MXPA99009672A - New compounds of dihydro-and tetrehydro-quinoline, a procedure for its preparation and pharmaceutical compositions that contains them - Google Patents

Abstract

The present invention describes compounds of the general formula (I) :( See Formula) wherein: R1 represents a hydrogen atom or a group C (O) NH-A, wherein A is as defined in the description, - R2 and R3 , each independently, represent alkyl, cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted aminoalkyl, or R2 and R3, together with the carbon atom that carries them , form a cycloalkyl or monocyclic, unsubstituted or substituted heterocyclic group, R40 represents a hydrogen atom or a group selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, or a group Q or -VQ, wherein V represents a group alkylene, alkenylene or alkynylene, and Q represents a cycloalkyl group optionally substituted, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group, - R41 and R5 together form a bond or each represents a hydrogen atom, - Rc, R7, R8 and R9, each independently represents a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group of 3 to 8 carbon atoms, or -OW, wherein W is as defined in the description

Description

NEW COMPOUNDS OF DIHYDRO- AND TETRAHYDRO-QUINOLINE, A PROCEDURE FOR ITS PREPARATION AND COMPOSITIONS PHARMACEUTICALS THAT CONTAIN THEM DESCRIPTION OF THE INVENTION The present invention relates to new dihydro- and tetrahydro-quinoline compounds, to a process for their preparation, and to pharmaceutical compositions containing them. The preparation of compounds having a 1,2-dihydroquinoline structure has been described in Patent Specifications DD 227,434 and DE 4,115,535. Other compounds having the same nucleus, variously substituted, have been used in the preparation of smoked meats (GB 1,537,334) or as photochemical indicators (WO 89 05994). The antioxidant properties of the tetrahydroquinoline compounds have been used in the field of lubricants (EP 072,349). Compounds of this type have also been described as inhibitors of lipid absorption (EP 028, 765). According to Hartman's theory of free radical aging (J. Gerontol, 1956, 11, 298), successive oxidation attacks create "oxidation stress" conditions, which reflect an imbalance in the organism between the systems that produce species of free radicals and systems that are protective against these species (RE PACIFICI, KJA DAVIES, Gerontology, 1991, 3_7 ^, 166). Several defense mechanisms can act in synergy, allowing the action of free radicals to be controlled. These mechanisms can be enzymatic, as is the case for systems involving superoxide dismutase, catalase and glutathione peroxidase, or non-enzymatic, in the case of the involvement of vitamin E and vitamin C. With age, however, these natural defenses they become less and less efficient, especially as a result of the oxidative inactivation of a large number of enzymes (A. CASTRES de PAULET, Ann. Biol. Clin., 1990, 48_, 323). It has been possible to link oxidation stress conditions with disorders associated with aging, ie atherosclerosis, cataracts, non-insulin dependent diabetes, and cancer (M. HAYN et al., Life Science, 1996, 59, 537 ). The central nervous system is especially sensitive to oxidation stress, due to its high oxygen consumption, the relatively low level of its anti-oxidation defenses, and the high iron content of some brain regions (SA BENKOVIC et al., J Comp.Neurol., 1993, 338 92; D. HARTAMAN, Drugs Aging, 1993, 3_, 60). Therefore, successive attacks of oxidation constitute one of the main etiological factors of brain aging and associated disorders, that is, Alzheimer's disease and chronic neurodegenerative disorders, neurodegenerations of the basal ganglia (Parkinson's disease, Huntington's disease,. .), (B. HALLIWELL, J. Neurochem., 1992, 59_, 1609). In addition to the fact that the compounds of the present invention are new, they exhibit valuable pharmacological properties. Its antioxidant character, being a trap for reactive oxygenated species, especially at the level of the central nervous system, means that they can be considered for use against the effects of oxidation stress, especially at the brain level. Most of them, on the other hand, have the advantage of not causing a hypothermic effect in the doses used to obtain the neuroprotective action. They will therefore be useful in the treatment of disorders associated with aging, such as atherosclerosis and cataracts, in the treatment of cancer, in the treatment of cognitive disorders, and in the treatment of acute neurodegenerative disorders, such as cerebral ischemia. and epilepsy, and in the treatment of chronic neurodegenerative disorders, such as Alzheimer's disease, Pick's disease and neurodegenerations of the basal ganglia (Parkinson's disease, Huntington's disease). The present invention relates especially to the compounds of the general formula (I): wherein: Ri represents a hydrogen atom or a group -C (0) NH-A, wherein A represents a hydrogen atom or a group -BNZ? Z2, in which B represents an alkylene group of 1 to 6 atoms linear or branched carbon, and Zi and Z2 independently represent a hydrogen atom or an alkyl group, cycloalkyl of 3 to 8 carbon atoms, or optionally substituted aryl or, together with the nitrogen atom carrying them, forms a heterocycloalkyl group or optionally substituted heteroaryl, R2 and R3, each independently, represent an alkyl group, a cycloalkyl group of 3 to 8 carbon atoms, a heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a cycloalkylalkyl group, a heterocycloalkylalkyl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, or an aminoalkyl group (optionally substituted on the nitrogen atom) ene by one or two groups selected from alkyl, cycloalkyl, aryl and arylalkyl), or R2 and R-3 together with the carbon atom carrying them, form a cycloalkyl group of 3 to 8 carbon atoms, or a monocyclic heterocycloalkyl group unsubstituted or substituted by an alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl group, R 0 represents a hydrogen atom or a group selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, or a group Q or -VQ, wherein V represents an alkylene, alkenylene or alkynylene group, and Q represents a cycloalkyl group from 3 to 8 optionally substituted carbon atoms, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group, • R 4? and R5 together form a bond or each represents a hydrogen atom, • R6, R7, β and R9 each independently represents a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group of 3 to 8 carbon atoms; carbon, or a group -OW, wherein W represents a hydrogen atom or an alkyl group, an acyl group, a cycloalkyl group of 3 to 8 carbon atoms, a heterocycloalkyl group, an optionally substituted aryl group, a heteroaryl group optionally substituted, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group, (with the proviso that R6, 7, Rs, and 9 can not all simultaneously represent a hydrogen atom, and that at least one of them represents a group - OW defined above), with the proviso that: - when R2 and R represent an alkyl group: if each of R6 to R? independently represents a hydrogen atom, an alkyl group or a group -OW wherein W represents an alkyl group, and R4i and R5 together form a bond, then R4Q is different from a hydrogen atom or an alkyl group, • if a single group -OW is present in the molecule, and represents a hydroxy group, then R or is different from a hydrogen atom, if a single -OW group is present in the molecule, and represents a methoxy group, then R40 is different from a hydroxyalkyl group,, the compound of formula (I) is different from 7-methoxy-2,2-diphenyl-1,2-dihydroquinoline, it being understood that; - the term alkyl denotes a straight or branched chain of from 1 to 6 carbon atoms, - the term acyl denotes an alkyl-carbonyl group, the alkyl is as defined above, - the term alkenyl denotes a straight or branched chain of from 2 to 6 carbon atoms, containing from 1 to 3 double (s) bond (s), the term a ^ l-ynyl denotes a straight or branched chain of from 2 to 6 carbon atoms, containing from 1 to 3 triple (s) bond (s), - the term "alkylene" denotes a linear or branched bivalent group containing from 1 to 6 carbon atoms, the term "alkenylene" denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms, and from 1 to 3 double bonds, the term alkynylene denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms, and from 1 to 3 triple bonds, - the term aryl denotes a phenyl, naphthyl or biphenyl group, - the term heterocycloalkyl denotes a mono- or bi-cyclic group, of 4 to 11 members, containing from 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur, being possible for the group to contain one or more unsaturations without this having an aromatic character, the term "heteroaryl" denotes an aromatic or partially aromatic, mono- or bi-cyclic group, of 4 to 11 members, containing from 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur, the substituted term used with respect to of the aryl and arylalkyl expressions indicates that the groups concerned are substituted by one or more halogen atoms, or alkyl groups, straight or branched alkoxy of 1 to 6 carbon atoms, perloalkyl d and 1 to 6 straight or branched carbon atoms, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, linear or branched alkoxycarbonyl of 1 to 6 carbon atoms, aminocarbonyl (optionally substituted on the nitrogen atom by 1). or 2 alkyl groups), nitro or hydroxy, - the substituted term used with respect to the terms alkyl, alkenyl, alkynyl and cycloalkyl indicates that such groups are substituted by one or more groups selected from hydroxy, alkoxy of 1 to 6 linear carbon atoms or branched, linear or branched alkylthio of 1 to 6 carbon atoms, amino (optionally substituted by 1 or 2 alkyl groups), carboxy, nitro, cyano, linear or branched alkoxycarbonyl of 1 to 6 carbon atoms, and aminocarbonyl (optionally substituted on the nitrogen atom by 1 or 2 alkyl groups), - the substituted term used with respect to the terms heterocycloalkyl, heteroaryl and heteroarylalkyl indicates that the groups concerned are substituted by one or more halogen atoms or alkyl groups, linear to branched or branched alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 straight or branched carbon atoms, amino (optionally substituted by 1 or 2 alkyl groups) ), cyano, carboxy, linear or branched alkoxycarbonyl of 1 to 6 carbon atoms, aminocarbonyl (optionally substituted on the nitrogen atom by 1 or 2 alkyl groups), nitro, hydroxy or oxo, enantiomers and diastereomers thereof, and salts of addition thereof with a pharmaceutically acceptable acid or base. Among the pharmaceutically acceptable acids, hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, jpiruvic, alonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic, etc. acids can be mentioned among the pharmaceutically acceptable acids. canphoric and oxalic, etc. . . Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. may be mentioned without implying any limitation. The present invention advantageously relates to compounds of formula (I) wherein Ri represents a hydrogen atom. Preferably, in the compounds of formula. { I \, Re / 7 s and g each independently represents a hydrogen atom, an alkyl group or a group -0, wherein W represents an alkyl, acyl or phenyl group. More especially, W represents an alkyl group.

