EP2032561A2

EP2032561A2 - Dual molecules containing a peroxide derivative, their synthesis and therapeutic uses

Info

Publication number: EP2032561A2
Application number: EP07788851A
Authority: EP
Inventors: Bernard Meunier; Frédéric COSLEDAN; Alain Pellet
Original assignee: Centre National de la Recherche Scientifique CNRS; Sanofi Aventis France; Palumed SA
Current assignee: Centre National de la Recherche Scientifique CNRS
Priority date: 2006-06-13
Filing date: 2007-06-08
Publication date: 2009-03-11
Also published as: AR061347A1; MA30577B1; TW200817376A; TNSN08462A1; IL195394A0; EA200970002A1; BRPI0713739A2; AP2008004711A0; CA2665940A1; JP2009539946A; AU2007259116A8; MX2008015980A; PE20080335A1; ZA200810012B; FR2902100A1; UY30413A1; KR20090029208A; WO2007144487A3; NO20085308L; CN101466706A

Abstract

The invention concerns dual molecules corresponding to formula (I): in which: - A represents a molecular residue with antimalarial activity of formula (IIa) or (IIIa) or a residue facilitating bioavailability; - B represents a cycloalkyl group potentially substituted, or B represents a bi- or tricyclic group capable of being substituted, or B represents 2 cycloalkyl groups linked together through either a single bond or an alkylene chain; - m and n represent independently of one another 0, 1 or 2; - R5 represents a hydrogen atom, an alkyl, cycloalkyl or C1-3-alkylene-cycloakyl group; - Z1 and Z2 represent an alkyl radical, the group Z1 + Z2 + Ci + Cj representing a mono- or polycyclic structure, with one of the Z1 or Z2 being able to represent a single bond; - R1 and R2, identical or different, represent a hydrogen atom or a functional group capable of increasing hydrosolubility; - Rx and Ry forming together a cyclic peroxide including 4 to 8 links and including 1 or 2 additional oxygen atoms in the cyclic structure, possibly substituted by one or more R3 groups; as a base or a salt to be added to an acid, as a hydrate or solvate, in racemic form, isomers and their mixtures, in addition to their diastereoisomers and their mixtures. Preparation method and use as medications with antimalarial activity.

Description

Dual molecules containing a peroxidic derivative, their synthesis and their therapeutic applications

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);

- the increase of the population in the areas at risk and, mainly,

the resistance of numerous strains of Plasmodium falciparum, a parasite responsible for the deadly forms of the disease, to the drugs conventionally used, such as chloroquine and mefloquine.

The discovery of artemisinin, a potent anti-malarial drug extracted from Artemisia annua, has drawn attention to molecules with, like artemisinin, an endoperoxide function. 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. However, the high cost of these naturally occurring compounds and the vagaries of supply limit their use. The value of synthetic antimalarial compounds, which would be accessible at low cost, will therefore be measured. In addition, such molecules are generally highly metabolized, thus making their use as a therapeutic substance less easy. International applications published under the numbers WO 01/77105 and

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.

It therefore appears necessary to search for new compounds having an effective antimalarial activity, while having improved pharmacological properties, including ADME properties (Absorption, Distribution, Metabolism, Elimination), making them particularly suitable for their use as a drug.

For this purpose, 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.

The subject of the invention is compounds of formula (I):

A- (CH ₂ ) _m B (CH ₂ ) _n

(I) in which: A represents: a residue of molecule with antimalarial activity chosen from:

An aminoquinoline of formula (IIa):

(IIa) in which:

R and R ', which are identical or different, each represent one or more substituents (for example 1 to 5) occupying distinct positions on the rings to which they are attached, chosen from:

. a hydrogen or halogen atom, a -OH, -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,

. -NO ₂ or -N (R ₃₁ R _b), wherein R ₃ and R _b, identical or different, 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;

- R ₄ represents a hydrogen atom or an alkyl group may contain from 1 to 5 carbon atoms or R ₄ represents a cycloalkyl group may contain from 3 to 5 carbon atoms, - B ₁ represents a nitrogen atom and B ₂ represents a -CH = chain, or B ₁ represents a -CH = chain and B ₂ represents a nitrogen atom.

. a group of formula (Wa):

R ₆ -CHOH- (UIa) in which R ₆ represents an aryl radical, preferably a 9-phenanthrenyl or a nitrogenous heterocyclic residue, preferably a 4-quinolinyl optionally substituted with one or more (for example from 1 to 5) groups; R as defined for the compound of formula (IIa);

Or A represents a residue facilitating the bioavailability, the latter having one or more heteroatoms chosen from N, O and S in a mono- or polycyclic molecule which may contain from 6 to 18 carbon atoms, saturated or unsaturated or in a chain which may have from 1 to 18 optionally substituted linear carbon atoms, such as a guanidinium, morpholino, peptide or polyamine residue;

B represents a cycloalkyl group which may contain from 3 to 8 carbon atoms, optionally substituted 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,

Or else 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:

Or 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;

. or two 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,

. or else two groups R ₃ carried by the same carbon atom of the peroxidic ring which can together form a cycloalkyl group which can comprise from 3 to 7 carbon atoms or a bicyclic or tricyclic group which can comprise from 4 to

18 carbon atoms (which will therefore be located spiro position on the peroxide cycle).

Advantageously, 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.

In the definition of compounds of formula (I) above and in the following, unless otherwise stated in the text, the following terms mean:

halogen atom: a fluorine, chlorine, bromine or iodine atom;

alkyl group: a saturated monovalent aliphatic group, linear or branched. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups;

radical or alkylene chain: a divalent saturated, linear or branched aliphatic group. By way of example, a 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. By way of examples, mention may be made 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:

. merged, that is, they have a common link between them. By way of example, mention may be made of the perhydronaphthyl group:

. or bridged, that is to say that at least 2 atoms of the bicyclic structure are connected by a single bond or a carbon chain may contain from 1 to 4 carbon atoms. may mention:

bicyclo [3.2.1] octyl

. or else in spiro junction, that is to say that they are connected by a common carbon atom. By way of example, mention may be made of the cyclopentane-spiro-cyclobutyl group:

a tricyclic structure: a structure comprising 3 saturated cyclic aliphatic groups comprising from 4 to 18 carbon atoms, said groups possibly being fused (as defined above) or bridged (as defined above). As an example of a fused tricyclic structure, mention may be made of the group perhydroanthracene:

As an example of a bridged tricyclic structure, mention may be made of the adamantyl group which is a tricyclic structure comprising 10 carbon atoms:

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

a cyclic peroxide group: a cyclic alkyl group comprising 2 adjacent oxygen atoms;

an aryl group: a monocyclic or polycyclic aromatic system comprising from 6 to 18 carbon atoms, preferably from 6 to 14 carbon atoms and preferably from 6 to 10 carbon atoms. When the system is polycyclic, at least one of the rings is aromatic. By way of examples, mention may be made of phenyl, naphthyl, tetrahydronaphthyl and indanyl groups;

a heteroaryl group: monocyclic or polycyclic aromatic system comprising from 5 to 18 ring members, preferably from 5 to 14 ring members and preferably from 5 to 10 ring members and comprising one or more heteroatoms such as nitrogen, oxygen or of sulfur. When the system is polycyclic, at least one of the rings is aromatic. Nitrogen atoms can be in the form of N-oxides. By way of examples of monocyclic heteroaryl groups, mention may be made of thiazolyl, thiadiazolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl and pyridazinyl groups. As examples of 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;

- residue facilitating bioavailability:. 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.

As examples of residues facilitating bioavailability, mention may be made of guanidinium, morpholino, peptide or polyamine residues;

functional group capable of increasing the water solubility of the molecule dual: a group preferably chosen from -COOH, -OH or -N (R ₃₁ R _b ) with R _a and R _b , identical or different, representing a hydrogen atom, an alkyl group may comprise from 1 to 5 atoms of carbon or a cycloalkyl group may contain from 3 to 5 carbon atoms.

Among the compounds that are the subject of the invention, there may be mentioned a first group of compounds of formula (I) in which A, B, m, n, Z ₁ , Z ₂ , the set Z ₁ + Z ₂ + Ci + Cj , _Ri> R2, 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.

Among the compounds that are subjects of the invention, there may be mentioned a second group of compounds of formula (I) in which: A represents an aminoquinoline of formula (IIa):

(IIa) in which: R and R ', which are identical or different, each represent one or more substituents (for example 1 to 5) occupying distinct positions on the rings to which they are attached, chosen from:

. a hydrogen or halogen atom, a -OH, -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,

. -NO ₂ or -N (R ₃₁ R _b ), wherein 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 ₁ represents a nitrogen atom and B ₂ represents a -CH = link, or Bi represents a -CH = link and B ₂ represents a nitrogen atom.

Among the compounds which are the subject of the invention, there may be mentioned a third group of compounds of formula (I) in which A represents an aminoquinoline of formulas (Nb) or (IIc) which follow:

(iib) (Ile) in which R, R 'and R ₄ are as defined for the compound of formula (Ma).

