EP2032561A2 - Doppelmoleküle mit einem peroxidderivat, ihre synthese und therapeutische verwendung - Google Patents

Doppelmoleküle mit einem peroxidderivat, ihre synthese und therapeutische verwendung

Info

Publication number
EP2032561A2
EP2032561A2 EP07788851A EP07788851A EP2032561A2 EP 2032561 A2 EP2032561 A2 EP 2032561A2 EP 07788851 A EP07788851 A EP 07788851A EP 07788851 A EP07788851 A EP 07788851A EP 2032561 A2 EP2032561 A2 EP 2032561A2
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
formula
group
compound
sub
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07788851A
Other languages
English (en)
French (fr)
Inventor
Bernard Meunier
Frédéric COSLEDAN
Alain Pellet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Original Assignee
Centre National de la Recherche Scientifique CNRS
Sanofi Aventis France
Palumed SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37719816&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2032561(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Centre National de la Recherche Scientifique CNRS, Sanofi Aventis France, Palumed SA filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP2032561A2 publication Critical patent/EP2032561A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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 hybrid molecules containing a peroxidic derivative, having in particular antimalarial activity, their synthesis and their therapeutic applications.
  • Malaria is one of the leading infectious causes of death in the world and affects every year 100 to 200 million people. The strong upsurge of the disease observed in recent years is due to several factors, including:
  • vectors namely anopheles, which become resistant to conventional and inexpensive insecticides, such as DDT (abbreviation for 1,1,1-trichloro-1-bis (p-chlorophenyl) -2,2-ethane);
  • DDT abbreviation for 1,1,1-trichloro-1-bis (p-chlorophenyl) -2,2-ethane
  • artemisinin a potent anti-malarial drug extracted from Artemisia annua
  • Artemisinin and some of its hemi-synthetic derivatives, such as artemether and artesunate have been shown to be very active on resistant strains of P. falciparum.
  • artemether and artesunate have been shown to be very active on resistant strains of P. falciparum.
  • synthetic antimalarial compounds which would be accessible at low cost, will therefore be measured.
  • such molecules are generally highly metabolized, thus making their use as a therapeutic substance less easy.
  • WO2005 / 04619 disclose hybrid molecules consisting of a compound with antimalarial properties and a peroxidic derivative. These coupling products, although effective, are however strongly metabolized.
  • ADME Absorption, Distribution, Metabolism, Elimination
  • the inventors have developed a new family of hybrid molecules, having an effective antimalarial activity and which also have improved ADME properties.
  • This new family of molecules corresponding to Compounds of formula (I) described below, in particular has improved metabolic stability, on human liver microsomes, thus confirming the interest of the compounds according to the invention for their use as a drug.
  • the invention thus relates to compounds of formula (I), their synthesis and their biological applications, in particular to treat parasitic diseases such as malaria.
  • A represents: a residue of molecule with antimalarial activity chosen from:
  • 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, -CF 3 , -OCF 3 , aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl group, said alkyl groups comprising from 1 to 5 carbon atoms; ,. a cycloalkyl or -O-cycloalkyl group, said cycloalkyl groups possibly containing from 3 to 5 carbon atoms,
  • R 3 and R b each represents independently of the other a hydrogen atom or an alkyl group comprising 1 to 5 carbon carbon; or else R a and R b , which may be identical or different, represent a cycloalkyl group which can contain from 3 to 5 carbon atoms, or else R 3 and R b form together with the nitrogen atom to which it is attached a pyrrolidinyl or piperidinyl group;
