EP1272485A1

EP1272485A1 - Novel 1,2,3,4-tetrahydrosioquinoline, their preparation method and their use as fungicides

Info

Publication number: EP1272485A1
Application number: EP01921468A
Authority: EP
Inventors: Didier Babin; Yannick Benedetti; Fabienne Chatreaux; John Bernard Weston
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 2000-04-05
Filing date: 2001-04-04
Publication date: 2003-01-08
Also published as: AU2001248456A1; CA2405126A1; WO2001074808A1; MXPA02009764A; JP2003529599A; US20030187267A1; IL152072A0; FR2807434A1; FR2807434B1

Abstract

The invention concerns compounds of formula (I) wherein: p = 1 or 2; X, X1 and X2 represent N or CH=; R1, R2, R3, R4, R5 and R6 represent a hydrogen atom, a halogen atom, alkyl, O-alkyl, S-(O)nalkyl, alkenyl, O-alkenyl, S-(O)nalkenyl, alkynyl, O-alkynyl, S-(O)nalkynyl; n = 0, 1 or 2, or NO2, NH2 or C=N or R1, R2, R3 or R5, R6 form a cycle, or R4A can be cycloalkyl, heterocycle, aryl, O-aryl or oxygenated or nitrogenated chain; R7 represents H, OH, SO3H or OPO(OH)2; A and B = hydrogen or oxygenated or nitrogenated chain; C and D = hydrogen, halogen or alkyl or together form with the carbons bearing them a cycle. The compounds of formula (I) have antifungal properties.

Description

New derivatives of 1,2, 3,4-tetrahγdroisoquinoline, their preparation process and their application as fungicides.

The present invention relates to new derivatives of 1, 2, 3, 4-tetrahydroisoquinoline, their preparation process and their application as fungicides.

The subject of the invention is, in all the possible stereoisomeric forms, as well as their mixtures, the compounds of formula (I):

in which p represents the number 1 or 2,

X, X _x and X _2, identical or different, represent a nitrogen atom or a CH = radical,

Ri, R ₂ , R ₃ , R5 and R ₆ identical or different from each other in any position on the rings which carry them, represent a hydrogen atom, a halogen atom, an alkyl radical, O -alkyl, S (0) _n -alkyl, alkenyl, O-alkenyl, S (0) _n -alkenyl, alkynyl, O-alkynyl, S (0) _n -alkynyl containing up to 8 carbon atoms, optionally substituted by one or more halogen atoms, n representing the number 0, 1 or 2, or represent a radical N0 ₂ , NH ₂ or C≡N, R _{X /} R _{2 /} R ₃ on the one hand and R ₅ and R ₆ on the other hand being able to form cycles two by two,. R ₇ represents a hydrogen atom or an OH, OSO3H or OPO (OH) ₂ radical,

R ₄ A represents a radical R _{4 which} can take one of the values indicated above for Ri, R ₂ , R3, R5 or R ₆ , and can also represent an unsubstituted or substituted heterocycle, an aryl or O-aryl group containing up to 14 unsubstituted or substituted carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms unsubstituted or substituted by an aryl optionally substituted by one or more halogen atoms and which may also represent an oxygen or nitrogen chain linked to the phenyl or heteroaryl nucleus by an oxygen or nitrogen atom, A and B identical or different from each other represent a d atom hydrogen or an oxygen or nitrogen chain linked to the phenyl nucleus by an oxygen or nitrogen atom,

C and D, which are identical or different from each other, represent a hydrogen or halogen atom or an alkyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms or form together with the carbons which carry them a ring optionally substituted by one or more halogen atoms, one or more alkyl radicals containing up to 8 carbon atoms or together form a double bond, excluding the compounds of formula (IA) :

in which the various substituents retain their previous meaning, as well as their addition salts with acids. The compounds of formula (I _A ) are described and claimed in European patent application 992502 filed on October 5, 1999 by the applicant company.

Of course, when X _x and X ₂ both represent a nitrogen atom, at least one of the substituents R ₄ A, R ₅ , R ₆ or R ₇ of the heteroaryl radical represents a hydrogen atom. Among the addition salts with acids, there may be mentioned those formed with mineral acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acids or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic acid, citric, maleic, fumaric, succinic, tartaric, alkanesulfonic, such as methane or ethane sulfonic acids, arylsulfonic such as benzene or paratoluenesulfonic acids.

Substituents A and B are preferably in position 5 or 7.

In the definition of the substituents, the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, or cyclic radical. such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the halogen is preferably fluorine or chlorine, or bromine, when C and D form a cyclic radical, it may for example be a cyclopropyl radical optionally substituted by a fluorine atom or a dimethyl gem, the aryl radical is preferably the phenyl radical, the heterocycle radical may contain one or more heteroatoms, it is preferably a 5 or 6-membered radical optionally containing one or two double bonds, and one or more nitrogen atoms, for example

each of these radicals being able to be substituted, they can especially be radicals

Among the preferred compounds of the invention, mention may be made of the compounds of formula (I _x ):

in which X, Xi and X _2, identical or different, represent a nitrogen atom or a radical -CH =, R _{λ l} R ₂ , R ₃ , R ₅ , R _6; R identical or different being in any position on the rings which carry them, those in which X, Xi and X ₂ represent a radical -CH =, those in which X represents a radical CH = and either Xi or X ₂ represents an atom nitrogen, those in which R _x and R ₂ represent a halogen atom, those in which R ₄ is a halogen atom, and more particularly those in which Ri and R ₂ and / or R ₄ represent an atom of chlorine, those in which R ₃ represents a hydrogen atom, those in which C and D form a double bond, and among these, particularly, those in which the geometry of the double bond is E, those in which the radical dioxoxaryl is in the cis position.

A more particular subject of the invention is the compounds of formula (I) defined above in which R ₇ represents an OH, OS0 ₃ H or OPO (OH) ₂ radical.

A more specific subject of the invention is the compounds of formula (I), in which A or B does not represent a hydrogen atom.

Among the preferred compounds of the invention, there may be mentioned very particularly those in which A or B represents a radical

W (CO) _r (CH ₂ ) _s Z

in which r represents the number 0 or 1, s represents an integer varying from 0 to S, W represents an oxygen atom or a radical -N (Rn) -, Ru representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, Ru can also form a ring with the nitrogen atom which carries it and another atom in the chain (CO) _r (CH ₂ ) _S -Z, Z represents a hydrogen atom , a radical S0 ₃ H or OSO3H, PO (OH) ₂ or OPO (OH) ₂ , or C0 ₂ H as well as the alkali, alkaline earth or amine salts of these radicals, or a radical

R ₈ and R ₉ representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, Rio representing an alkyl radical containing up to 8 carbon atoms, R ₈ and R ₉ may form a ring optionally containing a other heteroatom, and being optionally substituted, or else Z represents an optionally substituted heterocyclic radical.