Preferred compounds of the invention are those in which R2 and R3 each represent an alkyl group, for example methyl. Other preferred compounds of the invention are those wherein R2 and R3 together form an optionally substituted cycloalkyl or heterocycloalkyl group, and more especially, a cycloalkyl group, for example cyclohexyl. In the compounds of formula (I), R4o preferably represents a hydrogen atom or a group V-Q, V is more especially an alkylene group, and Q is more especially a heterocycloalkyl group. The preferred aryl group of the invention is the phenyl group. An advantageous aspect of the invention relates to compounds of formula (I) wherein Ri represents a hydrogen atom, R2 and R3 represent an alkyl group, or together they form a cycloalkyl group, R4o represents a hydrogen atom or a group -VQ , wherein V represents an alkylene group, and Q represents a heterocycloalkyl group, and R6, 7, β and 9 each independently represents a hydrogen atom, an alkyl group or a -OW group, wherein W represents an alkyl group, acyl or phenyl, it being understood that R6, R7, R8 and R9 can not all represent a hydrogen atom, and that at least one of them represents a -OW group defined above. Among the preferred compounds of the invention, there may be mentioned: 6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane, 6-ethoxy-5,7,8-trimeti-1-1,2-dihydroquinoline-2-spirocyclohexane , - 8-ethoxy-l, 2-dihydroquinolin-2-spirocyclohexane, - 5,7-diisopropyl-6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane, - 5,7-dimeti-1-6-ethoxy -1, 2-dihydroquinolin-2-spirocyclohexane, 6-ethoxy-2,2,5,7,8-pentamethyl-1,2,3,4-tetrahydroquinoline, 5,7-diisopropyl-2,2-dimethyl- 6-ethoxy-1, 2, 3, 4-tetrahydroquinoline, 6-ethoxy-2,2,5,7-tetramethyl-2, 3, 4-tetrahydro-quinoline, 6-ethoxy-5 , 7,8-trimethyl-l, 2,3, 4- tetra-idroquinolin-2-spirocyclohexane, 6-ethoxy-l, 2-dihydroquinolin-2-spiro-4'-piperidine, - 6-ethoxy-l., 2-dihydroqui-olin-2-e.spiro-4 '- (1'-cyclopropylmet, ilpiperidine), - dihydrochloride., Of 2, 2-dimethyl-6-ethoxy-3- (2-morphino-ethyl) -1,2-dihydroquinoline-6-tert-butoxy-1,2-dihydroquin-1-in-2-spirocyclohexane, - d-methoxy-1,2-dihydroquinolin-2-spirocyclohexane, - 6-phenoxy-1,2-dihydroquinoline in-2-spirocyanohexane, - 6-ethoxy-5, 7-dimeti 1-1, 2, 3, 4-tetra-idroquinolin-2-spirocyclohexane, -6-ethoxy-2,2-dimethyl-3- [2- (2,6-dioxopiperazine) 4-yl) -ethyl] -1,2-dihydroquinoline, -6-ethoxy-2,2-dimethyl-3- [2- (1-piperidinyl) ethyl] -1,2-dihydroquinoline, 2- [ 2- (6-ethoxy-2, 2-dimeti 1-1, 2-dihydro-3-yl) ethyl] -1H-isoindol-1,3 (2H) -dione, -3- [2- (6- ethoxy-2, 2-dimethyl-1,2-dihydro-3-quinoline-enyl) -ethyl] -4 (3H) -quinazolinone, -6-tert-butylcarbonyl-loxi-1,2-dihydroquinoline-2-spirocyclohexane, and very especially: - 6-ethoxy-2,2,5,7,8-pentamethyl-1, 2, 3, 4-tetrahydroquinoline, 6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane. The present invention also relates to a process for the preparation of the compounds of formula (I), which is characterized in that a differently substituted aniline of formula (II) is used as the starting material: wherein R6, R7 / Rs and 9 are as defined for formula (I), which is subject: either to the action, in a basic medium and optionally in the presence of a catalyst, of a halogenated acetylide of formula ( III): wherein 'R2 and R3 are as defined for formula (I), G represents a hydrogen atom or a trialkylsilyl group, and Hal represents a halogen atom, to provide a compound of formula (IV): (IV), wherein R2 R3 / R6, R7, R8, R9 and G are as defined above, or • to the action of a carbonyl compound of formula (V): wherein R2 and R3 are as defined for formula (I), to provide a compound of formula (VI): wherein R2, R3, R6, R7, Rβ and Rg are as defined above, the compound (VI) is subjected, in a basic medium, to the action of an acetylide of formula (III) defined above, to provide a compound of formula (IV) defined above, the compound of formula (IV) and when applicable after hydrolysis of J. trialkylsilyl group, is cyclized by heating in the presence of an appropriate catalyst, to provide a compound of formula (I / a): a particular case of the compounds of formula (I) wherein R.sup.2, R.sup.3 / R.sup.6 R.sup.and R.sup.g are as defined above, which: may be subjected to either a reduction reaction to provide a compound of formula I / b): a particular case of the compounds of formula (I) wherein R2, R3 / R6, R7, e and Rg are as defined above, the compounds of formula (I / a) and (I / b), after chloroformylation of the Nitrogen of the ring, are subjected to the action of an amine of formula (VII): H2N-A. (VII), wherein A is as defined for formula (I), to provide a compound of formula (I / c): where R2, R3, ß r i ß and 9 are as defined above, and R4? and R5 are as defined for formula (I), * t > or, after protection of the ring nitrogen atom, it can be successively subjected to a hydroxyhalogenation reaction, and to an oxidation reaction in the benzylic position to provide a compound of formula (VIII): wherein R 2, R 3, R 6, R 7, R 3 and R g are as defined above, Hal represents a halogen atom, and P is a protecting group for the ring nitrogen (for example an acetyl group, trifluoroacetyl, ter- butoxycarbonyl or benzyloxycarbonyl), which is subjected to a nucleophilic substitution reaction to provide a compound of formula (IX): wherein R2 R3, R6, R7, R8 and R9 and P are as defined above, and Y represents either a R4o / 'group which is as defined for formula (I), but is different from an atom of hydrogen, or a precursor of such a group, which, after deprotection of the ring nitrogen, is subjected to a reduction reaction of the carbonyl function, followed by an elimination reaction, to provide a compound of the formula (X): (X), wherein R 2, R 3, R 6, R 7 R 1 and Y are as defined above, the compound of formula (X) can, when Y is a precursor of a group R or defined above, be subjected to a succession of conventional reactions directed to provide a compound of formula (I / d): a particular case of the compounds of formula (I) wherein R2 / R3 / Re, Ri, R8, R9 and R40 are as defined above, which can be reduced to provide a compound of formula (I / e): a particular case of the compounds of formula (I) wherein R2 / R3, R or /? R7,? r and 9 are as defined above, the compounds of formula (I / d) and (I / e), after of chloroformylation of the ring nitrogen, are subjected to the action of an amine of formula (VII) defined above, to provide a compound of formula (1 / f): wherein R2, R3, Re r Ri, ß, R9 and A are as defined above, R40 has the same meanings as in formula (I) other than a hydrogen atom, and R4i and R5 are as defined for the formula (I), the compounds (I / a) to (I / f) constitute the totality of the compounds of the formula (I): - which can be, if necessary, purified according to a conventional purification technique , the stereoisomers of which are, when appropriate, separated according to a conventional separation technique, which are, if desired, converted into their addition salts with a pharmaceutically acceptable acid or base. The present invention also relates to pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I), alone or in combination with one or more inert and non-toxic excipients or carriers. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral and nasal administration, tablets or lozenges, sublingual tablets, gelatin capsules, diamond-shaped tablets, suppositories, creams, ointments, gels can be mentioned more especially. dermal, etc. The dosage used varies according to the sex, age and weight of the patient, the nature and severity of the disorder and the route of administration, which may be oral, nasal or parenteral. Generally, the unit dose is in the range from 0.1 to 500 mg for a treatment in from 1 to 3 administrations per 24 hours. The following examples illustrate the invention, but do not limit it in any way.