Among the compounds of the invention, there may be mentioned a fourth group of compounds of formula (I) in which 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, transΛ, 4-cyclohexyl, c / s-1,4-cyclohexyl, cis / trans-1,4-cyclohexyl mixture, c / s / mixture 1,1-Cyclohexyl, cis / trans-λ, 3-dimethylenecyclohexyl, cis-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane.

Among the compounds which are the subject of the invention, there may be mentioned a fifth group of compounds of formula (I) in which A represents an aminoquinoline nitrogen-containing heterocycle of formula (IIa) and which corresponds to formula (1.1) which:

in which 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).

In the compounds 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. Such peroxide rings may in particular consist of: trioxanes of formula (XI):

in which R ₃ represents 1 to 4 groups, identical or different, as defined for the compound of formula (I) or - trioxepanes of formula (XII):

in which R ₃ represents 1 to 6 groups, identical or different, as defined for the compound of formula (I), or

trioxecanes of formula (XIII):

(XIII) wherein R ₃ represents 1 or 8 groups, identical or different, as defined for the compound of formula (I).

In the formulas (Xl), (XII) and (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 .

In the formula (Xl), 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. Among the compounds that are the subject of the invention, there may be mentioned a sixth

in which 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).

Among the compounds that are the subject of the invention, there may be mentioned a seventh

in which 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 ).

Among the compounds of the invention, mention may in particular be made of the compounds of formulas (1.1), (I.2) and (1.3) in which 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-λ, 3-cyclohexyl mixture, cis / trans-λ, 3-dimethylenecyclohexyl, c / s-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane mixture.

Among the compounds of the invention, there may be mentioned an eighth group of compounds of formula (I) in which: A represents an aminoquinoline of formulas (Hb) or (IIc) which follow:

(Hb) (Ile) wherein R, R 'and R ₄ are as defined for the compound of formula (IIa);

B represents a group chosen from: • a cycloalkyl group which may contain from 3 to 8 carbon atoms, optionally substituted with one or more groups chosen from: a halogen atom, a hydroxyl group, an alkyl group which can comprise from 1 to 6 carbon atoms or a cycloalkyl group 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;

- R ₅ represents a hydrogen atom; 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:

Or a cycloalkyl group which may contain from 3 to 10 carbon atoms,

Or a polycyclic structure that may contain from 4 to 18 carbon atoms, one of 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:

. 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,

. or else two groups R ₃ carried by the same carbon atom of the peroxidic ring which may together form a cycloalkyl group which may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group may contain from 4 to 18 carbon atoms (which will be therefore located in a spiro position on the peroxide cycle).

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned in particular a ninth group of compounds chosen from: PA1103, PA1265, PA1251, PA1252, PA1253, PA1255, PA1271, PA1269, PA1259, PA1258, PA1256, PA1268, PA1260, PA1188, PA1261, PA1207, PA1262, PA1263, PA1264.

Finally, among the compounds of formula (I) that are subjects of the invention, mention may be made in particular of a tenth group of compounds chosen from:

PA1305, PA1308, PA1329, PA1333, PA1335, PA1278, PA1279, PA1280, PA1286, PA1330, PA1331, PA1332, PA1336.

The references indicated above refer to the compounds exemplified below.

The invention also relates to a process for preparing the compound of formula (I).

According to the invention, to prepare the compound of formulas (I), a compound of formula (III) is reacted which follows:

wherein B, R, R ', B ₁ , B ₂ and R ₄ are as defined for the compound of formula (IIa) and B, m and n are as defined for the compound of formula (I), with a compound of formula (II) which follows:

wherein 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. .

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.

The compounds of formula (III) are obtained by reacting, for example, a compound of formula (V) which follows:

(V) wherein B ₁ , B ₂ , R and R 'are as defined in the compound of formula

(Ma), it being understood that at least one of R or R 'represents a halogen atom, with a diamine of formula (IV) which follows:

_/ (CH ₂ ) _m - B- (CH ₂ ) _n NH ₂

(IV)

The synthesis of the peroxidic derivatives of formula (II) containing the residues R _x and Ry can generally be carried out by analogy with the techniques presented in the book by S. Pataï: "The Chemistry of Peroxides", John Wiley and Sounds Ltd, 1983.

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):

^(XX) (XXI) to yield trioxane derivatives of the general formula (IIa):

wherein Z ₁ , Z ₂ , R 1, R ₂ Q, C _j and R ₃ are as defined for the compound of formula (I).

These 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. 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.

The examples which follow describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and only illustrate the present invention. In the following: Me = methyl, Et = ethyl,

HPLC = High Pressure Liquid Chromatography, min = minute (s)

1 - Synthesis of PA 1103. (Figure 1)

Λ / - (7-chloro-quinolin-4-yl) -Λ / ^I - (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) - cyclohexane-trans-1 , 4-diamine

1-1: Synthesis of 3-methyl-3-r (triethylsilyl) dioxy-butanol 1

The method is described by P. M. O'Neill et al. (Tetrahedron Letters, 42, 2001, 4569-4571)

1-2: Synthesis of 3,3-dimethyl-1,2,5-trioxa-spiror5.51undecan-9-one:

PA1004

7.84 g (35 mmol) of 3-methyl-3 - [(triethylsilyl) dioxy] butanol 1 and 11.96 g (106 mmol) of 1,4-cyclohexanedione are solubilized in 200 ml of chloroform. 4.63 g (24 mmol) of para-toluenesulphonic acid are added at room temperature under argon, and the mixture is left stirring for 30 minutes. The reaction medium is then directly purified by chromatography (SiO ₂ 60ACC 70-200μm, eluent: CH ₂ Cl ₂ , ether (95/5, v / v)). The solvents of the phases containing PA1004 are evaporated and 2.13 g (yield = 30%) of the compound is obtained in the form of a white solid. Melting Point: 71 ⁰ C.

1-3: Synthesis of Λ / - (7-chloro-quinolin-4-yl-cyclohexane-trans-1,4-diamine: PA1019

58 g (0.29 moles) of 4,7-dichloroquinoline and 100 g (0.87 moles) of trans-1,4-diaminocyclohexane are heated at 135 ° C. for 1 hour and then the mixture is heated to 190 ^° C. over 45 ^° C. min. When the reaction medium has solidified, the heating is stopped and the mixture is allowed to return to ambient temperature. 300 ml of 1M NaOH are added to the reaction medium and a precipitate is formed. The medium is filtered and the precipitate washed with 1 L of distilled water. The precipitate is dried and engaged without further purification in the next step: 73 g (Yield = 91%). Obtaining PA1019 follows the purification protocol described below: 3 g of crude are solubilized in 10 ml of CH ₂ Cl _2, then 50 ml of n-hexane are added and the mixture is filtered. The precipitate obtained is dissolved under heat in a minimum of ethyl acetate and then poured over 5 times the volume of n-hexane and filtered. PA1019 is obtained in the form of a beige powder (yield = 37%). Melting Point: 174 ° C.

1-4: Synthesis of PA1103

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 . This organic phase is dried over Na ₂ SO ₄ , filtered and the solvents are evaporated. The crude product thus obtained is purified by flash-chromatography on a silica column (eluent: CH ₂ Cl ₂ / Et ₃ N, gradient: 10 min: CH ₂ Cl ₂ / Et ₃ N 98/2, v / v; 10 to 60 min: CH ₂ Cl ₂ / Et ₃ N 98/2, v / v to CH ₂ Cl ₂ / Et ₃ N, 90/10, v / v, 60 to 90 min CH ₂ Cl ₂ / Et ₃ N, 90 / 10, v / v). The phases containing PA1103 are combined, evaporated and the crude is redissolved hot in 400 mL of ethyl acetate and 400 mL of distilled water. This organic phase is washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated. 3.2 g (yield = 58%) of the compound PA1103 is obtained in the form of a powder. Melting Point: 176 ° C (dec).

¹ H NMR (250 MHz, 298 K, CDCl ₃ ): δ, ppm: 8.49 (d, J = 5.4 Hz, 1H, HCZ), 7.93 (d, J = 1, 9 Hz, 1H , HC8 '), 7.62 (d, J = 9.0 Hz, 1H, HC5'), 7.32 (dd, J = 9.0Hz, J = 2.2Hz, 1H, HC6 ') , 6.40 (d, J = 5.5 Hz, 1H, HC3 '), 4.87 (d, J = 7.2 Hz, 1H, NH), 3.90-3.20 (m, 2H + 1H, HC5 + HC11 '), 2.90-2.50 (m, 1H + 1H + 1H, HC14' + HC11 + HCcyclohexyl), 2.25-1, 18 (m, 15H + 1H + 3H, HC cyclohexyl + NH + HC7.8), 1.09 (bs, 3H, HC7.8). MS (DCI / NH ₃ > 0) m / z (%): 460 (MH +, 100%).

1-5: Separation of the two isomers of PA1103

The two isomers of PA1103 are separated by supercritical HPLC chromatography: Berger Prep SFC Supercritical Chromatography System. (Chiral phase: CHIRALPAK AD-H δμm, 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.

PA1249:

Melting Point: 176 ° C (dec).

