AU9751798A - Aminomethyl-benzo{a}quinolizidine derivatives, preparation and therapeutic applications for neurodegenrative diseases - Google Patents
Aminomethyl-benzo{a}quinolizidine derivatives, preparation and therapeutic applications for neurodegenrative diseases Download PDFInfo
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- AU9751798A AU9751798A AU97517/98A AU9751798A AU9751798A AU 9751798 A AU9751798 A AU 9751798A AU 97517/98 A AU97517/98 A AU 97517/98A AU 9751798 A AU9751798 A AU 9751798A AU 9751798 A AU9751798 A AU 9751798A
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- benzo
- hexahydro
- methyl
- methoxy
- quinolizinyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
WO 99/21856 - 1 - PCT/FR98/02281 Aminomethyl-benzo [a] quinolizidine derivatives, preparation and therapeutic application thereof for neurodegenerative diseases 5 The present invention relates to novel benzo[a]quinolizidine derivatives, and to the processes for preparing them. It also relates to the use of these compounds as a medicament, as well as for the preparation of a medicament used as antagonist of the 10 a 2 -adrenergic receptors and which are thereby intended for treating neurodegenerative diseases. The diseases concerned are: Parkinson's disease, Alzheimer's disease, Huntington's chorea, cognitive and memory disorders, attention and vigilance deficiencies in 15 elderly subjects, as well as cerebral ischemic and post-ischemic disorders. It has been shown that the locus coeruleus plays a predominant role in recovering the dopaminergic functions impaired by administration of MPTP in monkeys 20 (Mavridis, Neuroscience (1991) , 41, 507) . Its destruction causes a reduction in recovery. Moreover, compounds having an a2 antagonist action are capable of reducing Parkinsonian symptoms in monkeys (Colpaert, Brain Res. Bull., (1991), 26, 627) 25 or in rats (Colpaert, Neuropharmacology (1987), 26, 143), and this may be by increasing the release of dopamine (Marien, Noradrenergic Mechanisms in Parkinson's Disease, p. 139, (1994), CRC Press, Boca Raton; Marien and Colpaert, Effect of (+)- efaroxan on 30 mouse striatal dopamine metabolism in vivo. Dopamine 94 - Satellite Meeting of the XIIth Int. Congr. Pharmacology, Quebec City, Canada, July 20-24, 1994). Furthermore, Idazoxan, a known a 2 antagonist compound, has shown a beneficial action on the 35 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 paralysis, also a neuro degenerative disease (Ghika, Neurology, (1991), 41, - 2 986) . It has also been shown that compounds having an a 2 antagonist activity cause an increase in the release of acetylcholine in the prefrontal cortex (Tellez, J. Neurochem. (1997) , 68, 778). 5 Thus, a substance activating the noradrenergic system can have the property of preventing the progression of the degeneration of the neurons involved by reactivating the systems of the different cerebral locations, whether they are dopaminergic, cholinergic 10 or whether this involves the release of growth factors. These compounds are therefore useful in the case of Parkinson- or Alzheimer-type neurodegenerative diseases and for their progression. Many derivatives having an a 2 -noradrenergic 15 receptor antagonist activity are known, and more particularly those described in patents US4855308, EP486385, W091/18886, US4497818, EP524004, as well as in J. Med. Chem., 1991, 34, 705. The compounds of the present invention are 20 distinguishable by the fact that they correspond to a benzo[a]quinolizidine substituted at the 2-position with an aminomethyl group substituted on the nitrogen to constitute ureas or amides. These novel products possess particularly advantageous pharmacological 25 properties which distinguish them from the other related a 2 antagonist compounds. In particular, they possess an action at the central level which is selective on the noradrenergic target (a 2 ), in contrast to the dopaminergic target (D2). 30 The conventional treatment of Parkinson's disease is based on a dopaminergic agonist effect, to compensate for the excessively low levels of endogenous dopamine. Thus, 1-Dopa has been used for nearly 30 years. However, this treatment is not free of side 35 effects, both on the dopaminergic action itself (exhaustion of the effect), and on the dyskinesias and the undesirable peripheral cardiovascular disorders. A compound having a dopaminergic agonist component can - 3 have a presynaptic effect on the autoreceptors and for this reason behave unfavorably for a desirable increased release of dopamine. It has been shown that dopaminergic agonists or 5 partial agonists can have an unfavorable effect on the survival of the neurons. Indeed, the survival of the dopaminergic neurons appears to be linked to the increase in the formation of cyclic AMP at the level of the 2nd messenger (Michel P. Agid Y, J. Neurochem., 10 (1996), 67, 1633) . However, the D2 agonists will cause a reduction in formation of cyclic AMP as has been shown by Weiner and Molinoff (1994) (Catecholamines in Basic Neurochemistry: Molecular, Cellular and Medical aspects; 5th Ed. G.J. Siegal et al., Raven Press, NY. 15 pp. 261-281). The compounds of the present invention lack dopaminergic effects and have the characteristic feature of having an excellent passage at the central level, and a very long duration of action. A compound selectively having an antagonist activity on the 20 a 2 -adrenergic receptors will be able, through the release of noradrenaline, to reactivate the intrinsic function of the other neurons, whether they are dopaminergic or cholinergic. Thus, they will be able to prevent pathological degeneration and to slow the 25 progression of the disease, or even to stop it. These compounds have a selective action on the central nervous system, and are free of side effects of a peripheral cardiovascular nature. The present invention relates particularly to 30 the compounds of general formula I: R ' N 11b 2 N I RI -4 in which: R, represents a hydrogen atom or a linear, branched or cyclic C 1
.
6 alkyl group, a hydroxyl group or a 5 branched, linear or cyclic C 1 6 alkoxy group, a halogen atom such as F or Cl.
R
2 represents a hydrogen atom or a C 1
.
6 alkyl group. 10 R 3 represents a hydrogen atom or alternatively con stitutes a unit (C=X)-NR 4
R
5 and in that case constitutes a urea or thiourea with X=oxygen or sulfur. 15 R 4 and R 5 may independently be a hydrogen atom or alternatively a linear, branched or cyclic C 1
..
8 alkyl group, an aryl, aralkyl or aroyl group. These aryl groups may also be substituted. 20 R 4 and R 5 may be linked by a carbon chain optionally incorporating a heteroatom.
R
3 may also represent an alkylsulfonyl or alternatively arylsulfonyl group which is optionally substituted. 25 R 3 may constitute an aminosulfonyl unit.
R
3 represents an acyl or thioacyl group such as
(C=X)-R
6 , where X represents an oxygen or sulfur atom.
R
6 may represent a hydrogen or a linear, branched or cyclic C 1
..
10 alkyl or alkenyl group 30 incorporating a heteroatom or not, such as an oxygen or a sulfur, incorporating a double bond conjugated with the carbonyl C=X or not.
R
6 may also represent a linear, branched or cyclic C 1
.
8 alkoxy group, an aralkoxy group which is 35 optionally substituted.
R
6 also represents an aryl or heteroaryl group optionally substituted one or more times with a Ci alkyl, C1.6 alkoxy, hydroxyl, halogen, Cl, F, NO 2 , CF 3
,
- 5 CN or a thiophene, furan, pyrrole, pyridine and their benzofused derivatives.
R
6 represents an aralkyl or aryloxyalkyl group in which the aryl portion may be substituted, and in 5 which the alkyl chain may be linear, branched or cyclic.
R
6 may comprise several cyclic systems, aromatic or not, such as a 2-indanyl or a fluorenyl, a coumarinyl, a benzopyranyl. 10 R 6 may also represent an aralkenyl or aralkynyl group. The aryl group conjugated with a double bond may be phenyl, naphthyl, polyaromatic such as biphenyl or fluorenyl, heteroaromatic and its benzofused derivatives. This aryl group may be optionally sub 15 stituted one or more times with C 1
.
8 alkyls, hydroxyl, C1. alkoxy, halogens such as Cl or F, NO 2 , CF 3 , CN,
OCF
3 , OCH 2 0 or form a bicyclic system with a saturated or unsaturated ring possessing a heteroatom or not such as 0, N or S, thus forming an indole, benzofuran or 20 benzothiophene. The alkenyl group may be optionally substituted with halogens, CN, alkyl, phenyl. The unit
(C=X)-R
6 thus forms a cinnamoyl group. If in particular the R 3 group forms a group
(C=X)R
6 and R 6 represents an aralkenyl group, the group 25 (C=X)R 6 is chosen from the cinnamoyl or thiocinnamoyl groups substituted on the aromatic portion with one or more C 1 alkoxy, methylenedioxy, C 1 -6 alkyl, OH, halogens such as F, Cl. The term aryl represents a phenyl or naphthyl 30 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 being capable of being a 5- or 6-membered aromatic ring possessing one or more 35 heteroatoms chosen from N, 0 or S, as well as their benzofused derivatives. They thus form a pyridine, a furan, a thiophene, an indole, a benzofuran, a benzo- - 6 thiophene, a benzoxazine, a quinoxaline, a quinazoline, a benzimidazole, a benzopyrazole. The invention also extends to the nonexclusive process for preparing these compounds, characterized in 5 that a compound of formula I with the specifications R 1 as indicated above and R 2
=R
3 =H is prepared in order to form the intermediate of formula II N N Nd
NH
2 O FORMULA II FORMULA III 10 The benzo[a]quinolizidine-2-one of formula III is prepared according to Brossi (Helv. Chim. Acta 1958, 41, 119). Depending on the substituent at the 9-position of formula I, the process may be modified. 15 Thus, the intermediate II (Ri=F) is prepared from 3-F phenethylamine by Pictet-Spengler reaction followed by acid hydrolysis in order to obtain the 6-F tetrahydroisoquinoline. The conversion to 3,4-di H isoquinoline is carried out by treating with NBS 20 followed by NaOH. In the case of the intermediate II (Ri=Me), the 3,4-di-H-6-Me-isoquinoline is described (D. Pitea et al., Gazz-Chim. Ital., (1984), 114). The cyanation of the ketone at the 2-position is carried out with the aid of tosylmethylisonitrile in the 25 presence of potassium tert-butoxide according to the process described by Oldenziel (J.O.C. (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 30 borohydride in the presence of NiC1 2 or alternatively aluminum hydride to give the aminomethyl derivative - 7 (II) . The reaction of an acid chloride R 6 COCl on this amine in the presence of a base is carried out in a conventional manner. The intermediate of formula I where R 2 =alkyl, 5 R 3 =H, is obtained by reducing (LAH) , the corresponding amide compound formed from I (R 2 =CHO or COCH 3 ) The sulfurization of the amide obtained is carried out either in the presence of P 2 Ss in toluene or with the Lawesson's reagent. The reaction of these 10 amines with the alkyl chloroformates give the corresponding carbamates. The compounds for which R 3 represents (C=X) -NR 4
R