The starting materials used are known products, or are prepared according to known procedures.

Preparation A: 4-Ethoxy-3,5,6-trimethylaniline Step 1: 2-Ethoxy-1,3,4-trimethylbenzene 734 mmol (101.5 g) of potassium carbonate and 917 mmol (143.1 g) of sodium hydroxide were added in succession. Ethyl iodide to a solution of 367 mmol (50 g) of 2,3,6-trimethylphenol in 1500 ml of acetonitrile. The whole was refluxed for 48 hours. The reaction mixture was subsequently cooled, and then filtered, and the filtrate was concentrated. The obtained residue was dissolved in ethyl acetate, washed with water, and then with 10% aqueous sodium chloride solution. After drying the organic phase and then concentrating it, an oily residue was obtained, which was purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate 95: 5 as eluent, to provide the expected product. Step 2: 4-Ethoxy-3,5,6-trimethyl-iodobenzene 222 mmol (50 g) of N-iodosucciniide was added to a solution of 171 mmol (28.03 g) of the compound described in the above Step in 650 ml of acetonitrile, and the whole was heated to reflux for 24 hours. The solvent was then removed by evaporation in vacuo, and the residue was dissolved in ether. The solution was washed with saturated NaHCO 3 solution, and then with 10% aqueous sodium chloride solution. The organic phase was dried and concentrated. The oily residue obtained was purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate 95: 5 as eluent, to provide the expected product. Step 3: 4-Ethoxy-3,5,6-trimethylaniline 0.46 mmol (0.426 g) of Pd2 (dba) 3 and 1.39 mmol (0.947 g) BINAP were placed in a 1 liter round bottom flask under an inert atmosphere. In a second round bottom flask, 46.5 mmoles (13.5 g) of the compound described in the above Step, 65.1 mmoles (6.26 g) of sodium tert-butanolate, 65.1 mmoles (17.21 g) of 18-crown-6 were dissolved. and 65.8 mmoles (10.12 g) of benzophenone in 250 ml of anhydrous THF. The solution that was in the second round bottom flask was introduced into the round bottom flask containing the catalyst system, with the help of a cannula. The whole was heated at 60 ° C for 3 hours, and then the reaction mixture was diluted with ether. The formed precipitate was filtered on sintered glass, and the filtrate was then evaporated. The residue obtained was redissolved in 300 ml of THF. 30 ml of hydrochloric acid solution (2 N) were added thereto, and the solution was stirred at room temperature for 1 hour. The whole was then diluted with an excess of hydrochloric acid (1 N) and a mixture of heptane: ethyl acetate 2: 1. The aqueous phase was separated and then neutralized using 1 M sodium hydroxide solution. After extracting with dichloromethane, drying the organic phase and evaporating the solvent, the expected product was obtained.

Preparation B: 3, 5-Diisopropyl-4-ethoxyaniline Step 1: 2,6-Diisopropyl-4-nitrophenol 78.3 mmoles (4.93 g) of fuming nitric acid were added dropwise to a solution, cooled to 0 ° C, of 53.9 mmoles (9.62 g) of 2,6-diisopropyl phenol in 350 ml of acetic acid. The reaction mixture was stirred at 0 ° C for 1 hour 30 minutes, and then poured into a mixture of ethyl acetate and ice. The organic phase was isolated and then washed with water. After drying and evaporating the solvent, an oily residue was recovered, which was purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate 9: 1 as eluent.

Step 2: 2,6-Diisopropyl-l-ethoxy-4-nitrobenzene The expected product was obtained according to the procedure described in Step 1 of Preparation A, starting from the compound described in the above Step. Step 3: 3, 5-Diisopropyl-4-ethoxyaniline A solution of 19.9 mmol (5.0 g) of the compound described in the above Step in 135 ml of absolute ethanol in the presence of 1.5 g of palladium on carbon (10%) was placed. under 1033 kg / cm2 (1 atm.) of hydrogen at room temperature for 4 hours. After this period, the reaction mixture was filtered, and then the filtrate was concentrated to provide the expected amount.

Preparation C: 3, 5-Dimethyl-4-ethoxyaniline Step 1: 3, 5-Dimethyl-4-ethoxy-nitrobenzene 300 mmol (326 g) of cesium carbonate and 374 mmol (58.5 g) of ethyl iodide were added in succession to a solution of 149.5 mmoles (25 g) of 2,6-dimethyl-4-nitrophenol in 1300 ml of acetonitrile. The whole was heated to reflux under an inert atmosphere for 15 hours. The reaction mixture was subsequently cooled, and filtered, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water and then with 10% aqueous sodium chloride solution. The expected product was obtained by drying the organic phase and then concentrating. Step 2: ^ 3. 5-Dimethyl-4-ethoxyaniline A solution of 149.5 mmol (29.19 g) of the compound described in the above Step in 1000 ml of absolute ethanol, in the presence of 9.4 g of palladium-SQbre-carbon ( 10%) was placed under a hydrogen atmosphere at room temperature for 4 hours. After this period, the reaction mixture was filtered, and then the filtrate was concentrated to provide the expected compound.

Preparation D: 4-tert-Butoxy-aniline Step 1: l-tert-Butoxy-4-nitrobenzene 43.79 mmol of di-tert-butyl acetal of N, N-dimethylformamide were added at room temperature to a solution of 10.78 mmol (1.5 g) of 4-nitrophenol in 10 ml of toluene. The reaction mixture was heated to reflux, with vigorous stirring, for 5 hours. The reaction mixture was diluted with ethyl acetate, and then washed with water, with saturated aqueous sodium bicarbonate solution, and then with 10% aqueous sodium chloride solution. The expected product was obtained by drying the organic phase and then concentrating.

Step 2: 4-tert-utoxy-aniline A solution of 4.61 mmol (0.90 g) of the compound described in the above Step in 15 ml of absolute ethanol containing 24.65 mmol (2.12 g) of cyclohexene and 0.29 g of palladium-on -carbon (10%) was heated to reflux, with vigorous stirring, for 2 hours. After this period, the reaction mixture was filtered, and then the filtrate was concentrated to provide the expected compound.

Preparation E: 4-tert-Butylcarbonyloxy-aniline Step 1: 1-tert-Butylcarbonyloxy-4-nitrobenzene 161.1 mmol (19.48 g) of pivaloyl chloride, 0 ° C, were added to a solution of 107.8 mmol (15 g) of 4-nitrophenol in 250 ml of pyridine. The reaction mixture was stirred for 72 hours at room temperature. The reaction mixture was evaporated in vacuo, and the oily residue was diluted with ethyl acetate, and then washed with aqueous hydrochloric acid solution (0.1 N), and then with 10% aqueous sodium chloride solution. The expected product was obtained by drying the organic phase and then concentrating. Step 2: A solution of 95.41 mmole (21.30 g) of the compound described in the above Step in 1200 ml of a 4/1 mixture of methanol and acetic acid containing 573 mmole (32.00 g) of iron was heated to 65 ° C. for 20 hours. After this period, the reaction mixture was filtered, and the filtrate was then concentrated to provide an oily residue, which was diluted with ethyl acetate, and washed with 10% aqueous sodium bicarbonate solution, and then with 10% aqueous sodium chloride solution. The expected product was obtained by drying the organic phase and then concentrating.

