MXPA97004289A - New polyinclinic aminopyridinic compounds inhibitors of acetilcolinesterase, procedure for its preparation and its use - Google Patents

Abstract

New polycyclic aminopyridine inhibitors acetylcholinesterase inhibitors, procedure for their preparation and use. The polycyclic aminopyridine compounds respond to the formula (See Formula) wherein the different radicals have the meanings indicated in the specification. The process for the preparation of these compounds is characterized in that ketones of the general formula (II) are reacted with aminonitriles of the general formula (III) and, if necessary, the compounds of the formula (I) are alkylated, aralkylated or acylated or either the corresponding ketonic precursor is reduced. The compounds of the general formula (I) are especially suitable for the preparation of medicaments against memory disorders, such as senile dementia or Alzheimers disease.

Description

NEW POLYPHYNINIC AMINOPYRIDINE COMPOUNDS INHIBITORS OF ACETILCOLINESTERASE, PROCEDURE FOR PREPARING AND USING IT Field of the art The present invention relates to new compounds to polycyclic inopyridines, and to their pharmaceutically acceptable salts, inhibitors of the enzyme acetylcholinesterase, with therapeutic utility in the treatment of memory dysfunctions, such as senile dementia or aging of Alzheimer's, in which the drugs are indicated capable of increasing the level of the neurotransmitter acetylcholine in the central nervous system. Prior art Hershenson et al., J. Med. Chem. 29, 1125-1130 (1986), have reported that the level of acetylcholine is decreased in the brain of patients with Alzheimer's disease and have studied the usefulness of physostigmine, which is an inhibitor of the enzyme acetylcholinesterase, in the treatment of such patients. W. K. Summers et al., Clin. Toxicol., 1 £, 269 (1980), have described that the known acetylcholinesterase inhibitor called tacrine, 9-amino-l, 2,3,4-tetrahydro-acridine, of formula administered intravenously in combination with lecithin is useful in the treatment of Alzheimer's disease, although it has the disadvantage of its high toxicity. Subsequently, GM Shuts e et al., J. Med. Chem. 32. 1805-1813 (1989), have described 9-amino-1, -2, 3, 4-tetrahydroacridin-1-ol derivatives that also exhibit activity inhibitor of acetylcholinesterase and the patents or patent applications published US-A-4546104, EP-A-0268871, US-A- RRp. I? Q c to -4735953, US-A-4753950, US-A-4762841, EP-A-394950 and JP-A-03002166 describe other compounds related to the aforementioned chemical structures that also exhibit acetylcholinesterase inhibitory activity. For their part, the authors of the present invention have described in the patent application WO 93/13100 a process for the preparation of bis-pyridine derivatives with acetylcholinesterase inhibitory activity. Another known inhibitor of the mentioned enzyme is the product called Huperzine A, of formula In any case, there remains a need for new alternative compounds, more effective as acetyl-cholinesterase inhibitors, which allow an increasingly effective and safe treatment of diseases as serious and as costly as Alzheimer's disease. The inventors of the present invention have discovered a group of novel polycyclic aminopyridines, some of which compounds are much more effective than tacrine in their acetylcholinesterase inhibitory action. OBJECT OF THE INVENTION The object of the present invention are new polycyclic aminopyridine compounds and their pharmaceutically acceptable salts, with a high inhibitory efficiency of the acetylcholinesterase enzyme. Another object of the present invention is the use of the novel polycyclic aminopyridine compounds, and their pharmaceutically acceptable salts, in the preparation of medicaments against memory disorders such as senile dementia or Alzheimer's disease, as well as pharmaceutical compositions which they contain them. Still another object of the present invention is a process for obtaining said new compounds. DESCRIPTION OF THE INVENTION The novel aminopyridine compounds object of the present invention correspond to the general formula (I) wherein R can be hydrogen, alkyl, aralkyl or acyl. R1 and R- can independently be hydrogen, alkyl, aralkyl, alkoxy, alkoxycarbonyl, amino, amino substituted with one or two alkyl, aralkyl or acyl groups. ra and n can adopt the values 1, 2 or 3. X and Y can be, independently, a bond between two carbons, an oxygen or sulfur atom, a group N- -R, an alkylene or alkenylene bridge containing from 1 to 5 carbon atoms which may contain one or more substituents R ". When X is an alkenylene group, it may be fused with a carbocyclic or heterocyclic, saturated or unsaturated nucleus, the ring being able to be substituted with one or more Rβ groups; for example, X may be an ortho-phenylene group. having p, q and r a value equal to or greater than one and where Rs and R are substituents which individually may be hydrogen, halogen, preferably fluorine or chlorine, lower alkoxy or lower alkyl. In the above definitions: The term "alkyl" represents a hydrocarbon radical of one to six carbon atoms with linear, branched, cyclic substituted or cycloalkyl chains, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, cyclopentyl, cyclopentyl ethyl, cyclohexyl, etc. The term "aralkyl" means phenylalkyl or phenylalkyl substituted on the phenyl, containing from -p to 12 carbon atoms. The term "phenylalkyl" or "phenylalkyl substituted on phenyl" means a straight chain alkylene group containing from one to four carbon atoms, for example methylene, ethylene, trimethylene, tetramethyle. The phenyl substituted on "phenylalkyl substituted on phenyl" is a phenyl group containing one or more substituents selected from the group consisting of halogen, for example fluorine, chlorine, bromine and iodine, lower alkyl including alkyl groups containing from one to four carbon atoms. carbon with straight or branched chains, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tere-butyl, and lower alkoxy including a straight or branched chain alkoxy group containing from one to four carbon atoms, Examples are methoxy, ethoxy, propoxy, isopropoxy, bu-toxy and sec-butoxy. Examples of such aralkyl groups include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 2- (4-methoxyphenyl) ethyl, 2- (2-methylphenyl) ethyl, 2- (4-fluorophenyl) ethyl and 4- (4-chlorophenyl) butyl. The term "acyl" means an alkylcarbonyl or aralkylcarbonyl group wherein the alkyl and aralkyl residues may adopt the values defined above. In the context of RL and R ,, the terms alkyl and aralkyl have the meaning given above for R. The alkoxy substituent and the alkoxy group of the alkoxycarbonyl substituent may take the meanings given above for the lower alkoxy group. The alkyl, aralkyl and acyl substituents of the amino group can also adopt the values given above in the context of R. The R group, of NR, can adopt the values defined above for R. The R groups' attached to the alkylene bridge or Alkenylene can be, independently, hydrogen, alkyl, alkenyl or lower alkylidene of one to four carbon atoms with straight or branched chain, phenyl, phenyl substituted with one or more lower alkyl groups of one to four carbon atoms, lower alkoxy from one to four carbon atoms or. halogen (fluorine, chlorine, bromine or iodine), aralkyl as defined above in the context of R, lower alkoxy containing from one to four carbons, and hydroxy. The R groups, substituents of the ring fused to X or Y, can be hydrogen, lower alkyl or lower alkoxy of one to four carbon atoms, or halogen (fluorine, chlorine, bromine and iodine). Since the compounds of general formula (I) have at least two chiral centers, that is to say two asymmetric carbons capable of generating optical isomerism, the present invention relates both to the racemic compounds and to all possible enantiomers thereof or to their mixtures in different proportions. The pharmaceutically acceptable addition salts may be of organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric and nitric acids between the inorganic and tartaric, succinic, maleic, fu aric and citric acids among the organic. The compounds of the general formula (I) object of the present invention, in which R is hydrogen, can be prepared, in general, by reaction of the ketones of the general formula (II) / R1 (CH2> m- / C / \ XY (ID ~ ((CH2) n with the aminonitriles of general formula (III) in whose general formulas (II) and (III) A, Rt, R ,, X, Y, m and n have the meanings defined above, in the presence of a Lewis acid as catalyst, or of a dehydrating agent, in a suitable solvent. Said reaction leads directly to the compounds of general formula (I) in which R is hydrogen, which can be purified by conventional methods such as, for example, column chromatography, selective dissolution with different solvents or crystallization, either in the form of of free bases or their addition salts of organic or inorganic acids. In ketones of general formula (II) it is necessary that at least one of the two be equal to or greater than one, that is to say, it is essential that there is at least one methylene group in alpha position with respect to the biological function. tonic. The Lewis acid used as catalyst in the condensation of the ketones (II) with the aminonitriles (III) can be, among others, aluminum trichloride, zinc dichloride, titanium tetrachloride, etc., all of them in anhydrous form. As the reaction solvent, aprotic solvents are used, for example nitrobenzene, 1,2-dichloroethane, dichloromethane and dimethylformamide, among others. The reaction is carried out at temperatures between 0 and 150 SC, with reaction times ranging from 1 to 48 hours, depending on the type of catalyst and the solvents used. The compounds of the general formula (I) in which R is different from hydrogen can be obtained by alkylation, aralkylation or acylation of the compounds of general structure (I) in which R is hydrogen, according to methods known to the person skilled in the art, for example, those described in US-A-4753950 and in published patent application JP-A-03002166. Some compounds (I), in which X or Y is an alkylene group substituted with a hydroxyl group, in the endo position, for example X-CH2-CH (endo-OH) -CH2-, can be obtained more conveniently from of the corresponding precursor compounds in which X or Y is an alkylene group substituted with an oxo group in the appropriate position, for example X = CH2-C0-CH2-, by reduction with suitable reducing agents such as complex metal hydrides, by Examples are boron sodium hydride or lithium aluminum hydride, hydrogenation in the presence of a catalyst, metals in a protic medium, for example sodium in ethanol, etc. All possible epantiomers of the compounds of general formula (I) can be obtained by conventional techniques well known to the person skilled in the art, for example by selective or fractional crystallization of their diastereoisomeric salts with optically active organic acids, by chromatographic methods, by enantioselective synthesis , etc. The formation reactions of the pharmaceutically acceptable salts of the compounds of general formula (I) are carried out by conventional methods, by reacting the basic organic compound with an organic or inorganic acid in an appropriate solvent, such as water, alcohols, for example, methanol, ethanol, isopropanol, etc., or ethers such as diethyl ether, tetrahydrofuran, dioxane, etc. Preferred, for the purpose of the present invention, are compounds which, within the framework of general formula (I), correspond to the general formula in which A, X and Y have the meanings already enunciated for the general formula (I). Said compounds can be obtained by reacting the ketones which, within the framework of the general formula (II), correspond to the general formula wherein X and Y have the meanings already mentioned, with the aminonitriles of the general formula (III), in the manner already explained for the preparation of the compounds of the general formula (I). Among the starting ketones (II) to obtain the compounds according to the invention, those represented in Table 1 can be mentioned as particular cases. ? abla 1. Examples of ketones given: i) Some of the ketones (II) used as starting materials in the preparation of the compounds (I) are previously described compounds and, therefore, can be prepared according to said earlier descriptions. Thus, Ha has been described by J. G. Henkel et al. J. Org. Chem. 48, 3858-3859 (1983); Hb by K. Kimoro et al., Bull. chem. Soc. Jpn. 45., 3698-3702 (1972); Ilf by H. Quast et al., Liebst Ann., 725-738 (1995); Hg for t. Momose et al., 'Chem, Pharm. Bull. 2 £, 238-295 (1978), llh by RS Henry et al., "J. Chem. = Oc, Perkin Trans. 2, 1549-1553 (1976), and n0 by R. Bishop, Aust. J. Chem 21, 319-325 (1984). The ketones, lid, lid, lie, Ili, pj and IIk as well as other ketones related thereto, can be prepared by a procedure consisting of the sequence of reactions of the following scheme: The diketones (VI), in which X has the aforementioned meaning, are reacted with organometallic reagents (organomagnesium or organolithic) to give rise to the oxaadamantanols (V) which, by reaction with methanesulfonyl chloride, give rise to the corresponding methanesulphonates (IV). These, by treatment with silica gel, are transformed into the corresponding ketones (II). Ketones III and Hm, as well as other ketones related thereto, can be obtained, according to the sequence of reactions of the following scheme: That is, by hydrolysis of the acetal esters (VII), whose preparation can be carried out according to the method described by AP Koziko ski et al., Heterocycles 39, 101-116 (1994), and the decarboxylation of the corresponding ketoacids (HIV). ). The ketone Hn has been prepared from ketone acetal IX, described by P. Camps et al., Tetrahedron Lett. 25., 3187-3190 (1994), by reaction with methyl-lithium followed by dehydration and hydrolysis of the alcohol X formed, according to the following scheme: Similarly, ketones related to Hn can be prepared. In general, the starting ketones (II) can be prepared by one of the described methods introducing, depending on the substituents desired, variations obvious to the skilled person. Among the starting aminonitriles (III) to obtain the compounds according to the invention, those represented in Table 2 can be mentioned as particular cases.

Table 2. Examples of starting aminonitriles (III) The aminonitriles HIv,? Nw and r? Lx can be purchased commercially. The remaining aminonitriles can be obtained according to the procedures described by F. Hunziker et al., Eur. J. Med. Chem. 16_, 391-398 (1981) and by H. E. Schroeder et al., J. Am. Chem. Soc. 71, 2205-2207 (1949). In general, the compounds of the general formula (III) are known and can be prepared by conventional means easily accessible to the expert. Among the compounds of general formula (i) obtained, those which are shown in Table 3 can be mentioned, in particular cases. Each compound is named with the Roman numeral I followed by two corresponding lowercase letters, first of all place with the one assigned in table 1 to the starting ketone from which it comes and, secondly, with the one assigned in table 2 to the aminonitrile from which it also comes.

Table 3.? JemDlc? of compounds of general formula (I) The formulas developed from the compounds of table 3 are the following: "The products Iqw, irw and rr2 are not obtained by direct reaction of a ketone (II) with an aminonitrile (III), but by reduction of direct ketonic precursors described by the authors of the present invention in the patent application WO 93 / 13100. However, for consistency the way of naming them has been maintained as if they came from hypothetical starting ketones Hq and Hr. The rest of the products of general formula (I) can be obtained by reaction of the ketones (II) with the aminonitriles (III) in the manner already explained The compounds of general formula (I) in enantiomerically pure form can be obtained by various methods: for example, by medium pressure column chromatography using microcrystalline cellulose triacetate 15 - 25 μm (Merck) as the chiral stationary phase, as described in examples 37 and 38. Alternatively, some of the compounds of general formula (I) in enantiomerically pure form can They can be obtained through enantioselective syntheses, in a manner analogous to the preparation of the corresponding radicle compounds, by reaction of the ketones which, within general formula (II), correspond to the general formula - enriched in one or the other of the enantiomers, with the arai-nitriles of general formula (III), in the manner already explained for obtaining the compounds of general formula (I) in racemic form. The ketone (He) (which corresponds to the above formula with X = CH, Rβ = CH, CH 3), as well as other ketones related thereto, can be obtained in enriched form in one or the other of the enantiomers through the Reaction sequence of the following scheme: (XI) (XII) (X? D (II) Achiral compound (XII). (Xpi) and (ID) Chiral compounds enriched in one of the enantisomers.