  • 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 with 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 else B represents a bicyclic or tricyclic group possibly comprising from 4 to 18 carbon atoms, optionally substituted by one or more groups chosen from a halogen atom, a hydroxyl group and an alkyl group which can comprise from 1 to 6 atoms. of carbon or a cycloalkyl group which may contain from 3 to 6 carbon atoms,
  • Or else B represents 2 cycloalkyl groups which may have from 3 to 6 carbon atoms, said cycloalkyls being linked together by a single bond or an alkylene chain which may contain 1 or 2 carbon atoms;
  • M and n independently of one another are 0, 1 or 2;
  • R 5 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,
  • R 5 represents a cycloalkyl group, a -C (O) -cycloalkyl group, a -C (O) O -cycloalkyl group or a C 1-3 -alkylene-cycloalkyl group, the said cycloalkyl groups possibly comprising from 3 to 6 carbon atoms;
  • Z 1 and Z 2 which may be identical or different, represent an alkylene radical which may contain from 1 to 4 saturated or unsaturated carbon atoms, the Zi + Z 2 + Ci + Cj combination thus representing:
  • a cycloalkyl group which can contain from 3 to 10 carbon atoms; or a polycyclic structure which may contain from 4 to 18 carbon atoms, one of Z 1 or Z 2 possibly representing a single bond between the carbon atoms Ci and Cj, it being understood that Z 1 and Z 2 can not represent a single bond at the same time;
  • - R 1 and R 2 identical or different, represent a hydrogen atom or a functional group capable of increasing the water solubility;
  • - R x and R y together form a cyclic peroxide comprising from 4 to 8 ring members and comprising 1 or 2 additional oxygen atoms in the ring structure (either in total of 3 to 4 oxygen atoms in the ring), Cj 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 any positions on the carbon atoms of the peroxide ring and being selected from the following atoms and groups: hydrogen, halogen, -OH, -CF 3 , -NO 2 , -OCF 3 , 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 from 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 contain 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;
  • R 3 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 R 3 group may itself be substituted with 1 to 6 substituents R 3 as defined above,
  • the residue A drains into the interior of the parasite the compound of formula (I) according to the invention, which then exerts an alkylating effect on the subject and / or the parasitic proteins.
  • 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.
  • halogen atom a fluorine, chlorine, bromine or iodine atom
  • alkyl group a saturated monovalent aliphatic group, linear or branched.
  • alkyl group a saturated monovalent aliphatic group, linear or branched.
  • radical or alkylene chain a divalent saturated, linear or branched aliphatic group.
  • a C 1-3 -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.
  • cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups examples of cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;
  • a bicyclic structure a structure comprising two saturated cyclic aliphatic groups comprising from 4 to 18 carbon atoms, said groups possibly being:
  • a tricyclic structure 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).
  • a fused tricyclic structure mention may be made of the group perhydroanthracene:
  • 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.
  • the system is polycyclic, at least one of the rings is aromatic.
  • phenyl, naphthyl, tetrahydronaphthyl and indanyl groups are examples of phenyl, naphthyl, tetrahydronaphthyl and indanyl groups;
  • 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.
  • the system is polycyclic, at least one of the rings is aromatic.
  • Nitrogen atoms can be in the form of N-oxides.
  • thiazolyl 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.
  • bicyclic heteroaryl groups mention may be made of the indolyl, benzofuranyl, chromen-2-on-yl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, indolizinyl, quinazolinyl, phthalazinyl and quinoxalinyl groups. , naphthyridinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl;
