FR2924343A1 - NOVEL THERAPEUTIC USES OF DUAL MOLECULES CONTAINING A PEROXYDIC DERIVATIVE. - Google Patents

Abstract

The invention relates to the use of dual molecules responding to the farmule (I): for the treatment or prevention of bilharziasis or schistozomiasis.

Description

NEW THERAPEUTIC USES OF DUAL MOLECULES CONTAINING A PEROXYDIC DERIVATIVE

The invention relates to the new therapeutic use for the treatment of bilharziasis or schistosomiasis of hybrid molecules containing a peroxidic derivative. Such molecules have in particular been described in patent applications WO 01/77105, WO 05/049619 and FR 06/05235 (filed by PALUMED, SANOFI-AVENTIS and CNRS on June 13, 2006). Their antimalarial activity is described, however, their anti-schistosome properties are neither described nor suggested. Schistosomiasis or bilharzia is a chronic disease that is caused by a parasite of the genus Schistosoma, identified by the parasitologist Théodore Bilharz in 1852). A recent WHO report estimates that in the world this disease affects 200 million people and 600 million people live in endemic areas. Schistosomiasis is associated with malfunctions in the kidney and bladder (S. haematobium), or liver and intestinal diseases (S. mansoni, S. japonicum, S. mekongi and S. intercalatum). Since 2005, Praziquantel (Biltricide) has been the first-line treatment for schistozomiasis, a human indication for which it is usually effective in a single dose. This drug is well tolerated and effective on all 5 pathogenic species. However, some cases of parasite resistance to this drug have already been described which makes it necessary to develop 25 new innovative therapeutics to fight against this disease. Unexpectedly, the present inventors have now discovered the anti-schistosome properties of the molecules described in patent applications WO 01/77105, WO 05/049619 and FR 06/05235.

The invention therefore relates to the use of the compounds of formula (I) as defined below for the treatment or prevention of schistozomiases. Said compounds correspond to the formula (I): R ~ R5 Z (I) in which: - A represents: • a residue of molecule chosen from: an aminoquinoline of formula (IIa): ## STR2 ##

(II a) wherein: R and R ', which are identical or different, each represent one or more substituents (for example 1 to 5) occupying distinct positions on the rings to which they are attached, chosen from: a hydrogen or halogen atom, a -OH, -CF3, -OCF3, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl group, said alkyl groups comprising from 1 to 5 carbon atoms, . a cycloalkyl or io-cycloalkyl group, said cycloalkyl groups possibly containing from 3 to 5 carbon atoms, -NO2 or -N (Ra, Rb), wherein Ra and Rb, identical or different, each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; or Ra and Rb, which may be identical or different, represent a cycloalkyl group which may contain from 3 to 5 carbon atoms, or else Ra and Rb together with the nitrogen atom to which it is attached form a pyrrolidinyl or piperidinyl group; R 4 represents a hydrogen atom or an alkyl group which may be in the range of from 1 to 5 carbon atoms or R 4 represents a hydrogen atom or an alkyl group which may be in the range of from 1 to 5 carbon atoms; cycloalkyl group may contain from 3 to 5 carbon atoms, - B1 represents a nitrogen atom and B2 represents a -CH = link, or B1 represents a -CH = link and B2 represents a nitrogen atom. . a group of formula (IIIa): R6-CHOH- (IIIa) in which R6 represents an aryl radical, preferably a 9-phenanthrenyl or a nitrogenous heterocyclic residue, preferably a 4-quinolinyl optionally substituted with one or more (for example from 1 to 5) R groups as defined for the compound of formula (IIa); Or A represents a residue facilitating the bioavailability, the latter having one or more heteroatoms chosen from N, O and S in a mono- or polycyclic molecule which may contain from 6 to 18 carbon atoms, saturated or unsaturated or in a chain which may have from 1 to 18 optionally substituted linear carbon atoms, such as a guanidinium, morpholino, peptide or polyamine residue;

B represents a cycloalkyl group which may contain from 3 to 8 carbon atoms, optionally substituted by one or more groups chosen from: a halogen atom, a hydroxyl group, an alkyl group which may comprise from 1 to 6 carbon atoms, or a cycloalkyl group may contain from 3 to 6 carbon atoms, + or B represents a bicyclic or tricyclic group may contain from 4 to 18 carbon atoms, optionally substituted with one or more groups selected from a halogen atom, a hydroxyl group, an alkyl group may contain from 1 to 6 carbon atoms or a cycloalkyl group may contain from 3 to 6 carbon atoms, or • B represents 2 cycloalkyl groups may contain from 3 to 6 carbon atoms, said cycloalkyl being interconnected by a single bond or an alkylene chain which may have 1 or 2 carbon atoms; Or B represents a linear or branched C1-C5 alkylene chain; Or B represents a chain -CH2-CH2-O-CH2-CH2-; m and n independently represent 0, 1 or 2;

R5 represents a hydrogen atom or an alkyl group, a C (O) alkyl group or a C (O) O-alkyl group, said alkyl groups may contain from 1 to 5 carbon atoms, or R5 is cycloalkyl, C (O) -cycloalkyl, C (O) O-cycloalkyl or C 1-3 alkylene-cycloalkyl, said cycloalkyl groups may have from 3 to 6 carbon atoms;

Z1 and Z2, which may be identical or different, represent an alkylene radical which may contain from 1 to 4 saturated or unsaturated carbon atoms, the Z1 + Z2 + U + Cj combination thus representing: • either a cycloalkyl group optionally comprising a carbon atom; nitrogen may comprise from 3 to 10 atoms, or a polycyclic hydrocarbon structure optionally comprising a nitrogen atom, which may comprise from 4 to 18 atoms, one of Z1 or Z2 may represent a single bond between the atoms U and Cj, it being understood that Z1 and Z2 can not represent a single bond at the same time; R1 and R2, which may be identical or different, represent a hydrogen atom or a functional group capable of increasing the water solubility;