The compounds (XI) in which X can adopt any of the values indicated above (for example, X = CH3, ortho-phenylene, etc.), can be obtained by acetaliZation of the corresponding compounds (VI) with ethylene glycol or other suitable reagents, according to procedures described [T. Mounted and o. Muroaka, Chem. Pharm. Bull. =., 288-295 (1978)] and are the starting products of this synthetic enantioselective sequence. The reaction of the achiral achiral ketones (XI) with a lithium amide derived from a chiral amine in an enantiomerically pure form, for example (+) - bis [(R) -l-phenylethyl amine, as described for related cases [NS Simpkins et al., Tetrahedron 49, 207-218 (1993) and references cited therein] leads to highly enolate anions in one of the enantiomers, by enantioselective abstraction of a proton from one or the other of the positions -carbonyls, which by reaction with N-phenylbis (trifluoromethanesulfonyl) imide [JE McMurry and WJ Scott, Tetrahedron Lett.2,979-982 (1983)] or with trifluoromethanesulfonic anhydride [PJ Stang and W. Treptow, Synthesis, 283-284 (1980)] give the corresponding enol trifluoro-romethanesulfonates (XII) enriched in one or the other enantiomer, depending on the configuration of the starting amine. These enol trifluoromethanesulfonates (XII) by reaction with Grignard reagents in the presence of complexes of Cu (I) c They arise from acetals (XIII) in which R represents an alkyl or aralkyl group, with the meaning given above in the context of R, or phenyl or substituted phenyl as defined above in the context of R ". The enantiomeric excess of the acetals (XIII) is apparently the same as that of their precursors (XII), that is to say that this reaction proceeds with minimal or no epimerization [for a related reaction, see: J. Kant, J. Org. . Chem. 58. 2296-2301 (1993)]. The hydrolysis of these acetals leads to the corresponding ketones (II), a process which, under the reaction conditions described in Examples 33 and 34, also proceeds with minimal or no epimerization, so that the enantiomeric excess of the ketones (II ) is similar to that of the precursor acetals (XIII). The reaction of these ketones (II) enriched in one or other of the enantiomers with the aminonitriles (III) under the conditions described above starting from the racemic (II) ketones, leads to the aminoquinolines (I) enriched in one or the other enantiomer depending on the ketone (II) used, although the enantiomeric excess of the aminoquinoline (I) obtained is usually lower than that of the ketone (II) starting due to to the epimerization of this last before the condensation. By fractional crystallization of these aminoquinolines or their salts, for example the corresponding hydrochlorides, the enantiomerically pure or highly enriched aminoquinolines (I) in one or the other of the enantiomers can be obtained. The compounds of general formula (I), object of the present invention, have a marked inhibiting activity of the acetylcholinesterase enzyme, some of them being considerably more active than tacrine, known inhi-bidor of said enzyme which is already used as a therapeutic agent in cases of senile dementia or Alzheimer's disease. The compounds object of the invention, as well as their pharmaceutically acceptable acid addition salts, can be administered orally or parenterally in the form of conventional pharmaceutical preparations, such as tablets, capsules, syrups and suspensions. Alternatively, they can be administered parenterally in the form of solutions or emulsions, etc. They can be applied directly to the rectum, in the form of suppositories. The preparations may contain physiologically acceptable carriers, excipients, activators, chelating agents, stabilizers, etc. In the case of injectables, physiologically acceptable buffers, solubilizing or isotonic agents can be incorporated. The daily dose may vary depending on the symptoms of the disease, age, body weight of patients, administration mode, etc. , and the normal dose of an adult person can be between 1 and 500 mg divided into several doses per day. Below is a series of examples that should be interpreted as illustrative of the object of the present invention and not as limiting the scope thereof. Examples The melting points of the compounds have been determined in a Gallenkamp apparatus, model MFB.595.01QM. The IR spectra were recorded on a Perkin Elmer FT-IR spectrophotometer, model 1600. Thin-layer chromatography was performed on silica gel 60 F254 (Alugran R sil / UV254). Silica gel 60 (Merck, 230-440 mesh) was used for column chromatography. The microanalyses were carried out in the Microanalysis Service of the Research and Development Center, C.I.D., Barcelona, Spain, and they agree with the theoretical values with an error of ± 0.3% except if indicated otherwise. In general, the compounds were dried under vacuum (1 Torr) at 80BC for 2 days (standard conditions). The NMR spectra ("c and XH) have been recorded in Varian Gemini 200, 300 and Varian VXR 500 spectrometers; the chemical shifts are given in ppm with respect to the TMS (es-cala d); the coupling constants are expressed in Hertz (Hz) and standard abbreviations have been used. The COSY 1H / 1H experiments were carried out using standard procedures and the COSY 1H / 13C experiments using the HMQC and HMBC pulse sequences with indi-straight detection probe. Tables 4 (1), 4 (2), 5 (1), 5 (2), 6, 7 (1) and 7 (2) show the chemical shifts and coupling constants of the compounds of general formula ( I) obtained in Examples 1 to 24. The annular carbons are identified with a lowercase letter, according to the following annular structures to which all the compounds obtained in the mentioned examples are assignable. The enantiomeric excesses of the compounds H- and (-) - Lbw. . ' -) - v t_ _ -lew, (.) - and (-) -? nx = CH2) have been established by liquid high-efficiency liquid chromatography (HPLC) using a waters 600 kit and the CHIRALCEL OD column. -H r25 x 0 6 cm) from Daicel Co. Ltd., containing the stationary phase tr? S- (3,5-dimethylphenylcarbamate) of cellulose. The enantiomeric excesses of the compounds (+) - and (-) - XIII (X - CH2, Rβ = CH, CH3) and (+) - and f ^ ?? (?. ^ ^ = ^^) have been established by gas-liquid chromatography (GC) using a Perkin-Elmer equipment model 8600 with a SUPELCO ß-DEX 110 column (30 mx 0.25 mm) containing B-cyclodextrin as the phase chiral stationary The compounds (±) -ibw and (±) -icw have been separated by medium pressure liquid-liquid chromatography (MPLC) using a Büchi equipment with a column (23 x 2.6 cm) containing microcrystalline cellulose tpacetate (15-25 μm) of the Merck firm as a chiral stationary phase, eluting with 96% ethanol.

Table 4 (1) Chemical shifts of 13 C-NMR (d ppm) '4 - "of the hydrochlorides of the compounds: Table 4 (2). Chemical shifts of "C-NMR { D, ppm) of the hydrochlorides of the compounds: lev Ida- 'lew liar * 1 na LM usa-'" ' C-a 140.4 138.8 138.9 138.6 139.3 139.0 143.6 C-b 104.8 120.0 120.0 119.7 120.6 120.1 125.3 C-c 166.3 134.3 134.4 134.0 134.0 134.6 139.8 C-d 116.6 127.1 127.1 126.8 126.9 127.3 132.6 C-e 127.8 124.2 124.2 124.0 124.0 124.2 128.9 Cf 113.7 116.7 116.7 116.5 116.9 116.6 121.5 cg 156.7 * 156.6 * 156.7 * 156.5 156.5 157.4 162.0 c- 115 , 0 114.9 114.9 114.3 113.7 114.8 119.0 ci 27.4 27.6 27.6 27.2 35.6 36.9 44.1 cj 34.3 34.0 34 , 0 33.0 35.8 33.8 40.9 ck 140.3 138.6 138.8 137.2 134.0 140.6 c-1 123.3 124.9 124.8 127.0 125, 2 122.9 129.2 C-m 28.0 28.2 28.2 28.3 37.8 36.1 44.7 C-n 36.0 36.0 36.1 35.4 33.3 35.2 40.6 C-o 153.0 * 152.3 * 152.4 * 151.5 153.1 151.1 156.6 C-s 29.4 29.5 29.5 28.9 74.5 74.1 100.4 k-CH3 12.5 13.7 14.1 22.7 23.1 28.6 k-CH2- Me! 30.9 21.6 23.0 k-CH2- • Et 40.3 30.8 k-CH2- -Pr 37.9 k-Cipso 141.7 k-Short 125.8 k-Cmeta 129.1 k- C for 128.1 s-CH, 19.8 20.2 s-OCH 3 49.3 49.7 a]. The values sarcsdaa with * inside da .na aiaaa colusna are intarcasßiablea. '°' -xeptus dend. i. indicate ots eos ». - loa aßpaetroa i. req_ «trarop .50, 3 me an ca ^ CO. -c 'Cata «apee-tro ae record to 75,4 mu'? l this s eesueato Mn otaMtvado .de-ala the following copatutea de acopluiento; Jc.a / r-tS, 2: c - (; / p-.5J, »t Jc.?/t-li,t. Jc_ß / p -.? O, 7. '' -ate spectrum is re in a lexela of CD-.0D and CSC1-. '-' This eapaasro sa record at 75.4 MKi an 020.

Table 5 (1) H-NMR data [chemical shifts (d ppm) and coupling constants (J, Hz) i of the hydrochlorides of the compounds: HCl. rjjy cje Displacements -iaSK I = x. chemical d, ppm bH 7.72 7.73 7.56 7.42 cH 7.75 7.72 7.57 7.79 7.85 7.82 dH 7.86 7.55 7.82 7.60 7 , 33 7,42 eH 7,56 7,61 7,33 8,31 8,34 8,43 iH 8,34 8,34 3,35 3,39 3,38 3,37 j-Hexo 3,38 3 , 40 2,51 3, 40 2,51 2,51 2,51 2,53 j-Hendo 2,53 2,54 2,08 1,98 1,98 1,97 2,00 kH 2,0Z 5, 64 2.02 1-H 5.82 5.57 5.57 5.57 mH 5.56 5.58 2.77 5.58 2.78 2.77 2.78 n-Hexo 2.80 2.80 2.80 3 , 20 3.20 3.19 3.19 n-Hendo 3.20 3.21 3.21 2.92 2.88 2.86 2.85 2.87 NH2 2.87 2.88 4.95 4, 82 4.87 4.87 NH * 4.82 4.87 4.83 4.95 4.82 4.87 4.87 4.82 k-CH, 4.87 4.83 1.57 1.59 1 , 57 0.89 k-CH2-Me 0.89 0.91 1.86 s-Hsin 1.88 1.89 1.96 1.95 1.95 1.94 1.95 s-Hanti 1.97 1 , 97 2.11 2.07 2.08 2.07 2.07 2.08 2.09 Coupling constants (J, Hz) Except where indicated otherwise eo ... lo. Spectrum, SA registered 500 KHL in COJOO.

Table 5 (2) -H-NMR data [chemical shifts (d ppm); and coupling constants (j, Hz) l of the nidrociorides of the compounds: ley. IdM Displacements isa I £ acb 'lia J > - chemical ikwc d, ppm Coupling constants (J, Hz) bH / cH 8.5 8.5 8.5 8.5 bH / dH 8.5 3.0 1.0 1.0 1.0 cH / dH 1.0 7.0 7.0 cH / eH 7.0 7.0 1.5 1.0 1.0 dH / eH 1.5 10.0 8.5 8.5 3.5 8.5 eH / cF 8.5 8, 5 5.5 iH / j-Hexo 5.5 5.0 5.0 4.5 6.0 j-Hexo / j-Hendo 5.5 18.0 18.0 17.5 17.5 18.5 1 -H / mH 17.0 18.0 5.5 5.5 5.5 6.0 6.0 mH / n-Hexo 6.0 5.5 5.5 5.5 5.5 5.5 mH / n-Hendo 6.0 6.0 1.5 2.0 2.0 1.0 n-Hexo / n-Hendo 1.5 13.0 18.0 18.0 18.5 18.0 n-Hendo / s-Hanti 13.5 18.0 1.5 2.0 2.0 s-Hsin / s-Hanti 12.5 12.5 12.5 13.0 ortho-H / meta-H 7.0 7.0 'M0, m,, nc ° 3ao' tbI "" • "-etrß - • * -, l-trrt '" Table 6. Chemical shifts of "C-NMR (d, ppm) -' * '* of the idrochlorides of the compounds: Ifil ras rnw! iS; o 'rast; cI lai isa iax ist lü Cs .68.6 »^ 3, -38.9 136.9 * .37.0 * .38.8 138.8 138.2 138.5 161.3 * cb 120.0 120.1 120.0 120.0 119, 9 119.9 119.6 120.0 -c 134.3 134.5 134.4 124.3 134.6 134.6 134.0 133.6 Cd 126.9 127.2 127.2 127.2 127.4 127.1 127.0 126.6 c- "124.2 124.3 124.2 124.2 124.4 124.1 124.2 124.0 Cf 122.6 * 116.4 116.6 116, (116, 7 116.8 116.6 116.6 116.4 119.9 C- < t 165.9, '.56, to -.56, J 156.4, 156.0 / .57.8 157.4 * 156.1 * .54.5 * 155.5 * ch 122.4 * 114 , 5 114.7 114, t 115.6 114.1 111.5 115.1 114.4 118.5 C-1 2 », 5 2a, 3 2», 1 30.6 38.7 «2.2 43.0 40, é 26.1 26.8 c-1 16.3 29.4 31.2 38, 1 39.1 39.1 31.9 37.8 35.6 / 36.2 ck 133.6 19.2 65.5 135.0 * 125.6 * 137.5 23.9 70.4 66.5 « C-1 125.7 33.7 12.9 125.7 124.7 121.1 34.0 39.0 39.1 Cs 21.1 27.3 29.5 39.4 31.6 42.2 42.1 10, 4 26.0 27.1 Cn 34.5 34.7 34.9 38.4 37.5 41.0 38.2 39.5 35.3 / 39.2 co 161.5 »154.4 153.5 152.4, -52.1» 154.2 156.1 * 156.2 * 153.5 * 149, l 'k-CH. 23.4 23.0 23.0 26.2 c-p 33.6 34.7 C-q 24.3 22.6 C-r 29.9 28.5 c-a 28.6 32.1 31, "138.8 * 138.8 * 31.9 32.4 Ct 141.0 144.8 141.7 Cu 118.1 * 130.0 129.9 cv 128.4 * 128.3 128.4 Cw 12 », 0 * 128.9 129.1 CK 130.0 * 129.4 129. i cr 145.2 145.0 144.6 s- HCij 116.5 116.6 S-CH-CH, 12.5 12.5 • "'Loa vaioraa aarcsdca with * o, damaging gives a' lama col uaná are intareaaelablas. • "" Except where another one is indicated, the spectra were recorded at 50.1 a "in C3-OD. This spectrum is realigned to 75.4 mi.