EXAMPLE 1: 6-Ethoxy-1,2-dihydroquinoline-2-spirocyclohexane hydrochloride Step 1: N- (4-Ethoxyphenyl) -N- [1- (1-ethynyl) -cyclohexyl] amine To one solution, cooled to 10 ° C, 18.2 mmoles (2.5 g) of p-phenetidine in a mixture of ether: water (4: 1; 30 ml) containing 24.5 mmol (3.42 ml) of triethylamine were added, in succession, 0.25 mmol (0.025 g). ) of CuCl, 0.39 mmol (0.025 g) of Cu and, dropwise, 28.0 mmol (4.0 g) of 1-ethynyl-1-chlorocyclohexane prepared according to the method described in J. Am. Chem. Soc., 8_3 725 , 1961, starting from 1-etylcyclohexanol. After stirring for 4 hours (allowing the temperature to increase to room temperature) the reaction mixture was diluted with ether, and then washed with 1 N sulfuric acid solution. The ether phase was removed, and the aqueous phase was neutralized (at 0 ° C) using potassium hydroxide pellets, and then re-extracted with ether. The organic phase was dried and then concentrated to provide the expected product. Step 2: 6-Ethoxy-l, 2-dihydroquinoline-2-spirocyclohexane hydrochloride 3.0 mmole (0.30 g) of CuCl was added to a solution of 14.79 mmole (2.89 g) of the compound described in the above Step 20 my toluene, and the whole was heated to reflux for 40 minutes. The solvent was then evaporated, and the oily residue was purified by chromatography on silica gel, using dichloromethane as eluent, to provide the expected product. The latter was precipitated as the hydrochloride, from a mixture of ethereal hydrogen chloride / isopropanol, to provide the corresponding hydrochloride. Melting point: 183 ° -186 ° C (decomposition, iPr20 / CH2Cl2) Elemental microanalysis: (empirical formula: C? 6H2? NO.HCl) c H N C l% found 68. 5 0 7 8 7 5. 0 8 1 2. 67% calculated 68. 68 7. 92 5. 0 1 1 2. 61 EXAMPLE 2: 6-Ethoxy-5,7,8-trimethyl-l, 2-dihydroquinoline-2-spiro-cyclohexane hydrochloride Step 1: N- (4-Ethoxy-2,3,5-trimethylphenyl) -N- [1- (1-ethynyl) cyclohexyl] amine The expected product was obtained according to the procedure described in Step 1 of Example 1, starting from the compound described in Preparation A. Step 2: β-Ethoxy-5,7 Hydrochloride, 8-trimethyl-l, 2-dihydroquinolin-2-spirocyclohexane The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in the above Step. The corresponding hydrochloride was obtained by precipitation of an ether / dichloromethane mixture to which ethereal liidrogen chloride was added. Melting point: 158 ° -161 ° C (Et20 / CH2C12) Elemental microanalysis: (empirical formula: C19H27NO.HCI) C H N Cl% found 71.13 8.68 4.30 11.24% calculated 70.90 8.77 4.35 11.01 EXAMPLE 3: 8-Ethoxy-l, 2-dihydroquinolin-2-spirocyclohexane hydrochloride Step 1: N- (2-Ethoxyphenyl) -N- [1- (1-ethynyl) -cyclohexyl] amine The expected product was obtained in accordance to the procedure described in Step 1 of Example 1, with replacement of p-phenetidine by o-phenetidine. Step 2: 8-Ethoxy-l, 2-dihydroquinolin-2-spirocyclohexane Hydrochloride The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in the above Step. The corresponding hydrochloride was obtained by precipitation of an ether / dichloromethane mixture to which ethereal hydrogen chloride was added. Melting point: 154 ° -155 ° C (Et20 / CH2C12) Elemental microanalysis: (empirical formula: C16H21N0.HC1) CHN Cl% found 68.62 7.65 4.84 12.59% calculated 68.68 7.92 5.01 12.67 EXAMPLE 4: 5,7-diisopropyl hydrochloride -6-ethoxy-l, 2- dihydroquinoline-2-spirocyclohexane Step 1: N- (3,5-Diisopropyl-4-ethoxyphenyl) -N- [1- (1-ethynyl) cyclohexyl] amine The expected product was obtained from according to the procedure described in Step 1 of Example 1, using as the starting material the compound described in Preparation B. Step 2: 5,7-Diisopropyl-6-ethoxy-1,2-dihydroquinolin-2-spirocyclohexane Hydrochloride E1 The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in the above Step. Melting point: 166 ° -169 ° C (with decomposition, Et20) Elemental microanalysis: (empirical formula: C22H33NO.HCI) C H N Cl% found 72.87 9.28 3.87 9.76% calculated 72.60 9.42 3.85 9.74 EXAMPLE 5: 5,7-Dimethyl-6-ethoxy-l, 2-dihydroquinolin-2-spirocyclohexane hydrochloride Step 1; N- (3, 5-Dimeti 1-4-ethoxy phenyl) -N- [1- (1-ethynyl) cyclohexyl] amine The expected product was obtained according to the procedure described in Step 1 of Example 1, using as a material The starting material was the compound described in Preparation C. Step 2: 5,7-Dimethyl-6-ethoxy-l, 2-dihydroquinoline-2-spirocyclohexane hydrochloride The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in the Stage above. Melting point: 175 ° -180 ° C (Et20) Elemental microanalysis: (empirical formula: C18H25N0.HC1) C H N Cl% found 70.47 8.55 4.57 11.56% calculated 70.23 8.51 4.55 11.52 EXAMPLE 6: 6-E-Toxi-2, 2, 5, 7, 8-pentamethyl-1,2,3,4-tetrahydroquinoline hydrochloride Step 1: N- (1, 1-Dimethyl-2-propynyl) -N- (4-Ethoxy-2,3,3-trimethylphenyl) amine The expected product was obtained according to the procedure described in Step 1 of Example 1, using as the starting material the compound described in Preparation A, and replacing 1- ethynyl-1-chlorocyclohexane by 2-chloro-2-methyl-3-butyne (prepared according to the method described in J. Am. Chem. Soc. 83, 725, 1961, starting from 2-methyl-3-butin -2-ol). Step 2: 6-Ethoxy-2, 2, 5, 7, 8-pentamethyl-l, 2-dihydroquinoline The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in Stage above. Step 3: 6-Ethoxy-2, 2, 5, 7, 8-pentamethyl-1, 2,3, 4- tetrahydroquinoline hydrochloride 0.9 g of palladium on carbon was added (10%) to a solution of 5.99 mmol (1.47 g) of the compound described in the Stage above in 55 ml of ethanol. The reaction mixture was stirred under 1.033. kg / cu2 (1 atm.) of hydrogen at room temperature for two hours. The reaction mixture was then filtered, and the filtrate was concentrated. The expected product was obtained in the form of hydrochloride by precipitation of ethereal hydrogen chloride. Elemental microanalysis: (empirical formula, C16H25NQ.HC1) .C H- JS -01% found 67.64 9.16 5.01 12.40% calculated 67.71 .3.23 4.93 12.49 EXAMPLE 7: Hydrochloride of 5, 7-diiso? Ropil-2, 2-dimethyl-6-ethoxy-1, 2,3,4-tetrahydroquinoli a Stage 1: N- (1, l-Dimethyl-2-propynyl) - N- (3,5-diisopropyl-4-ethoxyphenyl) amine The expected product was obtained according to the procedure described in Step 1 of Example 1, using as the starting material the compound described in Preparation B, and replacing 1- ethynyl-1-chlorocyclohexane by 2-chloro-2-methyl-3-butyne (prepared according to the method described in J. Am. Chem. Soc. 8_3_, 725, 1961, starting from 2-methyl-3-butin -2-ol).

Step 2: 5,7-Diisopropyl-2, 2-dimethyl-6-ethoxy-l, 2-dihydroquinoline The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in the Stage above. Step 3: 5,7-Diisopropyl-2, 2-dimethyl-6-ethoxy-1,2-dihydroquinoline hydrochloride The expected product was obtained according to the procedure described in Step 3 of Example 6, starting from the compound described in the Stage above. Melting point: 227 ° -230 ° C (Et20) Elemental microanalysis: (empirical formula: C19H31NO.HCI) C H N Cl% found 70.00 9.68 4.24 10.82% calculated 70.02 9.90 4.30 10.88 EXAMPLE 8: 6-E-toxy-2, 2, 5, 7, 7-tetramethyl-1,2,3,4-tetrahydroquinoline hydrochloride Step 1: N- (1, 1-Dimethyl-2-propynyl) -N- ( 3,5-Dimethyl-4-ethoxyphenyl) amine JE1 expected product was obtained according to the procedure described in Step 1 of Example 1, using as the starting material the compound described in Preparation C, and replacing 1-ethynyl-1 -chlorocyclohexane by 2-chloro-2-methyl-3-butyne (prepared according to the method described in J_ Am. Chem. Soc. 83, 725, 1961, starting from 2-methyl-3-butin-2-ol ). Step 2: 6-Ethoxy-2, 2, 5, 7-tetramethyl-1, 2-dihydroquinoline The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in Stage above. Step 3: 6-Ethoxy-2,2,7,7-tetramethyl-1,2,3,4-tetrahydroquinoline hydrochloride The expected product was obtained according to the procedure described in Step 3 of Example 6, starting from compound described in the Stage above. Melting point: 198 ° -200 ° C (Et20) Elemental microanalysis: (empirical formula: C? 9H31NO.HCl) CHN Cl% found 66.71 8.93 5.15 13.11% calculated 66.77 8.97 5.19 13.35 EXAMPLE 9: 6-Ethoxy-5-Hydrochloride , 7,8-trimethyl-1,2,3,4-tetrahydroquinoline-2-spiro-cyclohexane The expected product was obtained according to the procedure described in Step 3 of Example 6, starting from the compound described in Example 2. Melting point: 192 ° -198 ° C (with decomposition, Et20) Elemental microanalysis: (empirical formula; C? 9H29N0.HCl) CHN Cl% found 70.46 9.23 4.35 10.98% calculated 70.46 9.34 4.32 10.95 EXAMPLE 10: 6-Ethoxy-1,2-dihydroquinolin-2-spiro-4'-piperidine hydrochloride Step 1: 4- [(4-Ethoxyphenyl) imino] -1-piperidinecarboxylic acid tert -butyl ester 45 g were added of molecular sieve (5 A) to a solution of 202.6 mmole (27.8 g) of paraphenethidine and 169 mmole (33.7 g) of N-tert-butoxycarbonyl-4-piperidone in 60 ml of ether. The whole was stirred at room temperature for 15 hours. The reaction mixture was subsequently filtered, and then the filtrate was concentrated to provide the expected product.

