Lipid nanocapsule comprising at least one aminothiolester compound or one of its pharmaceutically acceptable derivatives

Abstract

Lipid nanocapsule comprising at least one aminothiol ester compound or one of its pharmaceutically acceptable derivatives. The present invention relates to a lipid nanocapsule comprising an oily core and a shell surrounding the oily core, wherein the oily core comprises at least one aminothiol ester compound or one of its pharmaceutically acceptable derivatives. It also relates to a pharmaceutical composition comprising said nanocapsule, as well as the use of said nanocapsule and the pharmaceutical composition as a medicinal product. Figure for abstract: none.

Description

Title of the invention: Lipid nanocapsule comprising at least one aminothiolester compound or one of its pharmaceutically acceptable derivatives

[0001] The present invention relates to a lipid nanocapsule comprising an oily core and a shell surrounding the oily core, wherein the oily core comprises at least one aminothiolester compound or a pharmaceutically acceptable derivative thereof. It also relates to a pharmaceutical composition comprising said nanocapsule, as well as the use of said nanocapsule and the pharmaceutical composition as a medicinal product.

[0002] Aminothiolesters are compounds with inhibitory properties of aldehyde dehydrogenase enzymes that have demonstrated efficacy in the treatment of cancers (EP1296946). However, due to their physicochemical characteristics, these compounds as free bases cannot be used as a drug, and a formulation in the form of fumarate salts has been developed (Venton, G., Pérez-Alea, M., Baier, C. et al. Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors. Blood Cancer Journal 6, e469 (2016)).

[0003] However, it has been observed that these molecules, in the form of fumarate salts, are rapidly neutralized by hydrolysis in aqueous solutions as well as in biological matrices, following the cleavage of their thiol-methyl group by esterases. In particular, some aminothiol ester compounds are very rapidly metabolized in the bloodstream, which reduces their therapeutic efficacy and limits their development as anticancer treatments. The major challenge for the development of these molecules therefore lies in improving their pharmacokinetic profile, and in particular in extending their half-life.

[0004] In order to overcome the development obstacles and exploit the therapeutic potential of these molecules, an innovative pharmaceutical form based on lipid nanocapsules has been developed, taking into account the difficulties related to the manufacture of the nanocapsule, the encapsulation efficiency of aminothiolesters, as well as the toxicity and in vivo efficacy of the nanoformulation.

[0005] Thus, the inventors of the present invention have developed a lipid nanocapsule capable of efficiently encapsulating aminothiolesters to increase their solubility in aqueous media, control their release and bioavailability, and improve their protection against chemical or enzymatic degradation.

[0006] Thus, the present invention relates to a lipid nanocapsule comprising:

[0007] - an oily core comprising between 25 and 90% by weight of chain triglycerides averages, preferably between 60 and 80%, relative to the total weight of the nanocapsule; and

[0008] - an envelope surrounding the oily core comprising between 3 and 25% by weight ratio to the total weight of the nanocapsule of at least one lipid surfactant, and at least one hydrophilic surfactant;

[0009] • wherein the oily core further comprises at least one compound of formula (I):

[0010] o D (I) rx1 «2 / \_ S—R3

[0011] in which:

[0012] - Ri and R2, identical or different, are chosen from a C1-C10 alkyl, a phenyl, a benzyl, CHR5CHR6OR4 and (CHR5)VOR4, or Ri and R2 together with the nitrogen atom to which they are bonded form a heterocycle, in particular a piperidine or a morpholine;

[0013] said phenyl and benzyl being optionally substituted by one or more substituents selected from: a linear or branched C1-C7 alkyl, halogen, NO2 and CONH2;

[0014] - R3 is a linear or branched C1-C7 alkyl,

[0015] - R4 is chosen from: H, a linear or branched C2-C7 alkyl group, an alkenyl group in C2-C7 linear or branched, -CONR7R8, aryl, heteroaryl, a (C2-C7)cycloalkyl, -(C1-C7)alkyl-aryl linear or branched and -(Ci-C7)alkyl-heteroaryl linear or branched;

[0016] said aryl, (C2-C7)cycloalkyl and heteroaryl being optionally substituted by one or more substituents selected from: halogen, linear or branched CrC7 alkyl optionally substituted by one or more halogen atoms, linear or branched CrC7 alkoxy optionally substituted by one or more halogen atoms, -COOH, aryl, -NRR', -NO2, or said aryl and heteroaryl are fused to form a heterocycloalkyl;

[0017] - R5 and R6, identical or different, are chosen independently from:

[0018] • H and alkyl in linear or branched CrC7, or

[0019] • R5 and R6 are bonded together to form with the carbon atoms to which they are linked to a cycloalkyl, aryl or heteroaryl, or

[0020] • R5 is H and Ri and R6 are bonded together to form with the nitrogen atom bonded to Ri a heterocycloalkyl or heteroaryl, or

[0021] • R6 is H and Ri and R5 are bonded together to Ri to form with the nitrogen atom bonded to Ri a heterocycloalkyl;

[0022] - v is chosen from 2 to 4;

[0023] - R7 is an (CrC3) alkyl;

[0024] - R8 is -(Ci-C3)alkyleNRR';

[0025] - R and R', identical or different, are chosen independently from H and an alkyl in linear or branched C1-C7

[0026] or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers; and

[0027] • wherein the weight ratio relative to the total weight of the nanocapsule between medium-chain triglycerides and said at least one compound of formula (I) is at least 4.

[0028] Lipid nanocapsule

[0029] By "lipid nanocapsule" or NCL, we mean a formulation having as solubilizing agent a solvent-free oil allowing to encapsulate lipo-soluble active ingredients.

[0030] In the context of the present invention and as described above, the nanocapsule comprises an oily core, in particular liquid / semi-liquid at room temperature, and a shell surrounding the oily core, in particular rigid at room temperature and with a high melting / transition temperature (i.e., in particular between 40°C and 85°C). The core of the particle is therefore composed of oil, in this case medium-chain triglycerides. The active ingredient is solubilized in this phase at the center of the nanocapsule. The surface of the nanocapsule or shell is formed of hydrophilic and lipid surfactants.

[0031] This structure can be illustrated by [fig. 1].

[0032] In particular, said nanocapsule has a diameter between 25 and 115 nm, more particularly between 40 and 80 nm, and for example 30, 40, 45, 50, 55, 60, 65 or 70 nm.