Table 7 (1). Chemical shifts of -RMN (d, ppm): a-- "of the compounds 'idrochlorides: IB ¡j¡¡ tt tv¡¡ 7.76 7.77 7.74 7.74 7.7ß 7, 3', 70 7 , 90 7,86 7, 97 7,86 7, ß5 7,35 7,92 7,60"\ 61 7,62 •" .si '.61 7,60 7,59", 65 9,32 5,35 , 37 9,35 9,41 9,34 9,34 3,37 3,11 3,28 3,38 1,11 3,74 '.ii:, 59 1,54 3,32 2,96 2,47 1.77 1.55 2.32 2.55 2.61 1.93 2.16 1.96- 1.8? 2,2 * 1,89 1,72 2,35 2,20 2.19 2,50 3,17 2,23 1,96- 1,9 »2,26 1,51 1,83 4,25 4,21 4 , 04 1,18 3, «« 1.62 5,5 * 1,77 1,64 5,54 5,54 5,81 1,32 2,21 l, 9ß- 1.87_ 2.26 1,77 2,20 2, 17 2.10 1.96- 1.9 »2.26 2.73 2.44 2.62 3.11 3.64 3.74 3.1» 3.4 »3.61 2.36 2.95 3.35 3.34 3.1? 3.15 3.38 * 3.51 3.44 3.40 3.32 2.58 2.36 2.92 3.05 3.08 3.54 * 3.47 1.6 * 3.13 2, 95 4.82 4.92 4.81 4.83 4.81 «, 9S«, 82 4.98 1.8 »4.82 4.82 '..91 4.81 1.83 4.85 4.93 4.99 4.8» 4.81 4.99 1.89 1 , 60 1.56 1.58 1.62 1.06 2.80 < t- »2 2.27 2.07 2.85 2.70 -" 2 s-Ksln 1.63 1.9 * l.ßß * 1.94- 1.7 »2.26 s-Hanti 1.91 2.04 1.9» * l , 9ß- '-, 87 2,26 7,21 »7,27 7,27 7,21» 7,15 7,17 7,21 »7,20 7,21 7,31»' .24 7,26 s-CHCIf.5.52 5.54 s ^ HCH »1.76 1.71 '.' '. coa values aerated with' within a column Beam column ir.tareuolaßles. '" 1 Except where otherwise indicated, the aa spectra realated 500 nts in CO-, 00.; s! This spectrum is reqistrd at 300 MHz.

Table 7 (2). Coupling constants of "H-NMR (J, Hz): a'-" of the hydrochlorides of the compounds: Example 1 12-Amins-6, 7,10, 11-tetrahydro-7. * l-methanocyclooctarb '-? -, p,? t j -na. Ta. A suspension of A1C13 (489 mg, 3.67 mmol) and 2-aminobenzonitrile (437 mg, 3.70 mmol) in 1,2-dichloroethane (120 ml) was prepared under argon and cooled in an ice bath. A solution of ketone lia (500 mg, 3.67 mmol) in 1,2-dichloroethane (20 ml) was added dropwise and the reaction mixture was refluxed for 1 h. The suspension was cooled to 0 * C, treated dropwise with a mixture of THF (120 ml) and water (60 ml) and basified with aqueous 2N NaOH solution, leaving stirring for 30 minutes. Evaporation of the organic solvent under reduced pressure and filtration of the resulting mixture separated a yellowish solid (1.20 g) which was subjected to silica gel column chromatography (25 g) using hexane / acetate mixtures as eluent. ethyl / methanol of increasing polarity. Upon elution with 90/10 ethyl acetate / methanol, Iaw was obtained (510 mg, 59% yield). Iaw.HCl: To a solution of Ia (510 mg) in methanol (50 mL) was added concentrated HCl (10 mL) and the mixture was heated to reflux for 20 minutes. Evaporation of the solvent to dryness gave a yellowish solid (520 mg) which was crystallized from ethyl acetate / methanol 1/1 (15 ml) to give after drying at 80 aC / l Torr for 2 days (standard conditions) Iaw. HCl.l, 75H20 (310 mg, 23% overall yield) as a white solid, mp 177-179SC (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3335 and 3176, NH, OH and NH * st), 1652 and 1586 (ar-C-C and ar-C-N st) cp '*. The elemental analysis was concordant for ClßH16N2.-HC1.175H20 Example 2 i -Amino-6.7.10. ll-tetrahydro-9-methyl-7.11-methanocyclooc- This reaction was carried out analogously to that described for the preparation of Ia, starting from A1C13 (1.5 g, 11.2 mmol), 2-aminobenzonitriio (1.15 g) , 9.73 mmol), 1,2-di-chloroethane (120 ml) and a solution of ketone IL (1.5 g, 9.79 mmol) in 1,2-dichloroethane (20 ml). The yellowish solid residue obtained (2.5 g) was subjected to silica gel column chromatography (50 g) using mixtures of hexane / ethyl acetate / methanol of increasing polarity as eluent. Upon elution with 90/10 ethyl acetate / methanol, Ibw (1.48 g, 60% yield) was obtained. Ibw.HCl: Prepared from Ibw (1.48 g) analogously to that described for Iaw.HCl. After evaporating the acid solution to dryness, the dark solid obtained (1.50 g) was decolorized with activated carbon and the resulting light brown residue (1.20 g) was crystallized from ethyl acetate / methanol l / l ( 20 ml) to give after drying under the standard conditions Ibw.HCl.H20 (980 mg, 33% overall yield) as a white solid, mp. 265-2689C (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3354 and 3202, NH, OH and NH * st), 1640 and 1588 (ar-CC and ar-CN st) cm "1. The elemental analysis was concordant for C17H18N- .. HCl.H.sub.2.sup.-3 T 2-Amino-1-fluoro-6.7.10.l-tetrahydro-Q-methyl-7,11-methanocylochlortarbinsuinoline Ibx.This reaction was carried out analogously to that described above. -to for the preparation of Iaw, starting from A1C1, (900 mg, 6.75 mmol), 2-amino-6-fluorobenzonitrile (1.00 g, 7.35 mmol), 1,2-dichloroethane (120 ml) and a solution of ketone Ilb (1.00 g, 6.67 mmol) in 1,2-dichloroethane (20 ral) The yellowish solid residue obtained (1.80 g) was subjected to chromatography on a gel column. silica (50 g) using hexane / ethyl acetate / methanol mixtures of increasing polarity as eluent, eluting with 90/10 ethyl acetate / methanol gave Ibx (1.18 g, 66% yield). : It was prepared from Ibx (1.18 g) analogously to that described for Iaw.HCl After evaporating the acid solution to dryness, the The obtained dark brown (1.20 g) was decolorized with activated charcoal and the residue obtained (1.00 g) was crystallized from ethyl acetate / methanol 1/1 (30 ml) to give after drying under standard conditions Ibx. HCl (459 mg, 23% overall yield) as a pinkish white solid, mp 2685C (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3408 and 3161, NH and NH * st), 1639 and 1595 (ar-CC and ar-CN st) crn "1. The elemental analysis was concordant for C17Hl7FN2.HCl. EXAMPLE 4 12-Amino-3-fluoro-6.7.10.l-tetrahydm-9-methyl-7.11-mephenoei-plooctarblsuinoline Ibv This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C, ( 2.8 g, 21.0 mmol), 2-amino-4-fluorobenzonitrile (2.0 g, 14.5 mmol), 1,2-dichloroethane (20 ml) and a solution of ketone Ilb (1.71 g. , 11.4 mmol) in 1,2-dichloroethane (120 ml) and heating the reaction mixture to reflux for 7 h The solid residue obtained (4.45 g) was subjected to silica gel column chromatography (110 g). g) using eluant mixtures of hexane / ethyl acetate / methanol of increasing polarity, eluting with 70/30 ethyl acetate / methanol gave Iby (2.27 g, 74% yield). A solution of Iby (2.09 g) in methanol (20 ml) was acidified with a solution of HCl in diethyl ether. After evaporating the acid solution to dryness, the solid obtained (2.54 g) was crystallized from methanol / water 1/3 (20 ml) to give after drying under the standard conditions Iby.HC1.2 / 3H20 ( 1.40 g, 42% overall yield) as a white solid, mp 220-222aC (methanol / water); IR (KBr) v: 3700-2000 (maximum at 3334, 3176 and 2926, NH, OH and NH * st), 1638 and 1591 (ar-C-C and ar-C-N st) c '1. The elemental analysis was concordant for Cl7H17FN2.HC1.2 / 3H20. Example 5 i '-Amino-2.3.5.6.9.10-hexahydro-a-methyl-6.10-ptetan-lH-ci-ni poetare I cyclopentafb-pyridine. Tbz. This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C, (4.40 g, 33.0 mmol), 2-aminociclopent-l-enecarbonitrilo (3.57 g, 33.0 mmol ), 1,2-dichloroethane (120 ml) and a solution of ketone IL (4.90 g, 33.0 mmol) in 1,2-dichloroethane (30 ml) and heating the reaction mixture to reflux for 12 hours. h. The yellowish solid residue obtained (6.50 g) was subjected to silica gel column chromatography (loo g) using mixtures of hexane / ethyl acetate / methanol of increasing polarity as eluent. Upon elution with 90/10 ethyl acetate / methanol, Ibz was obtained (760 mg, 10% yield). Ibz.HCl: Prepared from Ibz (760 mg) analogously to that described for iaw.HCl. After evaporating the acid solution to dryness, the solid obtained (863 mg) was crystallized from ethyl acetate / methanol 1/1 (30 ml) to give after drying under the standard conditions Ibz.HCl.3H20 (410 mg, 4 mg). % overall yield) as a white solid, mp 247-250aC (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3341 and 3187, NH, OH and NH * st), 1655 and 1620 (ar-CC and ar-CN st) cm "1. The elemental analysis was concordant for ClsH2oN2. HC1.3H20.Emplo ß 12-A? T? Ino-3-chloro-9-ethyl-6.7.10. Ll-tetrahydro-7,1-raetanoei-oooctablauolinoline This reaction was carried out analogously to the procedure described above. -to for the preparation of Iaw, starting with A1C13 (3.00 g, 22.5 mmol), 2-amino-4-chlorobenzonitrile (2.33 g, 15.3 mmol), 1,2-dichloroethane (20 mL) and a ketone-containing solution (1.80 g, 11.0 mmol) in 1,2-dichloroethane (115 ml) and heating the reaction mixture to reflux for 7 h. The solid residue obtained (4.2 g) was subjected to silica gel column chromatography (125 g) using mixtures of hexane / ethyl acetate of increasing polarity as eluent. Upon elution with hexane / ethyl acetate 40/60, lev (1.35 g, 41% yield) was obtained. lev.HCl: A solution of lev (1.35 g) in methanol (30 ml) was acidified with a solution of HCl in methanol.

