WO2009071553A1

WO2009071553A1 - New therapeutic uses of dual molecules containing a peroxide derivative

Info

Publication number: WO2009071553A1
Application number: PCT/EP2008/066651
Authority: WO
Inventors: Bernard Meunier; Frédéric COSLEDAN
Original assignee: Palumed SA
Current assignee: Palumed SA
Priority date: 2007-12-04
Filing date: 2008-12-02
Publication date: 2009-06-11
Anticipated expiration: 2010-06-04
Also published as: CN101909627A; AP2010005307A0; BRPI0819895A2; FR2924343A1; BRPI0819895A8; KR20100102127A

Abstract

The invention relates to the new therapeutic use of hybrid molecules containing a peroxide derivative to treat bilharziasis or schistosomiasis.

Description

New therapeutic uses of dual molecules containing a peroxide derivative

The invention relates to the new therapeutic use of hybrid molecules containing a peroxide derivative to treat bilharziasis or schistosomiasis. Molecules of this type have been described, in particular, in patent applications WO 01/77105, WO 05/049619 and WO2007/144487. The antimalarial activity of these molecules is described in the above documents. However, their anti-schistosomal properties are neither described nor suggested in said documents. Schistosomiasis or bilharziosis is a chronic disease caused by a parasite of the Schistosoma type, (identified by the parasitologist Theodore Bilharz in 1852). A recent WHO report estimates that this disease affects 200 million individuals worldwide and that 600 million people are living in endemic regions.

Schistosomiasis is associated with kidney and bladder malfunction (S. haematobium), or liver and intestinal diseases (S. mansoni, S. japonicum, S. mekongi or S. intercalatum).

Since 2005, Praziquantel (Bilthcide) has been the primary treatment for schistosomiasis, a human indication for which it is usually effective in a single dose. This medicament is well tolerated and is effective on the five pathogenic species. However, some cases of resistance of the parasite to this medicament have already been described, and this makes it necessary to develop new innovative treatments to combat this disease.

Surprisingly, the present inventors have now discovered anti- schistosomiasis properties of the molecules described in patent applications WO 01/77105, WO 05/049619 and WO 2007/144487.

The invention therefore relates to the use of compounds of formula (I), as defined hereinafter, to treat or prevent schistosomiasis. Said compounds are based on the formula (I):

(I) in which:

— A represents:

• a molecule residue selected from: an aminoquinoline of formula (Ma):

(Ha)

in which:

- R and R' are the same or different and each represent one or more (for example 1 to 5) substituents occupying separate positions on the cycles to which they are connected, selected from: a hydrogen or halogen atom, an -OH, -CF₃, -OCF₃ group, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 5 carbon atoms,

-N(Rg₁Rb), where R_a and Rb are the same or different and each represent, independently, a hydrogen atom or an alkyl group comprising from 1 to 5 carbon atoms;

- R₄ represents a hydrogen atom or an alkyl group which may comprise from 1 to

5 carbon atoms or a cycloalkyl group which may comprise from 3 to 5 carbon atoms;

— B represents a cycloalkyl group which may comprise from 3 to 8 carbon atoms, optionally substituted with one or more groups selected from: a hydrogen atom, a hydroxyl group, an alkyl group which may comprise from 1 to

6 carbon atoms or a cycloalkyl group which may comprise from 3 to 6 carbon atoms, • or B represents a bi- or tricyclic group which may comprise from 4 to 18 carbon atoms optionally substituted with one or more groups selected from a halogen atom, a hydroxyl group, an alkyl group which may comprise from 1 to 6 carbon atoms or a cycloalkyl group which may comprise from 3 to 6 carbon atoms, • or B represents 2 cycloalkyl groups which may comprise from 3 to 6 carbon atoms, said cycloalkyls being bonded together by a single bond, or an alkylene chain which may comprise 1 or 2 carbon atoms;

• or B represents a linear or branched C1 -C5 alkylene chain;

• or B represents a -CH₂-CH₂-O-CH₂-CH₂- chain;