[0033] This size makes it possible in particular to ensure optimal efficiency of the nanocapsule in vivo.

[0034] In particular, the said nanocapsule has a PDI or polydispersity index of less than 0.2, and in particular less than 0.1. This index, also called dispersity, has the common meaning known to those skilled in the art, i.e., the measure of the heterogeneity of the sizes of molecules or particles in a mixture. This notably allows the size distribution of the nanocapsules to be monodisperse.

[0035] As mentioned above, the oily core comprises between 25 and 90% by weight of medium-chain triglycerides, preferably between 60 and 80%, relative to the total weight of the nanocapsule, and for example, 40, 50, 55, 60 or 70% by weight of medium-chain triglycerides.

[0036] By "medium chain triglycerides" is meant the common meaning known to a person skilled in the art, i.e. triglycerides in which the three hydroxyl groups of glycerol are esterified by medium chain fatty acids.

[0037] By average chain, we mean in particular chains of 6 to 12 carbon atoms.

[0038] They are notably present in coconut oil, palm oil and butter.

[0039] In particular, the medium-chain triglycerides according to the invention are selected from mixtures of saturated fatty acid triglycerides, in particular caprylic (octanoic) acid and capric (decanoic) acid.

[0040] The fatty acids are obtained from the oil extracted from the hard and dried fraction of the albumen of Cocos nucifera L. or from the oil extracted from the dried albumen of Elaeis guineensis Jacq. meeting the prerequisite of the European Pharmacopoeia such as, more particularly, Kollisolv® MCT 70, MIGLYOL® 810 N, MIGLYOL® 812 N Excipient and Labrafac®, preferably Labrafac®.

[0041] In particular, an oily core according to the invention comprises between 25 and 90% by weight of Labrafac®, preferably between 60 and 80%, relative to the total weight of the nanocapsule; for example 40, 50, 55, 60 or 70%.

[0042] As mentioned above, the coating surrounding the oily core comprises between 3 and 25% by weight relative to the total weight of the nanocapsule of at least one lipid surfactant. In particular, the coating comprises between 3 and 20% by weight relative to the total weight of the nanocapsule of at least one lipid surfactant, more particularly between 5 and 20%, for example 5, 6, 8, 10, 12 or 20%.

[0043] This proportion of lipid surfactant makes it possible in particular to improve the stability of the nanocapsule during its storage at low temperature. Here, low temperature means a temperature below 0°C.

[0044] By "lipid surfactant", we mean the common meaning known to a person skilled in the art, i.e. an emulsifying agent having an increased tropism for lipid solutions and enabling the stabilization of the nanocapsule.

[0045] In particular, said at least one lipid surfactant is chosen from lecithins derived from soybean oil having a percentage of phosphatidylcholine greater than 90% corresponding to the prerequisite of the European Pharmacopoeia, in particular, Lipoid ®, preferably Lipoid ® S100.

[0046] More particularly, the envelope comprises between 3 and 20% by weight relative to the total weight of the Lipoïd ® S100 nanocapsule, more particularly between 5 and 20%, for example 5, 6, 8, 10, 12 or 20%.

[0047] As mentioned above, the envelope surrounding the oily core also includes at least one hydrophilic surfactant.

[0048] By "hydrophilic surfactant", we mean the common meaning known to a person skilled in the art, i.e. an amphiphilic molecule and / or emulsifying agent which enables and stabilizes the nanoparticles and makes the latter soluble in water.

[0049] In particular, said at least one hydrophilic surfactant is chosen from among the non-ionic solubilizing and / or emulsifying agents meeting the prerequisite described in the European Pharmacopoeia, in particular Macrogol 15 Hydroxy stearate, more particularly Kolliphor®, preferably Kolliphor® HS 15.

[0050] In particular, the envelope comprises between 15% and 60% by weight relative to the total weight of the nanocapsule of at least one hydrophilic surfactant, more particularly between 20% and 50%, for example 15; 20; 30; 35; 40 or 50%.

[0051] More particularly, the envelope comprises between 15% and 60% by weight relative to the total weight of the Kolliphor® HS 15 nanocapsule, more particularly between 20% and 50%, for example 15; 20; 30; 35; 40 or 50%.

[0052] Compounds of formula (I)

[0053] By "at least one compound of formula (I)", means 1, 2, 3, 4, 5, 6, 10, 15 or more compounds of formula (I).

[0054] When more than one compound of formula (I) is envisaged, this compound may be the same or different compounds of formula (I), in particular the same.

[0055] The compounds of formula (I) are as above described and are described in patent EP1296946 and in patent application EP19305989.6, as well as their preparation processes.

[0056] In particular, the compounds of formula (I) are characterized in that R3 is a linear or branched (Ci-C7) alkyl, preferably a methyl, Ri is a linear or branched (CrC7) alkyl, preferably a methyl, R2 is a (Ci-Ci0) alkyl, preferably a methyl or an octyl, CHR5CHR6OR4, (CHR5)VOR4 or Ri and R2 with the nitrogen atom to which they are bonded form a heterocycle, in particular a morpholine, and R5 and R6 are H.

[0057] For example, R4 is selected from H, a linear or branched (C2-C7) alkyl, a linear or branched (C2-C7) alkenyl, -CONR7R8, a linear or branched (C2-C7) cycloalkyl, -(Ci-C7) alkyl-heteroaryl, aryl or benzyl; said (C2-C7) cycloalkyl being substituted by one or more substituents selected from: a linear or branched (CrC7) alkyl; said benzyl being optionally substituted by one or more substituents selected from: a linear or branched (CrC7) alkyl optionally substituted by one or more halogen atoms, a linear or branched (Ci-C7) alkoxy optionally substituted by one or more halogen atoms, a halogen, or said benzyl being optionally fused to form 1,3-benzodioxole.

[0058] Alternatively, in particular, R4 is selected from H, linear or branched (C2-C7) alkyl, linear or branched (C2-C7) alkenyl, - (CrC7) alkyl heteroaryl, aryl, - (C rC7) alkyl-aryl or benzyl; said benzyl being optionally substituted by one or more substituents selected from: linear or branched (CrC7) alkyl optionally substituted by one or more halogen atoms, linear or branched (CrC7) alkoxy optionally substituted by one or more halogen atoms, halogen or pyridyl, or said benzyl being optionally fused to form 1,3-benzodioxole.