¹ H NMR (400MHz, 298K, CDCl _3): δ ppm: 8.54 (d, J = 5.2 Hz, 1H, HC2 '), 7.97 (d, J = 2Hz, 1H, HC8 '), 7.64 (d, J = 8.8 Hz, 1H, HC5'), 7.37 (dd, J = 8.8 Hz, J = 2 Hz, 1H, HC6 '), 6 , 45 (d, J = 5.2 Hz, 1H, HC3 '), 4.82 (d, J = 6.8 Hz, 1H, NH), 3.77-3.49 (m, 2H + 1H, HCI + HCI '), 2.90-2.69 (m, 1H + 1H + 1H, HC14' + HCI + HC cyclohexyl), 2.29-1.25 (m, 15H + 1H + 3H) , HC cyclohexyl + NH + HC7.8), 1, 15 (bs, 3H, HC7.8). LCMS (MeOH> 0) m / z (%): 460.2 (MH +, 100%).

PA1250:

Melting Point: 175 ° C (dec).

¹ H NMR (400MHz, 298K, CDCl _3): δ ppm: 8.53 (d, J = 5.4 Hz, 1H, HC2 '), 7.97 (d, J = 2Hz, 1H, HC8 '), 7.64 (d, J = 8.8 Hz, 1H, HC5'), 7.37 (dd, J = 8.8 Hz, J = 2 Hz, 1H, HC6 '), 6, 45 (d, J = 5.2 Hz, 1H, HC3 '), 4.82 (d, J = 7.2 Hz, 1H, NH), 3.84-3.47 (m, 2H + 1H) , HC5 + HC11 '), 2.94-2.70 (m, 1H + 1H + 1H, HC14' + HC11 + HCcyclohexyl), 2.28-1.23 (m, 15H + 1H + 3H) , HC cyclohexyl + NH + HC7.8), 1, 11 (bs, 3H, HC7.8). LCMS (MeOH> 0) m / z (%): 460.2 (MH +, 100%).

By way of example, corresponding salts of PA1103 are synthesized (1a, 1b and 1c).

1a. Synthesis of the di-phosphate salt of PA1103 (PA1278):

The previously obtained compound PA1103 (403 mg, 0.88 mmol) is dissolved in 5 ml of EtOH at 30 ^° C. and then 1.2 ml of a solution of 405 mg of phosphoric acid (H ₃ PO _{4) are added.} ) at 85% in 2 mL of EtOH. After stirring for 30 minutes at room temperature, the precipitate is filtered off, washed with 1.5 ml of EtOH and then dried under vacuum at 45.degree.

1b. Synthesis of the di-acetate salt of PA1103 (PA1279):

The compound 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):

The compound PA1103 (360 mg, 0.78 mmol) is dissolved in 4.5 ml of EtOH and then 1 ml of a solution of 310 mg of H ₂ SO ₄ in 2 ml of EtOH is slowly added. After stirring for 3 hours at room temperature, the precipitate is filtered off and then dried under vacuum at 45 ^° C.

2 - Synthesis of PA 1265, (Figure 2)

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

2-1: Synthesis of (cis-4-Fe / f-butoxycamonylamino-cyclohexyl) -carbarnic acid Fe / f-butyl ester

5 g (43 mmol) of a commercial mixture of cis / trans-1,4-cyclohexane diamine are dissolved in 50 ml of CH ₂ Cl ₂ . 18.8 g (86 mmol) of di-tert-butyl dicarbonate pre-dissolved in 50 ml of CH ₂ Cl _{2 are} added dropwise. The mixture is left stirring overnight at room temperature. 500 ml of distilled water and 200 ml of CH ₂ Cl ₂ are added and the organic phase is extracted and then dried over Na ₂ SO ₄ and filtered. The solvents are evaporated, giving a white powder: 11.3 g (Yield = 83%). These 11.3 g of the mixture cis / trans- (4-fur-butoxycarbonylamino-cyclohexyl) -carbamic acid fert-butyl ester are dissolved in 100 ml of acetonitrile. The mixture is refluxed for 20 min and then filtered. The filtrate is cooled in an ice bath for 1 hour and a precipitate appears. The mixture is then filtered. 4.8 g (yield = 36%) of cis- (4-te / t-butoxycarbonylamino-cyclohexyl) -carbamic acid tert-butyl ester 2 as d ¹ a formwork powder.

Melting Point: 144 ° C (dec).

2-3: Synthesis of cis-1,4-cyclohexane diamine 3 4.8 g (15 mmol) of cis- (4-Fe / t-butoxycarbonylamino-cyclohexyl) -carbamic acid ferf-butyl ester 2 are dissolved in 50 mL of ethyl acetate and 25 mL of 3M HCl in ethyl acetate are added to the mixture. The mixture is left stirring overnight at room temperature. The pH is then rocked by addition of 15 g of NaOH and the aqueous phase is extracted with 300 ml of CH ₂ Cl ₂ . The organic phase is then dried over Na ₂ SO ₄ and filtered. The solvents are evaporated. 1.7 g (quant.) Of the compound is obtained in the form of a colorless oil.

2-4: Synthesis of Λ- (7-chloro-quinolin-4-yl) -cis-1,4-cyclohexanediamine 4, 771 g (4.1 mmol) of 4,7-dichloroquinoline are heated and 1.4 g (12 mmol) of cis- 1, 4-diaminocyclohexane at 135 ° C for 1 h 45 and then the mixture is heated to 190 ⁰ C in 45 min. When the reaction medium has solidified, the heating is stopped and the mixture is allowed to return to ambient temperature. 10 ml of 1M NaOH are added. The reaction medium is left stirring overnight. The aqueous phase is removed and the crude is dissolved in 5 ml of methanol and then 50 ml of diethyl ether are added. The precipitate formed is filtered, redissolved in 1 mL of CH ₂ Cl ₂ and then 100 mL of n-hexane are added. After filtration, 0.5 g (yield = 44%) of compound 4 is obtained in the form of a beige powder.

2-5:

Compound 4 (0.5 g, 1.8 mmol) is dissolved in 20 ml of MeOH and then 0.2 ml of 5.5M HCl in isopropanol is added under argon at room temperature. 0.24 g (1.2 mmoles) of PA1004 ketone are then added and the mixture is left stirring for 1 h. NaBH ₃ CN (53 mg, 0.8 mmol) is then added to the mixture with stirring and under argon. The reaction medium is stirred at room temperature for 24 hours. The solvents are evaporated under vacuum and the crude reaction product is then purified by chromatography on a silica column (eluent: CH ₂ Cl ₂ ZEt ₃ N, 90/10, v / v). The phases containing PA1265 are combined, evaporated and the crude is redissolved in 100 mL of ethyl acetate. This organic phase is washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated to an oil. This oil is precipitated by addition of 1 mL of CHCl ₃ and 50 mL of n-hexane yielding a powder identified as PA1265: 10 mg (yield = 2%). Melting Point: 140 ⁰ C (dec). ¹ H NMR (250MHz, 298K, CDCl _3): δ ppm: 8.48 (d, J = 5.4 Hz, 1H, HC2 '), 7.92 (d, J = 1, 9 Hz, 1 H, HC8 '), 7.71 (d, J = 8.9 Hz, 1H, HC5'), 7.32 (dd, J = 8.9 Hz, J = 2.1 Hz 1H, HCQ ' ), 6.39 (d, J = 5.5 Hz, 1H, HC3 '), 5.16 (t, J = 6.2 Hz, 1H ₁ NH), 3.90-3.20 (m , 2H + 1H, HC5 + HC11 '), 2.87-2.21 (m, 1H + 1H + 1H, HC14' + HC11 + HC cyclohexyl), 2.25-1.18 (m, 15H + 3H, HC cyclohexyl) + HC7.8), 1.09 (bs, 3H, HC7.8). MS (DCI / NH3> 0) m / z (%): 460 (MH +, 100%). 3 - Synthesis of PA 1251, (Figure 3) γ- (2,8-bis-trifluoromethyl-quinolin-4-yl) -α- (3,3-dimethyl-1,2,5-trioxaporo [5.5] undec-9-yl) -cycIohexane-trans-1,4-diamine

3-1: Synthesis of trans-N- (2,8-bis-trifluoronethyl-αuinolin-4-yl) -cyclohexane

1,4-diamine

2 g (6.6 mmol) of 4-chloro-2,8-bis (trifluoromethyl) quinoline and 2.3 g (20 mmol) of trans-1,4-diaminocyclohexane are heated at 155 ° C. for 2 hours. The mixture is allowed to return to ambient temperature and 13 ml of 1M NaOH are added to the reaction medium, resulting in a precipitate. The medium is filtered and the precipitate washed with 2 × 20 ml of distilled water. The crude is dissolved in 30 ml of CH ₂ Cl ₂ and then 50 ml of n-hexane are added and the mixture is filtered. The precipitate obtained is dissolved in 100 ml of CH ₂ Cl ₂ , the organic phase is washed with 100 ml of distilled water and then dried over Na ₂ SO ₄ , filtered and evaporated. 1. 9 g (yield = 76%) of compound 5 are obtained in the form of a powder. PF: 173 ^° C.