— m = 0, 1 or 2; n = 0, 1 or 2;

— R₅ represents a hydrogen atom or an alkyl group, or a Ci_-3-alkylene-cycloalkyl group, said cycloalkyl groups possibly comprising from 3 to 6 carbon atoms;

— Z₁ and Z₂ are the same or different and represent a-(CH₂)₂- radical, Z₁ + Z₂ + U + Cj thus representing:

• either a cyclohexyl group when U = -CH<,

• or a piperidyl group when U = -N<, • or a hydrocarbonated polycyclic structure optionally comprising a nitrogen atom, possibly comprising from 4 to 18 atoms,

one of Z₁ or Z₂ possibly representing a single bond between the U and Cj atoms, it being impossible for Z₁ and Z₂ to represent a single bond at the same time;

— R₁ and R₂ are the same or different and represent a hydrogen atom;

— R_x and R_y form, together with Cj, a cyclic peroxide selected from the groups of formulae (Xl), (XII) and (XIII): - trioxanes of formula (Xl):

in which R₃ represents 1 to 4 groups which are the same or different, or

— trioxepanes of formula (XII):

in which R₃ represents 1 to 6 groups which are the same or different, or

- trioxecanes of formula (XIII):

(XIIi) in which R₃ represents 1 to 8 groups which are the same or different, where

R₃ representing from 1 to 8 groups which are the same or different, occupying any positions on the carbon atoms of the peroxide cycle and being selected from the following atoms and groups: hydrogen, halogen, an -OH, -CF₃, -NO₂, -OCF₃ group, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 10 carbon atoms, or two R₃ groups carried by the same carbon atom of the peroxide cycle together forming a cycloalkyl group which may comprise from 3 to 7 carbon atoms or a bi- or tricyclic group which may comprise from 4 to 18 carbon atoms (which will therefore be arranged in a spiro position on the peroxide cycle);

— U represents a -CH< or -N< group;

— p represents 0 or 1 ;

U representing -CH< when p=1 and U being bonded to -(CH₂)_n- by a single bond when p=0;

optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, and/or in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof. The residue A advantageously drains the compound of formula (I) according to the invention inside the parasite.

The compounds of formula (I) may be present in the form of bases or addition salts with acids. Addition salts of this type also form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids which may be used to purify or isolate the compounds of formula (I) also form part of the invention.

The compounds according to the invention may also be present in the form of hydrates or solvates, that is to say in the form of associations or combinations with one or more water molecules or with a solvent. Hydrates and solvents of this type also form part of the invention.

The invention relates to mixtures, at any ratio, of diastereiosomers as well as pure diastereiosomers of formula (I). The invention also relates to racemic mixtures as well as optically pure isomers of the molecules of formula (I) and even to mixtures, at any ratio, of said optically pure isomers. The invention also relates to achiral molecules.

In the definition of compounds of formula (I) above and hereinafter, unless otherwise stated:

- halogen atom means a fluorine, chlorine, bromine or iodine atom;

- alkyl group means a linear or branched, saturated, monovalent aliphatic group.

Examples are the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl and pentyl groups;

- alkylene radical or chain means a linear or branched, saturated, divalent aliphatic group. For example, a Ci-3-alkylene group represents a linear or branched, divalent carbon chain comprising from 1 to 3 carbon atoms, such as a methylenyl (-CH₂-), an ethylenyl (-CH₂CH₂-), a 1 -methylethylenyl (-CH(CH₃)CH₂-), a propylenyl (-CH₂CH₂CH₂-);

- cycloalkyl group means a saturated, cyclic aliphatic group. Examples are the cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;

- a bicyclic structure means a structure comprising two saturated cyclic aliphatic groups comprising from 4 to 18 carbon atoms, said groups possibly being:

. fused, that is to say they have a common bond. An example is the perhydronaphthyl group:

. or bridged, that is to say at least 2 atoms of the bicyclic structure are bonded by a single bond or a carbon chain which may comprise from 1 to 4 carbon atoms. An example is:

bicyclo[3.2.1]octyl

or in a spiro junction, that is to say they are bonded by a common carbon atom. An example is the cyclopentane-spiro-cyclobutyl group:

- a tricyclic structure means a structure comprising 3 saturated, cyclic aliphatic groups comprising from 4 to 18 carbon atoms, said groups possibly being fused (as defined above), or bridged (as defined above). An example of a fused tricyclic structure is the perhydroanthracene group:

An example of a bridged tricyclic structure is the adamantyl group which is a tricyclic structure comprising 10 carbon atoms:

- a polycyclic structure means a bi- or tricyclic structure as defined above;

- a cyclic peroxide group means a cyclic alkyl group comprising 2 adjacent oxygen atoms; - an aryl group means 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 cycles is aromatic. Examples are the phenyl, naphthyl, tetrahydronaphthyl and indanyl groups; - a heteroaryl group is a monocyclic or polycyclic aromatic system comprising from 5 to 18 chain links, preferably from 5 to 14 chain links and preferably from 5 to 10 chain links and comprising one or more heteroatoms, such as nitrogen, oxygen or sulphur atoms. When the system is polycyclic at least one of the cycles is aromatic. The nitrogen atoms may be in the form of N-oxides. Examples of monocyclic heteroaryl groups are the thiazolyl, thiadiazolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyle, pyrrolyl, pyrazolyl, pyrimidinyl and pyridazinyl groups. Examples of bicyclic heteroaryl groups are the indolyl, benzofuranyl, chromen-2-onyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, indolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphtyridinyl, 2,3-dihydro-1 H-indolyl, 2,3-dihydro-benzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl groups;

Examples of the compounds which are the subject of the invention are a first group of compounds of formula (I), in which A, B, m, n, Z₁, Z₂, p=1 , U=-CH< and Z₁ + Z₂ + U + Cj, R₁, R₂, R₅, R_x, R_y are as defined in claim 1 , said alkyl groups possibly comprising from 1 to 5 carbon atoms.

Examples of the compounds which are the subject of the invention are a second group of compounds of formula (I) based on the following formula (I.2):

in which R', R_4, B, Z₁, Z₂, Ci, C_j, Ri, R₂, R₃, R₅, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

Examples of the compounds which are the subject of the invention are another group of compounds of formula (I) based on the following formula (1.3):

in which R', R₄, B, R₃, R₅, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

Examples of the compounds which are the subject of the invention are another group of compounds of formula (I) based on the following formula (1.4):

in which R', R₄, B, C_j, Ri, R2, Zi, Z₂, R_x, R_y, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

Examples of the compounds which are the subject of the invention are another group of compounds of formula (I) based on the following formula (1.5):

in which R', R₄ and B, Zi, Z₂, C_j, Ri, R₂, R3, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

Examples of the compounds which are the subject of the invention are another group of compounds of formula (I) based on the following formula (1.6): P

in which R', R₄, B, R₃, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

Examples of the compounds of the invention are a group of compounds of formula (I), in which B represents a group selected from: c/s-1 ,2-methylenecyclopentyl, frans-1 , 2-cyclohexyl, c/s-1 ,2-cyclohexyl, c/s-1 ,2- methylenecyclohexyl, trans- 1 ,4-cyclohexyl, cis- 1 ,4-cyclohexyl, cis/trans- 1 ,4- cyclohexyl mixture, c/s/frans-1 , 3-cyclohexyl mixture, cis/trans- 1 ,3- dimethylenecyclohexyl mixture, c/s-1 ,4-dimethylenecyclohexyl, 4,4'-methylene-bis- cyclohexane.

Examples of the compounds of formula (I) which are the subject of the invention are, in particular, another group of compounds selected from: PA1079, PA1110, PA1120, PA1140, PA1103, PA1265, PA1251 , PA1252, PA1253, PA1255, PA1271 , PA1269, PA1259, PA1258, PA1256, PA1268, PA1260, PA1188, PA1261 , PA1207, PA1262, PA1263, PA1264, PA1305, PA1308, PA1329, PA1333, PA1335, PA1278, PA1279, PA1280, PA1286, PA1330, PA1331 , PA1332, PA1336, PA1338, optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

Most particularly preferred is the compound PA1259 of formula:

optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

According to an advantageous embodiment, the compounds of general formula (I) as defined above are preferred, in which p=1 , U=-CiH< and B represents a cycloalkyl group, a bi- or tricyclic group or 2 cycloalkyl groups, as described in application WO 2007/144487.