After evaporating the acid solution to dryness, the solid obtained (1.54 g) was crystallized from methanol / water 3/10 (26 ml) to give after drying under the standard conditions Icv.HC1.2 / 3HaO (0, 96 g, 25% overall yield) in form 5 of white solid, mp 202-206"C (ethanoi / water) (dec.); IR (KBr) v: 3700-2000 (maximum at 3333, 3177, 2816 and 2671, NH, OH and NH * st), 1652, 1634 and 1585 ( ar-CC and ar-CN st) cm'1 The elemental analysis was concordant for CLaHt9ClN2.IIC1.2 / 3H20 in em 7 10 i 2-Amino-9-etil-6.7,10. ll-tetrahidro-7.11- methanocyl-chloro-1-afl-quinoline, lew • This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (650 mg, 4.80 mmol), 2-aminobenzonitrile (567 mg, 4.87 mmol ), 1,2-di-15-chloroethane (120 ml) and a solution of ketone lie (800 mg, 4.87 mmol) in i, 2-dichloroethane (20 ml) The yellowish solid residue obtained (1.50 g) ) was subjected to silica gel column chromatography (25 g) using hexane / ethyl acetate / methanol mixtures of increasing polarity as eluent, eluting with ethyl acetate / methanol 90/10 to obtain lew (750 g. mg, 59% yield) .lew.HCl: Prepared from lew (750 mg) in a manner analogous to that described for Iaw-HCl. After evaporating the acid solution to dryness, the solid obtained (760 mg) , 25 crystallized from ethyl acetate / methanol 1/1 (25 mL) to give after drying under the standard conditions Icw.HCl.l, 25H20 (330 mg, 21% overall yield) as a white solid, m.p. 260-263aC (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3325 and 3150, NH, OH and NH * st), 1660 and 1587 (ar-CC and ar-CN st) cm "1. Elemental analysis was concordant for Riemelo 8 i2-Amino-9-ethyl-l-fluoro-6.7.10. Ll-tetrahydro-7.11-methanocyte This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C1, (1.35 g, 10.1 mmol), 2-amino-o-fluorobenzonitrile (1.06 g, 7.79 mmol ), 1,2-dichloroethane (10 ml) and a solution of ketone lie (0.35 g, 5.18 mmol) in 1,2-dichloroethane (40 ml) and heating the reaction mixture at reflux for 21 h. The solid residue obtained (3.18 g) was subjected to silica gel column chromatography (95 g) using mixtures of hexane / ethyl acetate of increasing polarity as eluent, eluting with hexane / ethyl acetate 30/70. obtained Icx (0.43 g, 29% yield) Icx.HCl: A solution of Icx (0.43 g) in methanol (8 ml) was acidified with a solution of HCl in methanol. After evaporating the acid solution to dryness, the obtained solid (0.47 g) was crystallized from acetonitrile (5 ml) to give after drying under the standard conditions Icx.HCl (0.24 g, 15% overall yield) in the form of white solid, mp 164-166JC (acetonitrile); IR (KBr) v: 3700-2000 (maximum at 3334, 3208, 2867 and 2823, NH and NH * st), 1638 and 1594 (ar-C-C and ar-C-N st) cm'1. EXAMPLE 9 L2-Amino-9-ethyl-3-fluoro-6.7.10. ll-tetrahydro-7.11-methanocyl-r; poetarblsuinolina. lev. This reaction was carried out analogously to that described for the preparation of law, starting from A1C13 (1.30 g, 9.74 mmol), 2-amino-4-fluorobenzonitrile (0.93 g, 5.84 mmol), 1 , 2-dichloroethane (10 ml) and a solution of ketone lie (0.80 g, 4.88 mmol) in 1,2-dichloroethane (55 ml) and heating the reaction mixture under reflux for 7 h. The solid residue obtained (1.57 g) was subjected to silica gel column chromatography (50 g) using mixtures of hexane / ethyl acetate of increasing polarity as eluent. When eluting with hexane / ethyl acetate 30/70, the law was obtained (0.55 g, 40% yield). HCl law: A law solution (0.55 g) in methanol (10 ml) was acidified with a solution of HCl in methanol. After evaporating the acid solution to dryness, the solid obtained (0.65 g) was crystallized from methanol / water 1/6 (10.5 ml) to give after drying under the standard conditions Icy.HCl.l / 2HaO ( 0.45 g, 23% overall yield) as a white solid, mp 202-206 = C (methanol / water) (desc.); IR (KBr) v: 3700-2000 (maximum at 3332, 3180, 2823 and 2696, NH OH and NH * st), 1640 and 1591 (ar-C-C and ar-C-N st) crn * 1. The elemental analysis was concordant for ClßH19FN2.HCl.l / 2H20. Example 10 12-Amino-6, 7, 1 Q, 1 - - etrahi dro-9-nrnni i -T-? EtapnH ^ "" "_ ta'blsuinoline, Idw. This reaction was carried out analogously to that described for the preparation of Iaw, starting from Alcl, (2.75 g, 20.6 mmol), 2-aminobenzonitrile (1.85 g, 15.5 mmol), 1.2- dichloroethane (20 ml) and a solution of ketone lid (1.84 g, 10.3 mmol) in 1,2-dichloroethane (120 ml) and heating the reaction mixture at reflux for 7 h. The solid residue obtained (4.32 g) was subjected to silica gel column chromatography (130 g) using hexane / ethyl acetate / methanol mixtures of increasing polarity as eluent. Upon elution with 70/30 ethyl acetate / methanol, Idw (2.82 g, 98% yield) was obtained. Idw.HCl: A solution of Idw (2.80 g) in methanol (15 ml) was acidified with a solution of HCl in diethyl ether. After evaporating the acid solution to dryness, the solid obtained (1.87 g) was crystallized from methanol / water 1/1 (20 ml) to give after drying under the standard conditions Idw.HCl (1.20 g, 37 % overall yield) as a white solid, mp 331-333aC (methanol / water) (dec.); IR (KBr) v: 3700-2000 (maximum at 3320, 3146 and 2820, NH and NH * st), 1662 and 1586 (ar-C-C and ar-C-N st) crn'1. The elemental analysis was concordant for Cl9H23N2.HCl. iS- fflJnO-g- U i -β, 7, 10. n -tPtrahi dt-n-7 μ- ^ nn j ^ o ^ _ tafblsuinoline. ew. This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (2.80 g, 21.0 mmol), 2-aminobenzonitrile (2.00 g, 16.95 mmol), 1,2-dichloroethane (20 ml) and a solution of ketone He (2.20 g, 11.4 mmol) an 1,2-dichloroethane (120 ml) and heating the reaction mixture to reflux for 7 h. The solid residue obtained (3.86 g) was subjected to silica gel column chromatography (150 g) using hexane / ethyl acetate / methanol mixtures of increasing polarity as eluent. Upon elution with 70/30 ethyl acetate / methanol, lew was obtained (2.40 g, 72% yield). lew.HCl: A solution of lew (2.40 g) in methanol (15 ml) was acidified with a solution of HCl in diethyl ether. After evaporating the acid solution to dryness, the obtained solid (2.66 g) was crystallized from methanol / water 2/3 (25 ml) to give after drying under the standard conditions lew.HCl (1.03 g, % overall yield) as a white solid, mp 328-330 * C (methanol / water) (dec.); IR (KBr) v: 3700-2000 (maximum at 3316, 3146, 2927, 2823 and 2691, NH and NH * st), 1663 and 1586 (ar-C-C and ar-C-N st) crn'1. The elemental analysis was concordant for C20H24N2.HC1. Example 12 2-Ami, nq-9-pheny-l-β, 7, 1Q. ll-tfittahidrn-7. l.-Hetannr < .. tafblsuinoline. If w. This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (627 mg, 4. 70 mmol), 2-aminobenzonitrile (554 mg, 4.69 mmol), 1,2-di-chloroethane (120 ml) and a solution of ketone Hf (1.00 g, 4. 71 mmol) in 1,2-dichloroethane (20 ml). The yellowish solid residue obtained (2.20 g) was subjected to silica gel column chromatography (50 g) using mixtures of hexane / ethyl acetate / methanol of increasing polarity as eluent. Upon elution with 90/10 ethyl acetate / methanol, Ifw was obtained (730 mg, 50% yield). Ifw.HCl: Prepared from Ifw (730 mg) in a manner analogous to that described for Iaw.HCl. After evaporating the acid solution to dryness, the obtained pink solid (750 mg) was crystallized from ethyl acetate / methanol l / l (lo mi) to give after drying under the standard conditions Ifw.-HC1.1.25H, 0 (610 g, 35% overall yield) as a white solid, mp 207 ° C (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3330 and 3200, NH, OH and NH * st), 1647 and 1589 (ar-C-C and ar-C-N st) crn * 1. The elemental analysis was concordant for C22H20N2.HCl.l, 25H20. Example 13 12-Amino-6.7.3.9.10. ll-hexahydro-7. ll-methanocyclohect rb Igpi-noline. Isw. This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (964 mg, 7. 23 mmol), 2-aminobenzonitrile (356 mg, 7.25 mmol), 1,2-di-chloroethane (120 ml) and a solution of ketone Hg (1.00 g, 7. 24 mmol) in 1,2-dichloroethane (20 ml) and heating the reaction mixture to reflux for 12 h. The yellow solid residue obtained (2.40 g) was subjected to silica gel column chromatography (50 g) using mixtures of hexane / ethyl acetate / methanol of increasing polarity as eluent. Upon elution with 90/10 ethyl acetate / methanol, Igw was obtained (430 mg, 25% yield). Igw.HCl: Prepared from Igw (430 mg) in a manner analogous to that described for Iaw.HCl. After evaporating the acid solution to dryness, the obtained solid (445 mg) was crystallized from ethyl acetate / methanol 1/1 (10 ml) to give after drying under the standard conditions Igw.HCl.H20 (310 mg, 15 mg). % overall yield) as a white solid, mp 254-2563C (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3450, 3165 and 2815, NH, OH and NH * st), 1664, 1632 and 1585 (ar-C-C and ar-C-N st) cm'1. The elemental analysis was concordant for C16Hl8N3.HCl .H20. Example 14 i? .- Amino-6.7.3.9.10. ll-hexahydro-7. ll-methanocyclooctarblcrui-l in-9-exo-ol. Ih This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (430 mg, 3.22 mmol), 2-aminobenzonitrile (382 mg, 3.23 mmol), 1,2-di-chloroethane (120 ml) and a solution of ketone Hh (500 mg, 3.24 mmol) in i, 2 -dichloroethane (20 ml). The yellowish solid residue obtained (l, g) was chromatographed on a silica gel column (50 g) using hexane / ethyl acetate / methanol mixtures of increasing polarity as eluent. When eluting with methanol, Ihw was obtained (400 mg, 48% yield). Ihw.HCl: Prepared from Ihw (400 mg) analogously to that described for Iaw.HCl. After evaporating the acid solution to dryness, the dark solid obtained (475 mg) was decolorized with activated carbon and the resulting residue (380 mg) was crystallized from ethyl acetate / methanol 1/9 (ml) to give after drying under standard conditions Ihw.HCl.l, 5H20 (200 mg, 19% overall yield) as a yellow-white solid, mp 260aC (ethyl acetate / -methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3342 and 3200, NH, OH and NH * st), 1654, 1640 and 1587 (ar-C-C and ar-C-N st) crn'-. The elemental analysis was concordant for C16HlßN20.-HC1.1, 5H20. Example 15 sip-i -apipq-6, 7,10,11 -tetra iriro-. - i-ni ^ ii-! • - ",, + • nv -. -7, ?? - methanocyclohectafbisuinoiin, Tl ^ f This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (488 mg, 3.57 mmol), 2-aminobenzonitrile (422 mg, 3.57 mmol ), 1,2-di-chloroethane (40 ml) and a solution of ketone Hi (631 mg, 3.25 mmol) in 1,2-dichloroethane (80 ml) and heating the reaction mixture to reflux for 6 h. The obtained brownish residue (0.90 g) was subjected to silica gel column chromatography using mixtures of hexane / ethyl acetate / methanol of increasing polarity as eluent. Upon eluting with 90/10 ethyl acetate / methanol, Iiw (470 mg, 49% yield) was obtained. Iiw.HCl: A solution of Iiw (470 mg) in methanol (10 ml) was acidified with a solution of HCl in diethyl ether. After evaporating the acid solution to dryness, the obtained dark solid (490 mg) was crystallized from 10/1 ethyl acetate / methanol (22 ml) to give after drying under the standard conditions Iiw.HCl (380 mg, 35 mg). % overall yield) as a white solid, mp 265-270 * C (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3331 and 3144, NH and NH * st), 1659 and 1588 (ar-CC and ar-CN st) cm "1. The elemental analysis was concordant for C19H22N20.HC1. Example 16 -7t;? - metanoc clQoetarblauinoiinal ^ .f This reaction was carried out analogously to-1 described for the preparation of Iaw, starting from A1C1, (160 mg, 1.20 mmol), 2-aminobenzonitrile (140 mg, 1, 19 mmol), 1,2-di-chloroethane (10 ml) and a solution of ketone II (200 mg, 1.03 mmol) in 1,2-dichloroethane (30 ml) and heating the reaction mixture under reflux for 4 hours. h. The yellowish solid residue obtained (204 mg) was subjected to silica gel column chromatography using mixtures of hexane / ethyl acetate / methanol of increasing polarity as eluent. Upon elution with ethyl acetate / methanol 95/5, Ijw (87 mg, 29% yield) was obtained. Ijw.HCl: A solution of Ijw (87 mg) in methanol (5 ml) was acidified with a solution of HCl in diethyl ether. After evaporating the acid solution to dryness, the solid obtained (120 mg) was crystallized from ethyl acetate / 10/1 methanol (22 ml) to give after drying under the standard conditions Ijw.HCl.i, 25H20 (60 mg, 16% overall yield) as a white solid, mp 220 aC (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3338 and 3179, NH, OH and NH * st), 1658 and 1587 (ar-CC and ar-CN st) cm "1. The elemental analysis was concordant for C19H22N20. -HC1.1,25H20, E mplo 17; 2-Amipo-6, 7,1Q, 1-tetrahydro-9-methyl-1-7, ll-tn ^ anoci r »" nnr-tarblsuinolin-13-one. tity. This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (0.81 g, 5.94 mmol), 2-aminobenzonitrile (0.70 g, 5.93 mmol), 1,2-di -chloroethane (20 ml) and a solution of ketone Hk (490 mg, 2.98 mmol) in 1,2-dichloroethane (30 ml) and heating the reaction mixture to reflux for 4 h. The solid residue obtained (1.64 g) was subjected to silica gel column chromatography using mixtures of hexane / ethyl acetate / methanol of increasing polarity as eluent. Eluting with ethyl acetate / methanol 95/5 gave Ikw (0.46 g, 58% yield). Hydrochloride of 12-amino-6,7, 10, 11-tetra-hydro-13, 13-dihydro-i-9-methyl-7, li-methanocycloocta (b -quinoline (hydrochloride of the hydrated form corresponding to the ketone base), Ikw.HCl: A solution of Ikw (0.46 g) in dichloromethane (10 ml) was acidified with a solution of HCl in diethyl ether.After evaporating to dryness the acid solution, the yellowish solid obtained (480 mg ) was crystallized from 10/1 ethyl acetate / methanol (22 ml) to give after drying under the standard conditions Ikw.HC1.0, lH2O (230 mg, 24% overall yield) as a white solid, mp 225 SC (ethyl acetate / raetanol) (dec.); IR (KBr) v: 3700--2000 (maximum at 3355 and 3215, NH, OH and NH * St), 1651 and 1588 (ar-CC and ar-CN st) c "1. The elemental analysis was concordant for C17HlßN20, .HC1.0, lH20. i2-Amino-6.7, 10, 11-tetrahydr-9-methyl-7.11-m (Z) propepilide-nocyclooctarblsuinoline. Ilw. This reaction was carried out analogously to that described for the preparation of Iaw, starting from A1C13 (539 g, 4.03 mmol), 2-aminobenzonitrile (476 mg, 4.03 mmol), 1,2-di-chloroethane (45 mi) and a solution of ketone III (473 mg, 2.69 mmol) in 1,2-dichloroethane (9 mL) and heating the reaction mixture to reflux for 16 h. The orange semisolid residue obtained (1.10 g) was subjected to silica gel column chromatography (70 g) using hexane / ethyl acetate mixtures of increasing polarity as eluent. Upon elution with hexane / ethyl acetate 1/1, Ilw (527 mg, 71% yield) was obtained. Ilw.HCl: A solution of Ilw (527 pg) in methanol (25 ml) was acidified with a solution of HCl in diethyl ether. After evaporating the acid solution to dryness, the orange solid obtained (645 mg) was crystallized from methanol (2.3 ml) to give after drying under the standard conditions Ilw.HC1.3 / 4H20 (263 g, 30% overall performance) in the form of a white solid, mp 320 aC (methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3334, 3188 and 2905, NH, OH and NH * st), 1640 and 1585 (ar-C-C and ar-C-N st) cm'1. The elemental analysis was concordant for Cl9H2oN2.HC1.3 / 4H20. Example 19 2 ^ ABÍC9-6, 7, ig, U-tetrahÍdrQ-9-mf-ti i -7. ??? r i ^ rF * n ron1 - j ^. pociclooctafblsuinolinaf y ^ This reaction was carried out in a manner analogous to that described for the preparation of Iaw, starting from A1C13 (682 mg, 5.11 mmol), 2-aminobenzonitrile (603 mg, 5.11 mmol), 1,2-diol, chloroethane (55 ml) and a ketone solution "heating the reaction mixture under reflux for 14 h. The orange semi-solid residue obtained (2.03 g) was subjected to silica gel column chromatography (70 g) using Eluant mixtures of hexane / ethyl acetate of increasing polarity were eluted, elution with hexane / ethyl acetate l / l gave Imw (740 mg, 79% yield) Imw.HCl: Imw solution (740 mg) methanol (30 ml) was acidified with a solution of HCl in diethyl ether. After evaporating the acid solution to dryness, the orange solid obtained (840 mg) was crystallized from methanol (2.5 ml) to give after drying under the standard conditions Imw.HCl (420 mg, 39% overall yield ) in the form of a white solid, mp 250 SC (methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3334, 3160 and 2905, NH and NH * st), 1652, 1627 and 1586 (ar-CC and ar-CN st) cm "1. The elemental analysis was concordant for CL9H20N2.HC1 EXAMPLE 20 13-AmJp? '- 6, 7, 1Q, 11-tCtrahl drQ-9-meti-7, 11-o-bgn enocyttab-1-aainoline Inw This reaction was carried out in a analogous to that described for the preparation of Iaw, starting from A1C13 (125 mg, 0.94 mmol), aminobenzonitrile (111 mg, 0.94 mmol), 1,2-dichloroethane (20 ml) and a solution of ketone A (200 mg, 0.94 mmol), in 1,2-dichloroethane (10 mL) and heating the reaction mixture to reflux for 12 h.The obtained yellowish solid residue (240 mg) was subjected to gel column chromatography of silica (15 g) using hexane / ethyl acetate / methanol mixtures of increasing polarity as eluent, eluting with 90/10 ethyl acetate / methanol gave Inw (210 mg, 71% yield). : Prepared from Inw (210 mg) in a manner analogous to that described for Ia w.HCl After evaporating the acid solution to dryness, the dark solid obtained (215 mg) was crystallized from ethyl acetate / methanol 1/1 (10 ml) to give after drying under the standard conditions Inw.HCl.2 , 25H, 0 (160 mg, 44% overall yield) as a white solid, mp 263-265aC (ethyl acetate / methanol); IR (KBr) v: 3700-2000 (maximum at 3362 and 3218, NH, OH and NH * st), 1655, 1635 and 1583 (ar-CC and ar-CN st) cm "- The elemental analysis was concordant for C22H2ON2.HCl.2,25H20, Example 21 12-Amino-6.7.8.9.10, ll-hexahydro-7,11-o-benzenecyclohexane-tallowinoline This reaction was carried out analogously to that described for Preparation of Iaw, starting with A1C13 (2.00 g, 15.0 mmol), aminobenzonitrile (1.77 g, 15.0 mmol), 1,2-dichloroethane (120 ml) and a solution of ketone lyso ( 3.00 g, 15.0 mmol), in 1,2-dichloroethane (20 ml) and heating the reaction mixture to reflux for 12 h.The yellowish solid residue obtained (2.9 g) was subjected to column chromatography. of silica gel (50 g) using hexane / ethyl acetate / methanol mixtures of increasing polarity as eluent, elution with ethyl acetate / methanol 90/10 gave Iow (1.25 g, 28% yield).