Rx and Ry together form a cyclic peroxide comprising from 4 to 8 members and having 1 or 2 additional oxygen atoms in the ring structure (ie a total of 3 to 4 oxygen atoms in the ring), Cj being one of the vertices of this cyclic peroxide, said cyclic peroxide being substituted by a group R 3, R 3 representing from 1 to 8 groups identical or different from each other, occupying any positions on the carbon atoms of the peroxide ring and being chosen among the following atoms and groups:. hydrogen, halogen, -OH, -CF3, -NO2, -OCF3, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 10 carbon atoms, a cycloalkyl group may contain from 3 to 7 carbon atoms and may further contain from 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, optionally substituted with one or more groups (for example 1 to 8) selected among a halogen atom, a hydroxyl group, an alkyl group which may contain from 1 to 8 carbon atoms or a cycloalkyl group which may contain from 3 to 8 carbon atoms, an O-cycloalkyl group which may have from 3 to 7 carbon atoms, a bicyclic or tricyclic group which may contain from 4 to 18 carbon atoms and may also contain from 1 to 6 heteroatoms chosen from oxygen, nitrogen and sulfur, optionally substituted by one or more groups selected from a hydrogen atom; halogen, a hydroxyl group, an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms; . or two R3 groups carried by adjacent carbon atoms on the peroxide ring which can together form a cycloalkyl group having 5 or 6 carbon atoms, saturated or unsaturated, said R3 group may itself be substituted with 1 to 6 substituents R3 such as defined above,. or else two R3 groups carried by the same carbon atom of the peroxidic ring which can together form a cycloalkyl group which may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group which may contain from 4 to 18 carbon atoms (which will therefore be located in the spiro position on the peroxide cycle);

U represents a group ûC; H <or ûN <; C; and Cj each represents a carbon atom; p is 0 or 1; with the proviso that when p = 1, U represents ûCH <, and when p = O, U is bonded to û (CH2) ä-by a simple bond to the base state or an acid addition salt, the state of hydrate or solvate, in racemic form, isomers and mixtures thereof, as well as their diastereoisomers and mixtures thereof.

Advantageously, the residue A drains inside the parasite the compound of formula (I) according to the invention. The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are also part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids which are useful for the purification or the isolation of the compounds of formula (I) also form part of the invention.

The compounds according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

The invention relates to mixtures in all proportions of diastereoisomers, as well as the pure diastereoisomers of formula (I). The invention also relates to the racemic mixtures, as well as the optically pure isomers of the molecules of formula (I), and further mixtures in all proportions of said optically pure isomers. The invention is also directed to achiral molecules.

In the definition of the compounds of formula (I) above and in the following, unless otherwise stated in the text, the following meanings: halogen atom: a fluorine, chlorine, bromine or iodine atom; alkyl group: a saturated monovalent aliphatic group, linear or branched.

By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups; radical or alkylene chain: a divalent saturated, linear or branched aliphatic group. By way of example, a C1 -3-alkylene group represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, such as a methylenyl (-CH 2 -), an ethylenyl (-CH 2 CH 2 -), a 1-methylethylenyl ( -CH (CH 3) CH 2 -), a propylenyl (-CH 2 CH 2 CH 2 -); cycloalkyl group: a saturated cyclic aliphatic group. By way of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups; a bicyclic structure: a structure comprising 2 saturated cyclic aliphatic groups comprising from 4 to 18 carbon atoms, said groups possibly being: merged, that is, they have a common link between them. By way of example, mention may be made of the perhydronaphthyl group: or bridged, that is to say that at least 2 atoms of the bicyclic structure are connected by a single bond or a carbon chain which can have 1 to 4 carbon atoms. By way of example, mention may be made of bicyclo [3.2.1] octyl or spiro junction, that is to say that they are connected by a common carbon atom. By way of example, mention may be made of the cyclopentane-spiro-cyclobutyl group: a tricyclic structure: a structure comprising 3 saturated cyclic aliphatic groups comprising from 4 to 18 carbon atoms, said groups being able to be fused (as defined previously ) or bridged (as defined above).

As an example of a fused tricyclic structure, mention may be made of the perhydroanthracene group: By way of example of a tricyclic bridged structure, mention may be made of the adamantyl group which is a tricyclic structure comprising 10 carbon atoms: a polycyclic structure a bi- or tricyclic structure as defined above; a cyclic peroxide group: a cyclic alkyl group comprising 2 adjacent oxygen atoms; an aryl group: a monocyclic or polycyclic aromatic system comprising from 6 to 18 carbon atoms, preferably from 6 to 14 carbon atoms and preferably from 6 to 10 carbon atoms. When the system is polycyclic, at least one of the rings is aromatic. By way of examples, mention may be made of phenyl, naphthyl, tetrahydronaphthyl and indanyl groups; a heteroaryl group: monocyclic or polycyclic aromatic system comprising from 5 to 18 ring members, preferably from 5 to 14 ring members and preferably from 5 to 10 ring members and comprising one or more heteroatoms such as nitrogen, oxygen or of sulfur. When the system is polycyclic, at least one of the rings is aromatic. Nitrogen atoms can be in the form of N-oxides. By way of examples of monocyclic heteroaryl groups, mention may be made of thiazolyl, thiadiazolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl and pyridazinyl groups. By way of examples of bicyclic heteroaryl groups, mention may be made of indolyl, benzofuranyl, chromen-2-one-yl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, indolizinyl, quinazolinyl and phthalazinyl groups. quinoxalinyl, naphthyridinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl; 30 - residue facilitating the bioavailability a cycloalkyl group may contain from 6 to 8 saturated or unsaturated carbon atoms, said cycloalkyl group containing one or more heteroatoms selected from N, O and S,. a bicyclic or tricyclic group which may contain from 6 to 18 carbon atoms, saturated or unsaturated, said two or tricyclic groups containing one or more heteroatoms chosen from N, O and S, a carbon chain possibly comprising from 1 to 18 carbon atoms, optionally substituted linear, said chain comprising one or more heteroatoms chosen from N, O and S.