[0059] Alternatively, in particular, R5 and R6 are H and R4 is selected from H, linear or branched (C2-C7) alkyl, linear or branched (C2-C7) alkenyl, linear or branched -(CrC7) alkyl-heteroaryl, -(Ci-C7) alkyl-aryl or linear or branched benzyl; said benzyl being optionally substituted by one or more substituents selected from: linear or branched (CrC7) alkyl optionally substituted by one or more halogen atoms, linear or branched (CrC7) alkoxy optionally substituted by one or more halogen atoms, halogen.

[0060] Alternatively, more particularly, the compounds of formula (I) are characterized in that R5 and R6 are H and R4 is selected from (C2-C7)cycloalkyl, linear or branched, -(Ci-C7)alkyl-heteroaryl, or benzyl; preferably benzyl, said (C2-C7)cycloalkyl being substituted by one or more substituents selected from: (Ci-C7)alkyl linear or branched, said benzyl being optionally substituted by one or more substituents selected from: (Ci-C7)alkyl linear or branched optionally substituted by one or more halogen atoms, (Ci-C7)alkoxy linear or branched optionally substituted by one or more halogen atoms, halogen.

[0061] In an alternative, even more particularly, Ri is methyl and R4 is chosen from: H, CONR7R8 with R7 being a methyl and R8 being NRR' with R and R' being methyl, ethyl, propene, benzyl, pyridyl, benzyloxybutyl, methyl-cyclohexenyl substituted by one or more methyl, and benzyl substituted by one or more fluorine, chlorine, methoxy or methyl.

[0062] Alternatively, even more particularly, Ri is a methyl and R4 is chosen from: H, ethyl, propene, benzyl, pyridyl, benzyloxybutyl and benzyl substituted by one of several fluorine, chlorine, methoxy or methyl.

[0063] More particularly, within the framework of the invention, said at least one compound of formula (I) is chosen from:

[0064] - S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate; - S-methyl 4-[2-allyloxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate; - S-methyl 4-[2-benzyloxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate;

[0065] - S-methyl 4-methyl-4-[methyl-[2-(m-tolylmethoxy)ethyl]amino]pent-2-ynethioate; - S-methyl 4-[2-[(3,4-dimethylphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-yn ethioate; - S-methyl 4-[2-[(4-methoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynet hioate; - S-methyl 4-[2-[(3,4-dimethoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-y nethioate; - S-methyl 4-[2-[(3-chlorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate; - S-methyl 4-[2-[(3-fluorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate; - S-methyl 4-methyl-4-[methyl-[2-(2-pyridylmethoxy)ethyl]ammo]pent-2-ynethioate; - S-methyl 4-methyl-4-[methyl-[2-(3-pyridylmethoxy)ethyl]ammo]pent-2-ynethioate; - S-methyl 4-methyl-4-[methyl-[2-(4-pyridylmethoxy)ethyl]ammo]pent-2-ynethioate; - S-methyl 4-((4-(benzyloxy)butyl)(methyl)amino)-4-methylpent-2-ynethioate; - S-methyl 4-((2-hydroxyethyl)(methyl)amino)-4-methylpent-2-ynethioate; - S-methyl 4-methyl-4-[methyl-[2-(2-naphthylmethoxy)ethyl]ammo]pent-2-ynethioate; - S-methyl 4-methyl-4-[methyl-[2-[(2,6,6-trimethylcyclohexen-l- yl)methoxy]ethyl]amino]pent-2-ynethioate; - S-methyl 2,5,10,11,1 l-pentamethyl-6-oxo-7-oxa-2,5,10-triazatetradec-12-yne-14-thioat e; - S-methyl 4-methyl-4-[methyl(2-phenoxycyclopentyl)amino]pent-2-ynethioate; - (S)-S-methyl 4-(2-((benzyloxy)methyl)pyrrolidin-l-yl)-4-methylpent-2-ynethioate; - S-methyl 4-[3(benzyloxy)-lpyrrolidinyl])-4-methylpent-2-ynethioate; - S-methyl 1- 4-Dimethylamino-4-methyl-pent-2-ynethioate; - S-methyl 5- 4-Methyl-4-morpholin-4-yl-pent-2-ynethioate; - S-methyl 4-methyl-4-[methyl(octyl)amino]pent-2-ynethioate

[0066] or its pharmaceutically acceptable optical, racemate, diastereomer, enantiomer or tautomer salts or isomers.

[0067] Unless otherwise indicated, the terms used above or below with regard to compounds of formula (I) have the meanings ascribed to them below:

[0068] - v is chosen from 2 to 4 means that the substituent “CHR5” is repeated twice CHR5 CHR5OR4, three times CHR5CHR5CHr5OR4 or four times CHR5CHR5CHR5CHR5OR4;

[0069] - "halogen" means an atom of fluorine, chlorine, bromine or iodine, in particular an atom of fluorine or chlorine.

[0070] - "alkyl" represents an aliphatic hydrocarbon group that can be linear or Branched, having 1 to 10, 1 to 7, or 2 to 7 carbon atoms in the chain (Ci-Ci0) alkyl, (CrC7) alkyl, or (C2-C7) alkyl, unless otherwise specified. In particular, alkyl groups have 1 to 3 carbon atoms in the chain (alkyl to CrC3). Branched means that one or more alkyl groups, such as methyl, ethyl, or propyl, are bonded to a linear alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, n-hexyl, n-heptyl, octyl, especially methyl, ethyl, or octyl.

[0071] - "alkenyl" designates an aliphatic hydrocarbon group containing a double A carbon-carbon bond that can be linear or branched, having 2 to 7 carbon atoms in the chain (C2-C7) alkenyl, unless otherwise specified. Preferred alkenyl groups have 2 to 3 carbon atoms in the chain (C2-C3) alkenyl. Examples of alkenyl groups include ethenyl, n-propenyl, i-propenyl, n-butenyl, i-butenyl, 2,2-dimethylbut-l-enyl, n-pentenyl, and especially propenyl.

[0072] - "alkoxy" represents an alkyl group as defined above linked singly linked to oxygen. Examples of linear or branched alkoxy (in CrC7) include methoxy (CH3O-) and ethoxy (CH3CH2O-).