5 are ureas or thioureas are obtained by reacting either an alkyl, aryl or aroyl isocyanate or 15 isothiocyanate or a carbamoyl or thiocarbamoyl chloride either with aliphatic, aromatic or cinnamic acid chlorides with the amine II (R 2 =H or alkyl, R 3 =H). It is also possible to carry out the synthesis up to the final compound I with the mixture of the 20 diastereoisomers, and to carry out the separation only at the final stage (diastereoisomeric and enantiomeric separation). The invention also relates to the process for preparing a diastereoisomerically pure compound by 25 chromatographic separation or by crystallization of the mixtures of diastereoisomers obtained during the synthesis as soon as the chiral center appears at the 2-position. The enantiomerically pure compound thus 30 obtained according to claim 10 may be subjected to a HPLC chiral column separation. The basic compound obtained may then be treated with a stoichiometric quantity of the acidic agent. Preferably, the substituent R 1 is a hydrogen or 35 a methoxy, ethoxy, methyl, or fluorine and R 2 =H, methyl, ethyl, R 3 a group COCH 3 , CO-phenyl, CS-phenyl, cinnamoyl, optionally substituted with one or more - 8 methoxy, F, Cl, as well as a furanacryloyl or thienylacryloyl group. Still preferably, R 3 represents, with the nitrogen to which it is attached, a urea or thiourea 5 group, di-, tri- or tetrasubstituted or not with alkyls or aryls. The present invention also relates to their salified form with inorganic or organic acids. The invention relates to the various diastereoisomers 10 obtained between the two asymmetric centers at the 2 and lib-positions. The invention relates to their enantiomerically pure, levorotatory and dextrorotatory form as well as their addition salt, hydrochloride, sulfate, methane 15 sulfonate, maleate, fumarate, oxalate, tartrate, succinate, citrate. They correspond to the following compounds: (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl]propanamide 20 (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,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl]isobutanamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 25 benzo [a] quinolizinyl)methyllphenyl (a, a-cyclopropyl) acetamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyllphenylacetamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 30 benzo[a]quinolizinyl)methyll -9'H-fluorenyl -9' carboxami de (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -3 -phenylpropanamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 35 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 - 9 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl]-2',3',4',5',61 pen tafluorophenoxyacetani de (RS), (SR) -N- [2- (1,3,4,6,7, llb-hexahydro-9-rnethoxy-2H 5 benzo [a) quinolizinyl )rethyllphenoxyacetamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl )methyllmethoxyacetamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinol izinyl )methyl] ace tami de 10 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl) thioacetarnide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1 -'-me thoxy-2' -naphthalene carboxami de 15 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl 1-4' -pyridinecarboxanide (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl 1-2' -thiophenecarboxamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 20 benzo [a] quinolizinyl)methyl) -2' -furancarboxamide (RS), (SR)-N-[2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-2'-naphthalenecarboxamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl )methyl) -1' -naphthalenecarboxamide 25 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl 1-3' -trifluoromethyl benzami de (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl )methyl] -2' -me thoxybenzamide 30 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl 1-2' -chlorobenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl 1-3' -chlorobenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 35 benzo [a) quinolizinyl)methyl) -4' -chlorobenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl) -4' -trifluoromethyl benzami de - 10 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyllbenzamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyll thiobenzamide 5 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinol izinyl )methyl) thi ocinnamani de (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-nethoxy-2H benzo [a] quiriolizinyl )methyl] -3 -cyclohexylacrylarnide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 10 benzo [a] quinolizinyl)rnethyll -3- (2' -furyl)acrylamide (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-rnethoxy-2H benzo [a] quinolizinyl )rethyll -2' -benzofurancarboxamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [ajquinolizinyl)methyl) -3- (1' -naphthyl) acrylamide 15 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl 1-3- (2' -naphthyl) acrylarnide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-rnethoxy-2H benzo [a] quinolizinyl)rnethyl 1-9 'H-fluorenyl -9k methyl enecarboxami de 20 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-4'-phenylcinnamarnide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-3' -coumarinecarboxamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 25 benzo[alquinolizinyl)methyll -(2' -thienyl) -3-acrylamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo[alquinolizinyl)methyll -(3d -thienyl) -3-acrylamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-2H benzo [a] quinolizinyl)methyl] cinnamarnide 30 (RS), (SR) -N-[2- (1,3,4,6,7,llb-hexahydro-9-fluoro-2H benzo [a] quinolizinyl)methyl] cirinamarnide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo[alquinolizinyl)methyl]-2',3',4',5',6' pen taffi uorocinnarnami de 35 (RS), (SR) -N- [2- (1,3,4,6, 7,l1b-hexahydro-9-rnethoxy-2H benzo [a] quinolizinyl)methyl 1-2, 3-diphenylacrylamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-2-cyano-3-phenylacrylamide - 11 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] guinolizinyl)methyl I-2-me thyl-3-phenylacryl amide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 5 benzo [a) quiriolizinyl)methyl I-2-fluoro-3-phenylacryl amide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyll -3' -me thoxybenzamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 10 benzo [a] quinolizinyl )methyll -4 '-methoxybenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-4' -nitroberzzamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-3' -triffluoromethylcinnam 15 amide (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-2' -chiorocinnamanide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-3', 4',5' -trimethoxycinnam 20 amide (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 1-2' -ifluorocinnamamide 25 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [ajquinolizinyl)methyl] -2' -chloro-6' -ifluorocinnam amide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -2', 41, 51'-trimethoxycinnam 30 amide (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,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-4' -me thylcinnamamide 35 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2benzo [a] quinolizinyl)methyl I-2', 3'-dime thoxycinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [ajquinolizinyl)methyl] -2', 5'-dime thoxycinnamamide - 12 (RS), (SR) -NV-[2- (1,3,4, 6, 7, llb-hexahydro-9-methoxyv-2H benzo La)quinolizinyl)methyl I-2',4' -dime thoxycinnamamide (RS), (SR) -N-L2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo (a]quinolizinyl)methyll -2' -methoxycirrnamamide 5 (RS), (SR) -N- (2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl )methyll -4 '-fluorocinnamamide (RS), (SR) -N- (2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzofalquinolizinyl)methyl) -3',4' -methyl enedioxy cinnamami de 10 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyll -N' -(2-methoxyethyl) thiourea (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)rnethyl I-N' -ter-octylthiourea 15 (RS), (SR) -N- (2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl]I-N' -tertiobutylthiourea (RS), (SR) -N- (2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-NV'-cyclohexylmethyl thi ourea 20 (RS), (SR) -N- (2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyl I-N' -butylthiourea (RS), (SR) -N- (2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyl I-N' -2-phenylethylthiourea (RS), (SR) -N- (2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 25 benzo La]quinolizinyl)methyl I-N' -benzylthiourea (RS), (SR) -N- (2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyl I-N' ,N' -dime thylthiourea (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl )methyl] -N' -methyl thiourea 30 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyl] -N' -isobutyl thiourea (RS), (SR) -N- (2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl )methyl] -N'-cyclohexyl thiourea (RS), (SR) -N-L2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 35 benzo La]quinolizinyl )methyl) -N' -benzoyl thiourea (RS), (SR) -N-L2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyl] -N' -(2'-naphthyl) thiourea - 13 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)rnethyl I-N' -(1' -naphthyl) thiourea (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -N' -phenyl thiourea 5 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] -N' -phenyl urea (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] -N' -methyl urea (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 10 benzo [a] quinolizinyl)methyl I-N' ,N' -dime thyl urea (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, 7,12b-hexahydro-9-methoxy-2H benzo [a] quinol izinyl )methyl] me thylbenzami de 15 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] ethyl cinnamamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyllmethylcinnamamide (RS), (SR) -N-[2- (1,3,4,6, 7,l1b-hexahydro-9-methoxy-2H 20 benzo [a] quinolizinyl)methyllmethyl -N' -phenyl urea (RS), (SR) -N-[2- (1,3,4,6, 7,l1b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyllmethyl, NI -methyl thiourea (RS), (SR) -N- [2- (1,3,4,6, 7,12b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] formamide 25 (RS), (SR) -N- [2- (2,3,4,6, 7,l1b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -N' -benzoyl urea (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyllbenzylcarbamate (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 30 benzo [a]quinolizinyl)methyl] -N' ,N'-dime thyl sulfonyl urea (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyllmethylsulfonamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyllphenylsulfonanide 35 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyllmethyloxamamide - 14 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl ]-2 'H-benzopyran-3 ' carboxami de (RS), (SR) -N- [2- (1,3,4,6,7, llb-hexahydro-9-methoxy-2H 5 benzo [a) quinolizinyl)methyl ] -3, 3-dime thylacrylamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl ] -3' -phenylpropynamide (SS), (RR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyll cinnamamide 10 (RS), (SR) -N-[2- (1,3,4,6, 7,1lb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl -4'-ni trocinnamamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-ethoxy-2H benzo [a] quinol i zinyl ) methyl cinnamami de (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 15 benzo [a] quinolizinyl)methyl]methyl -N' ,N' -dimethylthio urea. The detection of the ca 2 -adrenergic antagonist activity of these compounds is carried out on the basis of the tests for binding to the a 2 -adrenergic receptor 20 using tritiated 2-methoxy-Idazoxan, [ 3 H]RX821002, as radioactive ligand for these receptors (N.J. Mallard et al., Br. J. Pharmacol. (1991), 102, 221). By way of example, the values for specific binding are indicated in the table: 25 COMPOUNDS OF THE BINDING a 2 EXAMPLES No. [ 3 H]RX821002 IC 5 0 (nM) 90 1 88 7 78 3 39 12 1 9 68 1.3 18 6 69 8.5 - 15 It is thus shown that the compounds of the invention according to general formula I have a potent affinity for the a 2 -adrenergic receptors. The in vivo study of the reversion of 5 hypothermia induced by guanabenz (a 2 agonist) is carried out according to the test described by S.C. Dilsaver, Pharmacol. Biochem. Behav. (1993), 45, 247. This test detects the a 2 -adrenergic receptor antagonist effect of the compounds of the invention, as 10 well as their activity at the central level. The inhibitory capacities are expressed as ED 50 which represent the doses producing a significant inhibition against hypothermia induced by guanabenz. These values are obtained using the method of J.T. Litchfield and 15 F. Wilcoxon (J. Pharmacol. Exp. Ther. (1949), 96, 99) calculated only when the inhibition occurs in more than 60% of the animals tested. The table below reproduces the values obtained by the intraperitoneal route for the products of the 20 present invention: COMPOUNDS OF THE HYPOTHERMIA INDUCED BY EXAMPLES No. GUANABENZ ED 50 MG/KG (I.P.) 39 0.47 88 0.34 78 0.91 1 0.56 70 0.63 55 0.53 18 0.98 31 0.71 The compounds of the invention according to general formula I are thus shown as a 2 -adrenergic 25 receptor antagonist agents and thus cause release of noradrenaline. They can be used in human therapy and are of interest for the treatment of neurodegenerative diseases and of their progression such as Parkinson's - 16 disease, Alzheimer's disease, Huntington's disease, progressive supranuclear paralysis, age-related cognitive disorders, attention and memory disorders, cerebral damage due to central ischemic accidents. 