As examples of residues facilitating bioavailability, mention may be made of guanidinium, morpholino, peptide or polyamine residues; functional group capable of increasing the water solubility of the dual molecule: a group advantageously chosen from -COOH, -OH or -N (Ra, Rb) with Ra and Rb, which may be identical or different, representing a hydrogen atom, a alkyl group may contain from 1 to 5 carbon atoms or a cycloalkyl group may contain from 3 to 5 carbon atoms.

Among the compounds that are the subject of the invention, there may be mentioned a first group of compounds of formula (I) in which A, B, m, n, Z1, Z2, the set Z1 + Z2 + U + Cj, R1, R2 , Rx, Ry are as defined above, p = 1 and R5 represents a hydrogen atom or an alkyl group, a C (O) -alkyl group or a C (O) O-alkyl group, said alkyl groups being have from 1 to 5 carbon atoms, or R5 represents a cycloalkyl group, a C (O) -cycloalkyl group or a C (O) O-cycloalkyl group, said cycloalkyl groups may contain from 3 to 6 carbon atoms.

Among the compounds that are the subject of the invention, there may be mentioned a second group of compounds of formula (I) in which A represents an aminoquinoline derivative, preferably chosen from the groups of formula (IIb) or (IIc): R (IIb) (IIc) in which: R and R ', which are identical or different, each represent one or more substituents (for example 1 to 5) occupying distinct positions on the rings to which they are attached, chosen from: a hydrogen or halogen atom, a -OH, -CF3, -OCF3, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl group, said alkyl groups comprising from 1 to 5 carbon atoms, a cycloalkyl or io-cycloalkyl group, said cycloalkyl groups possibly having from 3 to 5 carbon atoms, -NO2 or -N (Ra, Rb), where Ra and Rb, which may be identical or different, represent hydrogen atoms or alkyl group having 1 to 5 carbon atoms; or Ra and Rb, which may be identical or different, represent a cycloalkyl group which may contain from 3 to 5 carbon atoms, or else Ra and Rb together with the nitrogen atom to which it is attached form a pyrrolidinyl or piperidinyl group; R 4 represents a hydrogen atom, an alkyl group possibly containing from 1 to 5 carbon atoms, or R 4 represents a cycloalkyl group which may contain from 3 to 5 carbon atoms, - B represents a nitrogen atom and B2 represents a -CH = chain, or BI represents a -CH = chain and B2 represents a nitrogen atom.

Among the compounds of the invention, there may be mentioned a third group of compounds of formula (I) in which B represents a group chosen from: cis-1,2-methylenecyclopentyl, trans-1,2-cyclohexyl, cis-1 , 2-cyclohexyl, cis-1,2-methylenecyclohexyl, trans-1,4-cyclohexyl, cis-1,4-cyclohexyl, cis / trans-1,4-cyclohexyl mixture, cis / 1,3-cyclohexyl mixture cis-1,3-notchymethylenecyclohexyl, cis-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane. Among the compounds that are the subject of the invention, there may be mentioned a fourth group of compounds of formula (I) in which A represents a nitrogenous heterocycle of aminoquinoline type of formula (IIa), p = 1 and which corresponds to formula (1.1) which follows: wherein R, R ', BI, B2 and R4 are as defined for the compound of the formula (R1, R4, (CH2) m, N-B- (CH2), 1a) and B, Z1, Z2, C4, C1, R1, R2, Rx, Ry, R5, m and n are as defined for the compound of formula (I). In the compounds of formula (1), R 1 and R 4 together form a cyclic peroxide comprising from 4 to 8 members and having 3 or 4 oxygen atoms, C 1 being one of the members of this cyclic peroxide, said cyclic peroxide being substituted with a group R 3, R 3 representing from 1 to 8 groups identical or different from each other, occupying any positions on the carbon atoms of the peroxide ring. Such peroxidic rings may in particular consist of: trioxanes of formula (XI) ## STR3 ## in which R 3 represents 1 to 4 groups, which may be identical or different, as defined for the compound of formula (I) ) or - trioxepanes of formula (XII):

Wherein R3 represents 1 to 6 groups, identical or different, as defined for the compound of formula (I), or trioxecanes of formula (XIII): P R3 Cj LOGO ( X111) in which R3 represents 1 or 8 groups, identical or different, as defined for the compound of formula (I). In the formulas (XI), (XII) and (X111), the carbon Cj is as defined for the compounds of formula (1), that is to say that Cj corresponds to the carbon of junction between the cyclic peroxide and the ring formed with carbon Cj and radicals Zi and Z2. In formula (XI), R 3 advantageously represents 1 to 4 groups chosen from hydrogen atoms and alkyl groups which may contain from 1 to 10 carbon atoms, or two groups R 3 carried by the same carbon atom of the peroxide cycle. together form a cycloalkyl group which may contain

3 to 7 carbon atoms or a bicyclic or tricyclic group which may have from 5 to 18 carbon atoms. Among the compounds which are the subject of the invention, there may also be mentioned a fifth group of compounds which correspond to the following formula (I.2): ## STR2 ## where ## STR2 ## Wherein R, R ', BI, B2 and R4 are as defined for the compound of formula (IIa), and B, Z1, Z2, C1, C1, R1, R2, R3, R5, m and n are as defined for the compound of formula (I). Among the compounds that are the subject of the invention, there may also be mentioned a sixth group of compounds which correspond to the following formula (1.3): ## STR2 ## in which R, R ', BI, B2 and R4 are as defined in the compound of formula (11a) and B, R3, R5, m and n are as defined for the compound of formula (I).