[0073] - "aryl" designates a monocyclic aromatic hydrocarbon cyclic system or multicyclic groups of 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, benzyl, phenanthryl, biphenyl, particularly phenyl.

[0074] - "heteroaryl" refers to a mono-, bi- or multicyclic aromatic ring of 5 to 14 chains, preferably 5 to 10 chains, in which at least one ring member is a heteroatom. The heteroatoms can be O or N, especially N. In particular, each ring comprises 1 to 3 heteroatoms. Examples include pyrrolyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, pyrazinyl, indolyl, imi-dazolyl, especially pyridyl.

[0075] - "cycloalkyl" designates a monocyclic or bi-aromatic non-hydrocarbon ring a saturated cyclic group of 2 to 7 carbon atoms, preferably 3 to 6 carbon atoms, which may include one or more unsaturates. Specific examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Preferably, the The cycloalkyl group is cyclohexenyl.

[0076] - "- (Ci-C7) alkyl-aryl" or "- (C1-C7) alkyl-heteroaryl" means that R4 is bonded to the oxygen atom by the carbon of the alkyl group; in particular - (CrC7) alkyl-aryl is a benzyl.

[0077] - "Heterocycle" or "heterocyclloalkyl" designates a stable non-aromatic ring saturated or partially unsaturated from 3 to 14, preferably 5 to 10 mono-, bi-, or multicyclic links, optionally bridged, and in which at least one ring member is a heteroatom. Typically, heteroatoms include, but are not limited to, oxygen or nitrogen. In particular, each ring comprises 1 to 3 heteroatoms. Suitable heterocycles are also described in the Handbook of Chemistry and Physics, 76th edition, CRC Press, Inc., 1995-1996, pages 225-226, the disclosure of which is incorporated herein for reference. Examples of heterocycloalkyl include, but are not limited to, tetrahydropyridyl, tetrahydropyranyl, pyrrolidinyl, piperidyl, morpholinyl, imidazolidinyl piperidine, morpholine or benzodioxole, especially 1,3-benzodioxole.

[0078] - the term "substituted" means, unless otherwise indicated, a substitution by a or several substituents, identical or different, for example chosen from (C1-C7) linear or branched alkyl, halogen, NO2 and CONH2, (C1-C7) linear or branched alkyl substituted by one or more halogen atoms, (Ci-C7) linear or branched alkoxy, (Ci-C7) linear or branched alkoxy substituted by one or more halogen atoms, aryl, -COOH, -COOCH2CH3, -NRR', NH2, NHalkyl and N(alkyl)2. Examples include, but are not limited to, methyl, methoxy, chlorine, fluorine, CF3 and OCF3.

[0079] The compounds of formula (I) as described herein may comprise one or more asymmetric carbon atoms. They may therefore exist as enantiomers or diastereomers. These enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, are part of the invention.

[0080] The compounds of formula (I) as described herein can be supplied in the form of a free base or in the form of addition salts with acids, which are also part of the invention.

[0081] These salts are advantageously prepared with pharmaceutically acceptable acids, but salts with other acids, useful for example for the purification or for the isolation of compounds of formula (I) as described herein, are also part of the invention.

[0082] As used herein, the expression "pharmaceutically acceptable" refers to compounds, materials, excipients, compositions or dosage forms that are, based on sound medical judgment, appropriate for contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problematic complications proportionate to a reasonable benefit-risk ratio. soundable.

[0083] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the described compounds in which the parent compound is modified by producing acidic or basic salts thereof. Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and similar salts, including mono-, di-, or tri-salts thereof; and salts prepared from organic acids such as acetic, propionic, succinic, tartaric, citric, methanesulfonic, benzenesulfonic, glucoronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic, fumaric, maleic, lactic and the like.Other addition salts include ammonium salts such as tromethamine, meglumine, epolamine, etc., and metallic salts such as sodium, potassium, calcium, zinc, or magnesium.

[0084] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic fragment, by conventional chemical processes. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, PA, 2000, the disclosure of which is incorporated herein by reference.

[0085] In particular, within the framework of the present invention, said at least one compound of formula (I) is present in a concentration between 5 and 15 mg / mL, more particularly between 8 and 13 mg / mL, for example 9, 10 or 11 mg / mL.

[0086] This concentration makes it possible in particular to avoid the crystallization of the compound of formula (I) over time while limiting its hydrolysis.

[0087] As mentioned above, the nanocapsule according to the invention has a weight ratio relative to the total weight of the nanocapsule between the medium-chain triglycerides and said at least one compound of formula (I) of at least 4, in particular at least 5.

[0088] By "at least 4", we mean in particular between 4 and 100, more particularly between 5 and 50, for example 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100.

[0089] By "at least 5", we mean in particular between 5 and 100, more particularly between 10 and 50, for example 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100.

[0090] This ratio makes it possible in particular to avoid the crystallization of the compound of formula (I).

[0091] Thus, a nanocapsule according to the invention can, for example, be characterized in that it comprises:

[0092] - an oily core comprising between 25 and 90% by weight of Labrafac®, preferably between 60 and 80%, relative to the total weight of the nanocapsule; and

[0093] - an envelope surrounding the oily core comprising between 3 and 25% by weight relative to the total weight of the Lipoïd ® S100 nanocapsule, and between 15 and 60% by weight relative to the total weight of the Kolliphor® HS 15 nanocapsule, more particularly between 20 and 50%, for example 15; 20; 30; 35; 40 or 50%;

[0094] • wherein the oily core further comprises at least one compound of formula (I) as above; • wherein the ratio by weight relative to the total weight of the nanocapsule between Labrafac® and said at least one compound of formula (I) is at least 4, preferably at least 5.

[0095] In particular, said at least one compound of formula (I) may be S-methyl 4-dimethylamino-4-methylpent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0096] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0097] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-allyloxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0098] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-benzyloxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomer, enantiomer or tautomer salts or isomers.

[0099] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl-[2-(m-tolylmethoxy)ethyl]amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0100] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-[(3,4-dimethylphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate or its salts or optical isomers, racemates, diastereomers, enantiomers or pharmaceutically acceptable tautomers.