5 The present invention also relates to the pharmaceutical compositions comprising at least one compound of formula I and an appropriate excipient. The pharmaceutical compositions may be provided, in an appropriate manner, for administration by the oral, 10 injectable or parenteral route, in the form of soft gelatin capsules, hard gelatin capsules, tablets or injectable preparations, at the dose of 0.1 to 200 mg per day. The following examples illustrate the invention without 15 however limiting the scope thereof. Example 1: (RS), (SR) -9-methoxy-1, 3,4,6,7,llb-hexahydro-2H benzo [a] quinolizine-2-methanamine 20 This compound is synthesized in 6 stages: Stage 1 N-f ormyl -2- [3 '-me thoxyphenyl] ethyl amine A solution containing 31.2 g of 3-methoxyphen ethylamine (0.206 mol), 35.2 g of ethyl formate 25 (38.3 ml; 0.475 mol; 2.3 eq) in 125 ml of toluene is heated at 800C for 7 h. After evaporating the solvent, 37 g of an orange-colored oil are isolated, which oil is used as it is for the rest of the synthesis (quantitative yield). 30 Rf (CH 2 Cl 2 /MeOH 9/1) = 0.63 H NMR (400 MHz, CDCl 3 ) : 8.06 ppm (broad S; 1H; NH); 8.00 ppm (s; 1H; CHO); 7.20 ppm (m; 1H; H5'); 6.77 ppm (M; 3H; H2', H4', H6'); 3.74 ppm (s; 3H; OCH 3 ); 3.35 ppm (m; 2H; CH 2 N); 2.70 ppm (m; 2H; Ar-CH 2 ). 35 Stage 2 6-methoxy-3,4-dihydroisoquinoline hydrochloride A solution of 37 g of N-formyl-2-[3'-methoxy phenyl]ethylamine (0.206 mol) in 20 ml of CH 2 Cl 2 is - 17 added dropwise, over 2 h, to a solution of 48.12 g PCl 5 (0.23 mol; 1.12 eq) in 160 ml of CH 2 Cl 2 maintained at O*C on an ice bath. The reaction is maintained for a further 2 h at OWC and then the solvent is evaporated 5 off. The crude residue is taken up in petroleum ether and then treated carefully with ice-cold water. After extraction and decantation, the aqueous phase is basified with NaOH and then extracted with
CH
2 Cl 2 . The organic phase is then dried over MgSO 4 , 10 filtered and then evaporated to dryness. The crude oil (32.9 g) is taken up in ether. 72.4 ml of a 3.3N (0.22 mol) HCl/iPrOH solution are added. The crystals obtained are filtered and washed with ether. After drying in a desiccator at 550C, 15 35.3 g of yellow crystals are obtained (yield = 87%). Rf (CH 2 Cl 2 /MeOH 95/5) : 0.16 1H NMR (400 MHz, CDCl 3 ) : 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; OCH 3 ); 20 3.86 ppm (m; 2H; H3); 3.12 ppm (m; 2H; H4). Stage 3 9-methoxy-1,3,4,6,7,llb-hexahydro-2H-benzo[a)quinolizin 2-one A mixture containing 35.3 g of 6-methoxy-3,4 25 dihydroisoquinoline hydrochloride (0.178 mol) and 44.6 ml of methyl vinyl ketone (37.5 g; 0.535 mol; 3 eq) is heated at 600C for 3 h 30 min. The reaction medium which forms into a mass is taken up in acetone and then filtered. 30 The salmon-pink crystals obtained are dried in a desiccator at 55 0 C (m = 37.18 g; yield = 78%). The passage to the free base is achieved by treating with 1N NaOH a solution of the salt in CH 2 Cl 2 Rf (CH 2 Cl 2 /MeOH 95/5): 0.40 35 '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; OCH 3 ); 3.49 ppm (m; 1H; H 11b); 3.25 ppm (m; 1H; - 18 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; Hlax, H3eq). Stage 4 5 (RS), (SR) -9-methoxy-1,3,4, 6, 7,llb-hexahydro-2H benzo [a] quinolizine-2-carbonitrile A solution containing 30.18 g of ketone base (0.13 mol); 25.5 g of tosylmethylisonitrile (0.13 mol; 1 eq); 7.6 ml of ethanol (6.01 g; 0.13 mol; 1 eq) in 10 600 ml of DME is cooled to 0*C on an ice bath. After addition of 29.3 g of tBuOK (0.26 mol; 2 eq), the reaction mixture is maintained at OC for 1 h 30 min and then at room temperature for 1 h. The solution is then heated at 90*C for 2 h and then 15 abandoned 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). 20 The following are isolated 13 g of diastereoisomer A (equatorial CN): yield = 41% 2.8 g of a mixture fraction of the two diastereoisomers: yield = 9% 25 6.16 g of diastereoisomer B (axial CN): yield = 19.5% that is an overall yield of cyanated derivatives of 69.5%. Diastereoisomer A ((RS), (SR)) 30 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; OCH 3 ) ; 3.18 2.86 ppm (m; 4H; 4a, 6a, 7a, 11b) ; 2.73-2.22 ppm (m; 35 4H; Hla, H2, H7b, H6b); 2.11-1.88 ppm (m; 2H; H3a, H3b); 2.65 ppm (m; 1H; Hib). 13C NMR (50.32 MHz; CDCl 3 ) : 125.7 ppm (C11) ; 113.5 ppm (C8); 112.2 ppm (C10); 61.5 ppm (C11b); 55.2 ppm (OCH 3 - 19 and C4); 54.8 ppm (C6); 34.4 ppm (Cl); 29.6 ppm (C7); 28.7 ppm (C3); 27.4 ppm (C2). Diastereoisomer B ((RR), (SS)) Rf (AcOEt/MeOH 95/5): 0.49 5 1 H NMR (200 MHz; CDC1 3 ): 7.07 ppm (d; J = 8.5 Hz; 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;
OCH
3 ); 3.54 ppm (d; J = 11.5 Hz; 1H; H11b); 3.28 2.91 ppm (m; 4H; H2, H4a, H6a, H7a); 2.80-2.45 ppm (m; 10 4; Hla, H4b, H6b, H7b); 2.00 ppm (m; 2H; H3a, H3b); 1.70 ppm (m; 1H; Hib). 1C NMR (50.32 MHz; CDCl 3 ) : 125.7 ppm (C11) ; 113.5 ppm (C8); 112.2 ppm (C10); 58.8 ppm (C11b); 55.2 ppm
(OCH
3 ) ; 52.2 ppm (C4 and C6) ; 33.4 ppm (Cl) ; 29.7 ppm 15 (C7); 27.6 ppm (C3); 26.3 ppm (C2) Stage 5 (RS), (SR) -9-methoxy-1, 3,4,6,7, llb-hexahydro-2H benzo [a] quinolizine-2-methanamine A solution containing 9 g of nitrile diastereo 20 isomer A of the preceding stage (37 mmol) in 300 ml of MeOH is cooled to 0*C. 44.14 g of NiCl 2 -6H 2 0 (186 mmol; 5 eq) are added and the mixture is kept stirring for 15 mm at 0 0 C before the slow addition of 11.24 g of NaBH 4 (300 mmol; 8 eq) . The rate of addition of NaBH 4 25 should be such that the temperature of the reaction mixture should be kept below 5 0 C. The stirring is maintained from 0*C to room temperature for 2 h 30 min. The mixture is then evaporated to dryness and then the black residue is 30 taken up in 1N CH 2 Cl 2 /NaOH. The two phases are filtered on cellite. After abundantly 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 35 obtained (yield = 87%) 'H NMR (400 MHz; CDCl 3 ) : 7.20 ppm (d; J = 8.4 Hz; 1H; H11); 6.71 ppm (d, J = 8.4 Hz; 1H; H10); 6.62 ppm (s; 1H; H8) ; 3.77 ppm (s; 3H; OCH 3 ) ; 3.20-2.92 ppm (m; 4H; - 20 H4a, H6a, H7a, H11b); 2.72-2.62 ppm (m; 3H; H7b;
CH
2
NH
2 ); 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; Hib). 5 Stage 6 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [al quinolizinyl )methyllbenzamide 113 pil of benzoyl chloride (137 mg; 0.97 mmol; 1.2 eq) are added to a solution of 200 mg of amine 10 diastereoisomer A of the preceding stage (0.81 mmol) and 166 jl of pyridine (162 mg; 2.05 mmol; 2.5 eq) in 5 ml of THF. After 24 h of reaction at room temperature, the solvent is evaporated off. The residue is taken up in CH 2 Cl 2 and then washed with 1N NaOH. The 15 organic phase is dried over MgSO 4 , filtered and then evaporated to dryness. After purification by chromatography on a silica column (eluent
CH
2 Cl 2 /MeOH/NH 4 0H 95/5/1), 150 mg of pure compound are isolated. 20 Yield = 53% Rf (CH 2 Cl 2 /MeOH/NH 4 0H 90/102) : 0.53 m.p. (oxalate): 1120C 1H NMR (200 MHz; DMSO d6) (oxalate) : 8.61 ppm (t; 1H; NH): 7.87 ppm (m; 2H; H2'; H6'); 7.42-7.58 ppm (m; 3H; 25 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; H11b); 3.75 ppm (s; 3H; OCH 3 ); 3.58-2.87 ppm (m; 8H; Hla; H3a, H4a, H4b, H6a, H6b, H7a, H7b); 2.55 ppm (m; 1H; H2) ; 1.88 ppm (m; 1H; H3b); 1.45 ppm (m; 1H; 30 Hib). Elemental analysis: Theoretical: C (65.44), H (6.41), N (6.36); Experimental: C (64.89), H (6.21), N (6.18) In a manner similar to Example 1, but using the 35 corresponding reagents, the compounds of formula 1 are obtained and are listed by the examples in the following Table 1: -21 CA 'kD aN 00 CN 114, r H 0) co Olt m LO I~ LA ~ ~ ~ ~ ~ U LA L A Il L 0 L A L LA LA L z z z z m w- m .Ij4 m ":r H ~4 m H m 0 LA LA W N LA N LA N a) 0 m C) 11: LA m ( WLA LA LA LA LA LA N- N- k0 %.0 w. %D0 LA LA H coa 0 H 0 0 % 0) O C N m (N LA LA 0. N N N- (N N H (N 0) a) H 0) m 0 0 03 0 0: 0 0. H r.0 U- m a H w H 0 0 H) 0 H 0 H 0) 04) 0 - 4- ) 0 4 a ) 0 4 0 4 U:4 4H U) - u - u -H U -H U -H U 4-) o, 0 ( 0 U) 0 U) 0 U)I 0 Ud 0 Ud 0 m) Uo Q.I 0) i U) Q.i U) Q. N U) i co U) i Q. U H d w rd~ Hq m H ro H zN H -H4 -H > 4c HH0 0 0 0 0 0 0 04 0 0 0 0 5 00 0 0 02 4- 00 i0 0 0 mn m m m mm 04 U U U U U u U 0 0 0 0 0 0 0 0 (N Ml LA W. N- OD -22 z z z z z z z z z LA 14 '0 cq .0~ H CN O Cq- mn 0 vj mn a% N o v! LA 0N LA 0 O AH LA H H N- w. ON LA 0) 0) OD mn co 00 H,0 N '.0 V,0 HVn H- H Hd H Hd H Hd H d H r d H H LH0 H 0 H r. H 0 H 0l H 0 4o z L.) 4- 4)~ 1 5 41 rz -1- 41 r) = a) -H1 a) -H a) -H 0) -i a) -H1 Q) -H 0) Hi ) o 1 1 1 )0 0) 0 0 0 0 0 0 ) 0) W~0 . 0 2 0 Q 0 . 0 0 04 0 a) 0 4-) -H -H 4U 4-) 4) U 4 J U 4) 0 0 U U 0 rd 0 0 0 0 0 0 H 0 - 0 H 0 0 CO H1 mn Hq 0) H N H CD 0d C0 : LA M en H en 0d v 0d CN 0o w (a 0 x w. u w. v (d0 H- X< H- x H x H- >4 H-- 0 H- 0 H 0 H x 0 0 0 0 - 1-i 1- 0 00 o c U UU u u u u U) 0 0 0 0 0 0 0 0 0)0 H en9M LA '.0 H- H- H- H- H- H- H- - 23 r- 'J 0 0 f N MM LO T' LO (i N N (N LO 1n LO 0 03 CD D CD D W0 H M M M N M (N LO LA WO LA LA LA LA LA LA LA LA LA LA LA Ln LA L! O C ND O 0 r- N H r LA L I: O LO \O \O rO CO CO O 'I N i M m CD Ln H 0 N' 4 03 (N 'T1 O T4 In M 0i C H CD CD CD U U U U U U U U U U U U U U U U H H H H H H H H H ( d H ( H (c H (d H- (( H- (d H- d 4 H 4J r. u P: 0 ( u 0 P u i u P u r u 0 - () -H 0 -H 0 -H a) -H H ) -H 0 -H 0 41 4J -I1 E J- E 4-- 4.) 4 .J 0) - 0 - 0) - 0) -H 0) -H 0 - ( -H -H o 0 0 01 0 0 0 0i 0 0 0 0 0 0i 0 0 0) P4 0) P4 ci) P4 0) P4 0) P4 ci) P4 (1) P4 0 4 0 0 w 0 Q 0 )0 Q 0 0 0 0 (U 04a 0 W 04 a) W 0 04 U 1 U 41 U 4J U J-) U 41 U - U -) U o rd 0 (o 0 rd 0 ( 0 t 0 10 0 ( 0 rd CD H (N r-I N H r-I D r-I O r-1 r-i 0 H m3 v m ( (I M (d (N (d N (a m ( L In (d r-H X H H H X H r-I x H x H X 0 0 0 0 0 0 0 0 o000 0 0 0 0 NOD 0) 0 H (N m 4 H- H- H- (N (N4 (N (N (N -24 zzzzzzzz z z z z z H 0 N ~ N in (N n m m m 0 n w m 0 i9 (N in L9 in O Cn 02 N O 0 i N 0 02i 0i 02i .cq N- 0, CN (q in 14 in 0Iv ( 0 UUUUuU U U. U Z U U U z U U_ Hl H H H 1 w HV rf a H H) H- Ed HI- Ed H- Cd H 4J H= rdH Cd H C H o0 0 V0 V0 V0 V 0 V 0 V0 W a) . ~ V ~ V Q V Q ~ V Q ~ V Q JR. ~ N . ~ N . 0 Cd 0 Cd 0 Cd 0 (d 0 Cd 0 Cd 0 Cd 0 C N- H- wD H 0 H- 02 H- 02 H- (N H CD H- 02 H 0 Cd n Cd 11 Cd m' Cd H md (v C e d 02 C (N N H- x H r- H- N X 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 in ND 02 0D)C H (N (N (N (N (N (N en en en -25 (N (N H- ( H H (N m 11 4 4 H H N N z z z z z z z z zzzzzz N L9 ri H en CI (N ( C! en Hi 0 Co LA LA LA LA LA LA oD . D WW . . . H 0)en 0 0 .0 N a) a%~ N) 0) N LA H 1 1 4 U U U UU U U U UU U u HH H H) Ho Hl H1 ) rq a A a H H) 4J 00 1,0 .)1 5 d 4 -i 5 d 4J - r= 4J - Ed 4 J 5 d 4 - E d . r -H wn l a) -H C) *ri- ) - ) H C H C H C 0 a) ) 0 0 ) 0 C) 0 ) 0 0 ) 0 C) 0 C 04 W) W4 C4 Q4 04 W~C 4 C . ) ~ C E- ) C) A C)C C ) )C U 4J- U 4J 4-) U J Jii-J U 4- U 4IJ U 4-) 0 (a 0 as 0 rd1 0 Md a) d 0 (d 0 (10 0 (d %D0 H- O) H- w. H mn H- mn H (N4 H- 0 H- 1 1 H (N (0~) C N (0 en) C H Cd LA (d t.0 (a (N (a Hx H~ H x< H x x Hi x< HA X H x 0 0 0 0 0 0 0 0 UU U U U U U U 0 0 0 0 0 0 0 0 enLA No a) ODm 0 en) en en 'eVe e - 26 LA H Mm (D c O'\ tON LA LA H 0 H 0 0 03 m o LA LA LA LO LA LA '.O LA z z z z z z z LA M H - N LA (N LA M 0C 0 - W 0m H m N O O LO' LA C 0 0 'O C LA CO LA LA LA N N H 0 0 0 N N -I- \O) O 41f 4 o ) O 0 0 0 0 0 -o 0 0d 0 0 0 U U U U U U U U U o o O o D o e o e O) - U - O - U - U o ( 0 () 0 ( 0 0 0 U) H N n Ln - 27 Example 46: (SS), (RR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl] cinnamamide This compound is synthesized in 2 stages: 5 Stage 1 (SS), (RR) -9-methoxy-1,3,4,6, 7,llb-hexahydro-2H benzo [a ]quinolizinyl -2-me thananine 220 pl of H 2