Among the compounds of the invention, there may be mentioned especially the compounds of formulas (1.1), (1.2) and (1.3) in which B represents a group chosen from: cis-1,2-methylenecyclopentyl, 1,2-Crans cyclohexyl, cis-1,2-cyclohexyl, cis-1,2-methylenecyclohexyl, Crans-1,4-cyclohexyl, cis-1,4-cyclohexyl, cis / 1,4-1,4-cyclohexyl mixture, cis / notch mixture -1,3-cyclohexyl, cis / notch-1,3-dmethylenecyclohexyl, cis-1,4-dmethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane. Among the compounds of the invention, there may be mentioned a seventh group of compounds of formula (I) in which: A represents an aminoquinoline of the following formulas (IIb) or (IIc): R2 (12) R R4 / ( Wherein R, R 'and R4 are as defined for the compound of formula (IIa); embedded image in which R, R' and R4 are as defined for the compound of formula (IIa); B represents a group chosen from: • a cycloalkyl group which may contain from 3 to 8 carbon atoms, optionally substituted with one or more groups chosen from: a halogen atom, a hydroxyl group, an alkyl group which can comprise from 1 to 6 carbon atoms or a cycloalkyl group which may contain from 3 to 6 carbon atoms; or B represents 2 cycloalkyl groups which may contain from 3 to 6 carbon atoms, said cycloalkyls being linked together by a single bond or an alkylene chain which may have 1 or 2 carbon atoms; Or B represents a linear or branched C 1 -C 5 alkylene chain; m and n independently of one another 0, 1 or 2; ùp = 1 where R5 represents a hydrogen atom; Z1 and Z2, which may be identical or different, represent an alkylene radical which may contain from 1 to 4 saturated or unsaturated carbon atoms, the Z1 + Z2 + Ci + Cj combination thus representing: • either a cycloalkyl group which can comprise from 3 to 10 carbon atoms, or • a polycyclic structure which may contain from 4 to 18 carbon atoms, one of Z1 or Z2 may represent a single bond between the U and Cj atoms, it being understood that Z1 and Z2 can not represent a simple connection at the same time; R1 and R2 represent a hydrogen atom; RX and Ry together form a cyclic peroxide comprising from 4 to 8 members and having 1 or 2 additional oxygen atoms in the ring structure (ie a total of 3 to 4 oxygen atoms in the ring), Cj being the one of the peaks of this cyclic peroxide, said cyclic peroxide being substituted a group R3, R3 representing from 1 to 8 groups identical or different from each other, occupying any positions on the carbon atoms of the peroxide ring and being chosen from the atoms and following groups:. hydrogen, halogen, -OH, -CF3, -NO2, -OCF3, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 10 carbon atoms, or else two R3 groups carried by the same carbon atom of the peroxidic ring which may together form a cycloalkyl group which may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group which may contain from 4 to 18 carbon atoms (which will therefore be located in the spiro position on the peroxide cycle).

Among the compounds of formula (I) which are the subject of the invention, there may be mentioned an eighth group of compounds chosen from: PA1079, PA1110, PA1120, PA1140, PA1103, PA1265, PA1251, PA1252, PA1253, PA1255, PA1271, PA1269, PAl259, PAl258, PAl256, PAl268, PA1260, PA1188, PAl261, PAl207, PAl262, PAl263, PAl264, PAl305, PAl308, PA1329, PA1333, PA1335, PAl278, PAl279, PAl280, PAl286, PA1330, PA1331, PA1332, PA1336, PA1338, base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

Particularly preferred is the compound PAl259 of the formula: ## STR1 ## in the form of a base or an addition salt with an acid, a hydrate or a solvate, in racemic form, isomers and their mixtures, as well as their diastereoisomers and mixtures thereof. According to an advantageous embodiment, the compounds of general formula (I) as defined above, in which p = 1, U = -CiH <and B represents a cycloalkyl group, a bicyclic or tricyclic group or 2 cycloalkyl groups, as described in the application FR 06/05235. According to another advantageous embodiment, mention may also be made of the compounds of general formula (I) as defined above, in which p = 1, U = -CiH <and B represents a linear or branched C1 to c5 alkylene chain, as described in WO 01/77105. According to another advantageous embodiment, mention may also be made of the compounds of general formula (I) as defined above, in which p = 0, U = -N <as described in application WO 2005/049619. Mention may in particular be made of the compounds of the following general formulas (1-4), (1-5) and (1-6): ## STR2 ## in which

R, R ', B1, B2, and R4 are as defined for the compound of formula (11a) and B, Ci, R1, R2, Z1, Z2, Rx, Ry, m and n are as defined for the compound of formula (I);

Base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof; or

R

## STR2 ## wherein R 1, (CH 2) m -B- (CH 2) n -N C N Z Z / O R 'R 1 ~% -AB 1 R 2 Z / i. Wherein R, R ', BI, B2 and R4 are as defined for the compound of formula (IIa) and B, Z1, Z2, C1, R1, R2, R3, m and n are as defined for the compound of formula (I); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof; or R 'R

wherein R, R ', BI, B2 and R4 are as defined in the compound of formula (IIa) and B, R3, R5, m and n are as defined for the compound of formula (I); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. The references indicated above refer to the compounds exemplified in Application FR06105235 and WO2005 / 049619 defined below: PA1079: (7-Chloroquinolin-4-yl) - {2- [2- (3,3-dimethyl) 1,2,5-trioxa-9-azaspiro [5,5] undec-9-yl) -ethoxy] -ethyl} -amine PA 1110: (7-chloro-4-yl) n-4-yl ) - [2- (7,8,16-Trioxa-3-aza) -dispiro [5.2.5.2] hexadec-3-yl) -ethyl] -amine PA1120: (7-Chloro-quinolin-4-yl) - [2- (6,7,14-Trioxa-1-azadipine [4.2.5.2] pentadec-11-yl) -ethyl] -amine PAI 140: (7-Chloro-quinolin-4-yl) - [3- (6,7,14-trioxa-1-aza-dispiro [4.2.5.2] pentadec-11-yl) -propyl] -amine PA 1103: N- (7-chloroquinolin-4-) yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane-trans-1,4-diamine PAI278: di-phosphate salt of PA1103; PAl279: di-acetate salt of PA1103 PAl280: di-sulfate salt of PA1103 / o-R4 \, (CH2) rB- (CH2) nN PAl265: N- (7-chloro-quinolin-4-yl) -N N - (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane-cis-1,4-diamine