Step 2: 4- (4-Ethoxyaniline) -4- (2-trimethylsilyl-1-ethynyl) -1-piperidinecarboxylate tert -butyl 66.7 mmole (42 ml) of a 1.6 M solution of n-butyl were added dropwise. lithium in the course of 1 hour to a solution, cooled to -78 ° C, 77.8 mmole (7.64 g) of trimethylsilylacet in 160 ml of THF. The whole was stirred at -78 ° C for 1 hour, and then at room temperature for an additional hour. The lithium tri-ethylsilylacetyl formed in this manner was added dropwise to 155.5 mmol (49.5 g) of the compound described in the above Step, dissolved in 500 ml of THF. The reaction mixture was stirred at -78 ° C for 1 hour, and then at room temperature for 15 hours. The reaction mixture was then poured into a mixture of ethyl acetate and ice. The organic phase was isolated, washed with ammonium chloride (10%), dried and then concentrated. The oily residue obtained was purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate (4: 1) as eluent, to give the expected compound. Step 3: Tert-butyl 4- (4-ethoxyanilino) -4- (1-ethynyl) -1- piperidinecarboxylate 23.7 mmoles (24 ml) of a 1 M solution of tetrabutylammonium fluoride in THF were added dropwise to a solution, cooled to 0 ° C, of 21.38 mmoles (8.91 g) of the compound described in the above Step in 270 ml of THF. After stirring for 1 hour at 0 ° C, the mixture was diluted with ether, and then washed with water. The organic phase was dried and then concentrated, and the residue was purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate (4: 1) as eluent, to provide the expected product. Step 4: 6-Ethoxy-1,2-dihydroquinolin-2-spiro-4 '- (1'-tert-butoxycarbonylpiperidine) The expected product was obtained according to the procedure described in Step 2 of Example 1, starting at from the compound described in the above Step. Step 5: 6-Ethoxy-1,2-dihydroquinoline-2-spiro-4'-piperidine hydrochloride 30 ml of concentrated hydrochloric acid solution was added at room temperature to a solution of 5.99 mmol (2.06 g) of the compound described in the above Step in 100 ml of absolute EtOH.

After stirring for 1 hour 30 minutes, the solvents were evaporated and the residue was dissolved in a mixture of ethyl acetate / water. The two phase solution was poured to pH = 11 using 2 M sodium hydroxide solution. The organic phase was isolated and then dried and concentrated to provide the expected product. The corresponding hydrochloride was obtained by precipitation of an ether / dichloromethane mixture to which ethereal hydrogen chloride was added. Elemental microanalysis: (empirical formula: C? 5H20N2O.HCl) C H N Cl% found 63.47 7.58 9.66 13.58% calculated 64.16 7.54 9.98 12.63 EXAMPLE 11: 6-Ethoxy-1, 2-dihydroquinolin-2-spiro-4 '- (1'-cyclopropyl ethylpiperidine) 2.45 mmol (0.23 mL) of bromomethylcyclopropane were added, in the presence of 4 mmol (0.56 g) of potassium carbonate, to a solution of 2 mmoles (0.5 g) of the compound described in Example 10 in 30 ml of acetonitrile. The mixture was stirred at room temperature for 15 hours before being filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel, using a mixture of dichloromethane: ethanol 9: 1 as eluent, to provide the expected product. The corresponding hydrochloride was obtained by precipitation of a mixture of ethereal hydrogen chloride / dichloroethane.

Melting point: 170 ° C (with decomposition, Et20) Elemental microanalysis: (empirical formula: C? 5H20N2O- 1.6HC1) C H N Cl% found 64.36 7.50 7.86 16.20% calculated 63.96 7.81 7.85 15.90 EXAMPLE 12: 2,2-Dimethyl-6-ethoxy-3- (2-morpholino-yl) -1,2-dihydroquinoline dihydrochloride Step 1: l-Acetyl-2,2-dimethyl-6-ethoxy-2- dihydroquinoline. A solution of 30.2 mmoles (6.15 g) of 2,2-dimethyl-6-ethoxy-1,2-dihydroquinoline (prepared according to the procedure described in Steps 1 and 2 of Example 1, starting from 2-chloro- 2-methyl-3-butyne) in 45 ml of acetic anhydride was heated to 100 °.

C under an inert atmosphere for 3 hours. After cooling, the medium was concentrated, and the residue was purified by chromatography on silica gel, using a mixture of dichloromethane: ethyl acetate 95: 5 as eluent, to provide the expected compound. Step 2: l-Acetyl-3-bromo-2,2-dimethyl-6-ethoxy-4-hydroxy-1, 2,3,4-tetrahydroquinoline 28.37 mmol (5.05 q) of N-bromosuccinimide were added in portions to a solution, cooled to 0 ° C, of 24.7 mmol (6.06 g) of the compound described in the above Step in 154 ml of a 10: 1 dimethyl sulfoxide: water mixture. The reaction mixture was subsequently diluted with ethyl acetate, and then washed 3 times with 100 ml of water and once with 100 ml of saturated sodium chloride solution. The organic phase was dried and concentrated to provide the expected compound. Step 3: l-Acetyl-3-bromo-2, 2-dimethyl-6-ethoxy-1,2,3,4-tetrahydroquinolin-4-one 30 μg of activated molecular sieve from 4 Á to a solution of 24.51 is added mmoles (8.33 g) of the compound described in the above Step in 225 ml of dichloromethane. The reaction mixture was cooled to 0 ° C and 31.10 mmoles (23 g) of pyridinium dichromate were added thereto in portions. The reaction mixture was stirred at 0 ° C for 10 minutes, and then at room temperature for 2 hours. The mixture was filtered and the precipitate was rinsed with dichloromethane and with acetone. The filtrate was concentrated and purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate 70:30 as eluent, to provide the expected compound.

Step 4: l-Acetyl-2, 2-dimethyl-6-ethoxy-3- [(ethoxycarbonyl-tert-butoxycarbonyl) ethyl] -1,2,3,4-tetrahydroquinolin-4-one. They were added dropwise. 32.35 mmoles (6.09 g) of tert-butyl malonate dissolved in 30 ml of THF to a suspension, cooled at 0 ° C, of 29.75 mmoles (1.19 g) of 60% sodium hydride in oil in 85 ml of THF. After stirring for 30 minutes at 0 ° C, 21.57 mmoles (7.34 g) of the compound described in the above Step dissolved in 35 ml of THF were added dropwise. The reaction mixture was stirred for 10 minutes at 0 ° C and then at room temperature for 3 hours. The reaction mixture was neutralized with 100 ml of water, and the medium was diluted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried, concentrated and purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate 80:20 as eluent, to give the expected compound. Step 5: l-Acetyl-2, 2-dimethyl-6-ethoxy-3- (ethoxycarbonylmethyl) -1,2,3,4-tetrahydroquinolin-4-one 18.1 mmole (9.1 ml) of acid was added trifluoroacetic acid to a solution, cooled to 0 ° C, of 5.9 mmole (2.64 g) of the compound described in the above Step in 90 ml of dichloromethane. The reaction mixture was stirred at room temperature for 15 hours. The medium was subsequently diluted with ethyl acetate, and then washed with saturated NaHCO3 solution. The organic phase was removed, and the aqueous phase was brought to pH = 1 using concentrated hydrochloric acid solution, and then extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was dissolved in 110 ml of dioxane, and the mixture was heated to reflux for 9 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate 70:30 as eluent, to provide the expected compound. Step 6: 2, 2-Dimethyl-6-ethoxy-4-hydroxy-3- (2-hydroxyethyl) -1,2,3,4-tetrahydroquinoline 1.50 ml of water and 5.05 mmol (0.96 g) of water were added. p-toluenesulfonic acid to a solution of 10.05 moles (0.96 g) of the compound described in the above Step in 60 ml of toluene. The whole was refluxed for 2 hours, and then the solvents were evaporated. The residue was dissolved in ethyl acetate, and washed with saturated NaHCO 3 solution. The organic phase was dried and concentrated. The product obtained was dissolved in 15 ml of THF and added to 27.9 mmoles (1.06 g) of lithium aluminum hydride suspended in 100 ml of THF. After stirring for one hour at room temperature, the reaction mixture was cooled using an ice bath, and 1 ml of water and 1 ml of 15% sodium hydroxide solution were added. The mixture was then filtered, and the filtrate was concentrated to provide the expected compound. Step 7: 2, 2 -Dimethyl-6-ethoxy-3- (2-hydroxyethyl) -1,2-dihydroquinoline A solution of 1.73 mmol (0.46 g) of the compound described in the above step in 1 ml of dimethyl sulfoxide it was heated at 170 ° C for 1 hour 30 minutes. The mixture was cooled and then diluted with ethyl acetate. After washing with water, the organic phase was dried, concentrated and purified by chromatography on silica gel, using a mixture of petroleum ether: ethyl acetate 70:30 as eluent, to give the expected compound. Step 8: 3- (2-Bromoethyl) -2,2-dimethyl-6-ethoxy-1,2-dihydroquinoline 5.73 mmol (1.9 g) of carbon tetrabromide were added to a solution of 3.68 mmol (0.91 g) of the compound described in the Stage above in 20 ml of dichloromethane. The whole was cooled to 0 ° C and 5.71 mmoles (1.75 g) of triphenyl phosphine dissolved in 15 ml of dichloromethane were added. The reaction mixture was stirred at 0 ° C for 15 minutes, and at room temperature for 2 hours. The solvent was evaporated, and the obtained residue was purified by chromatography on silica gel, using dichloromethane as eluent, to provide the expected compound. Step 9: 2,2-Dimethyl-6-ethoxy-3- (2-morpholinoethyl) -1,2-dihydroquinoline j-ß-dihydrochloride added 2.15 mmole (0.19 g) of morpholine to a solution of 0.69 mmole (0.21 g) of the compound described in the above Step in 1 ml of acetonitrile. The reaction mixture was stirred at room temperature for 15 hours. The medium was then diluted with ethyl acetate and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel, using a mixture of dichloromethane: ethanol 95: 5 as eluent, to provide the expected compound. The latter was dissolved in ethyl acetate, and a 3M solution of hydrochloric acid in ethyl acetate was slowly added. After stirring for 15 minutesThe solvent was evaporated and the residue dissolved in isopropanol, washed and filtered to provide the expected dihydrochloride.