3-2:

Compound 5 (0.56 g, 1.5 mmol) is dissolved in 12 mL of MeOH and then 0.2 mL of 5.5M HCl in isopropanol is added under argon at room temperature. 0.20 g (1 mmol) of PA1004 ketone is then added and the mixture is stirred for 1 h. NaBH ₃ CN (44 mg, 0.8 mmol) previously dissolved in 2 mL of MeOH is then added to the mixture with stirring and under argon. The reaction medium is stirred at room temperature for 24 hours. The solvents are evaporated under vacuum and the crude reaction product is then purified by chromatography on a silica column (eluent: CH ₂ Cl ₂ / Et ₃ N, 95/5, v / v). The phases containing PA1251 are combined, evaporated and the crude is redissolved in 100 mL of ethyl acetate. This organic phase is washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated. The powder thus obtained is ground and 15 ml of n-hexane are added. This suspension is filtered and 1 mL of ether is added, the mixture evaporated under vacuum. 0.21 g (yield = 37%) of compound PA1251 is obtained in the form of a powder. Melting Point: 168 ° C (dec). ¹ H NMR (250MHz, 298K, CDCl _3): δ ppm: 8.04 (d, J = 7.2 Hz, 1H, HC7 '), 7.91 (d, J = 8.4 Hz, 1H, HC5 ¹ ), 7.53 (dd, J = 7.8 Hz, J = 7.9 Hz, 1H, HC6 ¹ ), 6.77 (s, 1H, HC3). )

5.09 (d, J = 7.3Hz, 1H, NH), 3.90-3.30 (m, 2H + 1H + 1H, HCI + HCI + HCI),

2.90-2.50 (m, 1H + 1H + 1H, HC14 '+ HC cyclohexyl), 2.27-1, (m, 14H + 1H + 3H,

HCcyclohexyl + NH + HC7.8), 1.10 (bs, 3H, HC7.8). MS (DCI / NH ₃ > 0): m / z (%): 562 (MH +, 100%).

4- Synthesis of PA 1252. (Figure 4) γ- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -Λ- (7-trifluoromethylquinolin-4-) yl) -cyclohexane-trans-1,4-diamine

4-1: Synthesis of trans-N- (7-trifluoromethyl-quinolin-4-yl) -cyclohexane-1,4-diamine 6

10 g (43 mmol) of 4-chloro-7-trifluoromethylquinoline and 14.8 g (129 mmol) of trans-1,4-diaminocyclohexane are heated at 130 ^° C. for 1 h and then the mixture is heated to 190 ^° C. h, the mixture is then allowed to return to room temperature. 85 ml of 1 M NaOH are added to the reaction medium, resulting in a precipitate. The medium is filtered and the precipitate washed with 250 ml of distilled water. The crude is dissolved in 100 ml of CH ₂ Cl ₂ and then 900 ml of n-hexane are added and the mixture is filtered, the precipitate obtained is then again solubilized in 500 ml of CH ₂ Cl ₂ , the mixture is filtered, the organic phase recovered and washed with 750 mL of distilled water and then dried over Na ₂ SO ₄ , filtered and concentrated to a volume of 100 mL. 900 ml of n-hexane are poured on this crude and a precipitate appears. This precipitate is filtered and dried. 4.8 g (yield = 36%) of compound 6 are obtained in the form of a powder. Mp 186.5 ° C.

4-2:

Compound 6 (0.46 g, 1.5 mmol) is dissolved in 12 mL of MeOH and then 0.2 mL of 5.5M HCl in isopropanol is added under argon at room temperature. 0.20 g (1 mmol) of PA1004 ketone are then added and the mixture is left stirring for 1 h. NaBH ₃ CN (44 mg, 0.8 mmol) previously dissolved in 2 mL of MeOH is then added to the mixture with stirring and under argon. The reaction medium is stirred at room temperature for 24 hours. The solvents are evaporated under vacuum and the crude reaction product is then purified by chromatography on a silica column (eluent: CH ₂ Cl ₂ / Et ₃ N, 95/5, v / v). The phases containing PA1252 are combined, evaporated and the crude is redissolved in 100 mL of ethyl acetate. This organic phase is washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated. 0.29 g (yield = 59%) of compound PA1252 is obtained in the form of a powder. Melting Point: 166.5 ^° C (dec).

¹ H NMR (250 MHz, 298 K, CDCl ₃ ): δ, ppm: 8.60 (d, J = 5.4 Hz, 1H, HC 2 '), 8.24 (s, 1H, HC 8'), 7 , 79 (d, J = 8.7 Hz, 1H, HC5 '), 7.56 (dd, J = 8.9 Hz, J = 1.7 Hz, 1H, HC6'), 6.51 ( d, J = 5.4 Hz, 1H, HC 3 '), 4.87 (d, J = 7.2 Hz, 1H, NH), 3.90-3.30 (m, 2H + 1H, HC5 + HC11 '), 2.90 to 2.50 (m, 1 H + 1 H + 1 H, HC14' + HC11 + HCcyclohexyle), 2,27- 1, 20 (m, 15H + 1H + 3H ₁ HCcyclohexyl + NH + HC7.8), 1.10 (bs, 3H, HC7.8). MS (DCI / NH ₃ > 0): m / z (%): 494 (MH +, 100%).

5- Synthesis of PA 1253. (Figure 5)

W- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -α- (6-dimethylaminoquinolin-4-yl) -cyclohexane-trans-1,4-diol diamine

5-1: Synthesis of trans-N- (6-β-, β-dimethyl-quinolin-4-yl) -cyclohexane-1,4-diamine 7 1, 5 g (7.3 mmol) of 4-chloro-6-dimethylaminoquinoline (prepared according to the method described by Riegel et al., J. Am Chem Soc, 1946, 68, 1264) and 2.5 g (22 mmol) of trans-1,4-diaminocyclohexane at 130 ° C. for 2 hours and then at 190 ^° C. for 9 hours. The mixture is then allowed to return to ambient temperature and 15 ml of 1 M NaOH are added to the reaction medium, giving an oil. The oil is washed with 10 ml of distilled water and 20 ml of CH ₂ Cl ₂ are added. The organic phase is decanted, washed with 3 × 20 mL of distilled water and then dried over Na ₂ SO ₄ , filtered and concentrated to a volume of 2 mL. 100 ml of n-hexane are then poured on the crude and a precipitate appears. This precipitate is filtered and dried. 0.5 g (yield = 24%) of compound 7 is obtained in the form of a powder.

5-2:

Compound 7 (0.43 g, 1.5 mmol) is dissolved in 12 mL of MeOH and then 0.2 mL of 5.5M HCl in isopropanol is added under argon at room temperature.

0.20 g (1 mmol) of PA1004 ketone is then added and the mixture is stirred for 1 h. NaBH ₃ CN (44 mg, 0.8 mmol) previously dissolved in 2 mL of MeOH is then added to the mixture. The reaction medium is stirred and under argon at room temperature for 24 hours. The solvents are then evaporated under vacuum and the crude reaction product is purified by chromatography on a silica column (eluent: CH ₂ Cl ₂ ZEt ₃ N, 95/5, v / v). The phases containing PA1253 are combined, evaporated and the crude is solubilized in 100 mL of ethyl acetate. This organic phase is washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated. 0.25 g (yield = 53%) of compound PA1253 is obtained in the form of a powder. Melting Point: 193 ° C (dec). ¹ H NMR (250 MHz, 298 K, CDCl ₃ ): δ, ppm: 8.35 (d, J = 5.2 Hz, 1 H ₁ HC 2 '), 7.86 (d, J = 9.3 Hz, 1H , HC8 '), 7.30 (dd, J = 9.3 Hz ₁ J =' 2.6 Hz, 1H, HCT), 6.53 (d, J = 2.6 Hz, 1H, HC5 ') , 6.38 (d, J = Hz, 1H, HC3 '), 4.56 (d, J = 7.1Hz, 1H, NH), 3.90-3.30 (m, 2H + 1), H, HCI + HCI '), 3.06 (s, 6H, HCI5 + HC16'), 2.90-2.50 (m, 1H + 1H + 1H, HC14 + HC1 + HC-cyclohexyl), 2.27-1, (m, 15H + 1H + 3H, HC cyclohexyl + NH + HC7.8), 1.10 (bs, 3H, HC7.8). MS (DCI / NH ₃ > 0): m / z (%): 469 (MH +, 33%).

6 - Synthesis of PA 1255 (Figure 6)

N- (7-Chloro-quinolin-4-yl) -N- (3,4-dimethyl-1,2,5-trioxa-5-yl) [5.5] undec-9-yl) -cyclohexane-trans-1,4- diamine

6-1: Synthesis of 3-hydroxypropoxybutan-2-ol 8

150 ml of ether and 8.3 ml (147 mmol) of 50% H ₂ O ₂ in solution in water are mixed in an Erlenmeyer flask at 0 ^° C. To this mixture is added in small portions 10 g (83 mmol) of anhydrous MgSO ₄ . The mixture is stirred for 20 min and then filtered on a frit. The filtrate is then poured into a 500 ml flask containing a mixture of 10 ml of ether, 0.23 g (0.7 mmol) of MoO ₂ (acac) ₂ and 1 g (14 mmol) of cis-2. 3-epoxybutane. The mixture is left at room temperature with stirring 24h. 100 ml of distilled water and 100 ml of ethyl acetate are added and the organic phase is extracted. The organic phase is washed with 100 ml of saturated NaCl solution and then dried over MgSO ₄ and filtered. The solvents are then evaporated. 0.5 g (yield = 34%) of compound 8 is obtained in the form of a colorless oil.