This is how A and B can represent in particular

OPO (OH) ₂ 'O

OSO ₃ H, O- sugar (pyranose, furanose), a radical

O OC-CH - NH ₂ , OCO (CH ₂ ) ₄ NH ₂ A more particular subject of the invention is the compounds of formula (I), in which represents a nitrogen atom.

In this case, A and B can represent a chain NHCOOR'i, NHCOR'2, NH-CONR ' ₃ R' ₄ ,

R'i, R ' ₂ , R' ₃ and R ' ₄ representing alkyl radicals containing up to 8 carbon atoms NHC0C0 ₂ H, NH-C0 ₂ P (0) (OH) ₂ , NHS0 ₃ H, NHP0 ₃ H ₂ , as well as the alkali, alkaline earth and amine salts of the latter two compounds

When R _4A represents an oxygen or nitrogen chain, it is preferably one of the preferred values indicated above for A and B, or else one of the 5 or 6-membered heterocycles containing one or more atoms of nitrogen and one or more double bonds.

A more particular subject of the invention is the compounds of Examples 3, 6, 10, 12 and 13.

The compounds of formula (I) have interesting antifungal properties; they are particularly active on Candida albicans and other Candida such as Candida glabrata, krusei, tropicalis, pseudotropicalis and parapsilosis, on Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger Cryptococcus néoformans, Microsporum canis, Trichophyton rubrun, Trichophyton mentagrophyton. The compounds of formula (I) can be used as medicaments in humans or animals, in particular for combating digestive, urinary, vaginal or skin candidiasis, cryptococcosis, for example neuromeningeal, pulmonary or skin cryptococcosis, bronchopulmonary and pulmonary aspergillosis and invasive aspergillosis of the immunocompromised.

The compounds of the invention can also be used in the prevention of fungal diseases in congenital or acquired immune depressed.

The compounds of the invention are not limited to pharmaceutical use, they can also be used as fungicides in fields other than pharmaceutical.

The subject of the invention is therefore, as antifungal compounds, the compounds of formula (I).

A subject of the invention is also the compounds of formula (I) as well as their pharmaceutically acceptable salts, as medicaments.

The invention particularly relates to pharmaceutical compositions containing as active ingredient. at least one compound of formula (I) or one of its pharmaceutically acceptable salts. These compositions can be administered by the oral, rectal, parenteral route or by the local route as a topical application to the skin and the mucous membranes, but the preferred route is the oral route.

They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels. ; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, cyclodextrins, vehicles aqueous or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

These compositions can also be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example sterile pyrogen-free water.

The dose administered is variable depending on the condition treated, the subject concerned, the route of administration and the product considered. It can be, for example, between 50 mg and 300 mg per day orally, in adults for the product of Example 3 or of Example 6.

The subject of the invention is also a method characterized in that a compound of formula (II) is subjected:

in which :

Y represents a mesyl or tosyl radical and the other substituents retain their previous meaning due to the action of a compound of formula (III)

in which the various substituents retain their previous meaning, in order to obtain the corresponding compound of formula (I), which is subjected if desired to the action of a reducing, substitution, addition or action agent of an acid to obtain the desired compound.

The products of formula (II) used as starting materials are generally known products and which can be prepared according to the method indicated in J. Med. Chem 1979 22 (8) 1003.

Some products of formula (III) are new products _/ they can be prepared as indicated in the experimental part.

The subject of the invention is also a method characterized in that a compound of formula (IV) is subjected:

in which alci, alk ₂ and alk ₃ represent an alkyl radical containing up to 8 carbon atoms, RI, R2, R3 and X retain their previous meaning, to the action of a compound of formula (V):

in which Hal represents a halogen atom and the other substituents retain their previous meaning in order to obtain the corresponding compound of formula (I), which is subjected if desired to the action of a reducing, substitution, d addition or action of an acid to obtain the desired compound. The products of formula (IV) are new products which can be prepared as indicated below in the experimental part.

The invention further relates to a variant of the preceding methods, characterized in that a compound of formula (VI) is subjected:

in which the substituents retain the same value as above, to the action of a compound of formula (VII):

in which the substituents retain the same value as previously, then to the action of a reducing agent to obtain the corresponding compound of formula (I) which is subjected if desired to the action of a reducing agent, substitution, addition or action of an acid to obtain the desired compound.

The compounds of formula (VI) are new products prepared as indicated below in the experimental part.

The following examples illustrate the invention without, however, limiting it. PREPARATION 1: 3- [4- [2,4-dihydro-2- (1-methylpropyl) -3-oxo 3H-1,2,4-triazol-4-yl] phenyl] -2 (E) -propenal . Stage A: 1, 1-dimethylethyl 2- [[[(4-iodophenyl) -amino] -carbonyl] -hydrazine-carboxylate.

A mixture of 20 g of l-iodo-4-isocyanoto-benzene and 100 ml of tetrahydrofuran (THF) is cooled to 0 ° C., then introduced at a temperature below -10 ° C., 11.84 g of tert-butylcarbazate (BOCNHNH ₂ ) in 100 ml of THF. The mixture is stirred for one hour at 0 ° C. and evaporated under reduced pressure. We take back with ether and stir for 2 hours at room temperature. It is wrung, rinsed and dried at 55 ° C. 30 g of sought product are obtained, melting at 55 ° C.

Stage B: N- (4-iodophenyl) -hydrazinecarboxamide. The mixture is stirred at reflux for 2 hours 30 minutes, a mixture containing 30 g of product from the previous stage, 250 ml of THF and 30 ml of a 6N hydrochloric acid solution. Cool to 0 ° C and add 150 ml of ethyl ether. Agitation is carried out for 1 hour 30 minutes at 0 ° C. We spin, rinse and dry. 22.69 g of sought product is obtained.

Stage C: 2,4-dihydro-4- (4-iodophenyl) -3H-1,2,4-triazol-3-one.