According to a further advantageous embodiment, the compounds of general formula (I) as defined above may also be cited, in which p=1 , U=-CiH< and B represents a linear or branched C1 to C5 alkylene chain, as described in application WO 01/77105.

According to a further advantageous embodiment, the compounds of general formula (I) as defined above may also be cited, in which p=0, U=-N<, as described in application WO 2005/049619.

The references indicated above refer to compounds given in application

WO 2007/144487 and WO 2005/049619 defined hereinafter:

PA1079: (7-chloro-quinolin-4-yl)-{2-[2-(3,3-dimethyl-1 ,2,5-trioxa-9-aza- spiro[5.5]undec-9-yl)-ethoxy]-ethyl}-amine PA1110: (7-chloro-quinolin-4-yl)-[2-(7,8,16-thoxa-3-aza dispiro[5.2.5.2]hexadec-3- yl)-ethyl]-amine

PA1120: (7-chloro-quinolin-4-yl)-[2-(6,7,14-thoxa-11 -aza-dispiro[4.2.5.2]pentadec-

11 -yl)-ethyl]-amine

PA1140: (7-chloro-quinolin-4-yl)-[3-(6,7,14-trioxa-11 -aza-dispiro[4.2.5.2]pentadec- 11 -yl)-propyl]-amine PA 1103: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,4-diamine

PA1278: diphosphate salt of PA1103

PA1279: diacetate salt of PA1103 PA1280: disulphate salt of PA1103

PA1265: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[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 PA1252: N-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9-yl)-N'-(7-tπfluoromethyl- quinolin-4-yl)-cyclohexane-trans-1 ,4-diamine

PA1253: 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

PA1255: N-(7-chloro-quinolin-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-trioxa- spiro[5.5]undec-9-yl)-cyclohexane-trans-1 ,4-diamine

PA1308: N-(7-chloro-quinolin-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-chloro-quinolin-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-chloro-quinolin-4-yl)-{3-[(3,3-dimethyl-1 ,2,5-thoxa-spiro[5.5]undec-9- ylamino)-methyl]-adamantan-1 -ylmethyl}-amine

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

PA1271 : N-(7-chloro-quinolin-4-yl)-cis-2-[(3,3-dimethyl-1 ,2,5-thoxa- spirotδ.δlundec-θ-ylaminoj-methyll-cyclopentylamine

PA1269: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-1 ,4-diamine PA1259: N-(7-chloro-quinolin-4-yl)-N'-(6,7,14-thoxa-dispiro[4.2.5.2]pentadec-11 - yl)-cyclohexane-trans-1 ,4-diamine

PA1258: N-(7-chloro-quinolin-4-yl)-N'-(7,8,15-thoxa-dispiro[5.2.5.2]hexadec-12-yl)- cyclohexane-trans-1 ,4-diamine PA1256: 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

PA1268: N-(7-chloro-quinolin-4-yl)-N'-(9,9-dimethyl-7,8,13-trioxa-spiro[5.7]tπdec-3- yl)-cyclohexane-trans-1 ,4-diamine PA1260: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-cis-1 ,2-diamine

PA1188: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,2-diamine

PA1261 : N-(7-chloro-quinolin-4-yl)-cis-2-[(3,3-dimethyl-1 ,2,5-trioxa- spiroβ.Slundec-θ-ylaminoJ-methyll-cyclohexylamine

PA1207: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-1 ,3-diamine

PA1262: (7-chloro-quinolin-4-yl)-{3-[(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- ylamino)-nnethyl]-cyclohexylnnethyl}-annine PA1263: (7-chloro-quinolin-4-yl)-{4-[(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- ylamino)-methyl]-cyclohexylmethyl}-amine