[0101] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-[(4-methoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0102] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-[(3,4-dimethoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0103] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-[(3-chlorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0104] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[2-[(3-fluorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0105] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl-[2-(2-pyridylmethoxy)ethyl]amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0106] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl-[2-(3-pyridylmethoxy)ethyl]amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0107] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl-[2-(4-pyridylmethoxy)ethyl]amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0108] Alternatively, said at least one compound of formula (I) may be S-methyl 4-((4-(benzyloxy)butyl)(methyl)amino)-4-methylpent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0109] Alternatively, said at least one compound of formula (I) may be S-methyl 4-((2-hydroxyethyl)(methyl)amino)-4-methylpent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0110] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl-[2-(2-naphthylmethoxy)ethyl]amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0111] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl-[2-[(2,6,6-trimethylcyclohexen-1-yl)methoxy]ethyl]amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0112] Alternatively, said at least one compound of formula (I) may be S-methyl 2,5,10,11,1 l-pentamethyl-6-oxo-7-oxa-2,5,10-triazatetradec-12-yne-14-thioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0113] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl(2-phenoxycyclopentyl)amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0114] Alternatively, said at least one compound of formula (I) may be (S)-S-methyl 4-(2-((benzyloxy)methyl)pyrrolidin-l-yl)-4-methylpent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomer salts or isomers.

[0115] Alternatively, said at least one compound of formula (I) may be S-methyl 4-[3(benzyloxy)-1pyrrolidinyl])-4-methylpent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0116] Alternatively, said at least one compound of formula (I) may be S-methyl 5-4-Methyl-4-morpholin-4-yl-pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomer, enantiomer or tautomer salts or isomers.

[0117] Alternatively, said at least one compound of formula (I) may be S-methyl 4-methyl-4-[methyl(octyl)amino]pent-2-ynethioate or its pharmaceutically acceptable optical, racemate, diastereomeric, enantiomer or tautomeric salts or isomers.

[0118] Preparation of compounds of formula (I)

[0119] The compounds of formula (I) can be prepared by a variety of synthetic routes. The reagents and starting materials are commercially available or readily synthesized by techniques well known to those skilled in the art. All substituents, unless otherwise specified, are as defined above.

[0120] The compounds of formula (I) can in particular be prepared by the processes described in patent EP1296946 and in patent application EP19305989.6 above. mentioned.

[0121] The compounds can be synthesized, for example, by applying or adapting the methods described below, or variations thereof, as understood by those skilled in the art. Appropriate modifications and substitutions will be readily apparent and well known or readily available from the scientific literature to those skilled in the art.

[0122] It should be noted that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic, and isomeric forms of a structure are included, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art to prepare and isolate such optically active forms.

[0123] For example, mixtures of stereoisomers can be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reversed-phase and chiral chromatography, preferential salt formation, recrystallization, etc., or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.

[0124] In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxyl, amino, imino, thio, or carboxy groups, when these are desired in the final product, to prevent their undesired participation in the reactions. Conventional protecting groups may be used in accordance with standard practice; for examples, see T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Chemistry, 4th ed. (2007), John Wiley & Sons Inc., 1999; J.F.W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

[0125] Certain reactions can be carried out in the presence of a base. There is no particular restriction on the nature of the base to be used in this reaction, and any base conventionally used in reactions of this type may also be used here, provided that it has no undesirable effect on other parts of the molecule, and unless otherwise specified. Examples of suitable bases include: sodium hydroxide, potassium carbonate, triethylamine, alkali metal hydrides, such as sodium hydride and potassium hydride; alkyllithium compounds, such as methyllithium and butyllithium; and alkali metal alkoxides, such as sodium methoxide and sodium ethoxide.

[0126] Conventionally, reactions are carried out in a suitable solvent. Various solvents can be used, provided they have no adverse effect on the reaction or on the reactants involved. Examples of suitable solvents include take: hydrocarbons, which can be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, benzene, toluene and xylene; amides, such as dimethylformamide; alcohols such as ethanol and methanol and ethers, such as diethyl ether and tetrahydrofuran.

[0127] The reactions can take place over a wide temperature range. In general, it is convenient to carry out the reaction at a temperature between 0°C and 150°C (more preferably between about room temperature and 100°C). The time required for the reaction can also vary widely, depending on many factors, including the reaction temperature and the nature of the reactants. However, provided that the reaction is carried out under the preferred conditions described herein, a period of 3 to 20 hours is generally sufficient.

[0128] The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by distilling the solvent from the reaction mixture or, if necessary, after distilling the solvent from the reaction mixture, pouring the residue into water followed by extraction with an organic solvent immiscible with water and distilling the solvent from the extract. Furthermore, the product can, if desired, be further purified by various well-known techniques, such as recrystallization, reprecipitation, or various chromatographic techniques, including column chromatography or preparative thin-layer chromatography.

[0129] A compound of formula (I) as described in the context of the invention can, for example, be obtained as follows:

[0130] a) reacting a compound of formula (II) with an organic or inorganic acid

[0131] (he);

[0132] b) react the compound obtained in step a) with a base;

[0133] c) react the compound obtained in step b) with CO2;

[0134] d) react the compound obtained in step c) with alkyl chloroformate, a a reagent capable of forming, with the compound obtained in step c), an acid halide or a reagent capable of forming, with the compound obtained in step c), an anhydride mixture;

[0135] e) react the compound obtained in step d) with an SMe- anion precursor compound;

[0136] where Ri and R2 are such as defined for compounds of formula (I).

[0137] In particular, the base of step b) has a pKa greater than 25, preferably the base used in step b) is chosen from lithium or magnesium bases, preferably the base is chosen from butyllithium, or hexyllithium.

[0138] In particular, the compound of formula (II) is obtained by a step al) of reaction between 3-chloro-3-methylbut-l-yne with RiR2NH in aqueous medium.

[0139] In particular, said compound obtained in step a1) is purified by one or more filtrations, for example by one filtration or in a succession of 2 to 10 filtrations, preferably in a succession of 2 to 5 filtrations, for example in 4 filtrations.

[0140] In one embodiment, 3-chloro-3-methylbut-l-yne is obtained by a reaction step of 2-methylbut-3-yn-2-ol with hydrochloric acid in the presence of a copper catalyst.

[0141] In another embodiment, the acid is a mineral acid selected from hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, preferably hydrochloric acid.