Iow.HCl: Prepared from Iow (1.25 g) analogously to that described for Iaw.HCl. After evaporating the acid solution to dryness, the dark solid obtained (1.3 g) was crystallized from ethyl acetate / methanol 1/1 (25 ml) to give after drying under the standard conditions low.HCl. - 2H20 (560 mg, 10% overall yield) as a yellowish white solid, m.p. 120-122aC (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3450, 3365 and 3250, NH, OH and NH * st), 1642 and 1570 (ar-C-C and ar-C-N st) crn'1. The elemental analysis was concordant for C21H2ON2.HC1.2H20. Example 2Z l2- mÍpQ-6, 7,8,9,10,11-xahídro-. ll-o-b ncenon-i r? ^ - tarblauinolin-9-endo-ol. iqw. A solution of 12-amino-6,7,8,9, io-H-hexahydro-7, 11-o-benzenecycloocta [b] quinolin-9-one (200 mg, 0.64 mmol) was prepared [request Patent WO 93/13100] in methanol (30 ml) and NaBH 4 (100 mg, 2.7 punol) was added in portions. The reaction mixture was stirred at room temperature for 12 h, the solvent was evaporated under reduced pressure and the resulting residue was suspended in 2N NaOH (30 mL). The mixture was refluxed for 30 min and filtered, washing the solid with water. After drying the solid, Iqw alcohol was obtained (175 mg, 87% yield). Iqw.HCl: Prepared from Iqw (175 mg) in a manner analogous to that described for law.HCl. After evaporating the acid solution to dryness, the dark solid obtained (197 rag) was crystallized from ethyl acetate / methanol l / l (lo mi) to give after drying under the standard conditions Iqw.- HC1.2H20 (130 mg , 53% overall yield) in the form of a yellowish solid, mp 259-261aC (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3374 and 3225, NH, OH and NH * st), 1637 and 1584 (ar-C-C and ar-C-N st) car1. The elemental analysis was concordant for C21H2ON20.HC1.2H20. EXAMPLE 23 12-AjBIPq-6,7,8,9, lQ, ll-he? Ahidro-7.11-m? Tanoeiplnn ^ t: arb1qinolinolin-9-endo-ol. Irw.

This reaction was carried out analogously to that described for the preparation of Iqw, starting from 12-amino-7,3,10,1-tetrahydro-7,1-methane-6H-cycloocta [b] quinoline-9 -one (200 mg, 0.79 mmol) [patent application WO 93/13100] methanol (20 ml) and NaBH, (60 mg, 1.6 mmol), obtaining the impure Irw alcohol (180 mg). Irw.HCl: was prepared from Irw (180 mg) analogously to that described for Iaw.HCl. After evaporating the acid solution to dryness, the obtained brown solid (200 mg) was crystallized from ethyl acetate / methanol 1/1 (12 -mi) to give after drying under the standard conditions Irw.- HC1.0.75H2O (145 mg, 68% overall yield), mp 197- -198-C (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximums at 3515, 3463, 3338, 3251 and 3080, NH, OH and NH * st), 1659, 1575 and 1565 (ar-CC and ar-CN st) crn'1 . The elemental analysis was concordant for C16HlßN2? .HCl.o, 75H2 ?. Siemplp 3 -ApÚnq-2, 3,5,6,7,8,9,1 Q-OC hidro-6 1 n-mefcann-7 - ^ ^ "^ _ tarelciclopentaíblpiridin-R-Qndo-n- jT7l ~ This reaction was carried out analogously to that described for the preparation of Iqw, starting from 11-amino-1,2,3,5,6,7,9, 10-octahydro-6, 10-methanocycloocta [e] cyclopenta [ b) pyridin-8-one (500 mg, 2.06 mmol) [patent application "WO 93/13100], methanol (50 ml) and NaBH <(150 mg, 3.96 mmol), _ obtaining the alcohol Irz (420 mg, 85% yield) Irz.HCl: was prepared from Irz (420 mg) in a manner analogous to that described for Iaw.HCl After evaporating the acid solution to dryness, the dark solid obtained ( 440 mg) was crystallized from ethyl acetate / methanol l / l (20 ml) to give after drying under the standard conditions Irz.- HC1.2.5H20 (330 mg, 50% overall yield), mp 162 - -164aC (ethyl acetate / methanol) (dec.); IR (KBr) v: 3700-2000 (maximum at 3500 and 3417, NH, OH and NH * St), 1640 (ar-CC and ar-CN) st) crn'1. The analysis elementa l was concordant for C15H2ON20.HC1.2,5H20.

Example 25 7-Ethylbicyclof 3.3.11non-6-en-3-one. TTr .. a) 3-Ethyl-2-oxa-l-adamantanol, V (X = -CH = -; R = -C2H,). A solution of bicyclo [3.3.1] nonane-3,7-dione (1.00 g, 6.57 mmol) in anhydrous THF (100 ml) was added, dropwise, to a solution of ethylmagnesium chloride at room temperature. % in THF (2.2 ml, 6.5 mmol) cooled in an ice bath. The reaction mixture was stirred for 3 h and treated with aqueous solution of 5% "C1" NH until complete dissolution of the white pre-precipitate formed (40 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried with anhydrous Na2SO4 and evaporated under reduced pressure. By sublimation of the resulting solid residue (1.10 g) at 100aC / 0, Torr yielded pure alcohol (X = -CH2-; R = -C2Ha) (890 mg, 74% yield), pf 109-110, 5aC (sublimated); IR (KBr) v: 3319 (OH st) cm "1. The elemental analysis was concordant for CxlH?, 02. b) 3-Ethyl-2-oxa-l-adamantyl methanesulfonate, IV (X = -CH2-; R = -C2H9) An alcohol solution V (X = -CH2-; R = -C2Hß) (5.47 g, 30.0 mmol) and anhydrous triethylamine (6.1 ml, 43.8 mmol) was prepared. in anhydrous dichloromethane (150 mL) and cooled to -10 SC Methanesulfonyl chloride (3.6 mL, 31.2 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes and poured over a mixture of 10% aqueous HCl / crushed ice (100 ml) The organic phase was separated and the aqueous phase was washed with dichloromethane (3 x 200 ml) The combined organic extracts were washed with saturated aqueous NaHCO 3 solution (50 ml). mi) and with brine (50 ml) and dried over anhydrous Na 2 SO.substituted by evaporation of the solvent under reduced pressure, the mesylate IV (X »-CHa-; R = -C 2 Hβ) (7.0 g, 89% yield) was obtained. ) in the form of a white solid, mp 44--46aC (dichloromethane), IR (KBr) v: 1356 and 1178 (S = 0 st) c "1 . The elementary analysis was concordant for C ^ H ^ O ^. c) 7-Ethylbicyclo [3.3.1] non-6-en-3-one, lye. A suspension of IV mesylate (X = * - CHa-; R ^ -CjH,) (7.31 s, 28.1 mmol) and silica gel (7.5 g) dichloromethane (75 ml) was stirred at room temperature At room temperature for 3 hours, evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (75 g) using hexane / ethyl acetate mixtures of increasing polarity as eluent. Upon elution with hexane / ethyl acetate 80/20, the ketone was obtained (1.94 g, 42% yield) as an oil. Continuing the elution with hexane / ethyl acetate 70/30, alcohol V (X-CH, -; R = -C2IS) (0.72 g, 14% yield). lie: IR (Nací) v: 1709 (c-0 st) cm "1. The elemental analysis was concordant for CuHw? o, lH20, Example 26 7-PrOPilbicichlor .3.11nnn-ß- nt ..,? na. T ra) 3-Propyl-2-oxa-l-adamantanol, V (? = - CHa-; R ^ -C,!,.) This reaction was carried out analogously to that described in the previous example, starting from a 2.0 M propylmagnesium chloride solution in diethyl ether (74.0 ml, 147.8 mmol) and a solution of bicycl [3.3.l] nonane-3,7-dione (15.0 g, 98 g) , 7 mmol) in anhydrous THF (300 ml) and stirring the reaction mixture for 30 min. By sublimation of the resulting semi-solid residue (18.8 g) at 80 * C / 0.5 Torr alcohol V was obtained (X = - CH2-; R = n-C3H7) pure (7.30 g, 33% yield), mp 66-67-C (sublimated); IR (KBr) v: 3317 (OH st) ^ cm "\ Elemental analysis was concordant for C12H, o02. b) 3-propyl-2-o? al-adamanti methanesulfonate "IV, (X = -CH2-; R = n-C3H7) This reaction was carried out analogously to that described in the previous example, starting from -propyl-2-oxa-l- -adamantanol V (X = -CH2-; R = n-C3H7) (0.80 g, 4.08 mmol), anhydrous triethylamine (0.83 ml, 5.95 mmol) , anhydrous dichloromethane (20 ml) and methanesulfonyl chloride (0.48 ml, 4.23 mmol), obtaining mesylate IV (X = * - CH2-; R = n-C3H7) (1.02 g, 91% yield) in the form of oil, IR (NaCl) v: 1357 and 1173 (S = 0 st) ca-1 The elemental analysis was concordant for C13H220? S • c) 7-Propylbicyclo [3.3.1] non-6- en-3-one, lid This reaction was carried out analogously to that described for the preparation of Lie, starting from IV mesylate (X-CH, -; R = n-C3H7) (0.88 g, 3.21 mmol), silica gel (lg) and dichloromethane (10 ml) The residue obtained was subjected to silica gel column chromatography (9 g) using hexane / ethyl acetate mixtures of increasing polarity as eluent. hexane ethyl acetate 90/10 the ketone lid was obtained (0.27 g, 47% yield). Continuing elution with hexane / ethyl acetate 70/30, alcohol V was obtained (X = -CH2-; R = n-C3H7) (70 mg,% yield). lid: colorless oil, IR (NaCl) v: 1718 (C = 0 st) car1. The elemental analysis was concordant for C12Hl80. Example 27 7-Butubic? f 3.3.1 Inon-fi-Pn-Lona, tTg, a) 3-Butyl-2-oxa-l-adamantanol, V (X = -CH2-; R = n-CtH,). This reaction was carried out analogously to that described in example 25, starting from a solution of 1.6 M n-butyl-lithium in hexane (70.0 ml, 112 mmol) and a bicyclo solution [3.3 .1] nonane-3,7-dione (10, oq, 65.8 mmol) in anhydrous THF (200 mL) and stirring the reaction mixture for 30 min. By sublimation of the resulting solid residue (12.8 g) at 60 = C / 0.5 Torr, pure V (? = - CH, -; R = nC, H,) alcohol was obtained (8.95 g, 65% performance), pf 58-59aC (sublimated); _ IR (KBr) v: 3334 (OH st) cm "1. The elemental analysis was concordant for C13H2202 b) 3-Butyl-2-oxa-l-adamantyl methanesulfonate, IV (X = -CH2-; R = nC «H,) This reaction was carried out analogously to that described for example 25, starting with 3-butyl-2-oxa-l-adamantanol V (X = -CH2-; R = nC, H ,) (8.83 g, 42.0 mmol), anhydrous triethylamine (8.5 ml, 61.0 mmol), anhydrous dichloromethane (210 ml) and methanesulfonyl chloride (5.0 ml, 63.0 mmol) , obtaining the mesylate IV (X = -CH2-; R = nC, H,) (10.6 g, 88% yield) in the form of oil, IR (NaCl) v: 1356 and 1177 (s = 0) st) cm - For this compound a satisfactory elementary analysis could not be carried out c) 7-Butylbicyclo [3.3.1] non-6-en-3-one, This reaction was carried out analogously to that described for for the preparation of lie, starting from IV mesylate (X = -CH2-; R = nC "H,) (13.6 g, 47.2 mmol), silica gel (14 g) and dichloromethane (140 ml). The obtained residue was subjected to silica gel column chromatography (120 g) using hexane / ethyl acetate mixtures of increasing polarity as eluent. Upon elution with hexane / ethyl acetate 95/5, the ketone was obtained (3.7 g, 41% yield). Continuing elution with hexane / ethyl acetate 90/10, alcohol V was obtained (X = -CH2-; R = n-C «H,) (2.8 g, 28% yield). lie: colorless oil, IR (NaCl) v: 1718 (C = 0 st) c '-. The elemental analysis was concordant for C ^ H8O.0, 1H20. .-j n-7.9-dimethyl-9-methoxyibicyclo 3.3. pnon-6-en-3-one. tri. and anti-7.9-dimethyl-9-methoxybicyclof3.3. llnon-6-ßn-3-one. TT. a) 9-Methyl-9-methoxy-benzyl [3.3.1] nonane-3,7-dione, VI (x »-c- (CH?) (OCHi) -). A solution of sodium (40 mg, 1.73 mmol) in methanol (30 mL) was prepared and a solution of 4-methyl-4-methoxycyclohexa-2,5-dienone (2.4 g) was added dropwise. , 17.4 mmol) in methanol (60 mL) and a solution of dimethyl acetonicarboxylate (6.1 g, 35.0 mmol) in methanol (60 mL). The reaction mixture was refluxed for 48 h and allowed to cool. Water (80 ml) and NaOH (2.0 g, 50.0 mmol) were added, the mixture was refluxed for 8 h and the organic solvent was evaporated under reduced pressure. The resulting aqueous phase was acidified with 2N HCl (30 mL), stirred for 1 h and extracted with dichloromethane (4 x 50 mL). The combined organic extracts were dried with anhydrous Na 2 SO 4 and evaporated under reduced pressure. Sublimation of the resulting solid residue (3.00 g) at 110ac / 1 Torr gave VI (X = -C (CH,) (OCH3) -) pure (2.73 g, 81% yield) as a solid white, mp 144aC (dichloromethane); IR (KBr) v: 1714 (C = 0 st) c "1. The elemental analysis was concordant for ClxHlß0 ,. b) Sin-3,6-dimethyl-6-methoxy-2-oxa-l-adamantanol, v (X = -c- (CH3) (sin-0CH3) -; R = -CH3), and anti-3, 6-dimethyl-6-methoxy-2-oxa-1-adamantanol, V. (-, (X = -C (CH3) (anti-0CH3) -; R = -CH3) This reaction was carried out analogously as described in Example 25, starting from a solution of 22% methylmagnesia chloride in THF (3.0 ml, 3.82 mmol) and a solution of 9-methyl-9-methoxy-cyclo [3.3.1] nonane-3,7-dione VI (1.10 g, 5.61 mmol) in anhydrous THF (60 ml) and stirring the reaction mixture for 30 min, obtaining an oily crude constituted by a mixture of syn and anti alcohols ( 1.05 g, 88% yield) in an approximate ratio of 3/4, crystallization of this crude with diethyl ether gave V (X = -C (CH3) (sin-OCH3) -; R = -CH3) pure ( 430 mg, 36% yield) as a white solid The mother liquor was subjected to silica gel column chromatography using hexane / ethyl acetate mixtures of increasing polarity as eluent. in hexane / ethyl acetate 80/20 V (X = -C (CH3) (anti-0CH3) -; R = -CH3) pure (217 mg, 18% yield) as an oil. (X = -C (CH3) (sin-0CH3) -; R = -CH3): p.f. 124-126aC (diethyl ether); IR (KBr) v: 3361 (OH st) cm "1. The elemental analysis was concordant for C12H2O03 V (X = -C (CH3) (antÍ-0CH3) -; R = -CH3): IR (NaCl) v : 3318 (OH st) cm "1. The elemental analysis was concordant for C12Hao03.l / 4H, 0. c.1) Syn-3, 6-dimethyl-6-methoxy-2-oxa-l-ada-mantyl methanesulfonate, IV (X = -C (CH3) (sin-0CH3) -; R ^ -CE,) . This reaction was carried out analogously to that described in example 25, starting from alcohol V (X = -c (CH3) (sin-OCH3) -; R = -CH3) (530 mg, 2.50 mmol), anhydrous triethylamine (0.69 mL, 4.95 mmol), anhydrous dichloromethane (15 mL) and methanesulfonyl chloride (0.38 mL, 4.89 mmol), yielding the mesylate IV (X = -C (CH 3) (sin-OCH 3 ) -: R = -CH3) (630 mg, 87% yield) as a brown oil; IR (NaCl) v: 1368 and 1173 (S = 0 st) cm'1. For this compound a satisfactory elementary analysis could not be performed. i.1) 5in-, 3-di-et i- -methoxy-cycof 3.3.1] non-6-en-3-one, IIÍ. A suspension of IV mesylate (X = -c (CH, j (sin-OCH,) -; R = -CH3) (630 mg, 2.17 mmol) and silica gel (6 g) in dichloromethane (50 mg). mi) was stirred at room temperature for 3 h, the mixture was filtered by washing with dichloromethane (3 x 50 ml) and with methanol (50 ml) and the combined washings were filtered off under reduced pressure, the oily residue obtained (550 mg. ) was subjected to silica gel column chromatography using hexane / ethyl acetate mixtures of increasing polarity as eluent, elution with hexane / ethyl acetate 90/10 yielded Ili ketone (190 mg, 45% yield) Continuing elution with hexane / ethyl acetate 80/20, alcohol was obtained v (X = -C (CH3) (sin-OCH3) -; R = -CH3) (120 mg, 26% yield). white, mp 37-38aC (sublimated at 100aC / l, 5 Torr); IR (KBr) v: 1711 (C = 0 st) cm "1. Elemental analysis was concordant for c13Hx, 02. c.2) Anti-3,6-dimethyl-6-methoxy-2-oxa-1 methanesulfonate adamantyl, IV (X = -C (CH3) (anti-OCH3) -; R = -CH3) This reaction was carried out analogously to that described in example 25, starting from alcohol V (X = -C (CH3 ) (anti-OCH,) -; R = -CH3) (560 g, 2.64 mmol), anhydrous triethylamine (0.73 ral, 5.23 mmol), anhydrous dichloromethane (15 ml) and methanesulfonium chloride ( 0.41 ml,? 30 mmol), obtaining the mesylate IV (X-C (CH). (Anti-OCH,) -: R = -CH3) (680 mg, 89% yield as brown oil; IR (NaCl) v: 1369 and 1173 (S = 0 st) cm "1. The elemental analysis was concordant for C13H ,, OsS.D.2) Anti-7,9-dimethyl-9-methoxy-benzyl (3.3.1 ] non-6-en-3-one, IIj This reaction was carried out analogously to that described for the preparation of Ili, starting from mesylate IV (X = -C (CH,) (anti-0CH3) -; -CH3) (680 mg, 2.34 mmol), silica gel (6 g) and diclorymethane (50 ml) and stirring the mixture for 36 h. The oily residue obtained (590 mg) was subjected to silica gel column chromatography using hexane / ethyl acetate mixtures of increasing polarity as eluent. Upon elution with hexane / ethyl acetate 90/10, the ketone was obtained (loo mg, 22% yield). Continuing elution with 50/50 hexane / ethyl acetate, V (X = -C (CH3) (anti-0CH3) -; R = -CH3) was obtained (300 mg, 60% yield). IIj: colorless oil, IR (NaCl) v: 1713 (c = 0 st) cm "1. The elemental analysis was concordant for Cl2H, .0 7-MetHlblicher3.3.11non-ß-gno-3.q-fii ^ n. TTT. a) 3-Methyl-6, o-dimethoxy-2-oxa-l-adamantanol, V (X = -c (0CH3) 2-; R = -CH3). This reaction was carried out analogously to that described in Example 25, starting from a solution of 22% methylmagnesium chloride in THF (2.91 ml, 8.55 mmol) and a solution of 6,6-dimethoxy-cyclic [3.3.1] nonane-3,7-dione (1.21 g, 5.70 mmol) in anhydrous THF (50 ml) and stirring the reaction mixture for 30 min. By crystallization of the resulting solid residue (900 mg) in diethyl ether, pure V (X = -C (0CH3) 2-; R = -CH3) alcohol (690 mg, 53% yield) was obtained as a white solid. , pf i32aC (diethyl ether); IR (KBr) v: 3327 (OH st) c * 1. The elemental analysis was concordant for C12H2o0. b) 3-Methyl-6,6-dimethoxy-2-oxa-l-adamantyl-1-methanesulfonate, IV (X = -C (0CH3) 2-; R = -CH3). This reaction was carried out analogously to that described in Example 25, starting with alcohol V (X = -C (0CH3) 2-; R = -CH3) (440 mg, 1.92 mmol), anhydrous triethylamine (0.40) mi, 2.9 mmol), anhydrous dichloromethane (10 mL) and methanesulfonyl chloride (0.22 mL, 2.8 mmol), yielding the mesylate IV (X = -C (OCH3) 2-; R = -CH3) (580 mg, 98% yield) as a colorless oil; IR (NaCl) v: 1359 and 1173 (S = 0 st) c * 1. The elemental analysis was concordant for C13H220ßS. c) 3-Methyl-2-oxa-6-oxo-l-adamantanol, V (X = -co-; R = -c? >) and 7-methylbicyclo [3.3.1] non-6-ene- 3, 9-dione, Ilk.