SO
4 (405 mg; 4.13 mmol; 1 eq) are added dropwise to a mixture containing 8.25 ml of 10 1M LiAlH 4 /Et 2 O solution (8.25 mmol; 2 eq) and 10 ml of THF. There is formation of a white precipitate and gas emission. The solution is stirred at room temperature for % h and then cooled to 0*C on an ice bath. A solution of 1 g of axial cyano obtained as 15 diastereoisomer B in stage 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 h. The hydrolysis of the reaction mixture is performed with Na 2
SO
4
/H
2 0. The precipitate formed is removed by 20 filtration 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,llb-hexahydro-9-methoxy-2H 25 benzo [a] quinolizinyl)methyl] cinnamamide Addition of 689 mg of cinnamoyl chloride (4.14 mmol; 1.1 eq) to a solution of 925 mg of amine of the preceding stage (3.76 mmol) and 577 pl of methylamine (419 mg; 4.14 mmol; 1.1 eq) in 10 ml of 30 CH 2 Cl 2 . The reaction is exothermic. After 1 / 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: 35 CH 2 Cl 2 /MeOH/NH 4 0H 98/1.7/0.3) . Rf (CH 2 Cl 2 /MeOH/NH 4 0H 95/5/0.5) : 0.31 m.p. (hydrochloride): 161 0
C
- 28 'H NMR (400 MHz; CDC1 3 ) (base) : 7.65 ppm (d; J = 15.6 Hz; 1H; CH=CH-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; 5 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; 1H; NH); 3.77 ppm (s; 3H; OCH 3 ); 3.62-3.50 ppm (m; 3H; H11b and
CH
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; 10 1H; Hla) ; 2.05 ppm (m; 1H; H2) ; 1.93 ppm (m; 1H; H3a); 1.83 ppm (m; 1H; H3b); 1.61 ppm (Hib). Elemental analysis: Theoretical : C (69.80), H (7.08), N (6.78); Experimental: C (69.75), H (7.04), N (6.76) 15 Example 47 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo[a]quinolizinyl)methyl]acetamide 139 jil of acetic anhydride (151 mg; 1.48 mmol; 1.2 eq) are added to a solution of 300 mg of amine 20 obtained in stage 5 of Example 1 (1.21 mmol) and 0.25 ml of pyridine (3 mmol; 2.5 eq) in 8 ml of THF. After 3 h of stirring at room temperature, the solvent is evaporated off and the residue is taken up in
CH
2 Cl 2 /NaOH 1N. After decantation, the organic phase is 25 dried over MgSO 4 , filtered and then evaporated to dryness. The crude product is purified by chromatography on a silica column (eluent
CH
2 Cl 2 /MeOH/NH 4 0H 90/9/1). 230 mg of a yellow oil are isolated (yield = 65%). 30 Rf (CH 2 Cl 2 /MeOH/NH 4 0H 90/10/2) : 0.50 m.p. (oxalate): 98*C H NMR (200 MHz; DMSO d6) (base) : 7.96 ppm (broad t; 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 = 35 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) (Hla, H3a, H4a, H4b, H6a, H6b, H7a, - 29 H7b); 2.40 ppm (m; 1H; H2); 1.78 ppm (m; 1H; H3b); 1.32 ppm (m; 1H; Hib). Elemental analysis: Theoretical: C (60.31), H (6.92), N (7.40); 5 Experimental: C (60.19), H (6.62), N (7.09) In a manner similar to Example 1, but using the corresponding reagents, the compounds of formula 1 are obtained and are listed by the examples in the following Table 2: -30 ~~4C co W V co v i W O~a 4 a A 0 O-4 a) i' CW H C) mi C) H a) r: a) W zzzzzz zzz z z z z z z H~ 0 a) H0 W - Af LA VA kD m4 W H r- w 0 HOI (Na r H H L LA l '.D W n a) m O (ND a N ND %) N. ID a) N N 10 w W. W a) ND N ND H- H) H N Hu1 ~ LA Lu u N u LA u uA (N u 4-irir' - * H- d rl m I r H m -A NH (d ' - L d HA 0 0 fd 4 d 41 r - ro 4- rd J M- 4J (d .0 (0 4 wd -ii a) -Ifi a) -ii Cd -4- 0) -4 a) i a) -i C 00) 00) 00a) 00) 00) 00) 00)U 00) 0) 4 0 4 0 4 0 4 0) P4 Q) 4 0) p ) 4 0 0)141- )0)0 04~ 0) 4~ 0 00 U4i - 4.) 00 u0 H H 0 (a 0 H- 0 H1 0 Co 0 (d 0 C0 0 Hq 0 H4 C (N Hi (N 4 o ,I' OH H- C - H m ., LA ,4 0 Cd I () w~ U LA Md fo Cd Cd ) U N u -H c H xr HOI HO H4 0< '14 HO HO)X ri 4)0 1-i 1- 0 0 0 1-4 1-i 0)>1 > 1 > m 0 0c 0 0 0- 0' 0 0 Z'LA LA LA LA LA LA -31 m~ co 0 0) in 00 t, o OD 'kD W mn %D LA W10 m LA LA LA U' LA LA L LA LA LA '.0 '.0 LA LA '0 z z z z z z z C j o a, k9 '.0 a, a, N , O i a, LA N m 14 m m~ a% N, N N t.0 %.0 1.0 LA LA w. w. '.0 r-0 LA LAA LA LAI M. '.0 '.0 (. A L . 0 L a U U. U U: U U: U Hr H) *D w * H - a) -Q EJ J-) 4E) 41 J-) Ed 4-i 4d4i C .. d 4 -H .(D -H w) -) .11 a) a) H a - ) - ~ o a) 0 () 0 a) 0 1) 0 a) 0 a) 0 a) 0 C a)~L u) U) U) a ) Cd 0 0dCdC 0 Cd 0 0 0 d o C HN ' LA H- H H H 0 H- 0 H- (N H- LA H m Cd Cd C1 d C d HN (d H XT Hy M d x x x H H >4 x 0 0 0 0 0 0 0 0 m m m m m UU U U U UUU '0 0 0a, 0 H 0 LA LA LA LA %D0 w. w. W.
- 32 Example 64 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl]phenyl sulfonamide Addition of 0.19 ml of phenylsulfonyl chloride 5 (263 mg; 1.49 mmol; 1.2 eq) to a solution of 300 mg of amine obtained in stage 5 of Example 1 (1.21 mmol) and 0.25 ml of pyridine (3 mmol; 2.5 eq) in 10 ml of THF. The reaction is maintained at room temperature for 10 days. After adding an additional 0.19 ml of 10 phenylsulfonyl chloride and reacting for a further 10 days, the solution is evaporated to dryness. The residue is purified by chromatography on a silica column (eluent CH 2 Cl 2 /MeOH 95/5) . 166 mg of an oil are isolated, which oil crystallizes on standing 15 (yield = 35%). Rf (CH 2 Cl 2 /MeOH 95/5) : 0.26 m.p. (oxalate): 130-135*C 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; 20 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 (broad t; 1H; NH) ; 3.77 ppm (s; 3H; OCH 3 ) ; 3.22-2.86 ppm (m; 6H; CH 2 N; H4a, H6a, H7a, H11b); 2.65 ppm (m; 1H; H7b) ; 2.48 ppm (m; 25 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). Elemental analysis: Theoretical: C (57.97), H (5.92), N (5.88); 30 Experimental: C (57.47), H (5.92), N (5.81) Example 65 (RS), (SR) -N- [2- (1,3,4,6,7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyllmethylsulffonamide In a manner similar to Example 64, but using 35 methanesulfonyl chloride, the title compound is obtained: m.p. (oxalate): 156*C - 33 Elemental analysis: Theoretical: C (52.16), H (6.32), N (6.76); Experimental: C (52.73), H (6.25), N (6.85) Example 66 5 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl ] -N' ,N' -dime thyl sulfonyl urea In a manner similar to Example 64, but using N,N-dimethylsulfamoyl chloride, the title compound is obtained: 10 m.p. (oxalate): 110*C Elemental analysis: Theoretical: C (51.45), H (6.59), N (9.47); Experimental: C (51.27), H (6.61), N (9.24) Example 67 15 (RS), (SR) -N-[2- (1,3,4,6, 7,l1b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyllbenzylcarbamate Addition dropwise of 0.18 ml of benzyl chloroformate (215 mg; 1.26 mmol; 1.05 eq) diluted in 1 ml of DME to a solution of 300 mg of amine obtained 20 in stage 5 of Example 1 (1.22 mmol) in 5 ml of water supplemented with a small quantity of DME. After 4 days of reaction at 100 0 C, the reaction mixture is evaporated to dryness, taken up in CH 2 C1 2 and then washed with 1N NaOH. After purification by 25 chromatography on a silica column, 118 mg of carbamate, the title compound, are isolated (yield = 36%). Rf (CH 2 Cl 2 /MeOH/NH 4 0H 90/9/1) : 0.54 m.p. (oxalate): 104 0 C H NMR (CDCl 3 ; 400 MHz) (base) : 7.28 ppm (m; 5H; Ph): 30 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 (s; 2H; Ph CH 2 0) ; 3.71 ppm (s; 3H;
OCH
3 ) ; 3.14-2.88 ppm (m; 6H; CH 2 N, H11b, H7a, H6a, H4a) ; 2.62 ppm (m; 1H; Hla); 2.45 ppm (m; 1H; H7b) ; 2.26 ppm 35 (m; 2H; H4b and H6b); 1.71 ppm (m; 2H; H2 and H3a); 1.35 ppm (m; 1H; H3b); 1.08 ppm (m; 1H; Hib).
- 34 Elemental analysis: Theoretical: C (63.82), H (6.43), N (5.95); Experimental: C (63.82), H (6.83), N (5.92) Example 68 5 (RS), (SR) -N- [2- (1,3, 4,6,7, llb-hexahydro-9-methoxy-2H benzo [a ]quinolizinyl)methyl] thiobenzamide 322 mg (0.80 mmol) of [2,4-bis-(4-methoxy phenyl) -1,3-dithia-2,4-diphosphetane-2,4-dithio] (Lawesson's reagent) are added to a solution of 305 mg 10 (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. The medium is heated under reflux and maintained stirring for 2 days. After evaporation of the solvent, 15 the residue is filtered on alumina, eluted with dichloromethane. The filtrate is evaporated off to give 250 mg (85%) of a yellow oil which is treated with oxalic acid to give 239 mg (77%) of pale yellow crystals of oxalate. 20 Rf (CH 2 Cl 2 /MeOH 90/9/1): 0.58 m.p. (oxalate): 165 0 C H NMR (200 MHz; CDCl 3 ) (base) : 7.81 ppm (broad s; 1H; 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 = 25 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; CH 2 N); 3.77 (S; 3H; OCH 3 ); 3.28-2.97 ppm (m; 4H; H4a, H6a, H7a, H11b) ; 2.77-2.38 ppm (m; 4H; Hla, H4b, H6b, H7b); 2.25 ppm (m; 1H; H3a); 1.88 ppm (m; 1H; H2); 30 1.68 ppm (m; 1H; H3b); 1.33 ppm (m; 1H; Hib). Elemental analysis: Theoretical: C (63.14), H (6.18), N (6.13); Experimental: C (63.38), H (6.16), N (6.07) Example 69 35 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl ] thioacetamide - 35 In a manner similar to Example 68, but using the corresponding reagents, the title compound is obtained: m.p. (oxalate): 113 0 C 5 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,llb-hexahydro-9-methoxy-2H 10 benzo [a] quinolizinyl )methyl) thiocinnamamide In a manner similar to Example 68, but using the corresponding reagents, the title compound is obtained: m.p. (oxalate): 128 0 C 15 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,llb-hexahydro-9-methoxy-2H 20 benzo [a] quinolizinyl ) methyl) -N' -phenyl urea Addition dropwise of a solution of 90 pl of phenyl isocyanate (98 mg; 0.82 mmol; 1 eq) in 5 ml of
CH
2 Cl 2 to a solution of 200 mg of amine obtained in stage 5 of Example 1 (0.82 mmol) in 5 ml of CH 2 Cl 2 . 25 After 16 h of reaction at room temperature, the solvent is evaporated off and then 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 are isolated, which oil crystallizes on standing (yield = 54%). 30 Rf (CH 2 Cl 2 /MeOH 90/10) : 0.35 m.p. (hydrochloride): 185 0 C H NMR (200 MHz; DMSO d6) (hydrochloride): 7.45 7.10 ppm (m; 5H; H2', H3', H5', H6', H11); 6.81 6.95 ppm (m; 3H; H4', H8, H10); 4.42 ppm (d; J = 35 11.3 Hz; 1H; H11b); 3.74 ppm (s; 3H; OCH 3 ); 3.62 2.92 ppm (m; 6H; CH 2 N, H4a, H6a, H6b, H7a, H7b); 2.92 ppm (m; 1H; H2): 1.95 ppm (m; 2H) and 1.70 1.30 ppm (m; 2H) (Hia, Hlb, H3a, H3b).
