and R6 represents a group aralkenyl. The group (C = X)R6 is chosen from the groups cinnamoyl or thiocinnamoyl substituted on the aromatic part by one or more C1-4 alkoxy, methylenedioxy, C1-6 alkyl, OH, halogen: like F, Cl. 7 - Compound according to claims 1 to 6, characterized in that that it is chosen from the following compounds:
(RS), (SR)-N-[2-(1, 3, 9, 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[a]quinolizinyl)methyl]-cyclohexylcarboxamide.
(RS), (SR)-N-[2-(1, 3, 4, 6, 7,11b-hexahydro-9-methoxy-2H-benzo[a]quinolizinyl)methyl]-isobutanamide.
(RS), (SR)-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.
(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, 9, 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]quinolizinyl)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, 9, 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, 9, 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, 9, 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]-9'-chlorobenzamide.
(RS), (SR)-N-[2-(1, 3, 4, 6, 7,11b-hexahydro-9-methoxy-2H-benzo[a]quinolizinyl)methyl]-9'-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, 9, 6, 7,11b-hexahydro-9-methoxy-2H-benzo[a]quinolizinyl)methyl]-thiobenzamide.
(RS), (SR)-N-[2-(1, 3, 9, 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]-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, 9, 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'-coumarincarboxamide.
(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-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)methylJ-2',3',4',5',6'-pentafluoro-cinnamamide.
(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, 9, 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'-trifluoromethyl-cinnamamide.

(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'-trimethoxy-cinnamamide.
(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'-fluorocin-namamide.
(RS), (SR)-N-[2-(1, 3, 4, 6, 7,11b-hexahydro-9-methoxy-2H-benzo[a]quinolizinyl)methyl]-2',4',5'-trimethoxycin-namamide.
(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'-methylenedioxycin-namamide.
(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, 9, 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-9-methoxy-2H-benzo[a]
quinolizinyl)methyl]-methyl-benzamide.
(RS), (SR) -N-[2- (1, 3, 4, 6, 7, 11b-hexahydro-9-methoxy-2H-benzo[a]
quinolizinyl)methyl]-N-ethyl-N-cinnamamide.
(RS), (SR)-N-[2-(1, 3, 4, 6, 7,11b-hexahydro-9-methoxy-2H-benzo[a]
quinolizinyl)methyl]-methyl-cinnamamide.

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

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

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

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

(RS),(SR)-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[a]
quinolizinyl)methyl]-3'phenylpropynamide.

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

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

(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]-methyl-N',N'-dimethylthiourea. 8 - Compound according to claims 1 to 7 characterized in that that it is in a diastereoisomerically pure form and enantiomerically pure, forming a salt with mineral acids or organic such as hydrochloride, sulfate, methanesulfonate, Maleate, Fuinarate, Citrate, Succinate, Tartrate. 9 - Process for the preparation of a compound according to one of claims 1 to 8, characterized in that one reacts a compound of formula III:
with tosylmethylisonitrile in a basic medium, which is separated diastereoisomers, which reduce the nitrile to an amine primary, that this amine is reacted either with isocyanates, alkyl or aryl isothiocyanates, carbamoyl or thiocarbamoyl chlorides, either with acid, aliphatic, aromatic or cinnamic chlorides. 10 - Process for the preparation of a compound diastereisomerically pure by chromatographic separation or by crystallization of mixtures of diastereoisomers obtained during synthesis according to claim 9 from the appearance of the chiral center in position 2. 11 - Process for the preparation of an enantiomerically pure compound from a compound obtained according to claim 10, by separation on a chiral HPLC column. 12 - Process for the preparation of the salt of a compound obtained according to claim 11 characterized in that the compound is treated basic by a stoichiometric quantity of the acidic agent. 13 - As a medicine, 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 intended for the treatment of neurodegenerative diseases, in especially Parkinson's disease, Alzheimer's disease, Huntington's disease, cognitive and memory disorders, attention and vigilance deficits in the elderly, disorders cerebral ischemic and post ischemic, as well as the progression of neurodegenerative diseases.