A mixture of alcohol V (X = -C (0CH,) 2-; R = -CH3) (4.79 g, 21.0 mmol) and P, Os (40.0 g, 232 mmol) in dichloromethane (200 mi) was heated to reflux for 8 h. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure to obtain a dark oil (4.14 g). The solid residue from the filtrate was dissolved in water and extracted with dichloromethane (4 x 40 mL). Evaporation of the combined organic extracts gave a dark oil (330 mg), which was combined with the previous crude oil and subjected to silica gel column chromatography using hexane / ethyl acetate mixtures of increasing polarity as eluent, obtaining Ilk ketone (690 mg, • 20% yield) and alcohol V (X = -C0-; R = -CH3) (1.41 g, 27% yield). Ilk: p.f. 66-67'C (sublimated at 60ßC / 0.5 Torr); IR (NaCl) v: 1731 and 1710 (C = 0 st) c "1. The elemental analysis was concordant for CloH1202.V (X = -C0-; R = -CH3): mp 136-139aC (diethyl ether) ); IR (KBr) v: 3334 (OH st) and 1727 (C = 0 st) car1 The elemental analysis was concordant for C10H1403 d) 3-Methyl-2-oxa-6-oxo-l-adamantyl methanesulfonate , IV (X = -CO-; R = -CH3) This reaction was carried out analogously to that described in Example 25, starting with alcohol V (X = -C0-; R = -CH3) (1.19 g) , 6.53 mol), anhydrous triethylamine (1.36 ml, 9.80 mmol), anhydrous dichloromethane (33 ml) and methanesulfonyl chloride (0.76 ml, 9.80 mmol), obtaining mesylate IV (X = -C0-, R = -CH3) (1.64 g, 96% yield) as a yellowish solid, mp 106-107aC (diethyl ether), IR (KBr) v: 1732 (C = 0 st), 1358 and 1183 (S = 0 st) cm * 1 The elemental analysis was concordant for e) 7-Methylbicyclo [3.3.1] non-6-ene-3,9-dione, Ilk A solution of mesylate IV (X = -CO-; R = -CH3) (400 mg, 1.53 mmol) and H2SO4 (0.2 mL, 2.0 mmol) in dichloromethane (10 mi) was stirred at room temperature for 4 days. The resulting mixture was washed with water (2 x 15 mL), dried with anhydrous Na 2 SO 4 and evaporated under reduced pressure. Distillation of the resulting brown oil (250 mg) at 125 ° C / l Torr yielded Ilk ketone (60 mg, 24% yield) Example 30 f -9-Ethylidene-7-methylbicyclic. -6-in-3-on. TTT. a) (Z) -9-ethylidene-3-methyl-7-oxo-bicyclo [3.3.1] non-3-ene-1-carboxylic acid, VIII (R = H; R '= Me). A mixture of methyl (Z) -7,7-ethylenedioxy-9-ethylidene-3-methyl-tilicicyclo [3.3.1] non-3-ene-l-carboxylate, VII (R = H; R'-Mß) (4.33 g, 15.6 mmol) [A. P. Koziko ski et al., Hetero-cycles 22., 101-116 (1994)], aqueous solution of 20% NaOHtal (325 ml, 1.63 mol), THF (325 ml) and methanol (325 ml) were heated to reflux for 48 h under argon. The organic solvent was evaporated under reduced pressure and the resulting aqueous phase was washed with dichloromethane (2 x 50 ml), acidified with c-n-centered HCl and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were washed with brine (100 ml) and dried with anhydrous Na 2 SO 4. Evaporation of the solvent under reduced pressure gave a yellow gelatinous residue (3.38 g), which was dissolved in dioxane (40 ml) and treated with 2N HCl (40 ml) at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure, diluted with water (50 ml) and extracted with diclorymethane (3 x 30 ml). The combined organic extracts were washed with brine (50 ml) and dried with anhydrous Na 2 SO 4. Evaporation of the solvent under reduced pressure gave the acid VIII (R = H; R '= Me) (2.92 g, 85% yield) as a yellowish solid, m.p. 134-136 * C (ethanol); IR (KBr) v: 2972 (COO-H st), 1724 (C = 0 st) cm "1. The elemental analysis was concordant for C13Htß03 b) (E) -9-ethylidene-7-methylbicyclo [3.3.1 ] non-6-en-3-one, III A suspension of acid VIII (R = H; R '= Me) (1.25 g, 5.68 mmol) and thionyl chloride (1.65 ral, 20) , 4 mmol) in anhydrous toluene (185 ml) was heated at 80 ° C. for 4 h and concentrated under reduced pressure, The resulting residue was dissolved in anhydrous toluene (15 ml) and evaporated under reduced pressure twice to remove the chloride. of thionyl, obtaining a yellow oily residue (1.35 a) On the other hand, a suspension of sodium salt of 2-thiopyridone-N-oxide (13 g, 7.53 mmol), 4-dimethylaminopyridine (75.5 g. mg, or, 62 mmol) and tert-utilmercaptan (3.44 mL, 30.6 mmol) in anhydrous toluene (60 mL) was heated to reflux and a solution of the above acid chloride in toluene was added over 15 minutes. Anhydrous (30 mL) The reaction mixture was heated to reflux for 14 h, washed with water (2 x 30 mL) and with brine (30 ml) and dried with Na2SO, anhydrous. Evaporation of the solvent under reduced pressure gave a brown-colored oily residue (2.22 g), which was dissolved er. hexane (15 mL), washed with 3 N HCl (3 x 2.5 mL) and dried with anhydrous Na3SO4. Evaporation of the solvent under reduced pressure gave an orange oil fl, 15 g), which was chromatographed on a silica gel column (75 g) using a hexane / ethyl acetate 99/1 as eluent, obtaining a ketone. Pure III (770 mg 77% yield) as a colorless oil; IR (CHCl) 'v: 1706 (C = 0 st) cm "1 The elemental analysis was concordant for C12HlβO Example .11 This reaction was carried out analogously to that described for the preparation of III, starting from HIV acid (R = Me; R'-H) (1.00 g, 4.54 mmol) [A. P. Koziko ski et al., Heterocyclßß 22, 101-116 (1994)], thionyl chloride (1.10 ml, 13.6 mmol) and anhydrous toluene (150 ml) for the preparation of the acid chloride and of sodium salt of 2-thiopyridone-N-oxide (0.82 g, 5.50 mmol), 4-dimethylaminopyridine (55.0 mg, 0.45 mmol), tert-butyl mercaptan (2.50 mL, 22%), 2 mmol) and anhydrous toluene (50 ml) and heating at reflux for 4 h to effect decarboxylation. The obtained brown oily residue (1.34 g) was dissolved in hexane (15 ml), washed with 3 N HCl (3 x 2.5 ml) and dried with anhydrous Na 2 SO 4. Evaporation of the solvent under reduced pressure gave the ketone lyra (614 mg, 77% yield) as a colorless oil. The waters from the acidic washings were combined and extracted with toluene (2 x 10 mL) and with organic water collected, evaporated and the aCt ° S -g) dissolved in hexane (10 mL) (4%). 2 ml) and evaporated under reductive pressure (8 X Ilm (35 mg, 4% yield "redUCXaa 'having more ketone" tg 4"overall yield 31%); C = 0 st) cm "1. The aannáálliissiiss ßellemental was conc (nr-rr ^), * - V: 1705 c12H16o concordant for EJemnln -i? 5,6,8, -Tetrahi? O-1 i-mo- i T -g Q-M i b) 5'6'8'9-Tetrahydro-i? -metp-? or r i i olohepten-7-ona. A. 5-9"U Jpropeno-SH-benzoc.- 53 hexane / ethyl acetate 80/20, Ketone Un (320 mg, 34% yield) was obtained as a colorless oil; IR (Nací) v: 1695 (C = 0 set) in "1. The elemental analysis was concordant for C1SH160. Example 33 Obtaining (-) -7-ethylbicition, • -. Nnon-6-gn-3-on. f -) -? j ^) (-) -7, 7-Ethylenedioxy-3- (trifluoromethanesulfonyloxy) bici-clo [3.3.1Jnon-2-ene, (-) - XH (x = CH2). 250 ml of 3 nozzles provided with internal thermometer, inert atmosphere and magnetic stirring was placed (+) - bis [(R) -l-phenylethyl] amine [2.76 g, 12.2 mmol, [a] »30 - »+165 (c = l,? O, CHCl,)] and anhydrous tetrahydrofuran (THF) (110 ml) The solution was cooled to -78 * C with an acetone-C02 bath, a water drop was added dropwise. solution of 1.6 M n-butyl lithium in hexane (7.65 ml, 12.2 mmol), stirred at that temperature for 5 min, and then allowed to warm to room temperature for 1 h. cooled again to -78 aC, a solution of lithium chloride (87.0 mg, 2.04 mmol) in anhydrous THF (9.50 ml) was added dropwise (2 min.), then drop was added a got a (2 min) a solution of the ketone XI (x = CH2) (2.0 g,?, o, 2 mmol) in anhydrous THF (12 mL). The mixture was stirred at that temperature for 15 min and then a solution of N-phenylbis (trifluoromethanesulfonyl) imide (5.46 g, 15.3 mmol) in anhydrous THF (10 ml) was added dropwise (10 min). ). The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure to a volume of about 10 ml, ethyl acetate (10 ml), hexane (220 ml) and water (50 ml) were added. The aqueous phase was decanted and the organic phase was washed successively with 2N aqueous sodium hydroxide solution (2 x 50 ml), 2N hydrochloric acid aqueous solution (2 x 50 ml) and water (2 x 55 ml), dried with anhydrous sodium sulfate and filtered. Evaporation of the solvent under reduced pressure gave a yellow residue (4.08 g) which was chromatographed on a silica gel column (60-200 μm, 150 g), eluting with a mixture of hexane / ethyl acetate 97.5 : 2,5, obtaining í - j -XII; X = CH,) i 2 15 ~ r s? , - eb. S5¡C / 1 Torr,;., .-. J ,, ß 'I' / ¡^ - o). P.