- 36 Elemental analysis: Theoretical: C (65.74), H (7.02), N (10.45); Experimental: C (65.32), H (6.97), N (10.19) Example 72 5 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl methyll -N' -methyl urea In a manner similar to Example 71, but using the corresponding reagents, the title compound is obtained: 10 m.p. (hydrochloride): 160*C Elemental analysis: Theoretical: C (60.08), H (7.71), N (12.36); Experimental: C (60.24), H (8.00), N (11.86) Example 73 15 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo[alquinolizinyl)methyll -N' -benzoyl urea In a manner similar to Example 71, but using the corresponding reagents, the title compound is obtained: 20 m.p. (oxalate): 210*C Elemental analysis: Theoretical: C (62.10), H (6.04), N (8.69); Experimental: C (62.00), H (5.87), N (8.37) Example 74 25 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl ] -N' ,N' -dime thyl urea A solution of 0.24 ml of dimethylcarbamoyl chloride (280 mg; 2.6 mmol; 1.2 eq) in 2 ml of THF is added dropwise to a solution of 530 mg of amine 30 obtained in stage 5 of Example 1 (2.15 mmol) and 0.44 ml of pyridine (425 mg; 5.4 mmol; 2.5 eq) in 30 ml of THF. The reaction is maintained at room temperature for 2 days and then heated at 80 0 C for 5 days after addition of a spatula-tip quantity of DMAP. 35 The reaction mixture is taken up in 1N NaOH/CH 2 Cl 2 . The organic phase is dried over MgSO 4 , filtered and then evaporated to dryness. The crude oil - 37 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 m.p. (oxalate): 122 0 C 5 '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; OCH 3 ); 3.28-3.08 ppm (m; 4H; H11b, H7a and CH 2 N) ; 3.03 ppm (m; 1H; H4a) ; 10 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; H2) ; 1.78 ppm (m; 1H; H3a) ; 1.41 ppm (m; 1H; H3b) ; 1.12 ppm (m; 1H; Hlb). 15 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,llb-hexahydro-9-methoxy-2H 20 benzo [a] quinolizinyl)methyl] -N' -phenylthiourea 230 pl (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 of CH 2 Cl 2 . The reaction is maintained at room temperature for 4 h. The 25 reaction mixture is treated with 1N NaOH. The organic phase is washed with saturated 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 0H 98/1.7/0.3). 30 Yield = 53% Rf (CH 2 Cl 2 /MeOH/NH 4 0H 90/9/1) : 0.38 m.p. (oxalate): 146*C H NMR (400 MHz; CDCl 3 ) (base) : 7.63 ppm (broad s; 1H; NH); 7.49 ppm (m; 2H; H3' and H5'); 7.35 ppm (t; J = 35 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 s; 1H; NH) ; 3.77 ppm (s; 3H; - 38 OCH 3 ); 3.64 ppm (m; 1H; HA (CH 2 N)); 3.53 ppm (M; 1H; HB
(CH
2 N)); 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 5 (m; 1H) (Hla 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; Hib). Elemental analysis: Theoretical: C (61.13), H (6.20), N (8.91); 10 Experimental: C (61.31), H (6.14), N (8.68) In a manner similar to Example 75, but using the corresponding reagents, the compounds of formula 1 are obtained by the examples in the following Table 3: -39 Wn m- c - OD r k9 H H CO H CO H O CO N C m OD r 0 r- OI %D H m H 0 O LA 0 on W co c *0 M Hn Hn On 0i On CO On 0 Co %O %D %D -I.. Wo 4m L d 41 MN J- (a H J J H r a) H N) H '(D H4 a) Hi a) LA LA WA CO CO CO CO CO 0i H 4 H 0 0v LA LA L LA L LA L LA 0 0 w 0 0 0 ( 40 104 H 4 U U 4- U 4- U U- U U- U 4 H Cdi H H w d H- Cd) H C H m d f d 43 ( d 'Im r d r I - (13 Ln ( d .J d .1J . - xI -H v -H x -H cv *HI cv 4--C 0 0 0)~ 0 0i 0 I) S .1-C U~) - U 4J U 43 U 43 U -- 4) 0 0 0 0 0 0 H R - OD m Hd -40 LA~ ON 11W H (N 1 D C LA m m 0 0 ' a! a' OD S r N 0) N 0 z zz z z z zz z z 0) Hh 00 a% '.D C' r0 O A LA LA O' 'D W 'D O ' ~ O ~ 0 0) Ch r-I W0 0 0 - N ' rO N 0 W~ o 0 ~ 0 LA ('~~ m ~ H H LA H ~ ~0 0 U) U U U u U U U U_ UU .- H 4)a ) -q a) -H 4) aH ) -Hi a) -H 4) -H a) -Hi a) -H 4 i -H a) o0 4 0 4) 0 4) 0 4) 0 4) 0 U u- U -I U 4) U 4-) u J-) u 4 0 l 0 (~ 0 (15 0 m~ 0 (0 0 ( o) C) ON Xi %J\ ,-4 '0 rq w 1.0 rd M 0 H- (d LA rd cq rd "; H cq .C i - H X H- x H X x 0 0 0 0 0 0 0 0 0 0 0 Nm wLA W N 00 CD 0) OD OD 0) - 41 Example 88 (RS), (SR) -N- [2- (1,3, 4,6,7, llb-hexahydro-9-methoxy-2H benzo [a ]quinolizinyl )methyl ]-N', N' -dimethyl thiourea Addition of 238 mg of dimethylthiocarbamoyl 5 chloride (2.11 mmol; 1.2 eq) dissolved in 5 ml of THF to a 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 under reflux for 48 h, 10 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 pure title 15 thiourea are isolated (yield = 23%). Rf (CH 2 Cl 2 /MeOH/NH 4 0H 90/9/1) 0.48 m.p. (oxalate): 105*C 1 H NMR (200 MHz; CDCl 3 ) :7.08 ppm (d; J = 8.6 Hz; 1H; H11); 6.69 ppm (dd; J = 8.6 and 2.4 Hz; 1H; H10); 20 6.58 ppm (d; J = 2.4 Hz; 1H; H8); 5.55 ppm (broad m; 1H; NH); 3.75 ppm (s; 3H; OCH 3 ); 3.6 ppm (m; 2H; CH 2 H); 3.27 ppm (5, 6H; NMe 2 ); 3.14-2.89 ppm (m; 4H; H4a; H6a; H7a; H11b); 2.66 ppm (m; 1H; H7b); 2.48 ppm (m; 1H; H6b); 2.33 ppm (m; 2H; Hla; H4b); 2.04 ppm (m; 1H; H2); 25 1.78 ppm (m; 1H; H3a); 1.46 ppm (m; 1H; H3b) ; 1.12 ppm (m; 1H; Hlb). Elemental analysis: Theoretical: C (56.72), H (6.90), N (9.92); Experimental: C (56.93), H (6.39), N (9.52) 30 Example 89 Stage 1 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl] formamide 193 mg (2.27 mmol; 1 eq) of 0-formylhydroxy 35 acetonitrile (prepared according to J. Prakt Chem, 1996, 338, 488-90) are added to a solution of 560 mg of amine obtained in stage 5 of Example 1 (2.27 mmol) in 10 ml of CH 2 C1 2 maintained on an ice bath.
- 42 The reaction is maintained at room temperature for 20 h. 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 5 chromatography on a silica column (eluent CH 2 Cl 2 /MeOH 92/8). 422 mg of formamide are isolated (yield = 68%). Rf (CH 2 Cl 2 /MeOH 9/1) : 0.38 H NMR (400 MHz; CDCl 3 ) : 8.22 ppm (s; 1H; CHO) ; 7.10 ppm (d; J = 8.6 Hz; 1H; H11); 6.71 ppm (dd; J = 8.6 Hz and 10 2.5 Hz; 1H; H10); 6.62 ppm (d; J = 2.5 Hz; 1H; H8); 5.69 ppm (broad s; 1H; NH); 3.78 ppm (s; 3H; OCH 3 ); 3.27 ppm (m; 2H; CH 2 N); 3.15 ppm (m; 1H; 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); 15 2.48-2.30 ppm (m; 2H; Hla, H4b); 1.85 ppm (m; 1H; H2); 1.77 ppm (m; 1H; H3a) ; 1.44 ppm (m; 1H; H3b) ; 1.17 ppm (m; 1H; Hib). Stage 2 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 20 benzo (a] quinolizinyl)methyl]methyl amine 640 mg of ground LiAlH 4 (16 mmol; 2 eq) are added in small fractions to a solution of 2.2 g of formamide of the preceding stage (8.02 mmol) in 50 ml of THF at 0*C. After heating at 45-50*C for 48 h, the 25 reaction mixture is hydrolyzed with Na 2
SO
4
/H
2 0. 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 0H 90/9/1) . 30 Rf (CH 2 Cl 2 /MeOH/NH 4 0H 80/18/2) : 0.56 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;
OCH
3 ) ; 3.15 ppm (m; 1H; H7a) ; 3.08 ppm (d; J = 11.2 Hz; 35 1H; H11b); 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; CH 2 N and H6b); 2.46 ppm (s; 3H; NMe); 2.42-2.30 ppm (m; 2H; - 43 Hla and H4b); 1.81-1.70 ppm (m; 2H; H2 and H3a); 1.39 ppm (m; 1H; H3b); 1.11 ppm (m; 1H; Hib). 13 C NMR (100.63 MHz; CDCl 3 ) : 157.7 ppm (C9); 135.8 ppm and 130.6 ppm (C7a and C11a); 125.8 ppm (C11); 5 113.3 ppm and 111. 8 ppm (C8 and C10) ; 62.4 ppm (OCH 3 ) ; 58.5 ppm (CH 2 N); 56.3 ppm (C4); 55.1 ppm (C11b); 52.4 ppm (C) ; 36.83 ppm and 36.80 ppm (NCH 3 and C2); 36.2 ppm (Cl); 30.2 ppm and 29.9 ppm (C3 and C7). Example 90 10 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl ) methyl]methyl -N' -methyl thiourea 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 of CH 2 Cl 2 . After 17 h 15 of reaction at room temperature, the reaction mixture is washed with 1N NaOH, dried over MgSO 4 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 0H 95/4.5/0.5). The pure thiourea is 20 isolated with a yield of 37%. Rf (CH 2 Cl 2 /MeOH 90/10) : 0.40 m.p. (oxalate): 105 0 C 1H 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); 25 6.62 ppm (d; J = 2.6 Hz; 1H; H8); 5.50 ppm (m; 1H; NH); 3.78 ppm (s; 3H; OCH 3 ); 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, H11b) ; 3.11-2.98 ppm (m; 2H; H6a and H4a); 2.72 ppm (m; 1H; H7a); 2.56 ppm (m; 1H; Hla); 30 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). Elemental analysis: Theoretical: C (56.72), H (6.90), N (9.92); 35 Experimental: C (56.64), H (6.71), N (9.68) Example 91 (RS), (SR) -N-[2- (1,3,4,6, 7,1lb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl]methyl -N' -phenyl urea - 44 In a manner similar to Example 90, but using the corresponding reagents, the title compound is obtained: m.p. (oxalate): 117*C 5 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,llb-hexahydro-9-methoxy-2H 10 benzo [a] quinolizinyl)methyl]methylcinnamamide In a manner similar to Example 1, but using the corresponding reagents, the title compound is obtained: m.p. (oxalate): 124*C Elemental analysis: 15 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, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl ] ethyl cinnamamide 20 In a manner similar to Example 1, but using the corresponding reagents where (RS) , (SR) -N- [2- (1, 3, 4, 6, 7, llb-hexahydro-9-methoxy-2H-benzo[a]quinolizinyl) methyllethylamine is obtained in a manner similar to the amine of Example 89 but using the compound of 25 Example 47, the title compound is obtained: m.p. (oxalate): 120*C Elemental analysis: Theoretical: C (68.00), H (6.93), N (5.66); Experimental: C (67.72), H (6.76), N (5.60) 30 Example 94 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl ) methyl]methylbenzamide In a manner similar to Example 1, but using the corresponding reagents, the title compound is obtained: 35 m.p. (oxalate): 150 0
C
- 45 Elemental analysis: Theoretical: C (66.06), H (6.65), N (6.16); Experimental: C (65.47), H (6.24), N (5.82) Example 95 5 (RS), (SR) -N- [2- (1,3,4,6,7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyll -3-cyclohexylacrylamide Stage 1 ethyl 3-cyclohexylacrylate 17.1 g of carboxymethylenetriphenylphosphorane 10 (49.1 mmol; 1.1 eq) are added to a solution of 5 g of cyclohexylcarboxaldehyde (44.6 mmol) in 100 ml of
CH
2 C1 2 . After 72 h of reaction at room temperature, the solvent is evaporated off and the residue is taken up in petroleum ether. The insolubles are separated by 15 filtration and then the filtrate is evaporated to dryness. 5.25 g of a light yellow oil are isolated (yield = 65%). 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; 20 H2) ; 4.11 ppm (q; J = 7.1 Hz; 2H; CH 3
CH
2 0) ; 2.15 ppm (m; 1H; Hi'); 1.73-1.59 ppm (m; 5H; equatorial H); 1.33 1.06 ppm (m; 8H; axial H and CH 3
CH
2 0). Stage 2 3-cyclohexylacrylic acid 25 A solution containing 5.25 g (28.8 mmol) of ethyl 3-cyclohexylacrylate, 50 ml of 1N NaOH and 50 ml of THF is stirred at room temperature for 50 h. After decantation, the aqueous phase is washed with ether, acidified with concentrated HCl and then extracted with 30 CH 2 Cl 2 . The organic phase is dried with MgSO 4 , filtered and then evaporated to dryness. 4.4 g of a cream colored solid are isolated (yield = 99%). 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; 35 H2); 2.12 ppm (m; 1H; Hi'); 1.75-1.58 ppm (m; 5H; equatorial H); 1.32-1.04 ppm (m; 5H; axial H).