  • a cycloalkyl group which can contain from 6 to 8 saturated or unsaturated carbon atoms, said cycloalkyl group comprising one or more heteroatoms chosen 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 which may have from 1 to 18 carbon atoms, optionally substituted linear, said chain comprising one or more heteroatoms chosen from N, O and S.
  • residues facilitating bioavailability mention may be made of guanidinium, morpholino, peptide or polyamine residues;
  • an alkyl group may comprise from 1 to 5 atoms of carbon or a cycloalkyl group may contain from 3 to 5 carbon atoms.
  • R x, R y are as previously defined and R 5 represents a hydrogen atom or an alkyl group, a -C (O) -alkyl or -C (O) O- alkyl, said alkyl groups may contain from 1 to 5 carbon atoms, or R 5 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.
  • A represents an aminoquinoline of formula (IIa):
  • 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, -CF 3 , -OCF 3 , aryl, -O-aryl, heteroaryl, alkyl or -O-alkyl group, said alkyl groups comprising from 1 to 5 carbon atoms; ,
  • a cycloalkyl or -O-cycloalkyl group said cycloalkyl groups possibly containing from 3 to 5 carbon atoms,
  • R a and R b which may be identical or different, represent hydrogen atoms or an alkyl group comprising from 1 to 5 carbon atoms; or R a and R b , which may be identical or different, represent a cycloalkyl group which may contain from 3 to 5 carbon atoms, or else R a and R b together with the nitrogen atom to which it is attached form a pyrrolidinyl group or piperidinyl;
  • R 4 represents a hydrogen atom, an alkyl group may comprise 1 to 5 carbon atoms or R 4 represents a cycloalkyl group which may contain from 3 to 5 carbon atoms,
  • B represents a group chosen from: c / s-1, 2-methylenecyclopentyl, frans-1,2-cyclohexyl, and / or s-1, 2-cyclohexyl, c / s-1, 2-methylenecyclohexyl, trans ⁇ , 4-cyclohexyl, c / s-1,4-cyclohexyl, cis / trans-1,4-cyclohexyl mixture, c / s / mixture 1,1-Cyclohexyl, cis / trans- ⁇ , 3-dimethylenecyclohexyl, cis-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane.
  • R, R ', B 1 , B 2 and R 4 are as defined for the compound of formula (IIa) and B, Z 1 , Z 2 , Ci, C j , R 1 , R 2 , R x , R y , R 5 , m and n are as defined for the compound of formula (I).
  • R x and R y together form a peroxide cyclic compound comprising 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 identical groups or different from each other, occupying any positions on the carbon atoms of the peroxide ring.
  • peroxide rings may in particular consist of: trioxanes of formula (XI):
  • R 3 represents 1 to 4 groups, identical or different, as defined for the compound of formula (I) or - trioxepanes of formula (XII):
  • R 3 represents 1 to 6 groups, identical or different, as defined for the compound of formula (I), or
  • trioxecanes of formula (XIII):
  • the carbon Cj is as defined for the compounds of formula (I), that is to say that Cj corresponds to the carbon of junction between the cyclic peroxide and the a ring formed with the carbon Cj and the radicals Z 1 and Z 2 .
  • 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 ring carbon atom. peroxidic together form a cycloalkyl group which may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group may contain from 5 to 18 carbon atoms.
  • peroxidic together form a cycloalkyl group which may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group may contain from 5 to 18 carbon atoms.
  • R, R ', B 1 , B 2 and R 4 are as defined for the compound of formula (IIa) and B, Z 1 , Z 2 , Ci, C j , R 1 , R 2 , R 3 , R 5 , m and n are as defined for the compound of formula (I).
  • R, R ', B 1 , B 2 and R 4 are as defined in the compound of formula (Ma) and B, R 3 , R 5 , m and n are as defined for the compound of formula (I ).
  • B represents a group chosen from: c / s-1, 2-methylenecyclopentyl, trans- 1H-cyclohexyl, cs-1, 2-cyclohexyl, cs-1, 2-methylenecyclohexyl, trans, 4-cyclohexyl, cs-1,4-cyclohexyl, cis / trans-1 mixture, 4-cyclohexyl, cis / trans- ⁇ , 3-cyclohexyl mixture, cis / trans- ⁇ , 3-dimethylenecyclohexyl, c / s-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane mixture.
  • 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 may contain from 3 to 6 carbon atoms, • or B represents 2 cycloalkyl groups may contain from 3 to 6 carbon atoms, said cycloalkyls being connected to each other by a single bond or an alkylene chain may have 1 or 2 carbon atoms;