'«-« MK (soo "? Z, cocí,, í: 1> 61 (dt / J-;') H2 -ej; .3» - «*. 1 H. 9-H" ,,!, 72, dm, J-? _, S Hl, 1 H ^ H) V7 complex, 3 H, ß-H ". 6-H ... and, _ "_ ,, 2/2? _ '* «« * "• i H. 4 -" _), 2.43, m, i ", 5_H), 2.57"' / 17 ^ Hz - 5 HZ, 1 H, 4-H., .), 2.65 (s broad, i H! _ ", '-.' H, and 3.91 (m, 2 H, (O-CH.-CH.O), ,, 7'6 ^ ' ^ < »'» 2-H). 'pZ' X H ' "C-NMR (75.4 MHZ, CDCl ,,, 6: 28.2 (CH, C5), 29.2 (CH Cl, 30 0 (C" "C9), 33.3 (CH" C), 33.0 «>.« 3.1 v 6, 3 (CH, O-CK.-CH.-o,, 1C7,7, C, C7, ll 3, "'CJ = 320 HZ, CF,), 120 , 9 (CH, C2,, 149.8 (C, C3 »» CCHCI,), "2928, 1414, 1244, 1143 < 1024, 978, 964, 375 cm" \ ' __ • ⇒ A 250-ml ratio of soil with an inert atmosphere and magnetic stirring was placed in a CuBr.Me.s complex (0.71 g, 22.9 mmol, Anhydrous THP (gray board was cooled to -78 ° C with an acetonitrile barium and a solution of 1 M stilmagnesium bromide in anhydrous THF (41.1 ml, 41 ml) was added dropwise. Mol.) 3ß shot .1 bath and stirred until the mixture turned black until the end of the addition formed a grayish paste which was made Stlrar ^ b3 ??) - ™™ *** »« no. min was re-cooled to -78 = c, a solution of (-, - 0 -XII (X-CH., fl, 50 g, 4.57 mmol, t "] p" (CHC1, ), EA 31%, in anhydrous THF (20 ml) The black mßzcll dß was stirred at room temperature for 16 h, allowed to settle for 10 min, and filtered, washing the black solid residue with hexane (35 ml) Evaporation of the filtrate solvent under reduced pressure gave a gel-like residue am (1, 05), which was chromatographed through neutral alumina (300 a), eluting with a hexane / ethyl acetate mixture 98: 2, obtaining (-) -? m (X = CH2, R = CH2CH3) in the form of a yellowish oil (616 mg). The analytical sample was obtained by distillation under reduced pressure p eb. 60 * 0 / 0.5 Torr, [a] - ° = -8, 6 (c = i, oa, CHC13). * H-NMR (500 MHz, CDC13), d: 0.97 (t, J = 7.5 Hz, 3 H CH2-CH,) 1.55 (broad d J = 12.0 Hz, 1 H, 9 -Hsntt), 1.65 (broad d, J = 12.0 Hz, 1 H, 9-H ^), 1.73 (m, 2 H, 8-H "0 and 8-Hβnd), 1.76 (m, 2 H, 6-H "0 and 6-Hβnd), 1.88 (d, J = 17, 0 Hz, 1 H, 4-Hβnd), 1.93 (m, 2 H, C ?L -CH,), 2.21 (complex abs, l H, 4-H "ß), 2.23 (broad s, 1 H, 5-H), 2.38 (broad s, 1 H, 1- H), 3, 71-3, 97 '(complex abs, 4 H, 0-CH2-CH2-0), 5.44 (dm, J = 6.5 Hz, 1 H, 2-H) "C -NMR (75.4 MHZ, CDCl,), d: 12.3 (CH "CH2-CH3), 27, 'd (CH | C5), 29.1 (CH, Cl), 30.1 (CH2, £ H2-CH3), 31.2 (CH2, C9), 34.4 (CH2, C4), 39.1 (CH2, C8), 41.7 (CH2, C6), 62.7 and 64.4 ( CH2, 0-CH2-CH2-0), 109.0 (C, C7), 122.6 (CH, C2), 139.6 (C, C3). " IR (CHC13), v: 2925, 1453, 1428, 1365, 1263, 1245, 1227, 1190, 1143, 1081, 1022, 947, 860 cu * 1. The elemental analysis was concordant for C13H2O02. c) (-) - 7-Ethylbicyclo [3.3.l] non-6-en-3-one, (-) - Ilc Into a 50 ml flask of a mouth provided with magnetic stirring was placed (-) - XIH ( X = CH2, R = CH2CH3) [494 mg, 3.37 mmol, [a] 0- ° = -82.6 (c = 1.08, CHC1,)], silica gel (40-60 [mu] m, 4 , 5 g) and CH2C12 (15 mL), and the mixture was stirred at room temperature for 27 h. , the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (60-200 μ, 15 g), eluting with a mixture of hexane and ethyl acetate 97: 3 obtaining (-) - II (X = CH2, R = CH2CH3) [179 mg, 30% yield from (-) - XII (X = CH2)], p. eb 45"C / 0.4 Torr, [a] D2 ° = -85 (c-0.93, CHCl3), ee = 81%. ^ H-NMR (500 MHZ, CDCl,), d: 0.92 ( t, J = 7.5 Hz, 3 H, CH2- -CS,), 1.80 (broad d, J = 18.0 Hz, 1 H, 8-Hßn < lß), 1.86 (broad c , J = 7.5 Hz, 2 H, Cg2-CH3), 1.92 (dm, = 12.5 Hz, 1 H, 9-Hantl), 1.98 (dm, J = 12.5 Hz, 1 H, 9-Hstn), 2.23 (de, J = 15.5 HZ, J '= 2.0 HZ, 1 H, 2-H, ndβ), 2.29 (de, J = 14.5 Hz , J '= 2.0 HZ, 1 H, 4-H "do), 2.33 (broad dd, J = 18.0 HZ, J' = 6.0 HZ, 1 H, 8-H".) , 2.41 (dd, J = 14.5 Hz, J '= 4.0 Hz, 1 H, 4- H "ß), 2.47 (ddt, J = 15.5 HZ, J' = 6 , 5 Hz, J "= 1.0 Hz, 1 H, 2-H, xo), 2.56 (m, 1 H, 1-H), 2.65 (3 broad, 1 H, 5-H) , 5.40 (dm, J = 6.0 HZ, 1 H, 6-H). L3C-NMR (50.3 MHZ, CDCl,), d: 12.3 (CH3, CH2-CH,), 29.8 (CH2, SH2-CH3), 30.2 (CH, Cl), 30.5 (CH2, C9), 30.9 (CH, C5), 35.7 (CH2, C8), 46.7 (CH2, C4), 49.1 (CH2, C2), 123.0 (CH, C6) , 138.3 (C, C7), 212.3 (C, C3). IR (NaCl), v: 1709 cm "1. The elemental analysis was concordant for CltHlβ Example 34 Obtaining (. +) - 7-ethylbicyclof 3.3.1 * non-6-en-j-one. (+) - a) (+) - 7, 7-Ethylenedioxy-3- (trifluoromethanesulfonyloxy) bicyclo (3.3.1) non-2-ene, (+) - XII (X - CH2) - In a 250 ml flask 3 mouths fitted with an internal thermometer, inert atmosphere and magnetic stirring were placed (-) - bis [(S) -l-phenylethyl amine [2], 07 g, 9.18 m ol, [a] D2 ° = -167 (c = 1.02, CHCl,)] and anhydrous THF (80 ml). The solution was cooled to -78 ° C with an acetone-C02 bath, a solution of 1.6 M n-butyllithium in hexane (5.74 ml, 9.18 mmol) was added dropwise, stirred thereto. temperature for 5 min. and then left at room temperature for 1 h. The solution was cooled again to -78 aC, a solution of lithium chloride (65.0 mg, 1.53 mmol) in anhydrous THF (7.0 ml) was added dropwise (2 min.), And then a solution of XI (X = CH2) (1.5 g, 7.65 mmol) in THF (9.0 ml) was added dropwise (2 min). The mixture was stirred at that temperature for 15 min, a solution of N-phenylbis (trifluoromethanesulfonyl) imide (4.10 g, 11.5 mmol) in anhydrous THF (8 mL) was added dropwise (10 min). The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure to a volume of about 8 ml, ethyl acetate (5 ml), hexane (165 ml) and water (40 ml) were added and decanted the aqueous phase. The organic phase was washed successively with 2N aqueous sodium hydroxide solution (2 x 40 ml), 2 l hydrochloric acid aqueous solution (2 x 40 ml) and water (2 x 50 ml), dried with sulphate. anhydrous sodium and filtered. Evaporation of the solvent under reduced pressure gave a yellow residue, a mixture of an oil and a crystalline solid (3.23 g), which was chromatographed on a silica gel column (60-200 μm, 140 g), eluting with a mixture of hexane / ethyl acetate 97.5: 2.5, obtaining (+) - XII (x = CH2) as a yellowish oil (1.99 g, 79% yield), p. eb 65-C / l Torr, [a] D2 ° = +43 (c = 1.08, CHC1,), ee = 80%. The NMR data of ^ H and "c coincide with those of (-) - XII (X = CH2) and the elemental analysis was concordant for C1H15F305S b) (+) - 7,7-Ethylenedioxy-3-ethylbicyclo [ 3.3.1] non-2-ene (+) - XIH (X = CH2, R = CH2CH3) In a 250 ml 3-neck flask fitted with a thermometer, inert atmosphere and magnetic stirring, CuBr.Me2S complex was placed ( 4.71 g, 22.9 mmol) and anhydrous THF (20 ml) The gray suspension was cooled to -78 ° C with an acetone-C02 bath and a solution of 1 M ethylmagnesium bromide was added dropwise to the solution. THF (41.1 ml, 41.1 mmol) The bath was removed and stirred until the mixture turned black (towards the end of the addition a grayish paste formed which fluidized upon removal of the bath). min? __ cooled again to -78"C (re-solidifying), a solution of (+) - XII (X = CH2) [1.50 g, 4.57 mmol, [] 020 = +43 was added (c = 1.08, CHC1,), ee = 80%] in anhydrous THF (20 ml). The black mixture was stirred at room temperature for 16 h. , it was left to settle for 10 min, and filtered, washing the black solid residue with hexane (30 ml). The filtrate was concentrated at low temperature and reduced pressure to about 25 ml in volume, filtered again and the solvent of the filtrate was evaporated under reduced pressure to obtain a yellowish gelatinous residue (0.94 g) which was chromatographed through neutral alumina. (300 g), eluting with a mixture of hexane and ethyl acetate 98: 2, obtaining (-) - ?? n (x = CH2, R = CH, CH3), in the form of yellowish oil (687 mg, 72 % yield), p. eb 60 * C / 0.5 Torr, [a] D-0 = +87.2 (c = 1.03, CHCl,). The NMR data of lH and 13c coincide with those of (-) - XIII (X = CH2, R = CH2CH3) and the elemental analysis was concordant for C13H2O02. c) (+) - 7-Ethylbicyclo [3.3.1] non-6-en-3-one (+) - IIc In a 50 ml one-well flask fitted with magnetic stirring was placed (+) - XIII (X - CH2, R = CH2CH,) [530 mg, 2.55 mmol, [a] 02 ° »+87.2 (c = 1.03, CHC13)], silica gel (40-60 μm, 6 , 5 g) and CH2C12 (15 mL), and the mixture was stirred at room temperature for 27 h. The solvent was evaporated under reduced pressure and the residue was chromatographed on a silica gel column (60-200 μm, 15 g), eluting with a mixture of hexane and ethyl acetate 97: 3, obtaining (+) - IIc in hexane. -ma of yellowish oil (340 mg, 81% yield), p. eb 45aC / 0, 4 Torr, [a] D2 ° = +81 (c = 0.96, CHCl,), ee = 80%. The NMR data of XE and "C coincide with those of (-) - IIc and the elemental analysis was concordant for cxlHxβ0 Example 35 (+) - 12-Amino-6.7.10. Ll-tetrahydro-9-ethyl-7 li-matanociclooc-tenofblsuinolina hydrochloride f +) - cw.HCl In a 2-neck 25 ml flask equipped with reflux condenser, inert atmosphere and magnetic stirring was placed anhydrous AlClj (81.0 mg, 0.61 mmol), 2-Aminobenzonitri-lo (54.0 mg, 0.46 mmol) and 1,2-dichloroethane (2.5 ml) A solution of (-) - IIc [50] was then added dropwise over 10 min. mg, 0.30 mmol, [a] B20-85 (c = 0.93, CHCl,), ee = 81%] in 1-dichloroethane (0.75 ml) and the mixture was refluxed for 14 minutes. h.The mixture was allowed to warm, water (2 ml), THF (2 ml) was added, the mixture was made alkaline with aqueous 5N NaOH solution (1 ml) and stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. and the resulting aqueous suspension containing a sticky orange solid was filtered, washing the residue with water (5 ml). The solid was dissolved in methanol (3 mL) and the solution was evaporated under reduced pressure to give an orange waxy residue (105 mg) which was chromatographed on a silica gel column (60-200 μm, 40 g), eluting first with hexane, mixtures of hexane / ethyl acetate, ethyl acetate and finally ethyl acetate / methanol mixtures, obtaining (+) - ic by eluting with ethyl acetate / methanol mixtures (64 mg, 80% yield, ee - fifty%). (+) - ic was converted into its hydrochloride by dissolving in methanol (2 ml) and adding a 0.38 N dilution of HCl in ethyl ether (3 ml). Evaporation of the solvent under reduced pressure gave (+) - Ic. HCl 90 mg). (+) - Ic. HCl (544 mg, ee = 53%), from an operation similar to the previous one, was crystallized from ethyl acetate (5 ml) and methanol (2.5 ml) obtaining (+) - Icw. HCl (188 mg, ee = 99%), [ß] D »= +353 (c = 0.95, MeOH), p. 320aC (with dec. Starting at 225aC). The NMR data of ^ and "C coincide with those of (±) -lc. IR (KBr) v: 3328, 3178, 2880, 2819, 1667, 1650, 1638, 1585, 1496, 1463, 1412, 1373, 1183 , 1158, 852, 771 cm "\ The elemental analysis was concordant for ClßH20N .HCl. Eiemolo 36 dyei "blguiolinina hydrullorurn." FiT w. ^ This reaction was carried out analogously to the one described for the above example for (+) - Ic.HCl Parti-A1C1, anhydrous (252 mg, 1.89 mmol ), 2-aminobenzonitr? ^ (168 mg, 1.42 mmol) and 1,2-dichloroethane (7 ml) and a solution of (+) - IIc [155 mg, 0.94 mmol, [a] D3 ° = + 81 (c = 0.96, CHCl,), ee = 81%] in 1,2-dichloroethane (1.5 ml) was obtained (-) - lew (199 mg, 80% yield, ee = 57 %) By crystallization of (-) - Icw.HCl (242 mg, 22% ee), from other operations such as the previous one in which it had started from a ketone (+) - lic of lower enantiomeric excess, in acetate of ethyl (5 mL) and methanol (2 mL) was obtained (-) - Icw.HCl (45 mg, >; 99% ee), [tt] B »= -345 (c = 0.99, MeOH), p. F. 310aC (with dec. Starting at 240aC). The NMR data of H and 13C coincide with those of (±) -Icw. IR (KBr), v: 3329, 3180, 2930, 2886, 2821, 1672, 1650, 1628, 1585 94 1461, 1412, 1373, 1184, 1162, 352, 763 cm "The elemental analysis was concordant for C18H20N2. 2 / 3H20, Example 37 The chromatographic separation of (±) -lcw was carried out using medium pressure liquid chromatography (MPLC) equipment consisting of a pump, a column on a chiral stationary phase and a UV detector. The stationary phase. Chiral is cellulose triacetate (Merck 16362) with a particle size of 15-25 μm. In the process, 4 introductions of (±) -icw base of 135 mg each were made, using as eluent 96% ethanol, a flow of 1.8-2.0 ml / min and a pressure of 8-12 bar. Globally, (-) - icw (269 mg) was obtained with an ee > 90% and (+) -? Cw (241 mg) with an ee > 85% (-) - Icw (269 mg) was dissolved in MeOH (10 mL) and a 0.38 N solution of HCl in ethyl ether (8 mL) was added. The organic solvents were evaporated under reduced pressure to obtain (-) - Icw.HCl (307 mg) which was crystallized from a mixture of ethyl acetate (3 ml) and methanol (2.2 ml) to obtain a brown crystalline solid. corresponding to (-) - Icw.HCl (130 mg, 99% ee), [«].» - -345 (c = o, 95, MeOH). (+) - Icw (241 g) was dissolved in MeOH (8 mL) and a 0.38 N solution of HCl in ethyl ether (7 mL) was added. The organic solvents were evaporated under reduced pressure, obtaining (+) - Icw.HCl (275 mg) which was crystallized from a mixture of ethyl acetate (2.5 ml) and methanol (1.8 ml) obtaining a crystalline solid of brown color corresponding to (+) - lew.HCl (85 mg,> 99% ee), [a] 0"= -Í3J50 (c = 0.99, MeOH) Note: The ee were determined in both cases on a sample of the (+) - or (-) - lcw base released from its hydrochloride Example 38 gepara ióp crom, .oqráffcñ G | P 1 * mazni * ^^ iC? + - t? -? p ? 1p »- 6.7.l0.ll-tetr-ahi o-9-methyl-7, ll-methanoociclooctenorbl iirn-lina. ±? -Ibw The chromatographic separation of (±) -Ibw was carried out using the equipment described in example 37. In the process 4 introductions of (-) - Ibw in base form (1 x 100 mg) - 3 x 150 mg) were performed using 96% ethanol as eluent, a flow of 2.0-2 , 5 ml / min and a pressure of 8-12 bar Overall (-) - Ibw (189 mg, ee> 90%) and (+) - Ibw (140 mg, ee> 80%) were obtained. (-) - Ibw disolved in MeOH (10 ml) and a solution 0.38 N of HCl in ethyl ether (10 ml) was added. The organic solvents were evaporated under reduced pressure, obtaining (-) - Ibw.HCl (264 mg) was dissolved in MeOH (0.25 ml) and ethyl acetate (1.5 ml) was added. The precipitate formed was filtered to obtain (-) - Ibw.HCl (124 mg, ee = 90%) as a brown powdery solid, e.g. F. 295 * C (with dec. Starting at 240 aC), [a] 02 ° = -328 (c = 1.0, MeOH). The NMR data of? and 13C coincide with those of (±) -lbw. IR (KBr) v: 3338, 3182, 2918, 2874, 2852, 2811, 1666 ,. 1650, 1634, 1585, 1495, 1457, 1414, 1374, 1187, 1160, 874, 841, 764 cm "1. The elemental analysis was concordant for CL7H13N2.HCl.l / 2H20. (+) - Ibw (140 mg, ee> 80%) was dissolved in MeOH (7 mL) and a 0.38 N solution of HCl in ethyl ether (8 mL) was added.The organic solvents were evaporated under reduced pressure to obtain (+) - Ibw. HCl (201 mg) which was dissolved in MeOH (0.20 ml), ethyl acetate (1.2 ml) was added and the formed precipitate was filtered, obtaining (+) - Ibw.HCl (114 mg, ee-87). %) in the form of a brown powdery solid, mp 300aC (with dec. starting at 250aC), [a] D2 ° = +309 (c = 1.0, MeOH). The NMR data of LK and 13C coincide with those of (±) -Ibw, IR (KBr), v: 3319, 3178, 2925, 2892, 2870, 2810, 1666, 1646, 1636, 1600, 1584, 1490, 1457, 1414, 1373, 1181, 1159 , 878, 845, 768 cm "1. The elemental analysis was concordant for C ^ H ^^. HCl ^ / S ^ O. Note: The ee were determined in both cases on a sample of (+) - or (-) - ibw base released from its hydrochloride Eiempln 19 Ability to inhibit it ™ d *, ^ t1 ^ jnM ^ r "1 The capacity of inhibition of the acetylcholinesterase of the compounds obtained in examples 1 to 24 and 35 to 38 was determined using the colorimetric method described by Ellman et al., Biochem. Pharmacol., 7, 88-95 (1961) All the compounds showed inhibitory activity of the enzyme acetylcholinesterase and some of them clearly superior to that of tacrine. As it can be seen, the two enantiomers of the same compound present notable differences in activity, being the levorotatory enantiomers (-) - Ibw and (-) - icw much more active than their enantiomers (+) - -Ibw and (+) - icw, respectively. In step 8, the inhibitory activity of the enzyme of some of the obtained compounds was muted, with respect to that shown by tacrine under the same conditions, expressed as the quotient of the tacrine ratio (concentration that inhibits 50% of the enzyme) and the ciso of each compound. Table 8. Acetylcholinesterase inhibitory activity of the compounds Ibw, Ibx, iby, lew, lfW (+) - Ibw (87% ßß) (..} .Ibw (90% ee), (+) - Icw (99% ee) and i (K- i) -ixccww ( { > > 93994% aß.e?) Compared to tacrine.

