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WO2009071553A1 - Nouvelles utilisations thérapeutiques de molécules doubles contenant un dérivé de peroxyde - Google Patents

Nouvelles utilisations thérapeutiques de molécules doubles contenant un dérivé de peroxyde Download PDF

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Publication number
WO2009071553A1
WO2009071553A1 PCT/EP2008/066651 EP2008066651W WO2009071553A1 WO 2009071553 A1 WO2009071553 A1 WO 2009071553A1 EP 2008066651 W EP2008066651 W EP 2008066651W WO 2009071553 A1 WO2009071553 A1 WO 2009071553A1
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WIPO (PCT)
Prior art keywords
quinolin
chloro
dimethyl
spiro
trioxa
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Ceased
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PCT/EP2008/066651
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English (en)
Inventor
Bernard Meunier
Frédéric COSLEDAN
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Palumed SA
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Palumed SA
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Priority to CN2008801238819A priority Critical patent/CN101909627A/zh
Priority to BRPI0819895A priority patent/BRPI0819895A8/pt
Priority to AP2010005307A priority patent/AP2010005307A0/en
Publication of WO2009071553A1 publication Critical patent/WO2009071553A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • 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).
  • 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.
  • 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):
  • - 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, -CF 3 , -OCF 3 group, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 5 carbon atoms,
  • 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;
  • R 4 represents a hydrogen atom or an alkyl group which may comprise from 1 to
  • — 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
  • R 5 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;
  • Z 1 and Z 2 are the same or different and represent a-(CH 2 ) 2 - radical, Z 1 + Z 2 + U + Cj thus representing:
  • Z 1 or Z 2 possibly representing a single bond between the U and Cj atoms, it being impossible for Z 1 and Z 2 to represent a single bond at the same time;
  • R 1 and R 2 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):
  • R 3 represents 1 to 4 groups which are the same or different, or
  • R 3 represents 1 to 8 groups which are the same or different, where
  • R 3 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, -CF 3 , -NO 2 , -OCF 3 group, aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl, said alkyl groups comprising from 1 to 10 carbon atoms, or two R 3 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 ;
  • 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.
  • - 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.
  • a Ci-3-alkylene group represents a linear or branched, divalent carbon chain comprising from 1 to 3 carbon atoms, 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 means a saturated, cyclic aliphatic group. Examples are the cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;
  • bicyclic structure means a structure comprising two saturated cyclic aliphatic groups comprising from 4 to 18 carbon atoms, said groups possibly being:
  • 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:
  • adamantyl group which is a tricyclic structure comprising 10 carbon atoms:
  • 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.
  • 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.
  • 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.
  • 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 second group of compounds of formula (I) based on the following formula (I.2):
  • R', R 4, B, Z 1 , Z 2 , Ci, C j , Ri, R 2 , R 3 , R 5 , 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):
  • R', R 4 , B, R 3 , R 5 , 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.
  • R', R 4 , B, C j , Ri, R2, Zi, Z 2 , 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):
  • R', R 4 and B, Zi, Z 2 , C j , Ri, R 2 , 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
  • R', R 4 , B, R 3 , 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.
  • B represents a group selected from: c/s-1 ,2-methylenecyclopentyl, frans-1 , 2-cyclohex
  • 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.
  • 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-
  • 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-t ⁇ fluoromethyl- 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- spirot ⁇ . ⁇ lundec- ⁇ -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-
  • PA1268 N-(7-chloro-quinolin-4-yl)-N'-(9,9-dimethyl-7,8,13-trioxa-spiro[5.7]t ⁇ dec-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- spiro ⁇ .Slundec- ⁇ -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-spirot ⁇ . ⁇ lundec- ⁇ -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 N 4 -(7-chloro-qu inol in-4-yl )- N 4 -[(3,3-dimethyl-1 ,2,5-trioxa-spiro[5.5]undec-
  • 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.
  • 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.
  • 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.
  • 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 rectal administration forms and implants.
  • the compounds according to the invention may be used in creams, gels, ointments or lotions.
  • Preferred administration routes are oral, rectal and injectable routes.
  • a unit administration form of a compound according to the invention in the form of a tablet may comprise the following components:
  • 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.
  • 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.
  • the host/parasite pair used for this study was constituted by a strain of
  • 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.
  • 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.
  • 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.
  • the PA1259 molecule was tested at doses of 300, 100, 10 and 5 ⁇ g/mL on the schistosomules and on the adult schistosomes. For each experiment, three controls were carried out: a 10 ⁇ g/ml praziquantel control, a 300 ⁇ g/mL artemether control and an untreated control.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention concerne la nouvelle utilisation thérapeutique de molécules hybrides contenant un dérivé de peroxyde pour traiter la bilharziase ou la schistosomiase.
PCT/EP2008/066651 2007-12-04 2008-12-02 Nouvelles utilisations thérapeutiques de molécules doubles contenant un dérivé de peroxyde Ceased WO2009071553A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN2008801238819A CN101909627A (zh) 2007-12-04 2008-12-02 含有过氧化物衍生物的二元分子的新治疗用途
BRPI0819895A BRPI0819895A8 (pt) 2007-12-04 2008-12-02 Usos terapêuticos de moléculas duplas que contêm um derivado de peróxido
AP2010005307A AP2010005307A0 (en) 2007-12-04 2008-12-02 New therapeutic uses of dual molecules containing a peroxide derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0759550A FR2924343A1 (fr) 2007-12-04 2007-12-04 Nouvelles utilisations therapeutiques de molecules duales contenant un derive peroxydique.
FR0759550 2007-12-04