PA1251: N- (2,8-bis-trifluoromethyl-quinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) cyclohexane-trans-1,4-diamine

PAI252: N- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -N'- (7-trifluoromethyl-quinolin-4-yl) -cyclohexane-trans-1 , 4-diamine

PAI253: N- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -N'- (6-dimethylamino-quinolin-4-yl) -cyclohexane-trans-1 , 4-diamine

PAI255: N- (7-Chloroquinolin-4-yl) -N '- (3,4-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -cyclohexane-trans-1 , 4-diamine

PA1305: N- (6-trifluoromethoxy-quinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane-trans-1,4 diamine

PA1308: N- (7-Chloroquinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -N'-methyl- cyclohexane-cis-1,4-diamine

PA1329: N- (7-Chloroquinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -N'-ethyl- cyclohexane-cis-1,4-diamine

PA1333: (7-Chloroquinolin-4-yl) - {3 - [(3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-ylamino) -methyl] -adamantane-1 ylmethyl} -amine

PA1335: (7-Chloroquinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -octahydro-pentalene-2,5 diamine

PAI271: N- (7-chloro-uminolin-4-yl) -cis-2 - [(3,3-dimethyl-1, 2,5-trioxaspiro [5.5] undec-9-ylamino) -methyl] -cyclopentylamine

PAI269: N- (7-chloro-quinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxo-spiro [5.5] undec-9-yl) -cyclohexane-1,4- diamine

PAl259: N- (7-Chloro-quinolin-4-yl) -N '- (6,7,14-trioxa-dispiro [4.2.5.2] pentadec-11-yl) -cyclohexane-trans-1,4- diamine

PAI258: N- (7-chloro-quinolin-4-yl) -N '- (7,8,15-triodispiro [5.2.5.2] hexadec-12-yl) -cyclohexane-trans-1,4-diamine

PA1,256: N- (7-chloro-quinolin-4-yl) -N '- (9,9-dimethyl-7,8,12-trioxa-spiro [5.6] dodec-3-yl) -cyclohexane-trans-1 , 4-diamine

PAl268: N- (7-chloro-quinolin-4-yl) -N '- (9,9-dimethyl-7,8,13-trioxaspiro [5.7] tridec-3-yl) -cyclohexane-trans-1,4 -Diamine PAI260: N- (7-chloro-quinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane-cis-1 2-diamine PAI 188: N- (7-chloro-quinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane- trans-1, 2-diamine PAl261: N- (7-chloro-quinolin-4-yl) -cis-2 - [(3,3-dimethyl-1,2,5-trioxasipiro [5.5] undec-9-ylamino ) -methyl] -cyclohexylamine PA1207: N- (7-chloroquinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane -1,3-diamine PAl262: (7-chloroquinolin-4-yl) - {3 - [(3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-ylamino) Methyl] -cyclohexylmethyl} -amine PAl263: (7-Chloroquinolin-4-yl) - {4 - [(3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-ylamino) -methyl ] -cyclohexylmethyl} -amine PAl264: (7-Chloroquinolin-4-yl) - {4- [4- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-ylamino) - cyclohexylmethyl] -cyclohexyl} -amine PAl278: N- (7-chloro) o-Quinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane-trans-1,4-diamine, dihydrogen PAl279: N- (7-Chloroquinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] undec-9-yl) -cyclohexane-trans-1,4-diamine PA1280: N- (7-Chloroquinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -cyclohexane- trans-1,4-diamine, sulfate PA1,286 :- (7-Chloro-quinolin-4-yl) -N '- [- 5-spiro- (3,3-dimethyl-1, 2,5-trioxan-6); 1-yl) octahydro-cis-pentalen-2-yl] -cyclohexane-trans-1,4-diamine PA1330: N- (7-chloro-uolin-4-yl) -N'-cyclopropylmethyl-N'- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -cyclohexane-1,4-diamine PA1331: N- (7-chloro-quinolin-4-yl) - N '- (3,3-dimethyl-1,2,5-trioxasulfon [5.5] u-ndec-9-yl) -N'-isobutyl-cyclohexane-1,4-diamine PA1332: N- (7-chloro) quinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxaspiro [5.5] u-ndec-9-yl) -N'-pentyl-cyclohexane-1,4-dlamine PA1336: N4- (7-chloro-quinolin-4-yl) -N4 - [(3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -bicycl 4,4'-diamine-4'-diamine PA1338: N- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -N '- (6-methoxyquinolin-8-yl) cyclohexane-1,4-diamine in the form of a base or of an addition salt with an acid, in the form of a hydrate or of a solvate, in racemic form, isomers and their mixtures, as well as their diastereoisomers and their mixtures.

The above compounds can be prepared by application or adaptation of the procedures described in WO01177105, WO2005 / 049619 and FR06105235.

The study of the pharmacological properties of the coupling products of formula (I) according to the invention has shown that they exhibit anti-schistosome activity. Thus, according to another of its aspects, the subject of the invention is pharmaceutical compositions for the prevention or treatment of schistozomiases comprising, as active ingredient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound of formula (I) according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (1) above, or its salt, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, for the prevention or treatment of schistozomiases. Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions. Preferred routes of administration are the oral, rectal and injectable routes.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyi-methylcellulose 2.25 mg Magnesium stearate 3.0 mg

There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

The present invention, according to another of its aspects, also relates to a method of treatment or prevention of schistozomiases which comprises the administration to a patient of an effective dose of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof or hydrates or solvates thereof.