6-2: Synthesis of 3,4-dimethyl-1,2,5-trioxa-spiror5.51undecan-9-one: PA1226 0.5 g (4.8 mmol) of 3-Hydroperoxybutan-2 are solubilized -ol 8 and 1, 61 g (14 mmol) of 1,4-cyclohexanedione in 50 mL of chloroform. 0.6 g (3.3 mmol) of para-toluenesulphonic acid are added at room temperature under argon, and the mixture is left stirring for 30 minutes. The reaction medium is then directly purified by chromatography (SiO ₂ 60ACC 70-200μm, eluent: CH ₂ Cl ₂ , ether (95/5, v / v)). The solvents of the phases containing PA1226 are evaporated. 0.38 g (yield = 39%) of compound PA1226 is obtained in the form of a colorless oil.

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 phases containing PA1255 are combined, evaporated and the crude is solubilized in 200 mL of ethyl acetate. This organic phase is washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated. 0.58 g (yield = 67%) of compound PA1255 is obtained in the form of a powder. Melting Point: 166 ° C (dec). ¹ H NMR (250 MHz, 298 K, CDCl ₃ ): δ, ppm: 8.50 (d, J = 5.4 Hz, 1H, HC 2 '), 7.94 (d, J = 2.1 Hz, H, HC8 '), 7.65 (d, J = 9.1Hz, 1H, HC5'), 7.34 (dd, J = 8.9Hz, J = 2.1Hz, 1H, HC6 '; ), 6.46 (d, J = 5.5Hz, 1H, HC3 '), 4.93 (s, 1H, NH), 4.01-3.71 (m, 1H + 1H, HC5 + HC6), 3.48 (m, 1H, HCl), 2.90-2.66 (m, 1H + 1H + 1H, HC14 + HC1 + HC cyclohexyl), 2.24-1. , (M, 15H + 1H, HC cyclohexyl + NH), 1, 14-1, 06 (m, 6H, HC7.8). MS (DCI / NH ₃ > 0) m / z (%): 460 (MH +, 100%).

7 - Synthesis of PA 1305. (Figure 7)

N- (6-trifluoromethoxy-quinolin-4-yl) -Λ / ^I - (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec-9-yl) -cyclohexane-trans-1, 4-diamine

7-1: Synthesis of 4-chloro-6-trifluoromethoxyquinoline 9

1 g (4.4 mmol) of 6-trifluoromethoxy-quinolin-4-ol are solubilized in 4.1 ml (44 mmol) of POCI ₃ . The mixture is heated at 115 ° C for 3 h. After returning to ambient temperature, the POCI ₃ is evaporated under vacuum. To the residue obtained are added 25 ml of distilled water and then a few drops of NH ₄ OH in order to bring the pH of the solution around pH 8-9. The compound is then extracted by adding 60 mL of CH ₂ Cl ₂ . The organic phase is dried over Na ₂ SO ₄ , filtered and the solvents are evaporated, resulting in a 0.9 g (yield = 92%) of a brown liquid identified as being 9.

7-2: Synthesis of N- (6-trifluoromethoxy-quinolin-4-yl) -cyclohexane-1,4-diamine

0.5 g (2 mmol) of 4-chloro-6-trifluoromethoxy-quinoline 9 are solubilized in 2 ml of N-methylpyrrolidinone. 0.7 g (6 mmol) of trans-1,4-diaminocyclohexane and 280 μl (2 mmol) of triethylamine are added to this solution; the mixture is then heated at 190 ^° C. for 6 h 30. The mixture is allowed to return to ambient temperature and 17 ml of 1 M NaOH and then 30 ml of ethyl acetate are added to the reaction medium. This mixture is heated at 50 ^° C. and the organic phase is recovered. The extraction is repeated by adding 40 ml of distilled water to the previously obtained aqueous phase and 40 ml of ethyl acetate. The organic phases are then combined, dried with Na ₂ SO ₄ , filtered and the solvents are evaporated yielding 0.4 g (Yield = 61%) of 10.

7-3: Synthesis of PA1305

10 (0.35 g, 12 mmol) are dissolved in 10 mL of MeOH under argon at room temperature. 158 μL (0.8 mmol) of 5.5 M HCl in isopropanol and 0.16 g (0.8 mmol) of PA1004 ketone are then added to this mixture. The mixture is stirred for 1 h. NaBH ₃ CN (0.035 g, 0.5 mmol) previously dissolved in 2 mL of MeOH is then added to the mixture with stirring and under argon. The medium is stirred at room temperature for 24 hours. 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). The phases containing PA1305 are combined. This organic phase is washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated. We obtain 0.19 g (Rdt = 31%) of the compound PA1305 as a powder. Melting Point: 165 ° C (dec).

¹ H NMR (250MHz, 298K, CDCl _3): δ ppm: 8.54 (d, J = 5.4 Hz, 1H, HC2 '), 7.99 (d, J = 9.5 Hz, 1 H, HC8 ¹ ), 7.49-7.47 (m, 1H, HC7 '+ HCS'), 6.46 (d, J = 2.3Hz, 1H, HCZ '), 4.68 (d. , J = 7.1Hz, 1H, NH), 3.90-3.20 (m, 2H + 1H, HC5 + HC11 '), 2.90-2.50 (m, 1H + 1H, HCI + NH), 2.23-1, (m, 17H + 3H, HC cyclohexyl + HC7.8), 1.09 (bs, 3H, HC7.8). MS (DCI / NH ₃ > 0) m / z (%): 510 (MH +, 37%).

8 - Synthesis of PA 1308. (FIG. 8) N- (7-Chloroquinolin-4-yl) -N '- (3,3-dimethyl-1,2,5-trioxa-spiro [5.5] undec 9-yl) -W-methyl-cyclohexane-cis-1,4-diamine

8-1: Synthesis of ethyl ester of [4- (7-chloro-quinolin-4-ylamino) -cyclohexyl-carbamic acid 11

A suspension of 2.2 g (7.9 mmol) of PA1019 in 400 ml of distilled water is prepared. 1.45 ml (11.9 mmol) of ethylchloroformate are added dropwise at room temperature. The mixture is left stirring overnight at room temperature. The pH of the mixture is then brought back to pH 8 by addition of NaHCO ₃ . The medium is then extracted with 1200 mL of CH ₂ Cl ₂ . The organic phase is dried over Na ₂ SO ₄ and filtered. The solvents are evaporated to a crude product which is purified by chromatography on a silica column (eluent: ethyl acetate / Et ₃ N, 95/5, v / v). The phases containing ΛΛ 2 are washed with 500 ml of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated, yielding a powder identified as the compound H: 1.04 g (yield = 38%).

Melting Point: 241 ⁰ C (dec).

8-2: Synthesis of N- (7-chloro-quinolin-4-yl) -N-methyl-cyclohexane-1,4-diamine: PA1307 1 g (2.9 mmol) in 50 ml of Dry THF This solution is added dropwise, under argon, for one hour to a solution, cooled with an ice bath, 25 mL of dry THF and 11.5 mL (11.5 mmol) of LiAlH ₄ 1 M. When the addition is complete, the mixture is refluxed for 30 min The reaction medium is then hydrolyzed and 250 ml of ethyl acetate are added The recovered organic phase is dried over Na ₂ SO ₄ filtered and evaporated to give a crude product which is purified by flash chromatography on a silica column (eluent: CH ₂ Cl ₂ / MeOH / Et ₃ N, gradient: 5 min CH ₂ Cl ₂ / MeOH / Et ₃ N 90/9 / 1, v / v / v, 10 to 40 min: CH ₂ Cl ₂ / MeOH / Et ₃ N 90/9/1, v / v / v, CH ₂ Cl ₂ / MeOH / Et ₃ N 80 / 18/2, v / v / v, 45 to 65 min: CH ₂ Cl ₂ / MeOH / Et ₃ N 80/18/2, v / v / v). The phases containing PA1307 are combined, evaporated and the crude is dissolved in 500 mL of ethyl acetate and 250 mL of a solution of NaHCO ₃ at pH 9. This organic phase is recovered, dried over Na ₂ SO ₄ , filtered. and evaporated to a powder identified as PA1307: 0.59 g (Yield = 71%). Melting Point: 185 ° C (dec).

0.46 g (1.6 mmol) of PA1307 are dissolved in 25 ml of MeOH and then 210 μl (1.15 mmol) of 5.5 M HCl in isopropanol are added under argon at room temperature. 0.21 g (1.0 mmol) of PA1004 ketone are then added and the mixture is left stirring for 1 h. NaBH ₃ CN (46 mg, 0.7 mmol) is then added to the mixture with stirring and under argon. The reaction medium is stirred at room temperature for 24 h. The solvents are evaporated under vacuum and the crude reaction product is then purified by flash chromatography on a silica column (eluent: ethyl acetate / Et ₃ N 95/5, v / v). The phases containing PA1308 are combined, washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated to yield a powder identified as PA 1308: 0.136 g (yield = 27%).