PA1264: (7-chloro-quinolin-4-yl)-{4-[4-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- ylamino)-cyclohexylmethyl]-cyclohexyl}-amine

PA1278:N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,4-diamine, diphosphate

PA1279: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,4-diamine, diacetate

PA1280: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,4-diamine, disulphate PA1286: -(7-chloro-quinolin-4-yl)-N'-[-5-spiro-(3,3-dimethyl-1 ,2,5-trioxan-6-yl)- octahydro-cis-pentalen-2-yl]-cyclohexane-trans-1 ,4-diamine

PA1330: N-(7-chloro-quinolin-4-yl)-N'-cyclopropylmethyl-N'-(3,3-dimethyl-1 ,2,5- thoxa-spirotδ.δlundec-θ-yO-cyclohexane-i ^-diamine

PA1331 : N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-N'-isobutyl-cyclohexane-1 ,4-diamine

PA1332: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-N'-pentyl-cyclohexane-1 ,4-diamine PA1336: N⁴-(7-chloro-qu inol in-4-yl )- N⁴-[(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-

9-yl)-bicyclohexyl-4,4'-diannine

PA1338: N-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9-yl)-N'-(6-methoxy-quinolin- 8-yl)-cyclohexane-1 ,4-diamine;

The compounds hereinbefore may be prepared by following or adapting the procedures disclosed in WO 01/77105, WO 2005/049619 and WO 2007/144487.

Studies on the pharmacological properties of the coupling products of formula (I) according to the invention have shown that they have an anti- schistosomal activity.

In accordance with another of its features, the invention thus relates to pharmaceutical compositions for the prevention or treatment of schistosomiasis comprising, as an 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 selected in accordance with the pharmaceutical form and the desired administration method from the conventional excipients which are known to the person skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermic or rectal administration, the active ingredients of formula (I) above, or its possible salt, solvate or hydrate, may be administered in unit administration form, mixed with the conventional pharmaceutical excipients, in order to prevent or treat schistosomiasis. Suitable unit administration forms comprise oral forms, such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration, administration by inhalation, topical, transdermic, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application the compounds according to the invention may be used in creams, gels, ointments or lotions. Preferred administration routes are oral, rectal and injectable routes.

By way of example, a unit administration form of a compound according to the invention in the form of a tablet may comprise the following components:

Compound according to the invention 50.0 mg

Mannitol 223.75 mg Croscaramellose sodium 6.0 mg

Cornstarch 15.0 mg

Hydroxypropyl-methylcellulose 2.25 mg

Magnesium stearate 3.0 mg

There may be special cases where higher or lower doses are appropriate; doses of this type are included within the scope of the invention. According to conventional practice, the dose suitable for each patient is determined by the doctor in accordance with the method of administration, the weight of the patient and his response to treatment.

The present invention, in accordance with another of its features, also relates to a method for treating or preventing schistosomiasis which comprises the administration to a patient of an effective dose of a compound of formula (I) according to the invention, or one of the pharmaceutically acceptable salts or hydrates or solvates thereof. Example

1) Obtaining schistosomes

The host/parasite pair used for this study was constituted by a strain of

Brazilian Schistosoma mansoni supported on an albino variety of B. glabrata, also Brazilian, and maintained on a SWISS OF1 mouse.

Harvesting of eggs and infestation of molluscs: The S. mansoni eggs were removed from the liver of a mouse infested 10 weeks before.

A double shock, thermal and osmotic, caused the eggs to hatch, releasing the miracidium larvae. The miracidium were removed and placed in the presence of the molluscs. 24 hours later, the molluscs were placed in trays and kept at 25O at a balanced photopehod: 12-12.

Harvesting cercaria and infestation of mice: 5 weeks after exposure, the molluscs issued cercaria. The cercaria removed using a Pasteur pipette were placed in batches of 160 to 400 in small glass crystallisers and the skin of the abdomen of the mice was contacted with this solution for 45 minutes.