[0142] In another embodiment, step d) is carried out with:

[0143] - an alkyl chloroformate having an alkyl group in (Ci-C6), which may comprise at minus one double bond, preferably methyl, ethyl, isoprenyl, tert-butyl or isobutyl chloroformate, preferably isobutyl chloroformate; or

[0144] - a reagent capable of forming with the compound obtained in step c) a mixed anhydride chosen from among the acid chlorides, for example pivaloyl chloride; or

[0145] - a reagent capable of forming with the compound obtained in step c), a halide acid chosen from SOC12, COC12, PC13, PC15, PBr3 or PPh3 Br2.

[0146] In one embodiment, the SMe- anion precursor compounds are chosen from salts of formula XSMe in which X represents an alkali or alkaline earth metal, for example Na, methyl mercaptan, or (SMe)2, preferably NaSMe.

[0147] This process is described in detail in patent applications PCT / EP2017 / 053457, the contents of which are incorporated by reference.

[0148] Alternatively, a compound of formula (I) can be prepared from the corresponding acetylenic amine treated successively with BuLi, COS, and Mel. A detailed preparation process can be found, for example, in G. Quash et al., European Journal of Medicinal Chemistry 43 (2008) 906–916, the contents of which are incorporated by reference, particularly in Part 2 of the Materials and Methods section.

[0149] The above reactions can be achieved by a person skilled in the art by applying or adapting the methods illustrated in the examples below.

[0150] Furthermore, the process for preparing compounds of formula (I) may also include the additional step of isolating the compound of formula (I) or (II). This can be carried out by a person skilled in the art by any of the conventional means known, such as the recovery processes described above.

[0151] In general, the starting products are commercially available mainly from Aldrich or Acros or another conventional chemical supplier or can be obtained by applying or adapting any known processes or those described in the examples.

[0152] Preparation of the lipid nanocapsule

[0153] Lipid nanocapsules can be prepared as mentioned in the experimental part.

[0154] For example, the nanocapsules are produced as follows:

[0155] - Weigh the medium-chain triglycerides, add at least one compound of formula (I) under stirring and mix;

[0156] - Weigh said at least one hydrophilic surfactant and said at least one surfactant lipid, add NaCl and water;

[0157] - Transfer the aqueous phase into the oily phase while stirring;

[0158] - Transfer to an oil bath and heat the solution under vigorous stirring;

[0159] - Once a certain temperature is reached, transfer to ice to cool;

[0160] - Transfer back to the oil bath to reheat;

[0161] - Repeat the cooling and heating steps several times;

[0162] - At the end of the last heating stage, transfer into the ice bath and cool ;

[0163] - When the formulation reaches a certain temperature, add cold water;

[0164] - Remove the ice bath and leave under agitation;

[0165] - Transfer the resulting formulation into a suitable container.

[0166] In one embodiment according to the invention, the nanocapsule is formulated in a formulation comprising water and a salt, such as NaCl.

[0167] Thus this formulation comprises the nanoparticle according to the invention, water, preferably between 50 and 70%, and for example 60%, by weight relative to the total weight of the formulation, and a salt, preferably between 1 and 5%, for example 2 or 3%, by weight relative to the total weight of the composition.

[0168] Pharmaceutical composition

[0169] The invention also relates to a pharmaceutical composition comprising a lipid nanocapsule according to the invention.

[0170] Optionally, the nanocapsule according to the invention can be mixed with one or more pharmaceutically acceptable excipients.

[0171] In particular, the pharmaceutical composition according to the invention comprises between 80 and 250 mg / ml of lipid nanocapsule, more particularly between 100 and 200 mg / ml, and for example 85, 90, 100, 105, 120, 125, 155, 225 mg / ml.

[0172] This concentration makes it possible in particular to avoid the crystallization of the compound of formula (I) over time while limiting its hydrolysis.

[0173] Such compositions may be prepared for use in oral administration, in particular in the form of tablets or capsules, in particular orodispersible tablets (lyoc); or parenteral administration, in particular in the form of emulsions.

[0174] It may be prepared by any of the processes well known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ed. Gennaro, AR, Ed. Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Pharmaceutically compatible binding agents and / or adjuvants may be included in the composition. Oral compositions will generally comprise an inert diluent carrier or an edible carrier. They may be administered as a unit dose, in which the term "unit dose" means a single dose that is capable of being administered to one patient and that can be readily handled and packaged, remaining in a physically and chemically stable unit dose form.

[0175] Tablets, pills, powders, capsules, lozenges, and similar products may contain one or more of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose or tragacanth gum; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a lubricating agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or methyl salicylate. Capsules may be in the form of a hard capsule or a soft capsule, which are generally made from mixtures of gelatin, possibly mixed with plasticizers, as well as a starch capsule.Furthermore, unit-dose dosage forms may contain various other materials that alter the physical form of the dosage unit, for example, sugar coatings, shellac, or enteric agents. Other oral dosage forms, such as syrups or elixirs, may contain sweeteners, preservatives, colorings, and flavorings. In addition, the active compounds may be incorporated into rapid-dissolving, modified-release, or extended-release preparations and formulations, with these extended-release formulations preferably being bimodal.

[0176] Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Liquid compositions may also include binders, buffers, preservatives, chelating agents, sweeteners, flavorings, colorings, and the like. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, and acrylate copolymers. Aqueous carriers include mixtures of alcohols and water, hydrogels, buffered media, and saline solution. In particular, a Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of active compounds. Intravenous vehicles may include fluid and nutrient regenerators, electrolyte regenerators such as Ringer's dextrose-based regenerators, and similar products.

[0177] Examples of routes of administration include the parenteral route, e.g. subcutaneous, intramuscular, intravenous, intradermal and oral administration.

[0178] Use

[0179] The present invention also relates to a lipid nanocapsule according to the invention or a pharmaceutical composition according to the invention, for its use as a drug.

[0180] More particularly, it relates to a lipid nanocapsule according to the invention or a pharmaceutical composition according to the invention for its use for the prevention and / or treatment of cancer.

[0181] The term “treatment” refers to a therapeutic treatment whose purpose is to eliminate or alleviate symptoms. Beneficial or desired clinical outcomes include, but are not limited to, the elimination of symptoms, the relief of symptoms, the reduction in the extent of the condition, the stabilization (i.e., non-aggravation) of the condition, and the delay or slowing of the progression of the condition.