- 46 Stage 3 3 -cyclohexylacryol chloride A solution containing 1 g of 3-cylcohexyl acrylic acid (6.5 mmol) and 2.83 g of SOCl 2 (4.63 g; 5 39 mmol; 6 eq) is heated at 75 0 C for 4 h. The residue is taken up in toluene and then evaporated to dryness. 1.1 g of a brown oil are obtained (yield = 98%). H NMR (400 MHz; CDC1 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; 10 H2); 2.15 ppm (m; 1H; Hl'); 1.80-1.58 ppm (m; 5H; equatorial H); 1.32-1.03 ppm (m; 5H; axial H). Stage 4 (RS), (SR) -N- [2- (1,3,4,6, 7, llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl ] -3-cyclohexylacrylamide 15 Addition dropwise 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 of THF. The reaction is maintained at room temperature for 48 h. The reaction mixture is then evaporated to 20 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 0H 98/1.7/0.3). 25 184 mg of brown solid are isolated (yield = 31%). Rf (CH 2 Cl 2 /MeOH/NH 4 0H 90/9/1) : 0.47 m.p. (oxalate): 140 0 C 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; 30 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; OCH 3 ); 3.29 ppm (m; 2H; CH 2 N); 3.23-3.10 ppm (m; 2H; H7a, H11b); 3.07 ppm (m; 1H; 35 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; equatorial H2 and cyclohexyl); 1.65 ppm (m; 1H, - 47 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); 5 Experimental: C (65.70), H (7.26), N (5.67) Example 96 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-2H benzo [a] quinolizinyl)methyl] cinnamamide Stage 1 10 3,4-dihydroisoquinoline hydrochloride 20 ml (150 mmol) of 1,2,3,4-tetrahydroiso quinoline dissolved in 350 ml of CH 2 Cl 2 , and 29.5 g (1.1 eq) NBS are introduced into a 1-1 round-bottomed flask. The reaction mixture is stirred for 4 h at room 15 temperature and then overnight after addition of 100 ml of concentrated NaOH. The organic phase is recovered after decantation, washed with water and then extracted with 1N HCl. The aqueous phase is basified with concentrated NH 4 0H and then extracted with CH 2 Cl 2 . The 20 new organic phase is then washed with a saturated NaCl solution, dried over MgSO 4 , filtered and then evaporated to dryness. A brown oil is recovered: m=16.5 g. The salt exists in the form of a yellow solid, it is obtained by addition of 44.6 ml of a 25 HCl/iPrOH solution at 3.1M. The overall yield is 73.4%. H NMR (400 MHz, DMSO d6) : 13.99 ppm (s, 1H, NH); 9.23 ppm (s, 1H, H1) ; 7.92 ppm (m, 1H, H8) ; 7.79 ppm (m, 1H, H5); 7.52 ppm (m, 2H, H6, H7); 3.94 ppm (t; J = 8 Hz, 2H, H3); 3.15 ppm (t, J = 8 Hz, 2H, H4). 30 Stage 2 1,3,4,6,7,llb-hexahydro-2H-benzo[a]quinolizin-2-one 10 g (60 mmol) of the hydrochloride of the preceding stage 1 and 15 ml (3 eq) of methyl vinyl ketone are heated at 60 0 C for 4 h in a round-bottomed 35 flask. 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 basifying, the aqueous phase is extracted with CH 2 C1 2 . The organic - 48 phase is filtered, dried over MgSO 4 and then evaporated to dryness. 9.52 g of a brown solid are obtained. The yield is 67%. 1 H NMR (400 MHz, CDCl 3 ) : 7.17 ppm (m, 3H, aromatic H); 5 7.08 ppm (m, 1H, aromatic H) ; 3.58 ppm (dd, J = 12 Hz and 2.4 Hz, 1H, H11b); 3.28 ppm (m, 1H, H4eq); 3.16 ppm (m, 2H, H7ax and H6eq); 2.95 ppm (dm, J = 14.4 Hz, 1H; Hleq) ; 2.83 ppm (m, 1H, H7eq) ; 2.74-2.62 ppm (m, 3H, H3eq, H4ax and H6ax) ; 2.52-2.42 ppm (m, 2H, Hlax and 10 H3ax). Stage 3 (RS), (SR) -1, 3,4,6,7, llb-hexahydro-2H-benzo [a] quinolizine 2 -carboni tri1e 8.52 g (42.3 mmol) of the ketone of the 15 preceding stage 2, 150 ml of DME, 8.26 g (1 eq) of TosMIC and 2.5 ml (1 eq) of ethanol are introduced into a 500-ml round-bottomed flask at 0*C. The reaction mixture is stirred for 30 min; 9.5 g (2 eq) of tBuOK are added and the stirring is continued for an 20 additional 30 min at 0*C. After returning to room temperature, the reaction mixture is heated at 90 0 C for 4 h, filtered and then evaporated to dryness. Flash chromatography (petroleum ether/ethyl acetate: 8/2) makes it possible to separate the two isomers. Three 25 fractions are recovered: 1st fraction, diastereoisomer A, 3.2 g of yellow solid (Y = 36%); 2nd fraction, 0.73 g of mixture of the diastereoisomers A and B (Y = 8.1%); 3rd fraction, diastereoisomer B, 1.17 g of yellow solid (Y = 13%). 30 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); 3.06 ppm (m, 1H, H7ax); 3.03 ppm (dm, J = 12 Hz, 1H, H4eq); 2.94 ppm (m, 1H, H6eq); 2.74-2.63 ppm (m, 3H, 35 Hlax, H2, H7eq); 2.55 ppm (dt, J = 11.6 Hz, J = 3.6 Hz, 1H, H6ax); 2.34 ppm (dt, J = 12 Hz, J = 2 Hz, 1H, H4ax); 2.08-1.92 ppm (m, 2H, H3ax and H3eq) ; 1.74 ppm (q, J = 12.4 Hz, 1H, Hleq).
- 49 diastereoisomer B: (RR),(SS)-7.19-7.09 ppm (m, 4H, aromatic H); 3.58 ppm (d, J = 11.2 Hz, 1H, H11b); 3.18 3.07 ppm (m, 2H, H7ax and H2) ; 2.98-2.94 ppm (m, 2H, H6eq and H6ax) ; 2.76-2.60 ppm (m, 3H, Hleq, H4eq and 5 H7ax); 2.53 ppm (d, J = 13.6 Hz, 1H, H4ax); 2.19 ppm (m, 2H, H3ax and H3eq); 1.17 ppm (dt, 1H, Hiax). Stage 4 2- (1,3,4,6,7, llb-hexahydro-2H-benzo[alquinolizinyl) methylamine 10 1 g (4.7 mmol) of nitrile diastereoisomer A is dissolved in 80 ml of methanol. The mixture is cooled to 0*C and then 5.2 g (5 eq) of nickel chloride are added. Sodium borohydride (8 eq) is slowly added. The reaction mixture is stirred at 0 0 C for 1 h and then at 15 room temperature for 30 min. The solvent is evaporated off. The nickel salts are suspended with 1N NaOH and the amine is extracted with CH 2 C1 2 . The nickel complexes are removed by filtration on celite. After several successive washes in CH 2 C1 2 , the filtrate is evaporated 20 to dryness. A brown oil of mass 0.9 g is obtained with a yield of 86%. H NMR (400 MHz, DMSO d6): 7.26 ppm (m, 1H, aromatic H); 7.14-7.05 ppm (unresolved complex, 3H, aromatic H); 3.30 ppm (broad s, 1H, NH 2 ) ; 3.03 ppm (d, 25 J = 10.8 Hz, 1H, H11b); 2.95-2.88 ppm (unresolved complex, 2H, H7ax and H4eq) ; 2.66-2.34 ppm (unresolved complex, 6H, CH 2
NH
2 , H7eq, H6eq, H4ax and Hleq); 2.22 ppm (m, 1H, H6ax) ; 1.68 ppm (d, J = 12.8 Hz, 1H, H3eq) ; 1.46 ppm (m, 1H, H2) ; 1.17 ppm (m, 1H, H3ax); 30 0.88 ppm (q, J = 12 Hz, 1H, Hlax). Stage 5 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-2H benzo [a] quinolizinyl)methyl] cinnamamide 450 mg (2 mmol) of the aminomethyl obtained in 35 the preceding stage 4, 15 ml of THF and 0.4 ml (2.5 eq) of pyridine are introduced into a 100-ml round-bottomed flask. 416 mg (1.2 eq) of cinnamoyl chloride dissolved in 10 ml of THF are added dropwise. The reaction - 50 mixture is stirred at room temperature overnight. The solvent is evaporated off and a brown solid is recovered. After extraction with CH 2 Cl 2 /NaOH 1N and purification by flash chromatography (eluent: 5 CH 2 Cl 2 /MeOH/NH 4 0H: 98/1.7/0.3), 279 mg of an orange colored solid are obtained (Y = 39%). 41 mg (1 eg) of oxalic acid dissolved in a minimum of acetone are added to this base dissolved in a minimum of MeOH. This makes it possible to form the oxalate salt of the title 10 compound, a yellow solid whose melting point is 188 0 C. H NMR (400 MHz, CDC1 3 ) of the base: 7.64 ppm (d, J = 15.6 Hz, 1H, Ph-CH=CH), 7.50 ppm (d, J = 6 Hz, 2H, orthocinnamic H), 7.34 ppm (m, 3H, metacinnamic H and paracinnamic H); 7.21-7.08 ppm (unresolved complex, 4H, 15 H8, H9, H10, H11); 6.40 ppm (d, J = 15.6 Hz, 1H, CH=CHCO); 5.79 ppm (broad s, 1H, NH); 3.37 ppm (m, 2H,
CH
2 NH) ; 3.18 ppm (d, J = 12 Hz, 1H, H11b) ; 3.16 ppm (m, 1H, H7ax); 3.01 ppm (d, J = 11.6 Hz, 1H, H4eq); 2.97 pm (m, 1H, H6eq) ; 2.71 ppm (d, J = 16 Hz, 1H, H7eq) ; 20 2.53 ppm (dt, J = 11.6 and 3.6 Hz, 1H, H6ax) ; 2.41 2.33 ppm (m, 2H, H4ax and Hleq) ; 1.92 ppm (m, 1H, H2); 1.80 ppm (d, J = 12.4 Hz, 1H, H3eq); 1.47 ppm (dq, J = 12.4 and 4 Hz, 1H, H3ax) ; 1.22 ppm (q, J = 12 Hz, 1H, Hax). 25 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 30 (RS), (SR) -N- [2- (1,3,4,6,7,llb-hexahydro-2H benzo [a] quinolizinyl )methyl] -N' -methyl thiourea 183 mg (1.2 eq) of methyl isothiocyanate dissolved in 20 ml of CH 2 Cl 2 are introduced dropwise into a solution of 450 mg (2 mmol) of the amine 35 obtained in stage 4 of Example 96 dissolved in 25 ml of
CH
2 C1 2 . The stirring is maintained at room temperature overnight. A brown oil is obtained after evaporation of - 51 the solvent. It is purified on a silica column (eluent:
CH
2 Cl 2 /MeOH/NH 4 0H: 97/2.5/0.5) . Rf (CH 2 Cl 2 /MeOH/NH 4 CH 90/9/1) = 0.37 m.p. (oxalate): 194 0 C 5 1H NMR (400 MHz, CDCl 3 ): 7.26-7.09 ppm (unresolved complex, 4H, aromatic H); 4.74 ppm (broad s, 2H, NH) ; 3.42 ppm (m, 2H, CH 2 NH); 3.17 ppm (d, J = 12 Hz, 1H, H11b) ; 3.15 ppm (m, 1H, H7ax) ; 3.03 ppm (s, 3H, CH 3 N); 3.12-2.96 ppm (m, 2H, H6eq, H4eq) ; 2.71 ppm (d, J = 10 16Hz, 1H, H7eq); 2.53 ppm (dt, J = 11.6 and 3.6 Hz, m, 1H, H6ax) ; 2.40-2.33 ppm (unresolved complex, 2H, H4ax and Hlax); 1.98 ppm (m, 1H, H2); 1.80 ppm (d, J = 12.8 Hz, 1H, H3eq) ; 1.45 ppm (dq, J = 12.4 and 4 Hz, 1H, H3ax); 1.18 ppm (q, J = 12 Hz 1H, Hlax). 15 Elemental 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- (1,3,4,6,7,llb-hexahydro-9-fluoro-2H 20 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 25 introduced. The reaction mixture is heated at 100 0 C for 6 h and then poured into water. The aqueous phase is washed with ether, basified with concentrated NaOH and extracted with CH 2 C1 2 . The organic phase is washed with a saturated NaCl solution, dried over MgSO 4 , filtered 30 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 aminal is hydrolyzed: in 1N HCl for 4 h at 75 0 C. The aqueous phase is neutralized with NaOH and 35 then extracted with CH 2 Cl 2 . After purification by flash chromatography in a CH 2 Cl 2 /MeOH/NH 4 0H: 95/4/1 mixture, 1.835 g of the title compound are recovered in the form of a yellow oil with a yield of 17.5%.