Compound Tacr ic ina / cißo composite Ibw 2.00 Ibx 4.14 Iby 15.28 lew 3.38 Ifw 1.03 (+) - Ibw 0.40 (-) - Ibw 2.80 (+) - Icw 0, 15 (-) - Icw 4.80 It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (11)

1. Polycyclic aminopyridine compounds d-f or-5 mule general I r and their pharmaceutically acceptable salts, characterized in that: R can be hydrogen, alkyl, aralkyl or acyl- and R2 can independently be hydrogen, alkylaryl, alkoxy, alkoxycarbonyl, amino, substituted amino! with one or two alkyl, aralkyl or acyl groups; m and n can adopt the values I, 2 or 3-X and can be, independently, a bond between two carbons, an oxygen or sulfur atom, a group N-R 3 - in which the group R 3 can adopt the values defined above for R -, an alkylene or alkenylene bridge containing the 5 carbon atoms which may contain one or more substituents R4 - which can be, independently, hydrogen, alkyl, alkenyl or lower alkylidene of one to four carbon atoms with straight or branched chain, phenyl phenyl substituted with one or more lower alkyl groups of one to four carbon atoms, lower alkoxy of one to four carbon atoms or halogen, aralkyl, lower alkoxy containing from one to four carbons, and hydroxy - , and when X is an alkenylene group, this may be fused with a carbocyclic or heterocyclic, saturated or unsaturated nucleus, the ring may be substituted with one or more Rs - which may be hydrogen, alkyl or erior or inferior aleoxi of one to four carbon atoms, or halogen - • and having p, q and r having a value equal to or greater than one and where Rβ and R are substituents which individually may be hydrogen, halogen, lower alkoxy or lower alkyl.

2. Compounds, according to claim 1, characterized in that R is hydrogen.

3. Compounds, according to claim 1, characterized in that ni and n are both equal to one.

4. Compounds, according to the claims 2 and 3, of general formula characterized in that A. X and Y have the meanings set forth in claim 1.

5. Compounds, according to any of the preceding claims, characterized in that R "being, halogen or lower alkyl having 1 to 4 carbon atoms and having r values 0, 1 or 2.

6. Compounds, according to any of the preceding claims, characterized in that X is an ortho-phenylene group, a methylene group, or a methylene group substituted with one or more R groups, said R groups being independently, equal to lower alkyl, lower alkoxy, hydroxy or, together, a lower alkylidene group.

7. Compounds according to any of the preceding claims, characterized in that Y is an alkylene or alkenylene bridge containing 3 carbon atoms, whose central carbon can be substituted with a group R4 having the meaning set forth in claim 1.

8. Compounds, according to claims 4 to 7, of general formula, characterized in that R, can be hydrogen, lower alkyl of 1 to 4 carbon atoms or phenyl and R7 can be hydrogen or halogen, preferably fluorine or chlorine.

9. A pharmaceutical composition, characterized in that it comprises at least one of the compounds of claims 1 to 8.

The use of the compounds of claims 1 to 8 for the preparation of medicaments against memory disorders such as senile dementia or Alzheimer's disease.

11. A process for obtaining polycyclic aminopyridine compounds of general formula (I), and their pharmaceutically acceptable salts, wherein: R can be hydrogen, alkyl, aralkyl or acyl; Ri and "2 can independently be hydrogen, alkyl, aralkyl, alkoxy, alkoxycarbonyl, amino, amino substituted with one or two alkyl, aralkyl or acyl groups, m and n can adopt the values 1, 2 or 3; X and Y can be , independently, a bond between two carbons, an oxygen or sulfur atom, a group N-R3 - in which the group R, can adopt the values defined above for R -, an alkylene or alkenylene bridge containing from 1 to 5 carbon atoms which may contain one or more substituents R4 - which can be, independently, hydrogen, alkyl, alkenyl or lower alkylidene of one to four carbon atoms with straight or branched chain, phenyl, fe-nyl substituted with one or more lower alkyl groups of one to four carbon atoms, lower alkoxy of one to four carbon atoms or halogen, aralkyl, lower alkoxy-having one to four carbons, and hydroxy-, and When an alkenylene group is present, it may be fused with a carbocyclic or heterocyclic, saturated or unsaturated nucleus, the ring may be substituted with one or more R5 groups - which may be hydrogen, lower alkyl or lower alkoxy of one to four carbon atoms. carbon, or halogen -; Y having p, q and r a value equal to or greater than one and where Rβ and R are substituents that individually can be hydrogen, halogen, lower alkoxy or lower alkyl, said process being characterized in that the ketones of general formula (II) are reacted. with the aminonitriles of general formula (III) .CN WL (? D, NH. in whose general formulas íli) and (III) A > R? R¡; ? and n have the meanings defined above and if necessary, when it is desired to obtain compounds in which R is different from hydrogen, proceeds to the algylation, aralganiction or acylation of the compounds of great structure (I) in which R is hydrogen; or, when it is desired to obtain compounds in which R.sup. ßs is an endo hydroxyl group, the reduction of! corresponding precursor catonice e that R, is a group o = o; then, if it is "to form a pharmaceutically acceptable addition salt with an appropriate acid." • • • • • Procedure, according to claim 11, characterized in that the useful starting ketones correspond to the formula general wherein X and Y have the meanings stated in claim 11. 13 * ün Proc? < In accordance with claim 11 and the reaction between the ketones (II) and the aminonitriles (III) is carried out in the presence of a Lewis acid as a catalyst or a dehydration agent.