Publications (1)

Publication Number Publication Date
WO2009071553A1 true WO2009071553A1 (fr) 2009-06-11

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/066651 Ceased WO2009071553A1 (fr) 2007-12-04 2008-12-02 Nouvelles utilisations thérapeutiques de molécules doubles contenant un dérivé de peroxyde

Country Status (6)

Country Link
KR (1) KR20100102127A (fr)
CN (1) CN101909627A (fr)
AP (1) AP2010005307A0 (fr)
BR (1) BRPI0819895A8 (fr)
FR (1) FR2924343A1 (fr)
WO (1) WO2009071553A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2340829A4 (fr) * 2008-07-01 2012-05-23 Univ Okayama Nat Univ Corp Nouvel agent antischistosomique
JP2013538881A (ja) * 2010-07-13 2013-10-17 ビーエーエスエフ ソシエタス・ヨーロピア 高官能性のウレタン基を有するポリイソシアネート
CN109843872A (zh) * 2017-09-20 2019-06-04 杭州英创医药科技有限公司 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物

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WO2001077105A1 (fr) * 2000-04-06 2001-10-18 Centre National De La Recherche Scientifique (C.N.R.S.) Molecules duales contenant un derive peroxydique, leur synthese et leurs applications therapeutiques
US6486199B1 (en) * 2001-06-21 2002-11-26 Medicines For Malaria Venture Mmv International Centre Cointrin Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040039008A1 (en) * 2002-06-21 2004-02-26 Medicines For Malaria Ventures Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040186168A1 (en) * 2002-06-21 2004-09-23 Medicines For Malaria Venture Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
WO2005049619A1 (fr) * 2003-11-14 2005-06-02 Centre National De La Recherche Scientifique Molecules duales contenant un derive peroxydique, leur synthese et leurs applications therapeutiques
FR2902100A1 (fr) * 2006-06-13 2007-12-14 Sanofi Aventis Sa Molecules duales contenant un derive peroxydique, leur synthese et leurs applications en therapeutique

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WO2001077105A1 (fr) * 2000-04-06 2001-10-18 Centre National De La Recherche Scientifique (C.N.R.S.) Molecules duales contenant un derive peroxydique, leur synthese et leurs applications therapeutiques
US6486199B1 (en) * 2001-06-21 2002-11-26 Medicines For Malaria Venture Mmv International Centre Cointrin Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040039008A1 (en) * 2002-06-21 2004-02-26 Medicines For Malaria Ventures Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040186168A1 (en) * 2002-06-21 2004-09-23 Medicines For Malaria Venture Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
WO2005049619A1 (fr) * 2003-11-14 2005-06-02 Centre National De La Recherche Scientifique Molecules duales contenant un derive peroxydique, leur synthese et leurs applications therapeutiques
FR2902100A1 (fr) * 2006-06-13 2007-12-14 Sanofi Aventis Sa Molecules duales contenant un derive peroxydique, leur synthese et leurs applications en therapeutique

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LAURENT S. A. L., ET AL.: "Synthesis of "trioxaquantel" derivatives as potential new antischistosomal drugs", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2008, pages 895 - 913, XP002472160 *
SHAOHONG LU ET AL: "Evaluation of the anthelmintic effects of artesunate against experimental Schistosoma mansoni infection in mice using different treatment protocols", PARASITOLOGY INTERNATIONAL, vol. 55, no. 1, March 2006 (2006-03-01), pages 63 - 68, XP002472158, ISSN: 1383-5769 *
XIAO SHU-HUA ET AL: "In vitro and in vivo activities of synthetic trioxolanes against major human schistosome species.", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY APR 2007, vol. 51, no. 4, April 2007 (2007-04-01), pages 1440 - 1445, XP002472157, ISSN: 0066-4804 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2340829A4 (fr) * 2008-07-01 2012-05-23 Univ Okayama Nat Univ Corp Nouvel agent antischistosomique
JP2013538881A (ja) * 2010-07-13 2013-10-17 ビーエーエスエフ ソシエタス・ヨーロピア 高官能性のウレタン基を有するポリイソシアネート
CN109843872A (zh) * 2017-09-20 2019-06-04 杭州英创医药科技有限公司 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物

Also Published As

Publication number Publication date
KR20100102127A (ko) 2010-09-20
BRPI0819895A2 (pt) 2015-05-19
CN101909627A (zh) 2010-12-08
BRPI0819895A8 (pt) 2016-01-26
FR2924343A1 (fr) 2009-06-05
AP2010005307A0 (en) 2010-06-30

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