Recovery of the schistosomes: 21 to 49 days after infestation, the mice were killed and the parasites were recovered from the blood of the mouse. Adult schistosomes were recovered 49 days after infestation and schistosomules (larval form of schistosomes) were recovered 21 days after infestation. The blood was filtered and the schistosomes were removed using a micropipette and washed in a RPMI solution supplemented with 25 mM Hepes + 2 mM of L-glutamine. The schistosomes were incubated at 37 O.

2) Test for chemosensitivity

Each molecule was tested twice. The tests were carried out in 24-well plates for the schistosomules and in Petri dishes (3 cm in diameter) for the adult worms. Each well contained 1 ml_ and each Petri dish 3 ml_ of a RPMI solution supplemented with 25 mM Hepes + 2 mM of L-glutamine. Artemether and praziquantel were used as reference molecules. Between 9 and 29 schistosomules (average 14) and between 6 and 20 adult schistosomes (average 10) were placed in the recipients. The different molecules were then removed at the desired concentration and survival was measured at 15 min, 30 min, 45 min, 1 h, 1 h30, 2h, 3h, 4h, 5h, 6h, and 7 hours. Between each measurement the recipients containing the worms were incubated at 37O. A worm was considered to be dead if no external (muscular, suction...) or internal (digestive tract, excretory system ...) movement was observed.

A preliminary study made it possible to calibrate the range of reference molecules on the adult schistosomes and the schistosomules. On the adult schistosomes, 10, 5,1 and 0.25 μg/mL doses were tested for praziquantel and 300, 100, 50 and 10 μg/mL doses were tested for artemether. On the schistosomules, 10, 5 and 1 μg/mL were tested for praziquantel and 300, 100 and 50 μg/mL were tested for artemether. An untreated control was carried out for each stage.

The PA1259 molecule was tested at doses of 300, 100, 10 and 5 μg/mL on the schistosomules and on the adult schistosomes. For each experiment, three controls were carried out: a 10 μg/ml praziquantel control, a 300 μg/mL artemether control and an untreated control.

3; Results

Parasiticide effect of Artemether, Praziquantel and PA1259

Effect of the compounds^* on the schistosomules (D21 )

Compound Concentration (μg/mL) Time (hours)

Praziquantel 5 5

Artemether 300 6

PA1259 5 3 ^* The minimum concentration required to kill 100 % of cultured parasites and the time necessary to obtain this effect are indicated.

Effect of compounds^* on the adult schistosomes (D49)

Compound Concentration (μg/mL) Time (hours)

Praziquantel 10 4

Artemether** >300

PA1259 100 1 ,5

^* The minimum concentration required to kill 100 % of cultured parasites and the time necessary to obtain this effect are indicated.

** In the case of 300 μg/mL Artemether after 7 hours of incubation, 45 % of the schistosomes were still alive.

Claims

1. Compound for the prevention or treatment of schistosomiasis, said compound being based on the following formula (I):

(I) wherein: — A represents:

• a molecule residue selected from: an aminoquinoline of formula (Ma):

(Ha)

in which:

- R₄ represents a hydrogen atom or an alkyl group which may comprise from 1 to 5 carbon atoms or a cycloalkyl group which may comprise from 3 to 5 carbon atoms;

— B represents a cycloalkyl group which may comprise from 3 to 8 carbon atoms, optionally substituted with one or more groups selected from: a hydrogen atom, a hydroxyl group, an alkyl group which may comprise from 1 to 6 carbon atoms or a cycloalkyl group which may comprise from 3 to 6 carbon atoms,

• or B represents a bi- or tricyclic group which may comprise from 4 to 18 carbon atoms optionally substituted with one or more groups selected from a halogen atom, a hydroxyl group, an alkyl group which may comprise from 1 to 6 carbon atoms or a cycloalkyl group which may comprise from 3 to 6 carbon atoms,

• or B represents 2 cycloalkyl groups which may comprise from 3 to 6 carbon atoms, said cycloalkyls being bonded together by a single bond, or an alkylene chain which may comprise 1 or 2 carbon atoms;