- 52 IH NMR (400 MHz, DMSO d6): 7.02 ppm (m, 1H, H8); 6.90 ppm (m, 2H, H5, H7); 3.78 ppm (s, 2H, H1); 2.90 ppm (t, J = 5.8 Hz, 2H, H4); 2.67 ppm (d, J = 5.8 Hz, 2H, H3). 5 "C NMR (100.6 MHz, CDCla): 161.09 ppm (d, 1JC-F = 243 Hz, C6); 136.76 ppm (t, 3 JC-F = 7 Hz, C4); 131.28 ppm (C8a) ; 127.61 ppm (d, 3 JCF = 7. 9 Hz, C8) ; 115.44 ppm (d, 2jC-F = 20.4 Hz, C5 or C7); 112.85 ppm 2 (d, JC-F = 21.4 Hz, C5 or C7); 47.70 ppm (Cl); 10 43.42 ppm (C3); 29.22 ppm (C4). Stage 2 6-fluoro-3,4-dihydroisoquinoline 350 mg (2.3 mmol) of the saturated compound of the preceding stage, 5 ml of CH 2 C1 2 and 451 mg (1.1 eq) 15 of NBS are introduced into a 100-ml round-bottomed flask. The same procedure as that for the compound obtained in Example 96, stage 1, is applied, 230 mg of a yellow oil are obtained (Y = 66.8%). 1 H NMR (400 MHz, DMSO d6): 8.32 ppm (s, 1H, H1); 20 7.46 ppm (dd, 1H, H8); 7.12 ppm (m, 2H, H7, H5); 3.62 ppm (t, 2H, H3); 2.70 ppm (t, 2H, H4). Stage 3 9-fluoro-1,3,4,6,7,llb-hexahydro(2H)benzo[a]quinolizin 2-one 25 2.03 g (10.9 mmol) of the hydrochloride of the compound obtained in the preceding stage and 2.7 ml (3 eq) of methyl vinyl ketone are introduced. The mixture is heated at 60 0 C for 3 h. 1.39 g of the salt of the title compound are obtained. After acid-base 30 extraction, 1.15 g of a brown oil are recovered with a yield of 48%. H NMR (400 MHz, CDCl 3 ) 7.03 ppm (dd, J = 8.6 Hz, J = 5.6 Hz, 1H, H11); 6.87 ppm (m, 2H, H8, H10); 3.54 ppm (d, J = 11.6 Hz, 1H, H11b) ; 3.28 ppm (m, 1H, 35 H4eq); 3.14 ppm (m, 2H, H7ax and H6eq); 2.92 ppm (dm, J = 14.4 Hz, 1H, Hieq); 2.83 ppm (m, 1H, H7eq); 2.73 2.61 ppm (m, 3H, H3eq, H4ax and H6ax) ; 2.50-2.42 ppm (unresolved complex, 2H, Hlax and H3ax).
- 53 Stage 4 (RS), (SR) -9-fluoro-1,3,4,6, 7,llb-hexahydro(2H)benzo[al quinolizine-2-carbonitrile The procedure is identical to that of stage 3 5 for compound 96. The quantities used are 1.15 g (5 mmol) of ketone of the preceding stage, 20 ml of dimethoxyether, 1.03 g (1 eq) of tosylmethylisonitrile, 0.3 ml (1 eq) of ethanol and 1.18 g of tBuOK. The overall yield of the reaction after flash 10 chromatography in a petroleum ether/ethyl acetate 5/5 mixture is 68.4%. 40.8% 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 15 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 = 12 Hz, 1H, H4eq) ; 2.94 ppm (m, 1H, H6eq) ; 2.74-2.65 ppm (m, 20 2H, H2, H6ax) ; 2.61 ppm (dm, J = 12.8 Hz, 1H, H7eq) ; 2.51 ppm (m, 1H, Hleq); 2.34 ppm (td, J = 12 Hz, J = 2.8 Hz, 1H, H4ax); 2.07 ppm (m, 1H, H3eq); 1.99 ppm (m, 1H, H3ax); 1.72 ppm (q, J = 11.6 Hz, 1H, Hlax). diastereoisomer B: (RR) , (SS) -7.10 ppm (dd, JmF = 5.6 Hz, 25 JoH = 8. 6 Hz, 1H, H11); 6 .88 ppm (ddd, JoF = 8. 4 Hz, JoH = 8. 6 Hz, JmH = 2.5 Hz, 1H, H8); 6.80 ppm (dd, JoF = 9.3, JmH = 2.5 Hz, 1H, H10); 3.53 ppm (d, J = 11.2 Hz, 1H, H11b) ; 3.18-3.07 ppm (m, 2H, H7ax and H2); 2.98-2.94 ppm (m, 2H, H6eq and H6ax); 2.76 30 2.60 ppm (m, 3H, Hleq, H4eq and H7ax); 2.49 ppm (d, J = 13.2 Hz, 1H, H4ax); 1.98 ppm (m, 2H, H3ax and H3eq); 1.70 ppm (ddd, 1H, Hlax). Stage 5 (RS), (SR) -2- (9-fluoro-1,3,4,6, 7,llb-hexahydro(2H)benzo 35 [a]quinolizinyl)methylamine The procedure is identical to that of stage 4 of Example 96. The quantities used are 494 mg (2.7 mmol) of nitrile A of the preceding stage, 3.16 g - 54 (5 eq) of nickel chloride, 649 mg (8 eq) of NaBH 4 , 40 ml of methanol. A brown oil is obtained with a yield of 97.8%. The amine is directly used in the next step. Stage 6 5 (RS), (SR) -N- [2- (9-fluoro-1,3,4,6, 7,llb-hexahydro-2H benzo [al quinolizinyl)methyl] cinnamamide The procedure is identical to that of stage 5 of Example 96. The quantities used are 498 mg (5 mmol, 1 eq) of the amine of the preceding stage, 15 ml of 10 THF, 0.4 ml (2.5 eq) of pyridine, 425 mg (1.2 eq) of cinnamoyl chloride. Purification on a silica column makes it possible to recover 304 mg of the title compound. Rf (CH 2 Cl 2 /MeOH/NH 4 CH 97/5/0.5) = 0.43 15 m.p. (oxalate): 164 0 C H NMR (400 MHz, CDCl 3 ) : 7.65 ppm (d, J = 15.6 Hz, 1H, Ph-CH=CH); 7.50 ppm (dd, J = 7.7 and 2.7 Hz, 2H, orthocinnamic H); 7.36 ppm (m, 3H, Hmeta and paracinnamic H); 7.15 ppm (dd, JmF = 5.7 Hz, 20 JoH = 8.6 Hz, 1H, H11); 6.83 ppm (dt, JoF = 8.5 Hz, JmH = 2.6 Hz, 1H, H10); 6.76 ppm dd, JOF = 9.4 Hz, JmH = 2.3 Hz, 1H, H8); 6.41 ppm (d, J = 15.6 Hz, 1H, CH=CHCO) ; 5.83 ppm (broad s, 1H, NH) ; 3.36 ppm (m, 2H,
CH
2 NH); 3.11 ppm (d, J = 11.6 Hz, 1H, H11b); 3.10 ppm 25 (m, 1H, H7ax) ; 3.03 ppm (dm, J = 11.6 Hz, 1H, H4eq) ; 2.96 pm (m, 1H, H6eq); 2.69 ppm (d, J = 16.8 Hz, 1H, H7eq); 2.50 pm (dt, J = 11.6 and 4 Hz, 1H, H6ax); 2.37 2.31 ppm (m, 2H, H4ax, Hleq); 1.91 ppm (m, 1H, H2); 1.80 ppm (d, J = 12.8 Hz, 1H, H3eq); 1.45 ppm (ddd, 30 J = 12.4 and 4 Hz, 1H, H3ax); 1.18 ppm (q, J = 14.2 Hz, 1H, Hlax). Elemental analysis: Theoretical: C (66.07), H (5.99), N (6.16); Experimental: C (65.72), H (6.02), N (6.13)
Claims (15)
1. Compound of formula I: R N N'R2 IR 5 in which in particular: Ri represents a hydrogen atom or a linear, branched or cyclic C 1 _ 4 alkyl group, a hydroxyl group or a branched, linear or cyclic C 1 4 alkoxy group, a 10 halogen atom such as F or Cl. R 2 represents a hydrogen atom or a C 1 _ 6 alkyl group. R 3 represents a hydrogen atom or alternatively may con 15 stitute a unit (C=X)-NR 4 R 5 and in that case constitutes a urea or thiourea with X=oxygen or sulfur. R 4 and R 5 may independently be a hydrogen atom or 20 alternatively a linear, branched or cyclic C 1 . 8 alkyl group, an aryl, aralkyl or aroyl group, these aryl groups also being capable of being substituted. 25 R 4 and R 5 may be linked by a carbon chain optionally incorporating a heteroatom. R 3 may also represent an alkylsulfonyl or alternatively arylsulfonyl group which is optionally substituted. - 56 R 3 represents a hydrogen or an acyl or thioacyl group such as (C=X)-R 6 , where X represents an oxygen or sulfur atom. R 6 may represent a hydrogen or a linear, 5 branched or cyclic Ci-io alkyl group incorporating a heteroatom or not, such as an oxygen or a sulfur, incorporating a double bond conjugated with the carbonyl C=X or not. R 6 may also represent a linear, branched or 10 cyclic C 1 . 8 alkoxy group, an aralkoxy group which is optionally substituted. R 6 also represents an aromatic or hetero aromatic group, such as a phenyl or naphthyl which is optionally substituted one or more times with a C 1 - 6 15 alkyl, C 1 - 6 alkoxy, hydroxyl, halogen, NO 2 , CF 3 , CN, COCH 3 or a thiophene, furan, pyrrole, pyridine and their benzofused derivatives. R 4 represents an aralkyl or aryloxyalkyl group in which the aryl portion may be substituted, and in 20 which the alkyl chain may be linear, branched or cyclic. R 6 may comprise several aromatic cyclic systems, such as a 2-indanyl, a fluorenyl, a coumarinyl or a benzopyranyl. 25 R 6 may also represent an aralkenyl group. The aryl group conjugated with a double bond may be phenyl, naphthyl, polyaromatic such as biphenyl or fluorenyl, heteroaromatic and its benzofused derivatives. This aryl group may be optionally substituted 30 one or more times with C 1 - 8 alkyls, hydroxyl, C1- 8 alkoxy, halogens, NO 2 , CF 3 , CN, OCF 3 , OCH 2 0 or form a bicyclic system with a saturated or unsaturated ring possessing a heteroatom or not such as 0, N or S, thus forming an indole, benzofuran or benzothiophene. The 35 alkenyl group may be optionally substituted with halogens, CN, alkyl, phenyl. The unit (C=X)-R 6 thus forms a cinnamoyl group. - 57 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. 5 The heteroaromatic group being capable of being a 5- or 6-membered aromatic ring possessing one or more heteroatoms chosen from N, 0 or S, as well as their benzofused derivatives. They thus form a pyridine, a furan, a thiophene, an indole, a benzofuran, a benzo 10 thiophene, a benzoxazine, a quinoxaline, a quinazoline, a benzimidazole, a benzopyrazole.
2. Compound according to claim 1, characterized in that R, represents a hydrogen, a methoxy group, a methyl or a fluorine. 15
3. Compound according to claims 1 and 2, characterized in that R 2 represents a hydrogen, a methyl or an ethyl.
4. Compound according to claims 1, 2 and 3, characterized in that R 3 represents a group (C=X)NR 4 R 5 20 and thus forms a urea or a thiourea, X=O or S.
5. Compound according to claims 1, 2 and 3, characterized in that R 3 forms a group (C=X)R 6 and R 6 represents an alkyl or aryl group.
6. Compound according to claims 1, 2 and 3, 25 characterized in that R 3 forms a group (C=X)R 6 and R 6 represents an aralkenyl group. The group (C=X)R 6 and chosen from the cinnamoyl or thiocinnamoyl groups substituted on the aromatic portion with one or more C 1 . 4 alkoxy, methylenedioxy, C 1 6 alkyl, OH, halogen: 30 such as F, Cl.