15.46 g of potassium hydroxide powder are added to a mixture of 22.70 g of product from the previous stage and 247 ml of butanol. The mixture is stirred for 30 minutes and 16.4 g of formamidine acetate are added. It is brought to 110 ° C. and maintained at this temperature for 5 hours. The mixture is brought to 0 ° C., 350 ml of water is added, the mixture is stirred for 30 minutes at 0 ° C. It is wrung, rinsed with water and ether. Dried at 50 ° C under reduced pressure and obtained 13.73 g of product melting at 258 ° C.

Stage D: 2, -dihydro-4- (4-iodophenyl) -2- (1-methylpropyl) -3H- 1,2,4-triazol-3-one.

A mixture of 1.15 g of product from the preceding stage, 10 ml of methyl isobutyl ketone, 0.87 ml of bromobutane, 0.14 g of aliquat 336 and 1.1 is brought to 110 ° C. ~ 120 ° C. for 4 hours. g of K ₂ C0 _3. obtained. Leave to return to room temperature, filter, rinse and evaporate to dryness. A product is obtained which is chromatographed on silica eluting with an ethyl acetate-cyclohexane 1-1 mixture. 1.19 g of sought product is thus obtained.

Stage E: 3- [4- [2,4-dihydro-2- (1-methylpropyl) -3-OXO-3H- 1,2,4-triazol-4-yl] phenyl] -2 (E) -propenoate methyl.

The mixture is brought to 110 ° C. for 30 minutes, a mixture of 1.14 g of 3- (tributylstannyl) -2 (E) -methyl propenoate, 1.15 g of the product of the preceding stage and 64 mg of dichlorobis (triphenylphosphine) -palladium (PdCl ₂ (PPh ₃ ) ₂ ) • 4 ml of a saturated solution of sodium hydrogen carbonate, 0.31 g of potassium fluoride, 4 ml of dimethylformamide (DMF) are added and stir for 1 hour at room temperature. It is filtered, rinsed, decanted and extracted with methylene chloride. It is dried, filtered and evaporated to dryness. 1.7 g of sought product is obtained. Stage F: 2,4-dihydro-4- [4- (3-hydroxy-1 (E) -propenyDphenyl] - 2- (1-methylpropyl) -3H-1, 2, 4-triazol-3-one.

4.4 ml of 1.5M diisobutylaluminum hydride (DIBAH) in toluene are added to a solution of 0.67 g of product from the preceding stage in 7 ml of THF. The mixture is stirred for 1 hour at room temperature. It is brought to 0 ° C. and an aqueous solution of THF (1-1) is poured. We filter and rinse. Decanted, extracted with methylene chloride, dried, filtered and evaporated to dryness. 0.547 g of the product is obtained which is chromatographed on silica eluting with an ethyl acetate-cyclohexane 1-1 mixture. 0.275 g of sought product is obtained.

Stage G: 3- [4- [2,4-dihydro-2- (1-methylpropyl) -3-oxo-3H- 1,2,4-triazol-4-yl] phenyl] -2 (E) -propenal .

A mixture of 0.268 g of product from the preceding stage, 5 ml of methylene chloride and 1.10 g of manganese oxide is stirred at ambient temperature for 3 hours. It is filtered, rinsed and evaporated to dryness. 0.244 g of product is obtained which is used as it is.

PREPARATION 2: Cis (±) 6- [[2- (2,4 dichlorophenyl) -2- (1H- imidazol-1-γl-methyl) -1,3-dioxolan-4-γl] -methoxy] -1, 2,3,4- t rahydro-isoquinoline Stage A:

A suspension containing 5.8 g of 1,2,3,4 tetrahydroisoquinoline 6-OH and 50 ml of THF is stirred for 15 hours at room temperature. 11.13 g of diterbutyl dicarbonate in 25 ml of THF are added at 20 ° C. Pour into an ice-cold solution of potassium hydrogen carbonate. Extraction is carried out with ethyl acetate. We dry. We filter and concentrate. The product obtained is taken up in pentane, primed and washed the crystals obtained with pentane. 9.26 g of sought product is obtained, F = 114 ° C. Stage B:

Is introduced over 20 minutes at room temperature into a solution of 24.63 g of the product prepared in stage A and 250 ml of DMF, 5.4 g of sodium hydride at 55 = 60% in dispersion in the oil. It is brought to 55 ° C for 2 hours. The mixture is allowed to return to room temperature and 54.6 g of cis- (+) -2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3 methane sulfonate are introduced. -dioxolane-4-methanol. The reaction mixture is brought to 80 ° C for 20 hours. Then stirred at room temperature for 72 hours. Poured onto ice, stir for one hour, decant, dry, filter and concentrate. 95.8 g of product are obtained which is chromatographed on silica eluting with the heptane acetone mixture (6/4). 45 g of sought product is thus obtained which is used as it is in the following stage.

Stage C: Cis (±) 6- [[2- (2,4 dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1, 3-dioxolan-4-yl] -methoxy] -1, 2,3,4-tetrahydroisoquinoline.

45 g of the product prepared in the preceding stage, dissolved in 200 cm ³ of ethyl acetate, are cooled to 10 ° C. 100 cm ³ of a solution containing 50 g of ice and 50 cm ³ of a 12N hydrochloric acid solution are added. The reaction mixture is stirred for 4 hours. It is concentrated under reduced pressure. The residue is taken up in ethyl acetate. A product is obtained which is taken up in ethyl ether. The product obtained is triturated, wrung, rinsed and dried. 60.8 g of product are obtained which is poured into 250 cm ³ of water. Cooled and poured 50 cm ³ of a 28% ammonia solution. The mixture is stirred for half an hour and 150 cm ³ of methylene chloride are added. The reaction mixture is kept under stirring for 30 minutes, extracted with methylene chloride, washed, dried, filtered and concentrated. 35.68 g of sought product is obtained.

PREPARATION 3: 3- [4- [2,4-dihγdro-2- ((1S, 2R) -2-hγdroxγ-l-methylpropyl) -3-oxo-3H-1,2,4 _/ triazol-4-yl ] phenyl] -2 (E) - propenal.