  • M and n independently of one another are 0, 1 or 2;
  • Z 1 and Z 2 which may be identical or different, represent an alkylene radical which may contain from 1 to 4 saturated or unsaturated carbon atoms, the Z 1 + Z 2 + Ci + Cj group thus representing:
  • a cycloalkyl group which may contain from 3 to 10 carbon atoms,
  • Z 1 or Z 2 may represent a single bond between the carbon atoms Ci and Cj, it being understood that Z 1 and Z 2 can not represent a single link at the same time;
  • - R 1 and R 2 represent a hydrogen atom; - R x and R y together form a cyclic peroxide comprising from 4 to 8 ring members and comprising 1 or 2 additional oxygen atoms in the ring structure (either in total of 3 to 4 oxygen atoms in the ring), Cj being one of the peaks of this cyclic peroxide, said cyclic peroxide being substituted a group R 3 , R 3 representing 1 to 8 groups identical or different from each other, occupying any positions on the carbon atoms of the peroxide ring and being selected from the following atoms and groups:
  • the invention also relates to a process for preparing the compound of formula (I).
  • R 1 , R 2 , Z 1 , Z 2 , R x and R y are as defined in the compounds of formula (I).
  • the coupling between the ketone and the primary amine is carried out in the presence of a reducing agent such as sodium cyanoborohydride, at room temperature, and an alcoholic solvent such as methanol, isopropanol or a mixture of alcohol. .
  • a reducing agent such as sodium cyanoborohydride
  • an alcoholic solvent such as methanol, isopropanol or a mixture of alcohol.
  • These compounds are, for example, used in a primary amine / ketone molar ratio of approximately 1.5, the reducing agent being used in a proportion of 0.7 equivalents / ketone.
  • Compounds of formula (II) may also be obtained by reaction of a triethylsilyldioxy alcohol or a suitable hydroperoxy alcohol with a diketone, such as 1,4-cyclohexadione of formula (XX) or cis-bicyclo [3.3. 0] octane-3,7-dione of formula (XXI):
  • trioxanes are obtained by reaction of a triethylsilyldioxy alcohol or a suitable hydroperoxy alcohol with a diketone, preferably 3 molar equivalents of diketone.
  • the reaction is carried out, for example, in the presence of para-toluenesulphonic acid, at room temperature for 30 minutes.
  • the functionalized trioxane is then purified. For example, column chromatography is used.
  • the coupling reaction of a compound of formula (III) with a compound of formula (II) is followed, if appropriate, by a reaction with a pharmaceutically acceptable acid, to obtain the coupling product in salt form.
  • a reaction with a pharmaceutically acceptable acid for this purpose, protonation of basic nitrogens is carried out by adding an organic or inorganic pharmaceutically acceptable acid.
  • the reaction can be carried out with 2 equivalents of acid.
  • the protonated product is then recovered and subjected to one or more purification steps if necessary.
  • the starting compounds and the reagents when their embodiment is not described, are commercially available or described in the literature, or they can be prepared according to methods described therein or which are known to humans. of career.
  • PA1019 (4.9 g, 18 mmol) is dissolved in 120 mL of MeOH and then 2.4 mL of 5.5M HCl in isopropanol is added under argon at room temperature. 2.4 g (12 mmol) of PA1004 ketone are then added and the mixture is left stirring for 1 hour. NaBH 3 CN (0.53 g, 8.4 mmol) previously dissolved in 25 mL of MeOH is then added to the mixture with stirring and under argon. The mixture is stirred at room temperature for 24 hours. 200 ml of distilled water and then 200 ml of CH 2 Cl 2 are added to the reaction medium and the organic phase is extracted by adding 200 ml of CH 2 Cl 2 .
  • the two isomers of PA1103 are separated by supercritical HPLC chromatography: Berger Prep SFC Supercritical Chromatography System. (Chiral phase: CHIRALPAK AD-H ⁇ m, Mobile phase: CO2 / polar modifier ⁇ ethanol (60% / 40%) (% by volume)). About 605 mg of PA1103 were dissolved in the ultrasound in about 25 ml of ethanol and then purified by supercritical HPLC chromatography. 116 mg of the first isomer, PA1249 and 127 mg of the second PA1250 isomer are recovered.