Example 1) Obtaining schistosomes The host-parasite pair used for this study consists of a strain of Schistosoma mansoni of Brazilian origin maintained on an albino B. glabrata variety also of Brazilian origin and maintained on SWISS OF1 mice.

Harvesting of eggs and infestation of molluscs: S. mansoni eggs are taken from the liver of a mice infested 10 weeks previously.

A double shock, thermal and osmotic causes the hatching of eggs and the release of miracidium larvae. Miracidia are collected and placed in the presence of molluscs. Twenty-four hours later, the molluscs are placed in tanks and kept at 25 ° C under a balanced photoperiod: 12-12.

Harvest of cercariae and infestation of mice: Five weeks after exposure, molluscs emit cercariae. The cercariae collected with the pasteur pipette are placed in batches of 160 to 400 in small glass crystallizers and the skin of the abdomen of the mice is brought into contact with this solution for 45 minutes.

Recovery of schistosomes: 21 or 49 days after infestation, the mice are sacrificed and the parasites are recovered from the blood of the mouse. Adult schistosomes are recovered 49 days after infestation and schistosomula (larval form of schistosomes) are recovered 21 days after infestation. The blood is filtered and the schistosomes are removed with the micropipette and then washed in a solution of RPMI supplemented with 25 mM Hepes + 2 mM L-glutamine. Schistosomes are incubated at 37 ° C. 2) Chemosensitivity test Each molecule is tested in duplicate. The tests are carried out in 24-well plates for schistosomules and in petri dishes (diameter 3 cm) for adult worms. Each well contains 1 mL and each petri dish 3 mL. RPMI solution supplemented with 25 mM Hepes + 2 mM L-glutamine. Artemeter and praziquantel are used as the reference molecule. From 9 to 29 schistosomules (average 14) and from 6 to 20 adult schistosomes (average 10) are placed in the containers. The different molecules are then deposited at the desired concentration and the survival is measured at 15 min, 30 min, 45 min, 1 h, 1h30, 2h, 3h, 4h, 5h, 6h, and 7 hours. Between each measurement the containers containing the worms are incubated at 37 ° C. An individual is considered dead if no external movement (musculature, sucker ...) or internal (digestive tract, excretory device ...) is detected.

A preliminary study was used to calibrate the range of reference molecules on adult schistosomes and schistosomulae. In adult schistosomes, the doses 10, 5, 1 and 0.25 μg / mL were tested for praziquantel and the doses 300, 100, 50 and 10 μg / mL were tested for artemether. On schistosomules, doses 10, 5 and 1 μg / mL were tested for praziquantel and doses 300, 100 and 50 μg / mL were tested for artemether. An untreated control was performed for each stage. The PAl259 molecule was tested at doses of 300, 100, 10 and 5 μg / ml on schistosomules and on adult schistosomes. For each experiment, three controls were performed praziquantel control 10 μg / ml, a control artemether 300 μgImL and an untreated control.

3) Results Parasiticidal effect of Artemether, Praziquantel and PAl259 Effect of compounds * on schistosomules (J21) Compound Concentration (pg / mL) Time (hours) Praziquantel 5 5 Artemether 300 6 PAl259 5 3 * Indicated concentration minimum to kill 100% of the parasites in culture and the time necessary to obtain this effect. Effect of compounds' on adult schistosomes (J49) Compound Concentration (pg / mL) Time (hours) Praziquantel 10 4 Artemether **> 300 PAl259 100 1.5 20 * Indicate the minimum concentration to kill 100% of the parasites in culture and the time needed to achieve this effect. ** In the case of Artemether at 300 μg / mL after 7h of incubation, 45% of schistosomes are still alive.

Claims (14)