Melting Point: 179 ° C (dec).

¹ H NMR (250MHz, 298K, DMSOd ₆₎ δ ppm: 8.37 to 8.31 (m, 1H + 1H, HC2 '+ HC5'), 7.75 (d, J = 0.6 Hz, 1H, HCI '), 7.42 (dd, J = 8.9Hz, J = 2.2Hz 1H, HC6'), 6.92 (d, J = 7.6Hz, 1H , NH), 6.51 (d, J = 5.6 Hz, 1H, HC3 '), 3.90-3.40 (m, 2H + 1H, HC5 + HCI'), 2.57 (m, 1 H + 1H, HC cyclohexyl + HCl), 2.17 (s, 3H, H ₃ CN), 2.05-1, (m, 16H + 3H, HC cyclohexyl + HC7.8), 1.05 (s). broad, 3H, HC7.8). MS (DCI / NH3> 0) m / z (%): 474 (MH +, 100%).

9 - Synthesis of PA 1329, (FIG. 9) W- (7-chloro-quinolin-4-yl) -Λ- (3,3-dimethyl-1, 2,5-trioxa-spiro [5.5] undec-9- yl) -N-ethyl-cyclohexane-cis-1,4-diamine 9-1: Synthesis of PA1329

0.2 g (0.4 mmol) of PA1103 are dissolved in 11 ml of CH ₂ Cl _2, and 73 μl (1.3 mmol) of acetaldehyde are added under argon at room temperature. 0.55 g (2.6 mmol) of NaBH (OAc) _{3 are then added} . The reaction medium is stirred at room temperature for 2 hours. Again, 36 μl (0.6 mmol) of acetaldehyde and 0.27 g (1.3 mmol) of NaBH (OAc) _{3 are added} and the mixture is left stirring for 2 h. The mixture is then purified by chromatography on a silica column (eluent: ethyl acetate / Et ₃ N, 80/20, v / v). The phases containing PA1329 are combined and washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated. The powder thus obtained is identified as the PA1329 compound: 0.13 g (yield = 63%). Melting Point: 165 ⁰ C (dec). ¹ H NMR (200 MHz, 298 K, CDCl ₃ ): δ, ppm: 8.50 (d, J = 5.4 Hz, 1H, HC 2 '), 7.94 (d, J = 2.0 Hz, H, HC8 '), 7.61 (dd, J = 9.1Hz, J = 2.7Hz, 1H, HC5'), 7.38-7.31 (m, 1H, HC6 '), 6.42 and 6.41 (d, J = 5.5 Hz, 1H, HC 3 '), 4.78 (d, J = 7.6 Hz, 1H, HN), 3.90-3.30. (m, 2H + 1H, HCI + HCI '), 2.68-2.54 (m, 1H + 2H + 2H, HCI + HC cyclohexyl + H ₂ CN), 2.27 (m, 2H, cyclohexyl), 1, 86-1, 22 (m, 13H + 3H, HC cyclohexyl + HC7.8), 1.10 (bs, 3H, HC7.8), 1.02 and 1.01 (t, J = 6.9 Hz, 3H, H ₃ CH ₂ N). MS (DCI / NH ₃ > 0): m / z (%): 448.5 (MH +, 100%).

Synthesis of PA 1333 (Figure 10)

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

10-1: Synthesis of di-ethyl ester of di-adamantane-1,3-carboxylic acid

11

Refluxed with 2.4 g (10 mmol) of adamantane-1,3-dicarboxylic acid and 4 ml of concentrated sulfuric acid in 100 ml of 95% ethanol for 9 h. The mixture is then allowed to return to room temperature. 50 ml of NH ₄ OH are added to the reaction medium and then the solvents are evaporated. The dry residue is taken up in 100 ml of water saturated with NaCl and then extracted with 200 ml of CH ₂ Cl ₂ . The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated, leading to an oil identified as being 12: 2.6 g (Yield = 93%)

10-2: Synthesis of (3-hydroxymethyl-adamantan-1-yl) -methanol 2.1 g (7.6 mmol) of Λ 2 are dissolved in 10 ml of dry THF. This solution is added dropwise, under argon, for one hour to a solution, cooled with an ice bath, 25 mL of dry THF and 30 mL (30 mmol) of 1 M LiAlH ₄ in ether. When the addition is complete, the mixture is refluxed for 1 h 30. The reaction medium is then hydrolyzed and 400 ml of ether are added. The recovered organic phase is dried over MgSO ₄ , filtered and evaporated, yielding a powder identified as 13: 0.63 g (yield = 42%).

10-3: Synthesis of (3-hydroxymethyl-adamantan-1-yl) -methanol A solution containing 0.62 g (3.2 mmol) of 13 and 1.3 ml (6.7 mmol) of diisopropyl was prepared azodicarboxylate in 50 mL of dry THF under argon. To this solution are added 1.79 g (6.7 mmol) of PPh ₃ and 0.99 g (6.7 mmol) of phthalimide. The mixture is stirred for 24 hours under argon at room temperature. The solvents are then evaporated and the residue is dissolved in 50 ml of methanol. To this solution are added 1, 2 mL (13 mmol) of hydrazine in 35% aqueous solution. The solution is then brought to reflux for 15 hours. After returning to ambient temperature, the solvents are evaporated off and the white solid obtained is dissolved in 50 ml of an aqueous acetic acid solution at pH 4. The suspension obtained is filtered and the pH of the filtrate is brought to pH 14 by addition. of KOH pellets. This aqueous phase is extracted with 200 mL of CH ₂ Cl ₂ , the organic phase is dried over Na ₂ SO ₄ , filtered and evaporated. The crude product obtained is then purified by chromatography on a silica column (eluent: CH ₂ Cl ₂ / MeOH / NH ₃ aq, 80/20/1, v / v / v). The phases containing 14 are combined and evaporated to give a solid identified as 14: 0.37 g (yield = 59%).

10-4: Synthesis of PA1328 0.3 g (1.6 mmol) of 4,7-dichloroquinoline and 0.37 g (1.9 mmol) are heated at 190 ^° C. in 5 ml of β-methylpyrrolidinone for 3 hours. h. The mixture is then allowed to return to ambient temperature and then 25 ml of water and 0.15 g (3.7 mmol) of NaOH are added. An oily residue is then recovered. This crude is then purified by chromatography on a silica column (eluent: CH ₂ Cl ₂ / Et ₃ N, 80/20, v / v). The phases containing PA1328 are combined, evaporated and the resulting liquid residue is poured into 50 mL of water. A precipitate then appears and the filtrate is removed. After drying under vacuum, this precipitate is dissolved again in 1 ml of CH ₂ Cl ₂ and 20 ml of n-hexane are added. The precipitate formed is filtered and dried under vacuum to give a powder identified as PA1328: 0.46 g (Yield = 80%). Fusion Point: 17O ⁰ C (dec).

10-5: synthesis of 3-K7-chloro-quinolin-4-ylarino) -methyl-adamantane-1-carboxaldehyde

0.45 g (1.3 mmol) of PA1328 are dissolved in 10 ml of dry CH ₂ Cl ₂ . To this solution are added, at room temperature and under argon, 5.3 ml of a solution of Dess-Martin periodinane (assayed at about 0.5 M) in CH ₂ Cl ₂ . The mixture is stirred for 1 h 30 and then 5.3 mL of a solution in CH ₂ Cl ₂ Dess-Martin periodinane (dosed at about 0.5 M) are added again. The mixture is left stirring for 30 min and then directly purified by chromatography on a silica column (eluent: ethyl acetate / Et ₃ N, 90/10, v / v). The phases containing 15 are combined. The organic phase is washed with 200 ml of distilled water and then dried over Na ₂ SO ₄ , filtered and evaporated, yielding a powder identified as 15: 0.13 g (yield = 28%).

10-6: Synthesis of 3,3-dimethyl-1,2,5-trioxa-spirof 5.5 lundec-9-ylamine 16 In a 50 ml flask are mixed with 5 ml of dry methanol under argon, 0.52 g (2.6 mmol) of PA1004, 2 g (26 mmol) of ammonium acetate and 1 mL of sieve 4 previously dried. To this mixture is added 0.16 g (2.6 mmol) of NaBH ₃ CN powder. The mixture is left stirring for 24 h. 10 ml of distilled water are then added and the pH is brought to pH 2 by addition of a 6M HCl solution. When the evolution of gas has ceased, the pH is raised to pH 8 by addition of a KOH solution. . The mixture is extracted with 100 mL of dichloromethane, the organic phase collected is dried with Na ₂ SO ₄ , filtered and then evaporated yielding an oil identified as 16: 0.28 g, (yield = 54%).