Stage A: 1,1-dioxide of (4R, 5R) -4,5-dimethyl-1,3,2-dioxathiolane

A mixture of 0.45 g of 2, 3-butanediol, 5 ml of carbon tetrachloride and 0.44 ml of thionyl chloride (SOCl ₂ ) is brought to reflux for 30 minutes. We bring to 0 ° C and 5 ml of acetonitrile, 1.5 mg of RuCl ₃ and 1.6 g of NaI0 _{4 are added.} The mixture is stirred at room temperature for 2 hours. Extracted with ethyl ether, washed with water with a solution of sodium hydrogen carbonate, with sodium chloride. It is dried, filtered and evaporated to dryness. Is obtained 0.6 g of product which is taken up with a mixture of 10 ml of CH ₃ CN, 7 mg of ruthenium chloride (RuCl _3), 1.6 g of ^sodium periodate (NaI0 ₄₎ and 1 ml of water. The mixture is stirred for 2 hours at room temperature, extracted with methylene chloride, washed with water, dried, filtered and evaporated to dryness. It is taken up in methylene chloride, filtered and evaporated to dryness. 0.539 g of sought product is obtained.

^" Stlade B: 2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -4- (4-iodophenyl) -3H-1, 2, 4-1riazol-3 -one. The mixture is brought to 110 ° C. for 2 hours 30 minutes.

0.861 g of 2,4-dihydro-4- (4-iodophenyl) -3H-1, 2, 4-triazol-3- one (stage C of preparation 1), 8 ml of methyl isobutyl ketone, 0.829 g of K2CO3 , 86 mg of Aliquat 336 and 0.913 g of product from the previous stage. Leave to return to room temperature, add water, decant, wash with water.

Evaporated to dryness, taken up with 6 ml of a hydrobromic acid solution (32%). It is heated for 2 hours at 50 ° C. and allowed to return to room temperature. Extraction is carried out with methylene chloride. It is dried, filtered and evaporated to dryness. 0.316 g of sought product is obtained.

Stage C: 3- [4- [2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -3-oxo-3H-1,2,4-triazol-4-yl ] phenyl] -2 (E) - methyl propenoate.

By operating as above (Stage E preparation 1), the desired product was obtained.

Stage D: 2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -4- [4- (3-hydroxy-1 (E) -propenyl) hényl] -3H-1 , 2, 4-triazol-3-one.

By operating as above (Stage F preparation 1), the desired product was obtained. Stage E: 3- [4- [2,4-dihydro-2- ((1S, 2R) -2-hydroxy-1-methyl-propyl) -3-oxo-3H-1,2,4-triazol-4 -yl] phenyl] -2 (E) -propenal.

By operating as above (Stage G preparation 1), the desired product was obtained. PREPARATION 4: (E) -2- [3- (4-chlorophenyl) -2-propenyl] - 1,2,3,4-tetrahydro-6-isoquinolinol.

A mixture of 2 g of 1,2,3,4-tetrahydro-6-isoquinolinol and 2.5 g of (E) -1-chloro- 4- [3 -chloro-1 is stirred for 36 hours at 25 ° C. -propenyl] -benzene, 2 g of potassium carbonate and 50 ml of DMF. The DMF is removed under reduced pressure. The residue is taken up in a mixture of methylene chloride and water. Filtered and 2.5 g of sought product is obtained. Mp 233-234 ° C. PREPARATION 5: trans (±) -2- (4-chlorophenyl) -cyclopropane carboxaldehyde.

8.1 ml of triethylamine is added to a solution of ^'1/4 g of trans (±) -2- (4-chlorophenyl) -cyclopropane ethanol and 7 ml of DMSO. 3.2 g of a pyridine SO ₃ solution are added at a temperature less than or equal to 25 ° C. Stirring is continued and poured into a water-ice mixture. Extracted with ether. We dry and concentrate. Chromatography on silica eluting with hexane-ethyl acetate mixture 6-2. 76 mg of sought product is obtained. PREPARATION 6: Cis (±) 6- [[2- (2,4 dichlorophenyl) -2- (1H- imidazol-1-γlmethyl) -1,3-dioxolan-4-γl] -methoxy] -1,2, 3,4- tetrahydro-2- [3-tributγlstannyl) -2 (E) -propenyl] -isoquinoleine Stage A: 3- (tributylstannyl) -2 (E) -propen-1-ol

12 g of methyl 3- (tributylstannyl) -2 (E) -propenoate are dissolved in 100 ml of THF. Cool to -78 ° C, add 67 ml of dibutylaluminum hydride. The temperature is brought to 0 ° C., poured into methanol, added water and stirred overnight. The aluminum salts are filtered, washed with ethyl acetate, the organic phases are decanted, dried, concentrated. 9 g of product are obtained, which product is purified by chromatography, eluting with an 8/2 hexane ethyl acetate mixture. 7.25 g of the desired product are obtained. Stage B: (3 -bromo-1- (E) -propenyl) tributyl-stannane

A solution of 5.5 g of triphenylphosphine in 10 ml of methylene chloride is poured in dropwise over 30 minutes at 0 ° C. in a solution containing 5.2 g of the product obtained in stage A in 50 ml of methylene chloride and 6 g of carbon tetrabromide. We maintain a hour at 0 ° C. Poured onto water and extracted with methylene chloride, dried, chromatography on silica eluting with heptane and obtained 5.06 g of the desired product. Stage C: Cis (±) 6- [[2- (2,4 dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1, 3-dioxolan-4-yl] - ethoxy] -1, 2, 3, 4-tetrahydro- 2- [3-tributylstannyl) -2 (E) -propenyl] -isoquinoleine.

A solution of 5.06 g of product prepared above and 20 ml of acetone is poured in dropwise with stirring and under a nitrogen atmosphere, in a mixture comprising 5.68 g of Cis (±) 6- [[2- ( 2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-methyl] -methoxy] -1,2,3,4-tetrahydro-isoquinoline prepared according to the patent No. WO 0020413, 1.5 g of Ag ₂ 0, 100 ml of acetone and 50 ml of DMF. It is kept overnight at room temperature. Filtered, taken up in water, extracted with ethyl acetate, purified by chromatography on silica (eluent: methylene chloride, methanol (95-5). 6.66 g of sought product is obtained.

EXAMPLE 1: 2,4-dihydro-4- [4- [3- [6- [[(cis) -2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-γlmethyl) - 1, 3-dioxolan-4-yl] - methoxy] -1,2,3,4-tetrahydro-2-isoquinoleinyl] -1 (E) -propenyl] - phenyl] -2- (1-methylpropyl) -3H- 1, 2, 4-triazol-3-one.