A compound for the prevention or treatment of schistozomiasis, said compound having the following formula (I): R 1 R 5 / Z 1 R x A 1 (CH 2) n, ùB - (CH 2) n - (N) p 1 C 1 Z2 / Ry (I) in which: A represents: a residue of a molecule chosen from: an aminoquinoline of formula (IIa): in which: R and R ', which may be identical or different, each represent one or more substituents (for example 1 to 5) occupying distinct positions on the rings to which they are attached; attached, chosen from: a hydrogen or halogen atom, a -OH, -CF3, -OCF3, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl group, said alkyl groups comprising from 1 to 5 carbon atoms, a cycloalkyl or io-cycloalkyl group, said cycloalkyl groups possibly containing from 3 to 5 carbon atoms, -NO2 or -N (Ra, Rb), where Ra and Rb, identical or different, each independently represent a hydrogen atom or an alkyl group comprising from 1 to 5 carbon atoms; or Ra and Rb, which may be identical or different, represent a cycloalkyl group which may contain from 3 to 5 carbon atoms, or else Ra and Rb together with the nitrogen atom to which it is attached form a pyrrolidinyl or piperidinyl group; R 4 represents a hydrogen atom or an alkyl group possibly containing from 1 to 5 carbon atoms, or R 4 represents a cycloalkyl group which may comprise from 3 to 5 carbon atoms, - BI represents a nitrogen atom and B2 represents a link -CH =, or BI represents a -CH = link and B2 represents a nitrogen atom. . a group of formula (IIIa): R 6 -CHOH- (IIIa) in which R 6 represents an aryl radical, preferably a 9-phenanthrenyl or a nitrogen-containing heterocyclic residue, preferably a 4-quinolinyl optionally substituted with one or more (by from 1 to 5) R groups as defined for the compound of formula (IIa); Or • A represents a residue facilitating the bioavailability, the latter having one or more heteroatoms selected from N, O and S in a mono- or polycyclic molecule which may contain from 6 to 18 carbon atoms, saturated or unsaturated or in a chain which may comprise from 1 to 18 optionally substituted linear carbon atoms, such as a guanidinium, morpholino, peptide or polyamine residue; B represents a cycloalkyl group which can have from 3 to 8 carbon atoms, optionally substituted by one or more groups chosen from: a halogen atom, a hydroxyl group, an alkyl group which can comprise from 1 to 6 carbon atoms or a cycloalkyl group may contain from 3 to 6 carbon atoms, • or B represents a bicyclic or tricyclic group may contain from 4 to 18 carbon atoms, optionally substituted with one or more groups selected from a halogen atom, a group hydroxyl, an alkyl group which may contain from 1 to 6 carbon atoms or a cycloalkyl group which may contain from 3 to 6 carbon atoms; or B represents 2 cycloalkyl groups which may contain from 3 to 6 carbon atoms, said cycloalkyls being interconnected by a single bond or an alkylene chain which may have 1 or 2 carbon atoms; Or B represents a linear or branched C 1 -C 5 alkylene chain; Or B represents a chain -CH2-CH2-O-CH2-CH2-; m and n independently represent 0, 1 or 2; R5 represents a hydrogen atom or an alkyl group, a C (O) alkyl group or a C (O) O-alkyl group, said alkyl groups possibly containing from 1 to 5 carbon atoms, or R5 represents a cycloalkyl group, a C (O) -cycloalkyl group, a C (O) O-cycloalkyl group or a C 1-3 -alkylene-cycloalkyl group, said cycloalkyl groups possibly containing from 3 to 6 carbon atoms; Z1 and Z2, which may be identical or different, represent an alkylene radical which may contain from 1 to 4 saturated or unsaturated carbon atoms, the Z1 + Z2 + U + Cj group thus representing: • either a cycloalkyl group optionally comprising a carbon atom or the nitrogen may comprise from 3 to 10 atoms, or a polycyclic hydrocarbon structure optionally comprising a nitrogen atom, which may comprise from 4 to 18 atoms, one of Z1 or Z2 possibly representing a single bond between the U atoms. and Cj, it being understood that Z1 and Z2 can not represent a single bond at the same time; R1 and R2, which are identical or different, represent a hydrogen atom or a functional group capable of increasing the water solubility; R 1 and R 4 together form a cyclic peroxide comprising from 4 to 8 members and having 1 or 2 additional oxygen atoms in the ring structure (ie a total of 3 to 4 oxygen atoms in the ring), C 1 being one of the peaks of this cyclic peroxide, said cyclic peroxide being substituted by a group R 3, R 3 representing from 1 to 8 groups identical or different from each other, occupying positions on the carbon atoms of the peroxide ring and being chosen from the following atoms and groups: hydrogen, halogen, -OH, -CF3, -NO2, -OCF3, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising 1 to 5 carbon atoms, a cycloalkyl group may contain from 3 to 7 carbon atoms and may further contain from 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, optionally substituted with one or more groups (for example 1 to 8) selected from among a halogen atom, a hydroxyl group, an alkyl group which can have from 1 to 8 carbon atoms or a cycloalkyl group which may contain from 3 to 8 carbon atoms, an O-cycloalkyl group which may have from 3 to 7 carbon atoms, a bicyclic or tricyclic group which may contain from 4 to 18 carbon atoms and which may also contain from 1 to 6 heteroatoms chosen from oxygen, nitrogen and sulfur, optionally substituted with one or more groups chosen from an atom halogen, a hydroxyl group, an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms; 20. or two R3 groups carried by adjacent carbon atoms on the peroxide ring which can together form a cycloalkyl group having 5 or 6 carbon atoms, saturated or unsaturated, said R3 group may itself be substituted with 1 to 6 substituents R3 such as defined above, 25. or else two R3 groups carried by the same carbon atom of the peroxidic ring which can together form a cycloalkyl group which may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group which may contain from 4 to 18 carbon atoms (which will therefore be located in the spiro position on the peroxide cycle); Where U represents a group ûC; H <or ûN <; C; and C 1 each represent a carbon atom; p represents 0 or 1; with the proviso that when p = 1, U represents ûCH <, and when p = O, U is bonded to û (CH2) n- by a simple bond to the base state or an acid addition salt, the state of hydrate or solvate, in racemic form, isomers and mixtures thereof, as well as their diastereoisomers and mixtures thereof. 2. Compound of formula (I) according to claim 1, wherein A, B, m, n, Z1, Z2, p = 1 and the set Zi + Z2 + Ci + Cj, R1, R2, Rx, Ry are as defined in claim 1 and R5 represents a hydrogen atom or an alkyl group, a C (O) alkyl group or a C (O) O-alkyl group, said alkyl groups may comprise from 1 to 5 atoms carbon, or R5 represents a cycloalkyl group, a C (O) -cycloalkyl group or a C (O) O-cycloalkyl group, said cycloalkyl groups may comprise from 3 to 6 carbon atoms; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. 