  • corresponding salts of PA1103 are synthesized (1a, 1b and 1c).
  • PA1103 (388 mg, 0.84 mmol) is dissolved in 4 mL of THF at room temperature and then 1.1 mL of a solution of 200 mg of AcOH in 2 mL of THF is added. After stirring for 1 h at room temperature, the precipitate is filtered off, washed with 0.5 mL of THF and dried in air. 1 C. Synthesis of the di-sulfate salt of PA1103 (PA1280):
  • reaction medium is then directly purified by chromatography (SiO 2 60ACC 70-200 ⁇ m, eluent: CH 2 Cl 2 , ether (95/5, v / v)).
  • the PA1019 compound (0.8 g, 2.8 mmol) is dissolved in 20 ml of MeOH and then 0.4 ml of 5.5M HCl in isopropanol is added under argon at room temperature. 0.38 g (1.8 mmoles) of PA1226 ketone are then added and the mixture is left stirring for 1 h. NaBH 3 CN (83 mg, 1.3 mmol) is then added to the mixture with stirring and under argon. The mixture is stirred at room temperature for 24 hours. The solvents are evaporated and the reaction medium is purified by chromatography on a silica column (eluent: CH 2 Cl 2 / Et 3 N, 80/20, v / v).
  • the mixture is then directly purified by flash-chromatography on a silica column (eluent: ethyl acetate / Et 3 N, gradient: 5 min, ethyl acetate / Et 3 N 98/2, v / v, 5 to 45 min: ethyl acetate / Et 3 N 98/2, v / v to ethyl acetate / Et 3 N 90/10, v / v, 45 to 65 min Ethyl acetate / Et 3 N 90/10 , v / v; 65 to 70 min: ethyl acetate / Et 3 N 90/10, v / v to ethyl acetate / Et 3 N 85/15, v / v, 70 to 95 min: Acetate d ethyl / Et 3 N 85/15, v / v).
  • 0.23 g (0.76 mmol) of 18 and 0.15 g (0.76 mmol) of PA1004 are mixed in 19 ml of CH 2 Cl 2 .
  • the mixture is stirred under argon for 24 h.
  • 0.23 g (1.1 mmol) of NaBH (OAc) 3 and 44 ⁇ L (0.76 mmol) of acetic acid are then added, and the mixture is stirred at ambient temperature for 12 hours.
  • 19 ml of a saturated aqueous solution of NaHCO 3 are then added .
  • the organic phase is recovered, dried over Na 2 SO 4 , filtered and the solvents are evaporated.
  • Strains of P. falciparum are continuously cultured according to the method of Trager and Jensen (Science, 1976, 193, 673-675): parasites are maintained in human red blood cells (O ⁇ ), diluted to 2% parasitaemia in RPMI 1640 medium supplemented with 25 mM Hepes + 24 mM NaHCO 3 + 2 mM L-glutamine and supplemented with 5% human serum from all groups. The parasites are incubated at 37 ° C., in a humid atmosphere and at 5% CO 2 .
  • the FcB1-Columbia and FcM29-Cameroon strains are respectively moderately (Cl 50 : 66nM) and very strongly (Cl 50 : 258nM) chloroquine-resistant.
  • the Cl 50 of artemisinin on these 2 strains are respectively 11 nM and 5 nM.
  • the antimalarial activity tests are carried out according to the radioactive micromethod of Desjardins et al. (Antimicrob Agents Chemother., 1979, 16, 710-718). Each molecule is tested in triplicate. The tests are carried out in 96-well microplates. Strains of P. falciparum are cultured in RPMI 1640 solutions supplemented with 5% human serum with 2% hematocrit and 1.5% parasitaemia. For each test, the parasites are incubated with decreasing concentrations of test compounds for 48 h at 37 ° C, in a humid atmosphere and at 5% CO 2 . Artemisinin and chloroquine di-phosphate are used as reference molecules.
  • the first dilution of the test compounds is carried out at 1 mg / ml in dimethylsulfoxide.
  • the dilution range of the successive daughter solutions is also carried out in dimethylsulfoxide.
  • Each daughter dilution is then diluted 1/50 in RPMI 1640 supplemented with 5% of human serum, all the dilutions being carried out at 37 ° C.
  • These dilutions are then added to the parasites in culture in the microplates.
  • the parasites are cultured in RPMI 1640 at 5% human serum and 1% dimethylsulfoxide.
  • the growth of the parasites is measured by the incorporation of tritiated hypoxanthine (added 24 hours after the beginning of the exposure to the test compound) and compared with the incorporation in the absence of the test compound (taken as 100%). .
  • Cl 50 values concentration required to inhibit parasite growth by 50% are determined by plotting the percent inhibition against the logarithm of the dose using GraphPad Prism 4 ® processing software (GraphPad software, Inc., 5755 Oberlin Drive, # 110, San Diego, CA 92121, USA).