A mixture of 0.325 g of product of preparation 2, 5 ml of methanol, 0.23 g of product of preparation 1 and 121 μl of acetic acid is stirred for 1 hour at room temperature. 0.067 g of NaBH ₃ CN is added. The mixture is stirred for 3 hours at room temperature. The residue is taken up in a mixture of methylene chloride and water. 0.4 ml of ammonia is added. Decanted, extracted with methylene chloride, dried, filtered and evaporated to dryness. 0.594 g of product is obtained which is chromatographed on silica eluting with a methylene chloride-isopropanol-ammonia mixture (94-6-0.3). 0.194 g of sought product is obtained. SM: M ⁺ H ⁺ = 715, 460, 256, 200.

EXAMPLE 2: 4- [4- [3- [6- [[(cis) -2- (2,4-dichloroρhenyl) -2- (1H- imidazol-1-ylmethyl) -1,3-dioxolan-4- γl] methoxy] -1,2,3,4- tetrahydro-2-isoquinoleinyl] -1 (E) -propenyl] phenyl] -2- ((1S, 2R) -2-hydroxy-1-methylpropyl) -3H- 1, 2, 4-triazol-3-one By operating as in Example 1, starting from the product of Preparation 3, the desired product was obtained. EXAMPLE 3: cis-2- [3- (4-chlorophenγl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl ) -1,3-dioxolan-4-yl] -methoxy] -1,2,3,4-tetrahydro-5-isoquinoline-amino. Stage A:

3 g of (E) -2- [3- (4-chlorophenyl) -2-propenyl] -1, 2, 3, 4-tetrahydro-6-isoquinolinol are suspended in 20 ml of ethanol. 4.12 g of hydrated ferric nitrate Fe (NO ₃ ) ₃ , 9H ₂ 0 are added and the mixture is heated at 40 ° C. overnight. The reaction is hydrolyzed with water and HCl 1.1N. The precipitate is filtered and the resulting aqueous phases are extracted with CH ₂ C1 ₂ . The precipitate and the dry extract are combined and chromatographed all on silica, eluting with the CH ₂ Cl ₂ -iPrOH mixture (95-5) to separate the 5 and 7 nitro isomers. 2.9 g of the product are obtained.

Stage B: cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl ) -1,3- dioxolan-4-yl] -methoxy] -5-nitro-1, 2,3, 4-tetrahydro-isoquinoleine

240 mg of product of stage A and 372.5 mg of toluenesulfonate of cis- (±) -2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) are heated at 80 ° C. for 8 hours. -methyl) -1, 3-dioxolan-4-methanol, 24 ml of methyl isobutyl ketone, 290 mg of potassium carbonate, 74.5 mg of Aliquat 336 and 240 ml of water. Let cool, filter and rinse. The filtrate is concentrated under reduced pressure and an oil is obtained which is purified on silica eluting with a methylene chloride-isopropanol mixture (94-6). 400 mg of the sought product is obtained. Stage C: cis-2- [3 - (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl ) -1,3- dioxolan-4-yl] -methoxy] -1, 2, 3, 4-tetrahydro-5-isoquinoline-amine.

Heated at 80 ° ~ 85 ° C for 8 hours a mixture of 4.51 g of product from the previous stage, 30 ml of ethanol, 33 g of FeS0 ₄ , 7H ₂ 0, 210 ml of water and 130 ml of concentrated ammonia at 20%. Filtered, rinsed with ethyl acetate, triturated the solid with ethyl acetate and with potassium acid carbonate and filtered. Decant and dry. 4.2 g of crude sought product are obtained which is chromatographed on silica eluting with a CH ₂ Cl ₂ -iPrOH-NH ₃ mixture (92-0.8-0.3) and 2.42 g of product are obtained research. MS: M ⁺ H ⁺ = 625. EXAMPLE 4: cis-7-chloro-2- [3- (4-chlorophenyl) -2 (E) - propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1, 3-dioxan-4-yl] -methoxy] -1,2,3,4-tetrahydro-isoquinoline.

328 mg of compound of the previous example (stage B) are introduced into a mixture of 3 ml of a 20% aqueous solution of TiCl ₃ and 5 ml of methanol. The mixture is stirred for 15 hours at room temperature, poured onto sodium hydrogen carbonate, the methanol is evaporated and extracted with methylene chloride. Chromatography on silica eluting with toluene-isopropanol (92-8) at 0.1% ammonia. 117 mg of sought product are isolated. MS: M ⁺ H ⁺ = 659 (4 Cl).

EXAMPLE 5: cis-1- [2- [3- (4-chlorophenγl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-γl -methyl) -1, 3-dioxolan-4-yl] -methoxy] -1,2,3,4-tetrahydro-isoquinolinyl] -2-pyrrolidinone.

Stirred at room temperature for 24 hours, a mixture of 125 mg of product from Example 3, 1 ml of methylene chloride, 40 mg of ClCO (CH ₂ ) ₃ Br and 30 mg of DMAP in 1 ml of methylene chloride. Poured onto a mixture of potassium acid carbonate and ethyl acetate. 160 mg of crude product are obtained, after chromatography, 80 mg of sought product is obtained. MS: M ⁺ H ⁺ ≈ 694. EXAMPLE 6: cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H -imidazol-1-yl-methyl) -1, 3-dioxolan-

4-yl] -methoxy] -1,2,3,4-tetrahydro-7-isoquinolineamine. Stage A: cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1, 3-dioxolan- 4-yl] -methoxy] -7-nitro-1, 2,3, 4-tetrahydro-isoquinoleine. By operating as in Example 3, the desired product is obtained. Rf = 0.35 (CH ₂ C1 ₂ -isopropanol 95-5). Stage B: cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1, 3-dioxolan- 4-yl] -methoxy] -1, 2, 3, 4-tetrahydro-7-isoquinolineamine.

By operating as in Example 3 from the product of the previous stage, the desired product was obtained.

EXAMPLE 7: cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6,7-bis- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1- yl-methγl) -1, 3-dioxolan-4-yl] -methoxy] -1,2,3,4-tee rahydro-isoquinoline. By operating as above from 1,2,3,4-tetrahydroisoquinoléoine 6,7-diol, we obtain (E) -2- [3- (4-chlorophenyl) -2-propenyl] -1,2, 3, 4-tetrahydro-5, 6-iso-quinoline-diol which is condensed with toluenesulfonate of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) - 1,3-dioxolan-4-methanol to obtain the desired product.

Rf = 0.37 (CH ₂ Cl ₂ -methanol 9-1).