20 3. A compound according to any one of the preceding claims wherein A represents an aminoquinoline nitrogen-containing heterocycle of formula (IIa) and having the following formula (1.1): R1 R (CH2) m Bù (CH2) n-ùNùCi Wherein R, R ', BI, B2, and R4 are as defined for the compound of formula (IIa) and B, Ci, Cj, R1, R2 Z1, Z2, Rx, Ry, R5, and n are as defined for the compound of formula (I); base or acid addition salt, hydrate or desolvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. A compound according to any one of the preceding claims, having the following formula (1.2): ## STR1 ## where in which R, R ', B1, B2 and R4 are as defined for the compound of formula (IIa) and B, Z1, Z2, Ci, Ci, R1, R2, R3, R5, m and n are as defined for the compound of formula (I) in the form of a base or of an addition salt with an acid, in the form of a hydrate or of a solvate, in racemic form, isomers and their mixtures, as well as their diastereoisomers and their mixtures. A compound according to any one of the preceding claims, having the following formula (1.3): R 'R wherein R, R', B1, B2 and R4 are as defined in the compound of formula (IIa) and B, R3, R5, m and n are as defined for the compound of formula (I); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. 6. A compound according to any one of claims 1 having the following formula (1.4): ## STR2 ## wherein R 1, R 2, R 4 In which R, R ', B1, B2, and R4 are as defined for the compound of formula (IIa) and B, Ci, R1, R2, Z1 , Z2, RX, Ry, m and n are as defined for the compound of formula (I), in the form of a base or as an acid addition salt, a hydrate or a solvate , in racemic form, isomers and mixtures thereof, as well as their diastereoisomers and mixtures thereof. 7. A compound according to any one of claims 1 to 6, having the following formula (1.5): ## STR2 ## wherein R 1, R 1, R 2, R 4 Wherein R, R ', B1, B2 and R4 are as defined for the compound of formula (IIa) and B, Z1, Z2, C1, R1, R2, R3, m and n are as defined for the compound of formula (I); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. 20 8. A compound according to any one of claims 1, 6 and 7, having the following formula (1.6): ## STR5 ## wherein R, R ', BI, B2 and R4 are as defined in the compound of formula (IIa) and B, R3, R5, m and n are as defined for the compound of formula (I); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. 9. Compound of formula (I) according to any one of the preceding claims, in which: the aminoquinoline is chosen from a group of formula (Ilb) or (IIc): ## STR5 ## wherein: R and R ', which are identical or different, each represent one or more substituents occupying distinct positions on the rings to which they are attached, chosen from: atonic hydrogen or halogen, -OH, -CF3, -OCF3, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising 1 to 5 carbon atoms, 20 . a cycloalkyl or ùO-cycloalkyl group, said cycloalkyl groups possibly having from 3 to 5 carbon atoms, -NO2 or -N (Ra, Rb), where Ra and Rb, identical or different, represent hydrogen atoms or an alkyl group comprising from 1 to 5 carbon atoms; Or Ra and Rb, which may be identical or different, represent a cycloalkyl group which may have from 3 to 5 carbon atoms; R and Ra together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group; R 4 represents a hydrogen atom, an alkyl group which may comprise from 1 to 5 carbon atoms, or R 4 represents a cycloalkyl group which may contain from 3 to 5 carbon atoms, - B represents a nitrogen atom and B2 represents a -CH = chain, or BI represents a -CH = chain and B2 represents a nitrogen atom; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. 10. Compound of formula (I) according to any one of the preceding claims, wherein B represents a group chosen from: cis-1,2-methylenecyclopentyl, Crans-1,2-cyclohexyl, cis-1,2-cyclohexyl, Cis-1,2-methylenecyclohexyl, Crans-1,4-cyclohexyl, cis-1,4-cyclohexyl, cis / trans-1,4-cyclohexyl mixture, cis / trans-1,3-cyclohexyl mixture, cis / mixture trans-1,3-dimethylenecyclohexyl, cis-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane. 20 11. Compound of formula (I) according to any one of the preceding claims wherein: A represents an aminoquinoline of formulas (IIb) or (IIc) which follow: (Ib) (IIc) in which R, R 'and R4 are as defined for the compound of formula (IIa); B represents a group chosen from: • a cycloalkyl group which may contain from 3 to 8 carbon atoms, optionally substituted by one or more groups chosen from: a halogen atom, a hydroxyl group, an alkyl group which may comprise from 1 to Carbon atoms or a cycloalkyl group which may have from 3 to 6 carbon atoms, or B represents 2 cycloalkyl groups which may contain from 3 to 6 carbon atoms, said cycloalkyls being linked together by a single bond or an alkylene chain may have 1 or 2 carbon atoms; Or B represents a linear or branched C1-C5 alkylene chain; m and n independently of one another 0, 1 or 2; UP = 1; R5 represents a hydrogen atom; Z1 and Z2, which may be identical or different, represent an alkylene radical which may contain from 1 to 4 saturated or unsaturated carbon atoms, the Zl + Z2 + Ci + Cj combination thus representing: • a cycloalkyl group which may contain from 3 to 10 carbon atoms, or • a polycyclic structure which may comprise from 4 to 18 carbon atoms, one of Z1 or Z2 may represent a single bond between the carbon atoms Ci and Cj, it being understood that Z1 and Z2 do not can not represent a single link at the same time; Wherein R1 and R2 represent a hydrogen atom; RX and Ry together form a cyclic peroxide comprising from 4 to 8 members and having 1 or 2 additional oxygen atoms in the ring structure, Cj being one of the peaks of this cyclic peroxide, said cyclic peroxide being substituted a group R3, R 3 represents from 1 to 8 groups identical or different from each other, occupying any positions on the carbon atoms of the peroxidic ring and being chosen from the following atonies and groups: hydrogen, halogen, -OH, -CF3, -NO2, -OCF3: aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 10 carbon atoms, or else two R 3 groups carried by the same carbon atom of the peroxide ring which may together form a cycloalkyl group which may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group which may contain from 4 to 18 carbon atoms; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof. Compounds according to any one of the preceding claims selected from PA1079, PA1110, PA1120, PA1140, PA1103, PA1265, PA1251, PA1252, PA1253, PA1255, PA1271, PA12269, PA1259, PA1258, PA1256, PA12268, PA1260, PA1188, PAl261, PAl207, PAl262, PAl263, PAl264, PA1305, PAl308, PA1329, PA1333, PA1335, PAl278, PAl279, PAl280, PAl286, PA1330, PA1331, PA1332, PA1336, PA1338 in the form of a base or as a an acid, in the form of hydrate or solvate, in racemic form, isomers and their mixtures, as well as their diastereoisomers and mixtures thereof. 13. Pharmaceutical composition for the prevention or treatment of schistozomiases, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 12. 14. Use of a compound of formula (I) according to any one of claims 1 to 12 for the preparation of a pharmaceutical composition for the treatment or prevention of schistozomiases.