  • Cl 50 of the compounds of formula (I) according to the invention are less than 1 ⁇ M. Of the strains used, these Cl 50 are, for most compounds of formula (I) tested, comparable to those of artemisinin, or better.
  • the IC50s of the compounds according to Example 1 on the FcM29-Cameroon strain are respectively equal to 6 nM for PA1103 and 4 nM for PA1188.
  • the aim of the invention is to take advantage of the properties of the compounds of the invention for their use as a medicament and for the preparation of pharmaceutical compositions with antimalarial properties.
  • the compounds according to the invention have been tested for their metabolic stability on human liver microsomes, in comparison with compounds of the state of the art.
  • the supernatant is analyzed by the high performance liquid chromatography method coupled to mass spectrometry (LC-MS / MS) and the degradation of each of the compounds tested is calculated as a percentage (%) with respect to T 0 .
  • microsomal fractions are prepared from human liver tissue from at least 12 different donors and frozen at -80 ° C.
  • the tissue is thawed and then dried, weighed and cut into thin strips before homogenization.
  • the homogenization of the fabric is carried out using a Potter-type homogenizer.
  • Tissue homogenates are then centrifuged at 10,000 g for 30 minutes at +4 ° C.
  • the supernatant is centrifuged at 105,000 g for 1 hour at + 4 ° C.
  • the pellet is finally resuspended in a final volume of KH 2 PO 4 / K 2 HPO 4 buffer containing 20% (v / v) glycerol (1 mL per 2 grams of tissue).
  • the hepatic microsomal fractions thus obtained are aliquoted (500 ⁇ l), rapidly frozen in liquid nitrogen and stored frozen at -80 ° C. until they are used.
  • the reaction is initiated by addition of 1 mM NADPH and incubated for 20 minutes at 37 ° C with shaking. The reaction is stopped by adding 1 volume of cold acetonitrile.
  • the compound according to Example 1 of the invention is about 3 times less degraded than chloroquine and about 10 times less degraded than the compounds of the state of the art.
  • the compound according to Example 1 of the invention is much more stable in human liver microsomes than the other compounds tested.
  • the compounds of the invention in addition to their good antimalarial activity, advantageously have a very good metabolic stability, making the compounds of the invention particularly interesting for their use in therapy.
  • the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).
  • the present invention relates to pharmaceutical compositions comprising, as active principle, 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.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) 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 malaria.
  • 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.
  • oral administration 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.
  • 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.
  • 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
  • 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 also relates to a method of treating or preventing malaria which comprises administering to a patient an effective dose of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof or hydrates or solvates thereof.
  • the invention also relates to biological reagents whose active ingredients are constituted by the compounds according to the invention. These reagents can be used as references or standards in studies of possible antimalarial activities.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP07788851A 2006-06-13 2007-06-08 Doppelmoleküle mit einem peroxidderivat, ihre synthese und therapeutische verwendung Withdrawn EP2032561A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0605235A FR2902100A1 (fr) 2006-06-13 2006-06-13 Molecules duales contenant un derive peroxydique, leur synthese et leurs applications en therapeutique
PCT/FR2007/000946 WO2007144487A2 (fr) 2006-06-13 2007-06-08 Molecules duales contenant un derive peroxydique, leur synthese et leurs applications therapeutiques