EXAMPLE 8: cis-2- [2-trans- (4-chlorophenγl) -cyclopropyl] - methyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl] -methoxy] -1,2,3,4-tetrahydroisoquinoline.

A mixture of 76.5 mg of product of preparation 5, 175 mg of product of preparation 2, 76 ml of acetic acid, 3 ml of methanol is stirred for 15 minutes at room temperature. 27 mg of sodium cyanoborohydride are added

(NaBH ₃ CN). The mixture is stirred for 15 hours. The pH is brought to 8.9 with ammonia, extracted with methylene chloride, washed with water, dried and concentrated. A product is obtained which is chromatographed on silica eluting with a hexane-ethyl acetate mixture (8-2). Concentrate and obtain 123 mg of the desired product.

MS: M ⁺ H ⁺ = 624, 460, 165.

EXAMPLE 9: cis-2- [3- [4- [(2-methoxyethoxy) methoxy] phenyl] - 2 (E) -propenyl] -6- [[2- (2,4-dichlorophenyl) -2 (1H- imidazol-1-yl-methyl) -1,3-dioxolan-4-yl] -methoxy] -1,2,3,4-tetrahydro-isoquinoline.

Adjusted to pH = 6 by adding 250 ml of acetic acid, a solution comprising 2.3 g of product obtained as in preparation 2 and 1.3 g of 3- [4- [(2-methoxyethoxy) methoxy] hényl] -2 (E) -propenal in 40 ml of methanol. Then added 930 mg of sodium cyanoborohydride and stirred

16 hours at room temperature. Concentrate under pressure reduced, taken up in sodium acetate, washed with an aqueous solution of sodium hydroxide then with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness under reduced pressure. 4.1 g of product are collected which is chromatographed on silica (eluent CH ₂ Cl ₂ / MeOH 93-7) and 2.52 g of expected product is obtained. rf = 0.30 (CH ₂ Cl ₂ / MeOH 93-7). EXAMPLE 10: cis-4- [3- [6- [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxan-4-yl] - methoxy] -1,2,3,4- tetrahydro-2-isoquinolinyl] -1 (E) -propenyl] -phenol.

2 g of the product obtained in Example 9 are cooled to 0 ° C. in 20 ml of methylene chloride and 20 ml of trifluoroacetic acid are added. It is kept stirring for 30 min at 0 ° C. and then 30 min at room temperature. It is concentrated to dryness under reduced pressure, the residue is taken up in methylene chloride, 20 ml of water are added, the mixture is cooled to 0 ° C., concentrated ammonia is added to pH = 10, extracted with methylene chloride, washed with water, dry, remove the solvents under reduced pressure and collect 1.81 g of the expected product used as it is for the next stage, rf = 0.40 (CH ₂ Cl ₂ / Methanol 90-10). NMR (CDC1 ₃ ): 2.81 (m) 2H: CH ₂ in 10; 2.89 (m) 2H: CH ₂ at 9; 3.25 (dd) 3.68 (dd) 2H - 3.74 (dd) 3.86 (dd) 2H: OCH ₂ -CH-CH ₂ -0; 4.36 (m) 1H: OCH ₂ -CH-CH ₂ -O; 4.41 4.52 AB 2H: N-CH ₂ -Cq; 3.31 (dl) 2H: N-CH ₂ -CH = CH-Φ; 6.10 (td) 1H: N-CH ₂ -CH = CH-Φ J = β, 5 16HZ; 6.48 (dl) 1H: N-CH ₂ -CH = CH-Φ J = 16HZ; 3.65 (si) 2H: CH ₂ in 2; 6.54 (d) 1H: H7; 6.60 (dd) 1H: H5; 6.90 (d) 1H: H4; 6.79-7.12 AA'BB 'O-Φ; 7.47 (d) 1H: Ha; 7.27

(mask): Hb; 7.61 (d) 1H: Hc; 7.58 (s) 1H: H2 '; 7.00 (d) 1H: H4 'and H5'.

EXAMPLE 11 Mono [cis-4- [3- [6- [[2- (2,4-dichloro phenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxan phosphate 4-yl] - methoxy] -1,2,3,4-tetrahydro-2-isoquinolinyl] -1 (E) -propenyl] - phenyl] and bis (phenylmethyl).

A solution comprising 592 mg of product obtained in Example 10 in 20 ml of chloride is cooled to 0 ° C. methylene then add 960 μl of carbon tetrachloride, 24 mg of dimethylaminopyridine and 732 μl of diisopropyl ethylamine then drop by drop 628 μl of dibenzylphosphite. Maintained for 3 hours with stirring at 0 ° C. and added 20 ml of a molar solution of sodium hydrogenophosphate, allowed to return to room temperature, extracted with methylene chloride, washed with an aqueous solution of sodium chloride and removes the solvents under reduced pressure. 725 mg of crude product is obtained which is purified by chromatography on silica (eluent CH ₂ Cl ₂ / MeOH 93-7) and 360 mg of expected pure product is collected, rf = 0.35 (CH ₂ Cl ₂ / MeOH 93-7).

EXAMPLE 12 [cis-4- [3- [6- [[2- (2,4-dichloro phenyl) -2- (1H-imidazol-1-yl-methγl) -1,3-dioxan-4 phosphate] -yl] - methoxy] -1,2, 3, 4-tetrahydro-2-isoquinolinyl] -1 (E) -propenyl] - phenyl] (trifluoroaceous salt ate).

Agitation is carried out for 5 hours at room temperature 360 mg of product obtained in Example 11 in 5 ml of methylene chloride and 5 ml of trifluroacetic acid. The solvents are removed under reduced pressure and 352 mg of crude product is recovered which is purified by chromatography on silica (eluent CH ₃ CN / CH ₂ C1 ₂ / TFA 40-60-0.03) and after lyophilization 118 mg of expected product and 26 mg of the monobenzylated phosphate intermediate of mono [cis-4- [3- [6- [[2- (2,4-dichloro phenyl) -2- (1H-imidazol-1-yl-methyl) -1, 3-dioxan-4-yl] -

^• methoxy] -1,2,3,4-tetrahydro-2-isoquinolinyl] -1 (E) -propenyl] - phenyl] and mono (phenylmethyl) (trifluoroacetate salt) • expected product rf = 3.70 (CH ₃ CN / H ₂ 0-TFA 40-60-0.03) • monobenzylated product rf = 5.08 (CH ₃ CN / H ₂ O 40-60) NMR (DMSO) of the expected product.