Elemental microanalysis: (empirical formula: C? 9H28N202.2HCl) C H N Cl% found 58.51 7.80 7.04 18.23% calculated 58.61 7.77 7.19 18.21 EXAMPLE 13: 6-tert-Butoxy-l, 2-dihydroquinolyl-2-spirocyclohexane hydrochloride Step 1; N- (4-tert-butoxyphenyl) -N- [1- (1-ethynyl) cyclohexyl] amine The expected product was obtained according to the procedure described in Step 1 of Example 1, starting from the compound described in Preparation D ,. Step 2: 6-tert-butoxy-l, 2-dihydroquinoline-2-spirocyclohexane J21 expected product hydrochloride was obtained according to the procedure described in Step 2 of Example 1, starting from the demerit compound in the above Step. The corresponding hydrochloride obtained βß r precipitation from ethyl acetate after addition of HCl in ethyl acetate (3 M) __, Melting point: 132 ° C (AcOEt) Microanalysis' elementa.! : C? 8H25N0.HCl) c H N Cl% found 70. 03 8.57 4.43 11. 34% calculated 70. 23 8.51 4.55 11. 52 EXAMPLE 14: 6-Methoxy-l, 2-dihydroquinoline-2-spirocyclohexane hydrochloride Step 1: N- (2-Methoxyphenyl) -N- [1- (1-ethynyl) -cyclohexyl amine The expected product was obtained according to procedure described in Step 1 of Example 1, with replacement of p-phenetidine by p-anisidine. Step 2: 6-methoxy-l, 2-dihydroquinolin-2-spirocyclohexane hydrochloride The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in the above Step. The corresponding hydrochloride was obtained by precipitation of ethyl acetate after addition of HCl in ethyl acetate (3 M). Melting point: 191 ° C (AcOEt) Elemental microanalysis: (empirical formula: C? 5H19NO.HCl) C H N Cl% found 67.31 7.59 5.11 13.42% calculated 67.79 7.58 5.27 13.34 0 EXAMPLE 15: 6-Phenoxy-1, 2-dihydroquinolin-2-espi-oxycyclohexane hydrochloride Step 1: N- (2-Phenoxyphenyl) -N- [1- (1-ethynyl) -cyclohexyl] -amine The expected product was obtained from according to the procedure described in Step 1 of Example 1, with replacement of p-phenetidine by 4-phenoxyaniline. Step 2: 6-phenoxy-1, 2-dihydroquinoline-2-spirocyclohexane hydrochloride The expected product was obtained according to the procedure described in Step 2 of Example 1, starting from the compound described in the above Step. The corresponding hydrochloride was obtained by precipitation of ethyl acetate after addition of HCl in ethyl acetate (3 M). Melting point: 176 ° C (AcOEt) Elemental microanalysis: (empirical formula: C20H21NO.HC1) C H N Cl% found 73.36 6.84 4.43 10.75% calculated 73.27 6.76 4.27 10.81 EXAMPLE 16: 6-Ethoxy-5,7-dimethyl-1,2,3,4-tetrahydroquinoline-2-spirocyclohexane hydrochloride The expected product was obtained according to the procedure described in Example 6, Step 3, using as a The compound described in Example 5 was split. Elemental microanalysis: (empirical formula: CLßH27N0.HCl) CHN Cl% found 69.27 9.11 4.52 11.44% calculated 69.57 9.21 4.48 11.72 EXAMPLE 17: 6-Ethoxy-2,2-dimethyl-3- [2- (2,6-dioxopiperazin-4-yl) ethyl] -1,2-dihydroquinoline hydrochloride The expected product was obtained according to the procedure described in Example 12, with replacement of morpholine by 2,6-dioxopiperazine in Step 9. Elemental microanalysis: CHN Cl% found 54.81 6.54 10.09 17.03% calculated 55.26 6.49 10.07 16.46 EXAMPLE 18: 6-Ethoxy-2, 2- Hydrochloride dimethyl-3- [2- (1-piperidinyl) ethyl] -1,2-dihydroquinoline The expected product was obtained according to the procedure described in Example 12, with replacement of the morpholine by piperazine in Step 9.

EXAMPLE 19: 2- [2- (6-Ethoxy-2, 2-dimethyl-1,2-dihydro-3-yl) ethyl] -lH-isoindol-1,3 (2H) -dione hydrochloride The expected product is obtained according to the procedure described in Example 12, with replacement of the morpholine by phthalimide in Step 9.

EXAMPLE 20: 3- [2- (6-Ethoxy-2,2-dimethyl-1,2-dihydro-3-quinoline) ethyl] -4 (3H) -quinazolinone hydrochloride The expected product was obtained according to the procedure described in Example 12, with replacement of the morpholine by 4 (3H) -quinazolinone in Step 9.

EXAMPLE 21: 6-tert-Butylcarbonyloxy-l, 2-dihydroquinoline-2-spirocyclohexane hydrochloride Step 1: N- (2-tert-Butylcarbonyloxy) -N- [1- (1-ethynyl) -cydohexyl amine The expected product was obtained according to the procedure described in Step 1 of Example 1, starting from the compound described in Preparation E. Step 2: 6-tert-Butylcarbonyloxy-l, 2-dihydroquinoline-2-spirocyclohexane hydrochloride The expected product was obtained from according to the procedure described in Step 2 of Example 1, starting from the compound described in the above Step. The corresponding hydrochloride was obtained by precipitation of ethyl acetate after addition of HCl in ether (1.3 M). Melting point: 180 ° C (Et20 / AcOEt) Elemental microanalysis: (Empirical formula: C? 9H25N02.HCl) CHN Cl% found 68.13 7.90 4.07 10.38% calculated 67.94 7.80 4.17 10.56 PHARMACOLOGICAL STUDY EXAMPLE A: Cytotoxicity test using L- homocis eine on HT22 murine hippocampal cells. Murine hippocampal cells were preincubated HT22 in culture (100 μl / well DMEM / F-12/25% FCS) for 1 hour in the presence of 2 concentrations (0.1 and 0.5 μM) of the -compound that was being studied. The cell cultures were then exposed for 48 hours to 2 mM L-homocysteine in the presence or absence of the compound being tested. Cytotoxicity was evaluated by the method of reducing the bromide of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium (MTT) (Mosmann, T., Imol. Methods 65: 55-63 ( 1983)). The results were expressed as% protection, compared to the cytotoxicity measured in the cell cultures in the absence of the compound being tested. It seems . that, at 0.5 μM, most of the compounds of the invention have a protection percentage of 100%.