Publications (1)

Publication Number Publication Date
EP2032561A2 true EP2032561A2 (de) 2009-03-11

Family

ID=37719816

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07788851A Withdrawn EP2032561A2 (de) 2006-06-13 2007-06-08 Doppelmoleküle mit einem peroxidderivat, ihre synthese und therapeutische verwendung

Country Status (24)

Country Link
US (1) US20120122923A1 (de)
EP (1) EP2032561A2 (de)
JP (1) JP2009539946A (de)
KR (1) KR20090029208A (de)
CN (1) CN101466706A (de)
AP (1) AP2008004711A0 (de)
AR (1) AR061347A1 (de)
AU (1) AU2007259116A1 (de)
BR (1) BRPI0713739A2 (de)
CA (1) CA2665940A1 (de)
CR (1) CR10469A (de)
EA (1) EA200970002A1 (de)
EC (1) ECSP088958A (de)
FR (1) FR2902100A1 (de)
IL (1) IL195394A0 (de)
MA (1) MA30577B1 (de)
MX (1) MX2008015980A (de)
NO (1) NO20085308L (de)
PE (1) PE20080335A1 (de)
TN (1) TNSN08462A1 (de)
TW (1) TW200817376A (de)
UY (1) UY30413A1 (de)
WO (1) WO2007144487A2 (de)
ZA (1) ZA200810012B (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2924343A1 (fr) * 2007-12-04 2009-06-05 Palumed Sa Nouvelles utilisations therapeutiques de molecules duales contenant un derive peroxydique.
SG192769A1 (en) 2011-03-04 2013-09-30 Glaxosmithkline Ip No 2 Ltd Amino-quinolines as kinase inhibitors
TWI547494B (zh) 2011-08-18 2016-09-01 葛蘭素史克智慧財產發展有限公司 作為激酶抑制劑之胺基喹唑啉類
AR092529A1 (es) 2012-09-13 2015-04-22 Glaxosmithkline Llc Compuesto de aminoquinazolina, composicion farmaceutica que lo comprende y uso de dicho compuesto para la preparacion de un medicamento
AR092530A1 (es) 2012-09-13 2015-04-22 Glaxosmithkline Llc Compuesto de amino-quinolina, composicion farmaceutica que lo comprende y uso de dicho compuesto para la preparacion de un medicamento
RU2662810C2 (ru) 2013-02-21 2018-07-31 Глэксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед Хиназолины в качестве ингибиторов киназы
CN119822967B (zh) * 2024-12-24 2025-12-30 万华化学集团股份有限公司 一种hmda的生产方法

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2133620A1 (en) * 1993-10-28 1995-04-29 Werner Hofheinz Aminoquinoline derivatives
PT876346E (pt) * 1995-11-16 2002-01-30 Hoffmann La Roche Derivados de quinolina com actividade anti-malaria
PL343680A1 (en) * 1998-04-29 2001-08-27 Smithkline Beecham Plc Quinolones used as mrs inhibitors and bactericides
FR2807433B1 (fr) * 2000-04-06 2002-09-20 Centre Nat Rech Scient Molecules duales contenant un derives 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
WO2003070244A1 (en) * 2002-02-22 2003-08-28 Abbott Laboratories Antagonist of melanin concentrating hormone and their uses
SE0202134D0 (sv) * 2002-07-08 2002-07-08 Astrazeneca Ab Therapeutic agents
US20050256157A1 (en) * 2002-08-23 2005-11-17 Chiron Corporation Combination therapy with CHK1 inhibitors
CA2496164C (en) * 2002-08-23 2010-11-09 Chiron Corporation Benzimidazole quinolinones and uses thereof
US20050197350A1 (en) * 2003-03-31 2005-09-08 Taisho Pharmaceutical Co., Ltd. Novel quinoline, tetrahydroquinazoline, and pyrimidine derivatives and methods of treatment related to the use thereof
HU227684B1 (en) * 2003-08-29 2011-11-28 Sanofi Aventis Adamantane and azabicyclo-octane and nonane derivatives and their use as dpp-iv inhibitors
FR2862304A1 (fr) * 2003-11-14 2005-05-20 Centre Nat Rech Scient Molecules duales racemiques ou achirales contenant un derive peroxydique, leur synthese et leurs applications therapeutiques
JP2007517868A (ja) * 2004-01-07 2007-07-05 アストラゼネカ アクチボラグ 治療薬ｉ
CA2571360C (en) * 2004-06-18 2014-11-25 3M Innovative Properties Company Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines useful in inducing cytokine biosynthesis in animals
FR2889525A1 (fr) * 2005-08-04 2007-02-09 Palumed Sa Nouveaux derives de polyquinoleines et leur utilisation therapeutique.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007144487A2 *