10-7: synthesis of PA1333

0.13 g (0.36 mmol) of 15 and 0.10 g (0.43 mmol) of 16 are mixed in 5 mL of CH ₂ Cl ₂ . The mixture is stirred under argon for 30 min. We add up then 0.15 g (0.71 mmol) of NaBH (OAc) ₃ and the mixture is stirred for 10 min. 20 μl (0.35 mmol) of acetic acid are then added to the mixture which is left stirring at room temperature for 12 h. The mixture is then purified by chromatography on a silica column (eluent: ethyl acetate / Et ₃ N, 98/2, v / v). The phases containing PA1333 are combined. The organic phase is washed with 200 ml of distilled water and then dried over Na ₂ SO ₄ , filtered and evaporated. To the crude obtained is added 1 ml of a n-hexane / Et ₂ O mixture, 50/50, v / v, then the solvents are evaporated leading to a powder identified as being PA1333: 0.14 g (Yield = 71% ). Melting Point: 95 ° C. ¹ H NMR (200 MHz, 298 K, CDCl ₃ ): δ, ppm: 8.47 (d, J = 5.4 Hz, 1H, HC 2 '), 7.92 (d, J = 1.0 Hz, 1 H , HC8 '), 7.83 (d, J = 9.2 Hz, 1H, HCδ'), 7.34 (dd, J = 8.9 Hz, J = 2.0 Hz, 1H, HC6 ' ), 6.41 (d, J = 5.5 Hz, 1H, HC3 '), 5.23 (m, 1H, NH), 3.90-3.30 (m, 2H, HC5), 3 , 00 (d, J = 2.9 Hz, 2H, HCl '), 2.57 (m, 1H, HCl), 2.32-1, 16 (m, 2H + 14H + 8H + 3H + 1H) , HC12 + HCadamantane + HC cyclohexyl + HC7.8 + NH), 1.10 (s, 3H, WC7.8). MS (DCI / NH ₃ > 0): m / z (%): 540.5 (MH +, 100%).

11- Synthesis of PA 1335. (Figure 11)

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

11-1: Synthesis of tetrahydro-pentalene-2,5-dione bis (O-methyl-oxime) 2 g (14.4 mmol) of cis-bicyclo [3.3.0] octane-3 are dissolved 7-dione in 21 ml of 95% ethanol and then 3.63 g (43.4 mmol) of methoxylamine hydrochloride and 21 ml of pyridine are added. The mixture is refluxed for 18 hours. Then 42 ml of distilled water are added and the mixture is extracted with 126 ml of ether. The organic phase is then dried over Na ₂ SO ₄ , filtered and the solvents are evaporated yielding the compound 16: 1, 96 g (yield = quantitative).

11-2: Synthesis of roctahydro-pentalene-2,5-diamine In a 250 ml flask under argon, 25 ml of THF and 1.93 g (51 mmol) of powdered NaBH ₄ were introduced at ambient temperature. To this mixture, 3.8 ml (51 mmol) of trifluoroacetic acid are slowly added. When the effervescence is complete, a solution of 1 g (5.1 mmol) of t6 dissolved in 14 mL of dry THF is added dropwise. When the addition is complete, the mixture is refluxed for 14 hours. The reaction medium is then poured into 65 ml of distilled water and then KOH pellets are added to the mixture to reach pH 14. The medium is extracted with 260 ml of CH ₂ Cl ₂ , the organic phase dried over Na ₂ SO ₄ , filtered and the evaporated solvents yielding compound 17: 0.7 g (yield = quantitative). 11-3: Synthesis of Λ / ² - (7-chloro-quinolin-4-yl-octahydro-pentalene-2,5-diamine 18

Dissolve 0.26 g (1.3 mmol) of 4,7-dichloroquinoline in 2 mL of N-methylpyrrolidinone. To this solution are added 0.74 g (5.3 mmol) 17 and 741 μl (5.3 mmol) of triethylamine; the mixture is then heated at 190 ^° C. for 3 hours.

The mixture is allowed to return to ambient temperature and 10 ml of 1 M NaOH and then 60 ml of distilled water are added to the reaction medium. This mixture is left stirring for 2 h. A pasty residue appears. This residue is recovered, dissolved in a minimum volume of CH ₂ Cl ₂ and precipitated by the addition of n-hexane. The precipitate is filtered and then dried under vacuum leading to a compound identified as being: 0.25 g (Yield).

= 63%).

11-4: Synthesis of PA1335

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 μL (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. The crude obtained is then purified by flash chromatography on a silica column (eluent: ethyl acetate / EtN, gradient: 5 min: ethyl acetate / Et ₃ N 98/2, v / v, 5 to 30 min: of ethyl acetate / Et ₃ N 98/2, v / v to ethyl acetate / Et ₃ N 95/5, v / v, 30 to 40 min: ethyl acetate / Et ₃ N 95/5, v / v: 40 to 60 min: ethyl acetate / Et ₃ N 95/5, v / v to ethyl acetate / Et ₃ N 90/10, v / v, 60 to 70 min: Acetate ethyl / Et ₃ N 90/10, v / v). The phases containing PA1335 are combined, washed with 200 mL of distilled water, dried over Na ₂ SO ₄ , filtered and evaporated to yield a powder identified as PA1335: 0.04 g (yield = 11%). Melting point: 11O ⁰ C.

¹ H NMR (200MHz, 298K, CDCl _3): δ ppm: 8.49 (d, J = 5.4 Hz, 1H, HC2 '), 7.92 (d, J = 2.1 Hz, 1 H, HC8 '), 7.63 (d, J = 9.0 Hz, 1H, HC5'), 7.34 (dd, J = 9.0 Hz, J = 2.2 Hz, 1H, HC6 6.43 (d, J = 5.4 Hz, 1H, HC3 '), 5.12 (d, J = 6.7 Hz, 1H, NH), 4.10-3.25 ( m, 2H + 1H, HCI + HCI '), 2.49 (m, 1H + 1H + 1H, HCl + HC15 + NH), 2.28-1.11 (m, 1H + 8H + 6H, HCoctahydro-pentalene + HCcyclohexyl + HC7,8). MS (DCI / NH ₃ > 0): m / z (%): 486 (MH +, 100%).

In addition to the compounds whose preparation protocols have been detailed in the foregoing, other compounds of formula (I) according to the invention are shown in Table 2 which follows; these examples are not limiting and only illustrate the present invention.

Table 1

-i

7.61 and

and

The study of the pharmacological properties of the coupling products of formula (I) according to the invention has shown that they exhibit an antimalarial activity.

Achieving such an effect is all the more advantageous when the phenomena of resistance of strains of Plasmodium falciparum, the deadly species, towards the usual antimalarial drugs develop and that, moreover, the vaccine protection , for which important research is carried out, can not be realized for several years.

A. Study of the antimalarial activity of the dual molecules according to the invention on P. falciparum

The results obtained in vitro on P. falciparum grown in human red blood cells are reported below.

1. Cultivation of P. falciparum

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.

2. Chemosensitivity test

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. After addition of the test compound, 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 (concentrations 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).

3. Results

Cl ₅₀ of the compounds of formula (I) according to the invention are less than 1 μM. Of the strains used, these Cl ₅₀ are, for most compounds of formula (I) tested, comparable to those of artemisinin, or better.

No significant difference was observed between the Cl ₅₀ of the compounds tested on one or other of the strains, namely on the strain FcB1-Colombia (strain moderately resistant to chloroquine) and on the strain FcM29-Cameroon (strain strongly resistant to chloroquine).

By way of example, 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.

B. Study of metabolic stability

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.

These experiments were performed on human liver microsomes, in the presence of NADPH cofactor required for the activity of the main enzymes Cytochromes P-450 (CYP) and Flavin Mono-Oxygenases (FMO). In the presence of NADPH, the substrates tested undergo oxidative biotransformation reactions. After 20 minutes, the reaction is stopped by adding 1 volume of acetonitrile. The supernatant is then removed after centrifugation (3000 g speed for 10 minutes at + 4 ° C.).

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 .

1. Preparation of human hepatic microsomal fractions

The 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.

Elvejheim at + 4 ° C. 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 μl), rapidly frozen in liquid nitrogen and stored frozen at -80 ^° C. until they are used.

2. Incubation of microsomes Incubation conditions: concentration of microsomal proteins: 1 mg / mL - concentration of BSA (Bovine Serum albumin (BSA): 1 mg / mL concentration of the substrate (test compound): 5 μM

- Co-factors of CYP and FMO: 1 mM NADPH

- Phosphate buffer (pH 7.4) 10 mM

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.

Total incubation volume = 300 μL

3. Results The results are recorded in Table 2 below:

From the results of Table 2, 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.

Thus, 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.

Thus, according to another of its aspects, 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).

These drugs are used therapeutically in the prevention and treatment of malaria.

According to another of its aspects, 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.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (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. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions. Preferred routes of administration are the oral, rectal and injectable routes.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg

Mannitol 223.75 mg

Croscaramellose sodium 6.0 mg

Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg

Magnesium stearate 3.0 mg

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

The present invention, according to another of its aspects, also relates to a method of 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.