7. Compound according to claims 1 to 6, characterized in that it is chosen from the following compounds: (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 35 benzo [a] quinolizinyl)methyl]propanamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl ) methyl] cyclohexylcarboxamide - 58 (RS), (SR) -N- [2- (1,3,4,6, 7,l1b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyl] isobutanamide (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)rnethyllphenyl (a, a-cyclopropyl) 5 acetamide (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyllphenylacetamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-9'H-fluorenyl -9' 10 carboxamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl )methyl) -3 -phenyipropanamide (RS), (SR) -N- [2- (1,3,4,6, 7,l1b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-2' -indanecarboxamide 15 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-4' -chiorophenoxyacetanide (RS), (SR) -N- [2- (1,3,,4,6, 7,11b-hexahydro-9-rnethoxy-2H benzo [a] quinolizinyl)methyl 1-2', 3', 4, 5', 6' pen tafl uorophenoxyace tami de 20 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-rnethoxy-2H benzo [a) quinolizinyl)methyllphenoxyacetanide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methylimethoxyacetanide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 25 benzo [a] quinolizinyl)methyllacetanide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a]quinolizinyl)methyli thioacetamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-rnethoxy-2H benzo [a] quinolizinyl)methyl] -1,-methoxy-2' -naphthalene 30 carboxarnide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] -4' -pyridinecarboxaiide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-2' -thiophenecarboxanide 35 (RS), (SR) -N-[2- (1,3,4,6,7,llb-hexahydro-9-methoxy-2H benzo[alquinolizinyl)methyl) -2' -furancarboxamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] -2' -naphthalenecarboxamide - 59 (RS), (SR) -N- L2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyll -1 -naphthalenecarboxamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La)quinoliziriyl )methyl) -3' -trifluoromethyl 5 ben zarnide (RS), (SR) -N-[2- (1,3,4,6, 7,l1b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] -2' -me thoxybenzamide (RS), (SR) -N-[2- (1,3,4,6, 7,Illb-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyl] -2' -chlorobenzamide 2.0 (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyll -3 '-chlorobenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl 1-4' -chlorobenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 15 benzo [a] quinolizinyl)methyl 1-4' -trifluoromethyl benzami de (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinol izinyl )methyl) benzami de (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 20 benzo [a] quinolizinyl)methyl Ithiobenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl Ithiocinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-3-cyclohexylacrylamide 25 (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)acrylarnide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 30 benzo La]quinolizinyl )methyl] -2' -benzofurancarboxamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-3- (1' -naphthyl) acrylamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-3- (2' -naphthyl) acrylamide 35 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyll -9 'H-fluorenyl -9' methyl enecarboxami de - 60 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyl] -4' -phenylcinnamamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [alqu~inolizinyl)methyl] -3' -coumarinecarboxarnide 5 (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 [alquinolizinyl)methyl - (3' -thienyl) -3-acrylamide (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-2H 10 benzo [alquinolizinyl)methyl) cinnarnamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-ffluoro-2H benzo [a) quinolizinyl)methyl] cinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-rnethoxy-2H benzo [a] quinolizinyl)methyvl]-2',3',4',51,6' 15 pen tafi uorocinnamami de (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl] -2, 3-diphenylacrylanide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] -2-cyano-3-phenylacrylamide 20 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-2-me thyl-3-phenylacryl arnide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [ajquinolizinyl)methyl] -2-fluoro-3-phenylacryl 25 amide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -3' -me thoxybenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-4' -me thoxybenzamide 30 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyl] -4' -nitrobenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [ajquinolizinyl)methyll -3' -trifluoromethylcinnam amide 35 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -2' -chiorocinnamamide - 61 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-nethoxy-2H benzo [a] quinolizinyl)methyl] -3',4',5 - trimethoxycinnam arnide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 5 benzo [a] quinolizinyl )methyl] cinnarnamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -2 '-ifluorocinnamarnide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyl] -2' -chloro-6' -ifluorocinnam 10 amide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl] -2', 4',51- trimethoxyciinan amide (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H 15 benzo [a] quinolizinyl)methyl I-3',4' -dime thoxycinnamamide (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'-dime thoxycinnamarnide 20 (RS), (SR) -N-[2- (1,3,4,6,7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-2',5'-dime thoxycinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl 1-2', 4'-dime thoxycinnamamide (RS), (SR) -N-[2- (1,3,4,6,7,11b-hexahydro--9-methoxy-2H 25 benzo [a] quinolizinyl )methyl] -2' -me thoxycinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo La]quinolizinyl)methyl] -4' -ifluorocinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl]1-3', 4'-methyl enedioxy 30 cinnamamide (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 35 benzo [a] quinolizinyl)methyl I-N' -ter-octylthiourea (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-N' -tertiobutylthiourea - 62 (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl )methyl] -N' -cyclohexylmethyl thi ourea (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 5 benzo [a] quinolizinyl )methyl] -N' -butyl thiourea (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-N' -2-phenylethylthiourea (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -N'-benzyl thiourea 10 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [alquinolizinyl)rnethyl] -N' ,N' -dimethylthiourea (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -N' -methyl thiourea (RS), (SR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H 15 benzo [alquinolizinyl)methyl] -N' -isobutylthiourea (RS), (SR) -N- [2- (1,3,4,6,7, 11b-hexahydro-9-methoxy-2H benzo [alquinoliziriyl)methyl] -N'-cyclohexylthiourea (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-rnethoxy-2H benzo [a] quinolizinyl )methyl] -N' -benzoyl thiourea 20 (RS), (SR) -N- [2- (1,3,4,6, 7,11b-hexahydro-9-rnethoxy-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,llb-hexahydro-9-methoxy-2H 25 benzo [a] quinolizinyl)methyl] -N' -phenylthiourea (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [alquinolizinyl)methyl] -N' -phenyl urea (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl] -N' -methyl urea 30 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl I-N' ,N' -dime thyl urea (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-2H benzo [alquinolizinyl)methyl] -N' -methyl thi ourea (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 35 benzo [a] quinolizinyl )methyllmethylbenzamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-.9-methoxy-2H benzo [a] quinolizinyl )methyl] ethylcinnamamide - 63 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl]methylcinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,1lb-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl]methyl -N' -phenyl urea 5 (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl )methyl]methyl, N' -methyl thiourea (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinol i zinyl ) methyl) formami de (RS), (SR) -N- [2- (1,3,4,6, 7,1lb-hexahydro-9-methoxy-2H 10 benzo [a]quinolizinyl)methyl] -N' -benzoyl urea (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl]benzylcarbamate (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl ] -N' ,N' -dime thyl sulfonyl urea 15 (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl]methylsulfonamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a]quinolizinyl)methyl]phenylsul fonamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 20 benzo [a] quinolizinyl)methyl]methyloxamamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl ] -2 'H-benzopyran-3' carboxami de (RS), (SR) -N- [2- (1,3,4,6, 7,1lb-hexahydro-9-methoxy-2H 25 benzo [a] quinolizinyl)methyl] -3, 3-dimethylacrylamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H benzo [a] quinolizinyl)methyl ] -3' -phenylpropynamide (SS), (RR) -N-[2- (1,3,4,6, 7,11b-hexahydro-9-methoxy-2H benzo [a) quinolizinyl)methyl ]cinnamamide 30 (RS), (SR) -N-[2- (1,3,4,6,7,llb-hexahydro-9-methoxy-2H benzo [a]quinolizinyl)methyl -4' -nitrocinnamamide (RS), (SR) -N-[2- (1,3,4,6, 7,llb-hexahydro-9-ethoxy-2H benzo [a] quinolizinyl)methyl] cinnamamide (RS), (SR) -N- [2- (1,3,4,6, 7,llb-hexahydro-9-methoxy-2H 35 benzo[a]quinolizinyl)methyl]methyl-N',N' -dimethylthio urea.
8. Compound according to claims 1 to 7, characterized in that it is provided in a - 64 diastereoisomerically pure and enantiomerically pure form, forming a salt with the inorganic or organic acids such as hydrochloride, sulfate, methanesulfonate, maleate, fumarate, citrate, succinate, tartrate. 5
9. Process for preparing a compound according to one of claims 1 to 8, characterized in that a compound of formula II is reacted with the tosylmethyl isonitrile in a basic medium, in that the diastereoisomers are separated, in that the nitrile is 10 reduced to a primary amine, in that this amine is reacted either with alkyl or aryl isocyanates or isothiocyanates, carbanoyl or thiocarbanoyl chlorides, or with acid, aliphatic, aromatic or cinnamic chlorides. 15
10. Process for preparing a diastereoisomerically pure compound by chromatographic separation or by crystallization of the mixtures of diastereoisomers obtained during the synthesis according to claim 9 as soon as the chiral center appears at the 2-position. 20
11. Process for preparing an enantiomerically pure compound from a compound obtained according to claim 10, by separation on the chiral HPLC column.
12. Process for preparing the salt of a compound obtained according to claim 11, characterized in that 25 the basic compound is treated with a stoichiometric quantity of the acidic agent.
13. As a medicament, the compound according to one of claims 1 to 8.
14. Pharmaceutical composition, characterized in 30 that it comprises at least one compound of formula I according to claims 1 to 8 and an appropriate excipient.
15. Use of a compound of formula I according to one of claims 1 to 8, for the preparation of a medicament 35 intended for the treatment of neurodegenerative diseases, in particular Parkinson's disease, Alzheimer's disease, Huntington's disease, cognitive and memory disorders, attention and vigilance - 65 deficiencies in elderly subjects, cerebral ischemic and post-ischemic disorders, as well as the progression of neurodegenerative diseases.
Applications Claiming Priority (3)
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FR9713499 | 1997-10-28 | ||
FR9713499A FR2770215B1 (en) | 1997-10-28 | 1997-10-28 | AMINOMETHYL-BENZO [A] QUINOLIZIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION FOR NEURODEGENERATIVE DISEASES |
PCT/FR1998/002281 WO1999021856A1 (en) | 1997-10-28 | 1998-10-26 | Aminomethyl-benzo[a]quinolizidine derivatives, preparation and therapeutic applications for neurodegenrative diseases |
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AU9751798A true AU9751798A (en) | 1999-05-17 |
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AU97517/98A Abandoned AU9751798A (en) | 1997-10-28 | 1998-10-26 | Aminomethyl-benzo{a}quinolizidine derivatives, preparation and therapeutic applications for neurodegenrative diseases |
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EP (1) | EP1027350A1 (en) |
JP (1) | JP2001521034A (en) |
CN (1) | CN1278260A (en) |
AU (1) | AU9751798A (en) |
BR (1) | BR9813303A (en) |
CA (1) | CA2307748A1 (en) |
FR (1) | FR2770215B1 (en) |
WO (1) | WO1999021856A1 (en) |
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GB0016454D0 (en) | 2000-07-04 | 2000-08-23 | Hoffmann La Roche | Thienopyrrolidinones |
JPWO2006054793A1 (en) * | 2004-11-19 | 2008-06-05 | 財団法人新産業創造研究機構 | Benzofuran compound and pharmaceutical composition containing the same |
EP2012833B1 (en) | 2006-05-02 | 2014-10-29 | The Trustees Of The University Of Pennsylvania | Radiolabeled dihydrotrabenazine derivatives and their use as imaging agents |
GB2463451A (en) * | 2008-09-08 | 2010-03-17 | Cambridge Lab | 3, 11b cis-dihydrotetrabenazine compounds for use in the treatment of dementia |
FR2976287B1 (en) | 2011-06-09 | 2013-07-05 | Pf Medicament | BENZOQUINOLIZIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS |
EP3330269B1 (en) * | 2011-09-19 | 2023-06-07 | Kumar, Ajay | Heterocyclic compounds as inhibitors of fatty acid biosynthesis for bacterial infections |
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-
1997
- 1997-10-28 FR FR9713499A patent/FR2770215B1/en not_active Expired - Fee Related
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1998
- 1998-10-26 BR BR9813303-9A patent/BR9813303A/en not_active Application Discontinuation
- 1998-10-26 CN CN98810769A patent/CN1278260A/en active Pending
- 1998-10-26 JP JP2000517966A patent/JP2001521034A/en active Pending
- 1998-10-26 EP EP98951548A patent/EP1027350A1/en not_active Withdrawn
- 1998-10-26 WO PCT/FR1998/002281 patent/WO1999021856A1/en not_active Application Discontinuation
- 1998-10-26 AU AU97517/98A patent/AU9751798A/en not_active Abandoned
- 1998-10-26 CA CA002307748A patent/CA2307748A1/en not_active Abandoned
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EP1027350A1 (en) | 2000-08-16 |
FR2770215B1 (en) | 2000-01-14 |
CA2307748A1 (en) | 1999-05-06 |
WO1999021856A1 (en) | 1999-05-06 |
CN1278260A (en) | 2000-12-27 |
FR2770215A1 (en) | 1999-04-30 |
JP2001521034A (en) | 2001-11-06 |
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