• or B represents a linear or branched C1 -C5 alkylene chain;

• or B represents a -CH₂-CH₂-O-CH₂-CH₂- chain;

— m = 0, 1 or 2; n = 0, 1 or 2;

• either a cyclohexyl group when U = -CH<,

• or a piperidyl group when U = -N<,

• or a hydrocarbonated polycyclic structure optionally comprising a nitrogen atom, possibly comprising from 4 to 18 atoms,

— R₁ and R₂ are the same or different and represent a hydrogen atom;

— R_x and R_y form, together with Cj, a cyclic peroxide selected from the groups of formulae (Xl), (XII) and (XIII):

- trioxanes of formula (Xl):

in which R₃ represents 1 to 4 groups which are the same or different, or

- trioxepanes of formula (XII):

in which R₃ represents 1 to 6 groups which are the same or different, or

- trioxecanes of formula (XIII):

(XIII) in which R₃ represents 1 to 8 groups which are the same or different, where R₃ representing from 1 to 8 groups which are the same or different, occupying any positions on the carbon atoms with the peroxide cycle and being selected from the following atoms and groups: hydrogen, halogen, an -OH, -CF₃, -NO₂, -OCF₃ group, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 10 carbon atoms, or two R₃ groups carried by the same carbon atom of the peroxide cycle together forming a cycloalkyl group which may comprise from 3 to 7 carbon atoms or a bi- or tricyclic group which may comprise from 4 to 18 carbon atoms (which will therefore be arranged in a spiro position on the peroxide cycle);

- U represents a -CH< or -N< group;

- p represents 0 or 1 ; U representing -CH< when p=1 and U being bonded to -(CH₂)_n- by a single bond when p=0;

2. Compound of formula (I) according to claim 1 , wherein A, B, m, n, Z₁, Z₂, p=1 , U=-CH< and Z₁ + Z₂ + U + Cj, R₁, R₂, R₅, R_x, R_y are as defined in claim 1 , said alkyl groups possibly comprising from 1 to 5 carbon atoms, optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

3. Compound according to any one of the preceding claims, based on the following formula (1.2):

3

wherein R', R_4, B, Z₁, Z₂, Ci, C_j, R₁, R₂, R₃, Rs, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

4. Compound according to any one of the preceding claims, based on the following formula (1.3):

wherein R', R_4, B, R₃, R₅, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

5. Compound according to claim 1 based on the following formula (I.4):

wherein R', R₄, B, C_j, R₁, R₂, Z₁, Z₂, R_x, R_y, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

6. Compound according to any one of claims 1 to 5 based on the following formula (I.5):

wherein R', R₄ and B, Z₁, Z₂, C_j, R₁, R₂, R₃, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

7. Compound according to any one of claims 1 , 5 and 6 based on the following formula (1.6):

wherein R', R₄, B, R₃, m and n are as defined for the compound of formula (I); optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

8. Compound of formula (I) according to any one of the preceding claims, wherein B represents a group selected from:

c/s-1 ,2-methylenecyclopentyl, frans-1 , 2-cyclohexyl, c/s-1 ,2-cyclohexyl, c/s-1 ,2- methylenecyclohexyl, trans- 1 ,4-cyclohexyl, cis- 1 ,4-cyclohexyl, cis/trans- 1 ,4- cyclohexyl mixture, c/s/frans-1 , 3-cyclohexyl mixture, cis/trans- 1 ,3- dimethylenecyclohexyl mixture, c/s-1 ,4-dimethylenecyclohexyl, 4,4'-methylene-bis- cyclohexane.