Claims

A compound of formula (I) which follows:

(I) in which:

- A represents:

A residue of molecule with antimalarial activity chosen from: m aminoquinoline of formula (Ma):

(IIa) in which:

R and R ', which are identical or different, each represent one or more substituents occupying distinct positions on the rings to which they are attached, chosen from:

. -NO ₂ or -N (R _a , R _b ), where R ₃ and R _b , identical or different, each independently represent a hydrogen atom or an alkyl group comprising from 1 to 5 atoms of carbon ; or else R ₃ 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 or an alkyl group may contain from 1 to 5 carbon atoms or R ₄ represents a cycloalkyl group which may contain from 3 to 5 carbon atoms, B ₁ represents a nitrogen atom and B ₂ represents a -CH = chain, or B ₁ represents a -CH = chain and B ₂ represents a nitrogen atom,

. a group of formula (Wa):

R ₆ -CHOH- (NIa) in which R ₆ represents an aryl radical, preferably a 9-phenanthrenyl or a nitrogenous heterocyclic residue, preferably a 4-quinolinyl optionally substituted with one or more R groups as defined for the compound of formula (Ma);

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,

M and n independently of one another are 0, 1 or 2;

Or else 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 Z ₁ + Z ₂ + Ci + Cj group thus representing:

Or a cycloalkyl group which may contain from 3 to 10 carbon atoms,

• a polycyclic structure that can contain from 4 to 18 atoms of carbon, one of 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 bond at the same time; - Ri 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 cyclic structure, Cj being one of the apexes of this cyclic peroxide, said cyclic peroxide being substituted by a group R ₃ , R ₃ representing from 1 to 8 groups identical to or different from each other, occupying any positions on the carbon atoms of the peroxide ring and being chosen 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 which may contain from 3 to 7 carbon atoms and may also contain from 1 to 3 heteroatoms chosen from oxygen, nitrogen and sulfur, optionally substituted by one or more groups chosen from a halogen atom, a hydroxyl group, an alkyl group possibly comprising from 1 to 8 carbon atoms or a cycloalkyl group possibly comprising 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 which may contain from 1 to

8 carbon atoms or a cycloalkyl group may contain from 3 to 8 carbon atoms; . or else two groups R ₃ 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 group R ₃ itself being capable of being substituted by 1 to 6 substituents R ₃ as defined above,

18 carbon atoms; in the form of a base or of an acid addition salt, in the hydrate or solvate state, under racemic form, isomers and mixtures thereof, as well as their diastereoisomers and mixtures thereof.

2. Compound of formula (1) according to claim 1, wherein A, B ₁ m, n, Z ₁ , Z ₂ , the set Z ₁ + Z ₂ + Ci + Cj, R ₁ , R ₂ , R _x , R _y are as defined in claim 1 and R ₅ represents a hydrogen atom or an alkyl group, a -C (O) -alkyl or -C (O) O-alkyl, the said alkyl groups have 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; carbon; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

3. Compound of formula (I) according to any one of claims 1 or 2 wherein:

- A represents an aminoquinoline of formula (IIa):

(IIa) in which:

. -NO ₂ or -N (R _a , Rb), wherein R ₃ and R _b , 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 contain from 1 to 5 carbon atoms or R ₄ represents a cycloalkyl group may contain from 3 to 5 carbon atoms,

B ₁ represents a nitrogen atom and B ₂ represents a -CH = chain, or B ₁ represents a -CH = chain and B ₂ represents a nitrogen atom; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

4. Compound of formula (I) according to claim 3, wherein A represents an aminoquinoline of formulas (Hb) or (IIc) which follow:

(Nb) (Hc) wherein R, R 'and R ₄ are as defined for the compound of formula (IIa); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

5. Compound of formula (I) according to any one of claims 1 or 2 wherein B represents a group chosen from: c / s-1, 2-methylenecyclopentyl, trans-1, 2-cyclohexyl, cis-1, 2 cyclohexyl, c / s-1, 2-methylenecyclohexyl, trans-1,4-cyclohexyl, c / s-1,4-cyclohexyl, cis / trans-

1,4-cyclohexyl, cis / trans-λ, 3-cyclohexyl mixture, cis / trans-λ, 3-dimethylenecyclohexyl, c / s-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

6. Compound according to any one of claims 1 or 2 wherein A represents an aminoquinoline nitrogen-containing heterocycle of formula (IIa) and having the following formula (1.1): ) in which

R, R ', Bi, B ₂ , and R ₄ are as defined for the compound of formula (IIa) and B, Ci, C _j , R ₁ , R ₂ , Z ₁ , Z ₂ , R _x , R _y R _5, m and n are as defined for the compound of formula (I); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

7. Compound of formula (1.1) according to claim 6 wherein B represents a group chosen from: c / s-1, 2-methylenecyclopentyl, frans-1, 2-cyclohexyl, c / s-1, 2-cyclohexyl, c / s-1, 2-methylenecyclohexyl, trans-1,4-cyclohexyl, c / s-1,4-cyclohexyl, cis / trans-1,4-cyclohexyl mixture, cis / trans-λ, 3-cyclohexyl mixture, mixture cis / trans-1,3-dimethylenecyclohexyl, cis-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

8. A compound according to any one of claims 1 or 2, corresponding to the formula

(1.2) which follows:

wherein 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 _j1 R _1, R _2, R _3, R ₅ , m and n are as defined for the compound of formula (I); in the form of a base or of an acid addition salt, in the form of a hydrate or of a solvate, in racemic form, isomers and their mixtures, as well as their diastereoisomers and their mixtures.

9. Compound of formula (1.2) according to claim 8 wherein B represents a group chosen from: c / s-1, 2-methylenecyclopentyl, trans-1, 2-cyclohexyl, c / s-1, 2-cyclohexyl, c / s-1, 2-methylenecyclohexyl, trans-1,4-cyclohexyl, c / s-1,4-cyclohexyl, cis / trans-1,4-cyclohexyl mixture, cis / trans-λ, 3-cyclohexyl mixture, mixture cis / trans, 3-dimethylenecyclohexyl, cis-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

10. Compound according to any one of claims 1 or 2, corresponding to formula (1.3) which follows:

in which R, R ', B ₁ , B ₂ and R ₄ are as defined in the compound of formula (IIa) and B, R ₃ , R ₅ , m and n are as defined for the compound of formula (I) ); base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

11. Compound of formula (I.3) according to claim 10, wherein B represents a group chosen from: c / s-1, 2-methylenecyclopentyl, frans-1, 2-cyclohexyl, c / s-1, 2- cyclohexyl, c / s-1, 2-methylenecyclohexyl, trans, 4-cyclohexyl, c / s-1,4-cyclohexyl, cis / trans-1,4-cyclohexyl mixture, cis / trans-1,3-cyclohexyl mixture, cis / trans-1,3-dimethylenecyclohexyl, cis-1,4-dimethylenecyclohexyl, 4,4'-methylene-bis-cyclohexane; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

12. Compound of formula (I) according to any one of claims 1 or 2 wherein: - A represents an aminoquinoline of formulas (Hb) or (Ile) which follow:

(Hb) (Hc) wherein R, R 'and R ₄ are as defined for the compound of formula (Ma);

B represents a group chosen from:

A cycloalkyl group which may contain from 3 to 8 carbon atoms, optionally substituted by one or more groups chosen from: a halogen atom, a hydroxyl group, an alkyl group possibly containing from 1 to 6 carbon atoms or a cycloalkyl group which may have from 3 to 6 carbon atoms,

M and n independently of one another are 0, 1 or 2;

- R ₅ represents a hydrogen atom;

Or a cycloalkyl group which may contain from 3 to 10 carbon atoms,

- R ₁ and R ₂ represent a hydrogen atom;

- R _x and Ry together form a cyclic peroxide comprising from 4 to 8 members and having 1 or 2 additional oxygen atoms in the ring structure, Cj being one of the peaks of this cyclic peroxide, said cyclic peroxide being substituted a group R ₃ , R ₃ representing from 1 to 8 groups identical to or different from each other, occupying any positions on the carbon atoms of the peroxidic ring and being chosen from the following atoms and groups:

. or else two groups R ₃ carried by the same carbon atom of the peroxide cycle may together form a cycloalkyl group may contain from 3 to 7 carbon atoms or a bicyclic or tricyclic group may contain from 4 to 18 carbon atoms; base or acid addition salt, hydrate or solvate, racemic, isomeric and mixtures thereof, as well as diastereoisomers and mixtures thereof.

13. Compounds according to claim 1, chosen from:

PA1103, PA1265, PA1251, PA1252, PA1253, PA1255, PA1271, PA1269, PA1259, PA1258, PA1256, PA1268, PA1260, PA1188, PA1261, PA1207, PA1262, PA1263, PA1264.

14. Compounds according to claim 1 chosen from:

15. Process for the preparation of the compounds of formula (I), characterized in that a compound of formula (III) is reacted which follows:

wherein B, R, R ', B ₁ , B ₂ and R ₄ are as defined for the compound of formula (IIa) and B, m and n are as defined for the compound of formula (I), with a compound of formula

wherein R ₁ , R ₂ , Z ₁ , Z ₂ , R _x and R _y are as defined in compounds of formula (I).

16. Compound of formula (III) which follows:

wherein B, R, R ', Bi, B ₂ and R ₄ are as defined for the compound of formula (IIa) and B, m and n are as defined for the compound of formula (I).

17. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 14.

18. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 14.

19. Use of a compound of formula (I) according to any one of claims 1 to 14 for the preparation of a medicament for the treatment and prevention of malaria.