3.10 (t) 3.46 (masked): N-CH ₂ -CH ₂ -CH-CH-CH ₂ ; 4.66 (s): N-CH ₂ -CH ₂ -CH-CH- CH ₂ : 3.96 (m) CH ₂ -CH = CH-: ΔE; 6.30 (dt): CH ₂ -CH = CH-; 6.85 (d, J = 16): CH ₂ -CH = CH-; 3.72 (m) 3.94 (m): 0-CH ₂ -CH-CH ₂ -0; 4.38 (m): 0-CH ₂ -CH-CH ₂ -O; 3.75 (m) 3.84 (m): 0-CH ₂ -CH-CH ₂ -0; 7.45 (dd) 7.61 (d) 7.64 (d): dichlorophenyl; 7.12 (si) 7.23 (si) 8.10 (si): CH imidazole; 4.29 (s): N-CH ₂ ; 6.79 (dd) 6.82 (d) 7.14 (d) and 7.20 7.46: CH of the phenyl rings.

EXAMPLE 13 Mono [cis-4- [3- [6- [[2- (2,4-dichloro phenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxan sulfonate) 4-yl] - methoxy] -1,2,3,4-tetrahydro-2-isoquinolinyl] -1 (E) -propenyl] - phenyl] (salt of N, N-diethylethanamine).

236 mg of product obtained as in Example 10 in 4 ml of dimethylformamide in the presence of 1 ml of pyridine and 1.5 g of N, N-dimethylformamide trioxide sulfide are stirred for 16 hours at room temperature. 20 ml of ether are then added, the supernatant phase is eliminated and 20 ml of ether are added again. Stirred for a few minutes, the precipitate is drained and 680 mg of crude product is recovered, which is purified by 2 chromatographies on silica (eluent CH ₂ Cl ₂ / MeOH / TEA 87-13-1). 239 mg of expected product is obtained rf = 0.40 (CH ₂ Cl ₂ / MeOH / TEA 87-13-1). NMR: (CDC1 ₃ )

1.27 (t): N- (CH ₂ ÇH ₃ ) 3; 2.98 (q): N- (CH ₂ CH ₃ ) ₃ ; 3.31 (dl) 2H: N-CH ₂ CH = CH-Φ; 6.26 (td) 1H: N-CH ₂ -CH = CH-Φ J = 16 6.5 HZ; 6.56 (dd) 1H: N-CH ₂ -CH = CH-Φ J = lβ HZ ΔE; 3.32 (m) 3.72 (dd) 2H - 3.75 (dd) 3.88 (dd) 2H: 0-CH ₂ -CH-CH ₂ -0; 4.35 (m) 1H: O-CH ₂ -CH-CH ₂ -O; 4.40 4.51 AB 2H: N-CH ₂ -Cq; 3.60 (si) 2H: CH ₂ in 2; 7.25 (dd) 1H: Hb; 7.46 (d) 1H: Ha; 7.50 (si) 1H: H ₂ '; 7.57 (d) 1H: Hc; 6.61 (dd) 1H: H ₅ ; 6.57 (si) 1H: H ₇ ; 6.97 (dl) 2H: H ₄ 'and H ₅ '; 6.92 (d) 1H: H ₄ ; 7.34 (m) 4H: Φ 2.77 (tl) 2H: CH ₂ in 9; 2.91 (tl) 2H: CH ₂ in 10.

By operating as above, the following products were prepared:

10

By operating as above, the following products were prepared:

R4A taking for example the value

We also prepared the products corresponding to the formula

Pharmaceutical compositions

Compounds containing

Product of Example 1 50 mg

Excipient q.s.p. 1 g

Details of the excipient: starch, talc, magnesium stearate. Biological activity

Antifungal activity of the product of Example 1 or product P. Female mice weighing 18 to 22 g are used. We give them administers a quantity of Candida Albicans 44858 into the tail vein at the rate of 10 ⁶ CFU per mouse (CFU: colony-forming unit). The mice are separated into 5 batches of 5 mice and they are treated as follows: One hour after infection

- group 1: the mice are treated with the product P 25 mg / kg orally group 2: the mice are treated with the product P intraperitoneally at a rate of 25 mg / kg - group 3: the mice are treated with the fluconazole ( 25mg / kg orally).

- group 4: the mice are treated with fluconazole (25 mg / kg intraperitoneally). group 5: the mice do not receive any antifungal treatment.

During a period of 22 days, dead mice are counted. Conclusion

The product at the dose used in the 2 modes of administration used has excellent activity.

Furthermore, the test was carried out with an administration ^' ' under order than those obtained with fluconazole.

The same treatments are also effective in the "topical model" with the dermal fungis, for example trichophyton and in the sublethal model. Minimum inhibitory concentration (MIC)

Candida albicans cells are prepared as indicated in the Journal of Antimicrobial chemotherapy 38, 579-587, washed 3 times with 0.1 M phosphate solution and used immediately to determine the minimum inhibitory concentration (MIC).

The MICs are determined by the modification of a microtiter plate according to the standard method of the National Committee for clinical laboratory standards. RPMI-1640 is used as medium, and L-glutamine buffered to pH7 with a 0.15 M solution of MOPS (3- [N-morpholino] propane sulfonic acid). Candida albicans cells (1.5 X 10 ³ cells / ml) are added to the wells of a 96-well plate containing RPMI-1640 and dilutions of antifungal agents. The results are read 48 hours after incubation at 35 ° C. and the MIC or minimum inhibitory concentration which inhibits the growth of Candida albicans cells is determined. Minimum fungicide concentration

After the MICs are read at 48 hours, the plates are shaken and 10 μL of aliquot are removed from the wells which are placed on rectangular disks containing dextrose agar. The plates are incubated for 48 hours at 35 ° C; The minimum fungicidal concentration and the concentration of the antifungal agent at which the number of colony forming units is zero.