9. Compounds according to any one of the preceding claims selected from: PA1079: (7-chloro-quinolin-4-yl)-{2-[2-(3,3-dimethyl-1 ,2,5-trioxa-9-aza- spiro[5.5]undec-9-yl)-ethoxy]-ethyl}-amine PA1110: (7-chloro-quinolin-4-yl)-[2-(7,8,16-thoxa-3-aza dispiro[5.2.5.2]hexadec-3- yl)-ethyl]-amine

11 -yl)-ethyl]-amine

PA1140: (7-chloro-quinolin-4-yl)-[3-(6,7,14-thoxa-11 -aza-dispiro[4.2.5.2]pentadec- 11 -yl)-propyl]-amine

PA 1103: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,4-diamine

PA1278: diphosphate salt of PA1103

PA1279: diacetate salt of PA1103

PA1280: disulphate salt of PA1103 PA1265: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[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

PA1252: N-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9-yl)-N'-(7-tπfluoromethyl- quinolin-4-yl)-cyclohexane-trans-1 ,4-diamine

PA1255: N-(7-chloro-quinolin-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-trioxa- spiro[5.5]undec-9-yl)-cyclohexane-trans-1 ,4-diamine

PA1308: N-(7-chloro-quinolin-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-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- ylJ-N'-ethyl-cyclohexane-cis-i ,4-diamine

PA1335: (7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-octahydro-pentalene-2,5-diamine PA1271 : N-(7-chloro-quinolin-4-yl)-cis-2-[(3,3-dimethyl-1 ,2,5-trioxa- spirotδ.δlundec-θ-ylaminoj-methyll-cyclopentylamine

PA1269: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-1 ,4-diamine

PA1259: N-(7-chloro-quinolin-4-yl)-N'-(6,7,14-thoxa-dispiro[4.2.5.2]pentadec-11 - yl)-cyclohexane-trans-1 ,4-diamine

PA1258: N-(7-chloro-quinolin-4-yl)-N'-(7,8,15-thoxa-dispiro[5.2.5.2]hexadec-12-yl)- cyclohexane-trans-1 ,4-diamine

PA1256: 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 PA1268: N-(7-chloro-quinolin-4-yl)-N'-(9,9-dimethyl-7,8,13-trioxa-spiro[5.7]tπdec-3- yl)-cyclohexane-trans-1 ,4-diamine

PA1260: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-cis-1 ,2-diamine PA1188: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,2-diamine

PA1262: (7-chloro-quinolin-4-yl)-{3-[(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- ylamino)-methyl]-cyclohexylmethyl}-amine

PA1263: (7-chloro-quinolin-4-yl)-{4-[(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- ylamino)-methyl]-cyclohexylmethyl}-amine PA1264: (7-chloro-quinolin-4-yl)-{4-[4-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- ylamino)-cyclohexylmethyl]-cyclohexyl}-amine

PA1280: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-cyclohexane-trans-1 ,4-diamine, disulphate

PA1286: -(7-chloro-quinolin-4-yl)-N'-[-5-spiro-(3,3-dimethyl-1 ,2,5-trioxan-6-yl)- octahydro-cis-pentalen-2-yl]-cyclohexane-trans-1 ,4-diamine PA1330: N-(7-chloro-quinolin-4-yl)-N'-cyclopropylmethyl-N'-(3,3-dimethyl-1 ,2,5- thoxa-spirotδ.δlundec-θ-yO-cyclohexane-i ^-diamine

PA1332: N-(7-chloro-quinolin-4-yl)-N'-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9- yl)-N'-pentyl-cyclohexane-1 ,4-diamine

PA1336: N⁴-(7-chloro-quinolin-4-yl)- N⁴-[(3,3-dimethyl-1 ,2,5-thoxa-spiro[5.5]undec-

9-yl)-bicyclohexyl-4,4'-diamine

PA1338: N-(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-9-yl)-N'-(6-methoxy-quinolin-

8-yl)-cyclohexane-1 ,4-diamine; optionally in the form of a base or an addition salt with an acid, in the form of a hydrate or a solvate, in racemic form, in the form of isomers and mixtures thereof, as well as the diastereiosomers thereof and mixtures thereof.

10. Pharmaceutical composition for the prevention or treatment of schistosomiasis, characterised in that it comprises a compound of formula (I) according to any one of claims 1 to 9.

11. Use of a compound of formula (I) according to any one of claims 1 to 9 to prepare a pharmaceutical composition for treating or preventing schistosomiasis.