EXAMPLE B: Lethality test using tert-butyl hydroperoxide in the NMRI mouse Intracerebroventricular (icv) administration of tert-butyl hydroperoxide (1 μl of a 70% solution) causes lethality in the adult male NMRI mouse (30-35) g). The lethality is measured 2 hours after the administration of tert-butyl hydroperoxide, and is expressed as a percentage of protection, compared with the lethality in the animals to which the carrier of the studied compounds has been given. The latter was administered by the intraperitoneal route, at a dose of 150 mg / kg i.p. 30 minutes before the administration of tert-butyl hydroperoxide. It appears that, for most of the compounds of the invention, the percentage of protection measured is from 70 to 100%.

EXAMPLE C: Evaluation of the effects on body temperature in the NMRI mouse The body temperature in adult male NMRI mice (25-30 g) was measured using a rectal probe (Physistemp, Bat-12) 30, 60, 90 and 120 minutes after administration by the intraperitoneal route of the compounds studied in a dose of 150 mg / kg. The results were expressed as the maximum average difference in temperature (° C) determined in the treated animals compared to the control animals, which had received only the carrier (20 l / kg). The results showed that, in a neuroprotective dose, the compounds of the invention do not induce an ipothermic effect, or induce only a slight hypothermic effect.

EXAMPLE D: Antagonism of dopaminergic striatonigral dysfunctions induced by the administration of methamphetamine in the mouse C57BL / 6. Male mice (C57BL / 6, 20-25 g) were administered four injections of d-methamphetamine (5 mg / kg base, i.p.) at 2-hour intervals (Sonsalla and Heijkila, Prog. Neuro-Psychopharmacolo. & Biol.

Psychiat., 12, 345-354, 1988) and the antioxidant being tested was administered (i.p.) 30 minutes before the first and third injections of d-ethamphetamine (Yamamoto and Zhu, J. Pharmacol. Exp. Ther. 287, 107-114, 1988). The rectal temperature was monitored throughout the duration of the experiment. The animals were sacrificed by decapitation 72 hours after the last injection of d-methamphetamine. The brains were removed quickly, and the striata was removed, frozen in liquid nitrogen and weighed. The striata was homogenized by sonication in 20 volumes of 0.1 N HC10, and the homogenate was subjected to centrifugation at 15,000 G for 20 minutes at 4 ° C. The supernatants were collected to test the dqpamine levels in striata tissue by CLAP coupled with coulometric detection (Bonhomme et al., Brain Res., 675, 215-233, 1995). The results were expressed as μg of dopamine / g of tissue. It appears that the compounds of the invention oppose the dopaminergic deficit induced by the administration of methamphetamine. This is especially true for the compound of Example 1 administered in a dose of 2 x 150 mg / kg i.p.

EXAMPLE E: Neuroprotection in the case of transient and global cerebral ischemia in the istar rat This animal model (Pulsinelli and Brieley, Stroke 10, 267-272, 1979) is commonly used for the detection of central anti-ischemic agents (Buchan et al., Neurosci, Lett., 132 (2), 255-258, 1991). Under anesthesia with pentobarbital, the vertebral arteries of Wistar male rats (280-320 g, Charles River) were permanently occluded by electrocoagulation, and carotid ligatures were placed around each common carotid. 24 hours later, ischemia was provoked for 10 minutes by pressing the carotids with the carotid ligatures. This ischemic episode caused delayed neuronal death at the level of pyramidal cells of the hippocampus. Neuronal death was measured by a count of neurons on sections of brain (7 μm, staining: hematoxylin-eosin) of rats sacrificed 7 days after the ischemic episode. The results were expressed as a percentage of viable hippocampal neurons compared to a total population of hippocampal neurons. It appears that the compounds of the invention significantly reduce neuronal death of the hippocampus following ischemia. This is true especially for the compounds of Example 1, which, with their administration 30 minutes before the onset of ischemia, induce a reduction by a factor of 2.7.

EXAMPLE F: Delayed neurodegeneration of the hippocampus induced by the administration of kainic acid in the Wistar rat. This method is frequently used as a model of temporal epilepsy in humans (Ben-Ari, Neurosci., 14, 375-403, 1985). They were administered kainic acid (12 mg / kg) to male Wistar rats (180-220 g, CERJ) by the subcutaneous route. The animals were sacrificed by decapitation 7 days later. The brains were removed and then cut, in a frozen state, into frontal sections of 7 μm, which were stained (hematoxylin-eosin). Neuronal death of the hippocampus was evaluated by a count of neurons at the level of the CA3 layer of the hippocampus. The results were expressed as a percentage of viable neurons in the CA3 layer compared to the total neuron population. It appears that the compounds of the invention significantly reduce neuronal death in the CA3 layer of the hippocampus. In particular, the compound of Example 1, administered in a dose of 150 mg / kg i.p. 30 minutes before the administration of kainic acid, it induces a reduction in neuronal death by a factor of 3.

EXAMPLE G: Pharmaceutical composition Formulation for the preparation of 1000 tablets, each comprising 10 mg of active ingredient: Compound of Example 1 10 g Hydroxypropyl cellulose 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g Talc 3 g

Claims (14)