Claims

claims

1) In all the possible stereoisomeric forms, as well as their mixtures, the compounds of formula (I):

wherein . p represents the number 1 or 2,

X, Xi and X _2, identical or different, represent a nitrogen atom or a CH≈ radical,

Ri, R ₂ , R3, R5 and R ₆ identical or different from each other in any position on the rings carrying them, represent a hydrogen atom, a halogen atom, an alkyl radical, O- alkyl, S (0) _n -alkyl, alkenyl, O-alkenyl, S (0) _n -alkenyl, alkynyl, O-alkynyl, S (0) _n -alkynyl containing up to 8 carbon atoms, optionally substituted by a or several halogen atoms, n representing the number 0, 1 or 2, or represent a radical N0 ₂ , NH ₂ or C≡N, R _lf R ₂ R3 on the one hand and R ₅ and R _e on the other hand being able to form cycles two by two, R ₇ represents a hydrogen atom or an OH radical, . R ₄ A represents a radical R _{4 which} can take one of the values indicated above for R _x , R ₂ , R ₃ , R5 or R ₆ , and which can also represent an unsubstituted or substituted heterocycle, an aryl or O group -aryl containing up to 14 unsubstituted or substituted carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms unsubstituted or substituted by an aryl optionally substituted by one or more halogen atoms and which may also represent an oxygen chain or nitrogen connected to the nucleus phenyl or heteroaryl by an oxygen or nitrogen atom,

A and B, which are identical or different from each other, represent a hydrogen atom or an oxygen or nitrogen chain linked to the phenyl ring by an oxygen or nitrogen atom,

in which the various substituents retain their previous meaning, as well as their addition salts with acids.

2) The compounds of general formula (I) defined in claim 1, corresponding to the formula:

in which X, Xi and X ₂ identical or different represent a nitrogen atom or a radical -CH-, Ri, R, R ₃ , R ₅ , R ₆ , R identical or different being in any position on the rings which carry. 3) The compounds of formula (I) defined in claim 1 or 2, in which X, Xi and X ₂ represent a radical -CH =. 4) The compounds of formula (I) defined in claim 1, 2 or 3, in which X represents a CH = radical and either X _x or X ₂ represents a nitrogen atom. 5) The compounds of formula (I) defined in any one of claims 1 to 4, in which Ri and R ₂ represent a halogen atom.

6) The compounds of formula (I) defined in one of claims 1 to 4, in which R ₄ is a halogen atom. 7) The compounds of formula (I) defined in claim 5 or 6, in which the halogen is a chlorine atom. 8) The compounds of formula (I) defined in any one of claims 1 to 5, in which R ₃ represents a hydrogen atom. 9) The compounds of formula (I) defined in any one of claims 1 to 8, in which C and D form a double bond.

10) The compounds of formula (I) defined in claim 9, in which the geometry of the double bond is E. 11) The compounds of formula (I) defined in any one of claims 1 to 10, in which the dioxoxaryl radical is in the cis position.

12) The compounds of formula (I) defined in any one of claims 1 to 8 in which R ₇ represents an OH, OSO3H or OPO (OH) ₂ radical.

13) The compounds of formula (I) defined in any one of claims 1 to 12, in which A or B does not represent a hydrogen atom.

14) The compounds of formula (I) defined in claim 13, in which A or B represents a radical

W (CO) _r (CH ₂ ) _s Z in which r represents the number 0 or 1, s represents an integer varying from 0 to 6, W represents an oxygen atom or a radical -N (Rn) -, Ru representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, Ru can also form a ring with the nitrogen atom which carries it and another atom in the chain (CO) _r (CH ₂ ) _S -Z, Z represents a hydrogen atom , a radical S0 ₃ H or OS0 ₃ H, PO (OH) ₂ or OPO (OH) ₂ , or C0 ₂ H as well as the alkali, alkaline earth or amine salts of these radicals, or a radical

R ₈ and R ₉ representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, R _i0 representing an alkyl radical containing up to 8 carbon atoms, R ₈ and Rg may form a ring optionally containing a other heteroato e, and being optionally substituted, or else Z represents an optionally substituted heterocyclic radical.

15) The compounds of formula (I) defined in claim 14, in which W represents a nitrogen atom.

16) The compounds of formula (I) defined in claim 1 whose names follow:

- cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6 - [[2- (2,4- dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) - 1, 3-dioxolan-4- yl] -methoxy] -1, 2, 3, 4-tetrahydro-5-isoquinolineamine,

- cis-2- [3- (4-chlorophenyl) -2 (E) -propenyl] -6 - [[2- (2,4- dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1 , 3-dioxolan-4- yl] -methoxy] -1, 2, 3, 4-tetrahydro-7-isoquinolineamine,

- cis-4- [3- [6- [[2- (2, -dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1, 3-dioxan-4-yl] -methoxy] - 1,2,3,4-tetrahydro-2- isoquinoline] -1 (E) -propenyl] -phenol, - [cis-4- [3- [6- [[2- (2,4-dichloro phenyl) phosphate phosphate ) -2- (1H- imidazol-1-yl-methyl) -1, 3-dioxan-4-yl] -methoxy] -1,2,3,4- tetrahydro-2-isoquinolinyl] -1 (E) - propenyl] -phenyl] (trifluoroacetate salt, - mono [cis-4- [3- [6- [[2- (2,4-dichloro phenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxan-4- sulfonate yl] -methoxy] -1,2,3,4- 2-tetrahydro-isoquinolinyl] -1 (E) -propenyl] -phenyl] (salt of N, N-diethylethanamine).

17) As medicaments, the compounds of formula (I) defined in any one of claims 1 to 16, as well as their pharmaceutically acceptable addition salts.

18) The pharmaceutical compositions containing as active principle at least one medicament according to claim 17.

19) Process for preparing the compounds of formula (I) according to any one of claims 1 to 16, characterized in that a compound of formula (II) is subjected:

in which :

in which the various substituents retain their previous meaning, in order to obtain the corresponding compound of formula (I), which is subjected if desired to the action of a reducing, substitution, addition or action agent of an acid to obtain the desired compound. 20) As new chemicals, the compounds of formula (III) defined in claim 19. 21) Process for the preparation of the compounds of formula (I) defined in claim 1, characterized in that one submits a compound of formula (IV)

in which Hal represents a halogen atom and the other substituents retain their previous meaning to obtain the corresponding compound of formula (I), which is subjected if desired to the action of a substitution reducing agent, addition or action of an acid to obtain the desired compound.

22) Process for the compounds of formula (I) defined in claim 1, characterized in that a compound of formula (VI) is subjected:

in which the substituents retain the same value as in claim 1, to the action of a compound of formula (VII):

wherein the substituents retain the same value as in claim 1, then to the action of a reducing agent to obtain the corresponding compound of formula (I) which is subjected if desired to the action of a reduction of substitution, addition or action of an acid to obtain the desired compound.

23) As new chemicals, the compounds of formula (IV) defined in claim 21.

24) As new chemicals, the compounds of formula (VI) defined in claim 22.