Also Published As

Publication number Publication date
WO2007144487A2 (fr) 2007-12-21
TNSN08462A1 (en) 2010-04-14
CR10469A (es) 2009-02-26
AP2008004711A0 (en) 2008-12-31
CN101466706A (zh) 2009-06-24
KR20090029208A (ko) 2009-03-20
JP2009539946A (ja) 2009-11-19
AU2007259116A1 (en) 2007-12-21
CA2665940A1 (fr) 2007-12-21
UY30413A1 (es) 2008-01-31
MX2008015980A (es) 2009-03-26
WO2007144487A3 (fr) 2008-02-07
TW200817376A (en) 2008-04-16
US20120122923A1 (en) 2012-05-17
NO20085308L (no) 2009-03-12
IL195394A0 (en) 2009-08-03
ECSP088958A (es) 2009-01-30
EA200970002A1 (ru) 2009-06-30
MA30577B1 (fr) 2009-07-01
ZA200810012B (en) 2010-05-26
FR2902100A1 (fr) 2007-12-14
BRPI0713739A2 (pt) 2013-06-18
PE20080335A1 (es) 2008-05-22
AR061347A1 (es) 2008-08-20
AU2007259116A8 (en) 2009-04-30

Similar Documents

Publication Publication Date Title
EP0946546B1 (de) Piridin-2-yl-methylamin-derivate, verfahren zu deren herstellung und ihre verwendung als arzneimittel
CA2761663C (fr) Derives de 7-aza-spiro[3.5]nonane-7-carboxylates, leur preparation et leur application en therapeutique
WO2003084943A9 (fr) Derives de terphenyle, leur preparation, les compositions pharmaceutiques en contenant
KR20040018538A (ko) Ｕｋ-2ａ의 엑소사이클릭 에스테르 또는 이의 유도체의환원성 분해 및 이로부터 형성된 생성물
EP2032561A2 (de) Doppelmoleküle mit einem peroxidderivat, ihre synthese und therapeutische verwendung
FR2891829A1 (fr) Derives de la 4-amino-quinazoline, leur preparation et leur application en therapeutique
JPH04338383A (ja) 置換されたベンゾキサゼピン類及びベンゾチアゼピン類
EP0346207B1 (de) 4-Amino-3-carboxynaphthyridin-Derivate, ihre Herstellung und pharmazeutische Zusammensetzungen
FR2880023A1 (fr) Derives de n-[(4,5-diphenyl-3-alkyl-2-thienyl) methyl] amine leur preparation et leur application en therapeutique
EP1440075B1 (de) Neue heteroaromatische amidderivate von 3beta aminoazabicyclooctanen, verfahren zu ihrer herstellung und ihre therapeutische verwendung
WO2005035488A2 (fr) Derives de thiophene-2-carboxamide et leurs utilisation comme antagonistes des recepteurs cb1 des cannabinoides
EP0591027A1 (de) Piperidin-Derivate, ihre Herstellung und ihre therapeutische Anwendung
FR2891825A1 (fr) Derives de la 1-amino-isoquinoline, leur preparation et leur application en therapeutique
EP1687312B1 (de) Ein peroxyderivat enthaltende duale moleküle, deren synthese und deren therapeutische anwendungen
EP1664055B1 (de) 9-aminopodophyllotoxinderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese derivate enthalten
US7423152B2 (en) Process for the manufacture of intermediates in camptothecin production
CN1310920C (zh) 消旋和光活胡桐素a及其类似物的制备方法
CA2502515A1 (fr) Derives de pyrrolo (3,4-c) carbazole et de pyrido (2,3-b) pyrrolo (3,4-e) indole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2827864A1 (fr) Nouveaux derives de benzo[b]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
MC1285A1 (fr) Derives d'isoquinoleine
EP0412898A1 (de) Oxazolopyridinderivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen
EP0000306A1 (de) Substituierte Hexahydro-benzopyrano(3,2-c)pyridine, Verfahren zu ihrer Herstellung und diese enthaltende Medikamente
JP2006248938A (ja) 含ホウ素キナゾリン誘導体
EP1561753A2 (de) Benzo[b]Chromennapthyridin-7-on- und Pyrano[2',3':7,8]quino[2,3-b]quinoxalin-7-on-Derivate, Verfahren zu ihrer Herstellung, diese enthaltende pharmazeutische Zusammensetzungen und ihre antitumoralen Eigenschaften zur Behandlung von Krebs
HK1133427A (en) Dual molecules containing a peroxide derivative, their synthesis and therapeutic uses

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090113

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

17Q First examination report despatched

Effective date: 20090330

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: PALUMED S.A.

Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (C.N.

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (C.N.

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20130823