CLAIMS 1. Compounds of the general formula (I): wherein: Ri represents a hydrogen atom or a group -C (0) NH-A, wherein A represents a hydrogen atom or a group -BNZXZ2, in which B represents an alkylene group of 1 to 6 carbon atoms linear or branched, and Z and Z2 independently represent a hydrogen atom or an alkyl group, cycloalkyl of 3 to 8 carbon atoms, or optionally substituted aryl or, together with the nitrogen atom that bears them, forms a heterocycloalkyl or heteroaryl group optionally substituted, • R2 and R3, each independently, represent an alkyl group, a cycloalkyl group of 3 to 8 carbon atoms, a heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a cycloalkylalkyl group, a group heterocycloalkylalkyl, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, or an aminoalkyl group (optionally substituted on the e. trógeno by one or two groups selected from alkyl, cycloalkyl, aryl and arylalkyl), or R2 and R3 / together with the carbon atom carrying them, form a cycloalkyl group of 3 to 8 carbon atoms, or a monocyclic heterocycloalkyl group not substituted or substituted by an alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl group, R40 represents a hydrogen atom or a group
1. Selected optionally substituted alkyl ,. optionally substituted alkenyl and optionally substituted alkynyl, or a group Q or -VQ, wherein V represents an alkylene, alkenylene or alkynylene group, and Q represents a cycloalkyl group of 3 to 8 optionally substituted carbon atoms, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group, • R4? and R5 together form a bond or each represents a hydrogen atom, • R6, R7, 8 and R-9 / each independently represents a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group of 3 to 8 carbon atoms, or a group -OW, wherein W represents a hydrogen atom or an alkyl group, an acyl group, a cycloalkyl group of 3 to 8 carbon atoms, a heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group, (with the proviso that R6, R7, R8, and R9 can not all simultaneously represent a hydrogen atom, and that at least one of they represent a group -OW defined above), with the proviso that: - when R2 and R3 represent an alkyl group: if each of R6 to R9 independently represents a hydrogen atom, an alkyl group or a group -OW wherein W represents an alkyl group, and R41 and R5 together form a bond, then R40 is different from a hydrogen atom or an alkyl group, • if a single -OW group is present in the molecule, and represents a hydroxy group, then R40 is different from a hydrogen atom, if a single -OW group is present in the molecule, and represents a methoxy group, then R40 is different from a hydroxyalkyl group, the compound of formula (I) is different from 7-methoxy-2,2-diphenyl-1,2-dihydroquinoline, it being understood that: - the term alkyl denotes a straight or branched chain of from 1 to 6 carbon atoms, - the "Acyl" denotes an alkylcarbonyl group, alkyl is as defined above, the term "alkenyl" denotes a straight or branched chain of from 2 to 6 carbon atoms, containing from 1 to 3 double bond (s), the term alkynyl denotes a straight or branched chain of from 2 to 6 carbon atoms, containing from 1 to 3 triple (s) bond (s), - the term alkylene denotes a linear or branched bivalent group containing from 1 to 6 carbon atoms, the term alkenylene denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms, and from 1 to 3 double bonds, - the term alkynylene denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms, and from 1 to 3 triple bonds, - the term aryl denotes a phenyl, naphthyl or biphenyl group, - the term heterocycloalkyl denotes a mono- or bi-cyclic group, from 4 to 11 members, containing from 1 to 6 hetero atoms selected of nitrogen, oxygen and sulfur, it being possible for the group to contain one or more unsaturations without this having an aromatic character, the term heteroaryl denotes an aromatic or partially aromatic, mono- or bi-cyclic group, of 4 to 11 members, which contains from 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur, the substituted term used with respect to the aryl and arylalkyl expressions indicates that the groups referred to are substituted by one or more halogen atoms, or alkyl groups, linear or branched alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 straight or branched carbon atoms, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, alkoxycarbonyl from 1 to 6 straight or branched carbon atoms, aminocarbonyl (optionally substituted on the nitrogen atom by 1 or 2 alkyl groups), nitro or hydroxy, the substituted term used with respect to the terms alkyl, alkenyl, alkynyl and cycloalkyl indicates that such groups are substituted by one or more groups selected from hydroxy, linear or branched alkoxy of 1 to 6 carbon atoms, linear or branched alkylthio of 1 to 6 carbon atoms, amino (optionally substituted by 1 or 2 alkyl groups), carboxy, Nitro, cyano, linear or branched alkoxycarbonyl of 1 to 6 carbon atoms, and aminocaxbonyl (optionally substituted on the nitrogen atom by 1 or 2 alkyl groups), the term subst The term used for the terms heterocycloalkyl, heteroaryl and heteroarylalkyl indicates that the groups referred to are substituted by one or more halogen atoms or alkyl groups, straight or branched alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 straight carbon atoms. or branched, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, alkoxycarbonyl of 1 to 6 straight or branched carbon atoms, aminocarbonyl (optionally substituted on the nitrogen atom by 1 or 2 alkyl groups), nitro, hydroxy or oxo, enantiomers and diastereoisomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
2. 2. Compounds of formula (I) according to claim 1, wherein Ri represents a hydrogen atom, enantiomers and diastereoisomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
3. 3. Compounds of formula (I) according to claim 1, wherein R6, R7, R8 and R9, each independently represents a hydrogen atom, an alkyl group, or a group -OW, wherein W represents an alkyl group, acyl or phenyl, enantiomers and diastereomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
4. 4. Compounds of formula (I) according to claim 1, wherein R2 and R3 each represent an alkyl group, enantiomers and diastereomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
5. 5. Compounds of formula (I) according to claim 1, wherein R and R3 together form an optionally substituted cycloalkyl or heterocycloalkyl group, enantiomers and diastereoisomers thereof, and addition salts thereof with a pharmaceutically acceptable base acid.
6. 6. Compounds of formula (I) according to claim 1, wherein R40 represents a hydrogen atom or a group VQ, V is an alkylene group, and Q is a heterocycloalkyl group, enantiomers and dia teresisomers thereof, and salts thereof. addition thereof with a pharmaceutically acceptable acid or base.
7. 7. Compounds of formula (I) according to claim 1, wherein R ± represents a hydrogen atom, R 2 and R 3 represent an alkyl group, or form a cycloalkyl group, R 4 represents a hydrogen atom or a group -VQ, in where V represents an alkylene group, and Q represents a heterocycloalkyl group, and R6, R7, R8 and R9, each independently represents a hydrogen atom, an alkyl group, or a group -OW, wherein W represents an alkyl group, acyl or phenyl, it being understood that Rβ, R7, R8 and R9 can not all represent a hydrogen atom, and that at least one of them represents a group -OW defined above, enantiomers and diastereoisomers thereof, and addition salts of them with a pharmaceutically acceptable acid or base.
8. 8. Compounds of formula (I) according to claim 7, wherein R2 and R3 together form a cycloalkyl group, enantiomers and diastereomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
9. 9. Compounds of formula (I) according to claim 7, wherein R and R3 represent an alkyl group, enantiomers and diastereoisomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
10. 10. Compound of formula (I) according to claim 1, which is 6-ethoxy-2, 2, 5, 7, 8-pentamethyl-1, 2, 3, 4-tetrahydroquinoline, and the addition salts thereof with a pharmaceutically acceptable acid.
11. 11. Compound of formula (I) according to claim 1, which is 6-ethoxy-1,2-dihydroquinolin-2-spirocyclohexane, and the addition salts thereof with a pharmaceutically acceptable acid.
12. 12. Process for the preparation of the compounds of formula (1) / characterized in that a differently substituted aniline of formula (II) is used as the starting material: wherein R6, R7 Re and R9 are as defined for the formula (I), which is subject: either to the action, in a basic medium and optionally in the presence of a catalyst, of a halogenated acetylide of formula ( III): wherein R2 and R3 are as defined for formula (I), G represents a hydrogen atom or a trialkylsilyl group, and Hal represents a halogen atom, to provide a compound of formula (IV): wherein R2, R3, R6 / 7, Rβ, R9 and G are as defined above, or • to the action of a carbonyl compound of formula (V): • wherein R2 and R3 are as defined for formula (I), to provide a compound of formula (VI): wherein R2, R3, R6, R7, Rs and R9 are as defined above, the compound (VI) is subjected, in a basic medium, to the action of an acetylide of formula (III) defined above, to provide a compound of formula (IV) defined above, the compound of formula (IV), when applicable after cleavage of the trialkylsilyl group, is cyclized by heating in the presence of an appropriate catalyst, to provide a compound of formula (I / a ): a particular case of the compounds of formula (I) wherein R2 / R3, Rg, R7, Re R9 are as defined above, which: • ^ can be subjected to either a reduction reaction to provide a compound of formula (I / b): (I), a particular case of the compounds of formula (I) wherein R2, R3, Re R7, Rs and R9 are as defined above, the compounds of formula (I / a) and (I / b), after chloroformylation of the ring nitrogen, they are subjected to the action of an amine of formula (VII): H2N-A (VII), wherein A is as defined for formula (I), to provide a compound of formula ( I / c): wherein R2, R3, R6, R7, Rs and R9 are as defined above, and R4i and R5 are as defined for formula (I), or, after protection of the ring nitrogen atom, may be successively subjected to a hydroxyhalogenation reaction, and to an oxidation reaction in the benzylic position to provide a compound of formula (VIII): wherein R2 R3, Re R7, Rs and g are as defined above, Hal represents a halogen atom, and P is a protection group for the ring nitrogen (for example an acetyl, trifluoroacetyl, tert-butoxycarbonyl or benzyloxycarbonyl group) ), which is subjected to a nucleophilic substitution reaction to provide a compound of formula (IX): wherein R2 / R3 / R6, R7, R8 and R9 and P are as defined above, and Y represents either a R40 group, which is as defined for formula (I), but is different from an atom of hydrogen, or a precursor of such a group, which, after deprotection of the ring nitrogen, is subjected to a reduction reaction of the carbonyl function, followed by an elimination reaction, to provide a compound of the formula (X): wherein R2, R3, R6, Ri, Rs, Rg and Y are as defined above, the compound of formula (X) can, when Y is a precursor of a group R40 defined above, be subjected to a sequence of conventional reactions directed to provide a compound of formula (I / d): a particular case of the compounds of formula (I) wherein R2, R3, R6, R7, Rs, R40 are as defined above, which can be reduced to provide a compound of formula (Ie): (I / e), a particular case of the compounds of formula (I) wherein R 2, R 3, R 0 R β R 7, R β, and R 9 are as defined above, the compounds of formula (1 / d) and ( I / e), after chloroformylation of the ring nitrogen, are subjected to the action of an amine of formula (VII) defined above, to provide a compound of formula (I / f): wherein R2; R3, R6, R7, R8, R9 and A are as defined above, R40 has the same meanings as in formula (I) other than a hydrogen atom, and R1 and R5 are as defined for the formula ( I), the compounds (I / a) to (I / f) constitute all of the compounds of formula (I): which can be, if necessary, purified, the stereoisomers of which are, when appropriate, separated, - which are, if desired, converted into their addition salts with a pharmaceutically acceptable acid or base.
13. 13. Pharmaceutical compositions comprising as active ingredient at least one compound according to any of claims 1 to 11, alone or in combination with one or more pharmaceutically acceptable, inert and non-toxic excipients or carriers.
14. 14. Pharmaceutical compositions according to claim 13, comprising at least one active ingredient according to any of claims 1 to 11, for use as anti-oxidation agents in the treatment of disorders associated with aging, such as atherosclerosis and cataracts, in the treatment of cognitive disorders, in the treatment of acute neurodegenerative disorders, such as cerebral ischemia and epilepsy, and in the treatment of chronic neurodegenerative disorders, such as Alzheimer's disease, Pick's disease and neurodegenerations of the basal ganglia (Parkinson's disease) , Huntington's disease). SUMMARY OF THE INVENTION The present invention describes compounds of the general formula (I): wherein: Ri represents a hydrogen atom or a group -C (0) NH-A, wherein A is as defined in the description, R2 and R3, each independently, represent alkyl, cycloalkyl, heterocycloalkyl, optionally substituted aryl optionally substituted heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted aminoalkyl, or R2 and R3 / together with the carbon atom bearing them, form a cycloalkyl or heterocyclic monocyclic, unsubstituted or substituted, R4o represents a hydrogen atom or a group selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, or a group Q or -VQ, wherein V represents an alkylene, alkenylene or alkynylene group, and Q represents a cycloalkyl group optionally substituted, an optionally substituted aryl group, a heterocyclic group optionally substituted alkyl, or an optionally substituted heteroaryl group, • R4i and R5 together form a bond or each represents a hydrogen atom, • R6, R7, e and Rg, each independently represents a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group of 3 to 8 carbon atoms, or -OW, wherein W is as defined in the description. Medicines