[0182] “Prevent” means to refer to the prevention of the onset, recurrence, or spread of a disease or disorder, or one or more of its symptoms. In some embodiments, the terms refer to treatment with or administration of a nanocapsule provided herein before the onset of symptoms, particularly in patients at risk of cancer. The terms encompass the inhibition or reduction of a symptom of the disease. Subjects with a family history of a particular disease are candidates for preventive regimens in some embodiments. In addition, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this respect, the term “prevention” may be used interchangeably with the term “prophylactic treatment.”

[0183] As used herein and unless otherwise specified, the term "cancer" refers to the growth, division, or proliferation of abnormal cells in the body. It refers to any type of malignant (i.e., non-benign) tumor. A malignant tumor may be a primary tumor or a secondary tumor (i.e., a metastasis). In addition, a tumor may be a solid malignant tumor, which includes, for example, carcinomas, adenocarcinomas, sarcomas, melanomas, mesotheliomas, blastomas, or a blood cancer such as leukemias, lymphomas, and myelomas. Cancer may, for example, be a solid carcinoma, a melanoma, lung cancer (including, but not limited to, non-small cell lung carcinoma (NSCLC), small cell lung carcinoma (SCLC), small cell combined carcinoma, pleuropulmonary blastoma, tumors, sarcomatoid carcinomas, carcinoid tumors, adenosquamous carcinomas, squamous cell lung carcinomas, adenocarcinomas, and large cell lung carcinomas), medulloblastoma, brain cancer (including, but not limited to, gliomas, glioblastomas, astrocytomas, oligoastrocytomas, oligodendrogliomas, and ependymomas), spinal cord cancer, neuroblastoma, breast cancer, skin cancer, myelodysplastic syndrome, pancreatic cancer, prostate cancer, colon cancer, anal cancer, gastrointestinal stromal tumor (GIST), small bowel cancer, stomach cancer, testicular cancer, cervical carcinoma, uterine cancer, ovarian cancer, vaginal cancerVulvar cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck, renal cell carcinoma, kidney cancer, Merkel cell carcinoma, PMBCL, classical Hodgkin lymphoma, osteosarcoma, desmoid tumor, bone cancer, thyroid cancer, cancer of the mouth and oropharynx, and leukemia.

[0184] In particular, the cancer may be a radioresistant or chemoresistant cancer.

[0185] In particular, the present invention relates to a nanocapsule according to the invention or a pharmaceutical composition according to the invention for its use for the prevention and / or treatment of hematological cancers, more particularly leukemia, and even more particularly acute myeloid leukemia.

[0186] In particular, the subject requiring treatment for cancer is a subject suffering from such a disease.

[0187] In the context of the present invention, the identification of subjects who require treatment for the diseases and conditions described herein is carried out as mentioned above and is well within the capabilities and knowledge of a person skilled in the art. A clinician competent in this field can easily identify, using the techniques mentioned above, the subjects who require such treatment.

[0188] A therapeutically effective amount can be readily determined by the diagnostician, as by a person skilled in the art, using conventional techniques and observing the results obtained under similar circumstances. To determine the therapeutically effective amount, a number of factors are taken into account by the diagnostician, including, but not limited to: the species of the subject; their size, age, and general health; the specific disease involved; the degree of involvement or severity of the disease; the individual subject's response; the particular compound administered; the route of administration; the bioavailability characteristics of the administered preparation; the chosen dosing regimen; and the use of other medications. concurrent; and other relevant circumstances.

[0189] As used herein, an "effective amount" refers to an amount that is effective in reducing, eliminating, treating, or controlling the symptoms of the diseases and conditions described herein. The term "control" is intended to refer to all processes in which there may be a slowing, interruption, halting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all symptoms of disease and condition, and is intended to include prophylactic treatment and chronic use.

[0190] The term “patient” or “subject” refers to a warm-blooded animal such as a mammal, in particular a human being, male or female, unless otherwise indicated, who is afflicted or has the potential to be afflicted with one or more of the diseases and conditions described herein.

[0191] The quantity of the nanocapsule according to the invention or the concentration of the compound of formula (I) in the nanocapsule, which is necessary to obtain the desired biological effect, will vary according to a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g. hydrophobicity) of the compounds used, the potency of the compounds, the type of disease, the pathological condition of the patient and the route of administration.

[0192] In the context of the present invention, it shall be understood that "a lipid nanocapsule for its use for the treatment or prevention of" is equivalent to "the use of a lipid nanocapsule for the treatment or prevention of" and to "the use of a nanocapsule for the manufacture of a medicinal product intended for the treatment or prevention of".

[0193] The various aspects of the invention are illustrated by the examples and figures that follow. FIGURES

[0194] [fig. 1]: illustration of a lipid nanocapsule according to the invention

[0195] [fig.2]: In vivo efficacy test on xenografts: comparison of efficacy between the compound no. 21 unencapsulated at 20 and 40 mg / kg and its encapsulated formulation at 20 mg / kg- EXAMPLES

[0196] Part 1: Preparation of compounds of formula (I)

[0197] Representative compounds of compounds of formula (I) are summarized in Table 1 below:

[0198] [Tables 1] Example Structure Name 1 / \ ( po O ( S-methyl 4- [2-ethoxyethyl(methyl)amino]-4-methylpent-2-ynethioate 2 0 " , 0 T S-methyl 4- [2-allyloxy ethyl(methyll)amino]-4-methylpent-2-ynethioate 3 ■>— / > .<2 / / 'o •' O ( / ......\ % S-methyl 4- [2-benzyloxyethyl(met hyl)amino]-4-methylpent-2-ynethioate 4 _ -=) O. , OW ) S-methyl 4-methyl-4- [methyl- [2-(m-tolylmethoxy)ethyl]amino]pent-2-ynethioate 5 / ) <> z O œ ( / S-methyl 4- [2- [(3,4-dimethylphenyl)methoxy]ethyl-methyl -amino]-4-methyl-pent-2 -ynethioate 6 ...•s^OMe '-n^aJU ^< 0 'X S-methyl 4- [2- [(4-methoxyphenyl) methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate 7 S-methyl X > / od / / / \ Z ,.0M® 4- [2- [(3,4-dimethoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate 8 ) oz O « / 'V' / ï n "CI S-methyl 4- [2- [(3-chlorophenyl)m ethoxy]ethyl-methyl-amino] -4-methyl-pent-2-yne thioate 9 ") / OV— W / ;# ' ZJ fx / fx X>-z Xx jp S-methyl 4- [2- [(3-fluorophenyl)m ethoxy]ethyl-methyl-amino] -4-methyl-pent-2-yne thioate 10 z . 0 Y -¾ S-methyl 4-methyl-4- [methyl- [2-( 2-pyridylmethoxy)ethyl] amino]pent-2-ynethioate 11 .0 T S-methyl 4-methyl-4- [methyl- [2-( 3-pyridylmethoxy)ethyl] amino]pent-2-ynethioate 12 sh- z .GT LJ S-methyl 4-methyl-4- [methyl- [2-( 4-pyridylmethoxy)ethyl] amino]pent-2-ynethioate . 13 S-methyl 4-((4-(benzyloxy)butyl)(methyl)amino)-4-methyl pent-2-ynethioate n ; v N ' ' ■ S Me 14 OH —N 0 C—| S-methyl 4-((2-hydroxyethyl)(met hyl)amino)-4-methylpent-2-ynethioate 15 1 |i S-methyl 4-methyl-4-[methyl-[2-(2-naphthylmethoxy)ethyl]amino]pent-2-ynethioate e 16 z ) °A / O" / / # X...... / ...... / Y<' S-methyl 4-methyl-4-[methyl-[2-[(2,6,6-trimethylcyclohexe n-1-yl)methoxy]ethyl]amino]pent-2-ynethioate 17 ......... or xhK xx Y 4x o XX -■■N -' S-methyl 2,5,10,11,11-pentamethyl-6-oxo-7-oxa-2,5,10-tria zatetradec-12-yne-14-thioate 18 ■ x Y\ ~X OBn zx^.0 Y S-methyl 4-methyl-4- [methyl(2-phenoxycyclopentyl)amino] pent-2-y nethioate 19 ry O 'NO (S)-S-methyl 4-(2-((benzyloxy)methyl )pyrrolidin- l-yl)-4-methylpent-2-ynethioate 20 O S-methyl 4-[(3(benzyloxy)-lpyrrolidiny 1] ) -4-methylpent-2-ynethioate 21 N' o / SMe S-methyl 4-dimethylamino-4-methylpent-2-ynethioate 22 ONO / s— S-methyl 4-methyl-4-morpholin-4-ylpent-2-ynethioate 23 y--CH, HÆ—NO h3c ch3 s—ch3 S-methyl 4-methyl-4- [methyl(octy l)amino]pent-2-ynethioate

[0199] Representative compounds of the compounds of formula (I) can be synthesized according to the following procedures. General analytical procedures

[0200] The 1H and 13C NMR spectra were recorded on a Bruker Advance ALS300 and DRX400 MHz instrument. Chemical shifts are given in ppm (δ) and were referenced to DMSO-d6 (1H, 2.50 ppm; 13C, 39.52 ppm) or CDC13 (7.26 ppm). Coupling constants (J) are given in Hz.

[0201] HRMS-ESI mass spectra were recorded in positive ion mode on a hybrid quadrupole time-of-flight mass spectrometer (MicroTOFQ-II, Bruker Daltonics, Bremen) with an electrospray ionization (ESI) source. For the spec Low-resolution mass trometry, LRMS-ESI mass spectra were recorded with a Thermo Finnigan MAT 95 XL spectrometer.

[0202] Example 1: 4- [2-ethoxvethvl (methvl)aminol -4-methvl-pent-2-vnethioate of S-methvl

[0203] Preparation of N-(2-ethoxyethyl)-N,2-dimethyl-but-3-yn-2-amine: To a solution of N-methyl-N-(2'hydroxyethyl)-3-amino-3-methyl-l-butyne (Easton, Nelson R.; Hennion, George FUS (1967), US 3337625 19670822.) (1.0 g, 7.08 mmol) and iodoethane (0.98 ml, 7.6 mmol) in THF (12 ml) NaH (0.459 g, 11.5 mmol) was added at room temperature and the mixture was heated under reflux for 3 h. The mixture was then thoroughly hydrolyzed at room temperature with water and extracted with EtOAc (3x25 ml). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification of the crude material by silica gel chromatography (petroleum ether / EtOAc = 70 / 30) yielded pure N-(2-ethoxyethyl)-N,2-dimethyl-but-3-yn-2-amine (0.479 g, 40%).

[0204] 1H NMR (300 MHz, DMSO) ô 3.45 - 3.36 (m, 4H), 3.11 (s, 1H), 2.51 (t, J = 6.7 Hz,. 2H), 2.20 (s, 3H), 1.27 (s, 6H), 1.09 (t, J = 7.0 Hz, 3H).

[0205] ESLLRMS 170.0 [M + H] +.

[0206] Preparation of S-methyl 4-[2-ethoxyethyl(methyl)amino] - 4-Methylpent-2-ynethioate:N-(2-ethoxyethyl)-N,2-dimethylbut-3-yn-2-amine (0.367 g, 2.17 mmol) in THF (11 mL) was added dropwise to a 2.28 M n-BuLi solution in hexane (1.14 mL, 2.60 mmol) at -70°C. After 5 min at -70°C, the reaction mixture was heated to 0°C, held at this temperature for 10 min, and then cooled to -70°C before being bubbled through the solution for 30 min with carbonyl sulfide (COS). The yellow solution was heated to 0°C and stirred for an additional 10 min at this temperature before the dropwise addition of iodomethane (0.162 mL, 2.60 mmol). The mixture was stirred for 2 h, thoroughly hydrolyzed at 0 C with water, and extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum.Purification of the crude oil by silica gel chromatography (petroleum ether / EtOAc = 90 / 10) yielded pure 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate (0.369 g, 70%) as an almost colorless oil.

[0207] 1H NMR (300 MHz, DMSO) ô 3.42 (t, J = 6.3 Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 2.56 (t, J = 6.3 Hz, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 1.36 (s, 6H), 1.10 (t, J = 7.0 Hz, 3H).

[0208] ESLHRMS calculated for C12H22NO2S [M + H] +: 244.1366, found: 244.1362.

[0209] Example 2: 4-[2-allyloxyethyl (methyl 4-methyl-pent-2-ynethioate of S-methyl

[0210] Preparation of N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine: At N- Methyl-N-(2'-hydroxyethyl)-3-amino-3-methyl-l-butyne (Easton, Nelson R.; Hennion, George FUS (1967), US 3337625 19670822.) (1.0 g, 7.08 mmol) in THF (12 ml) was added NaH (0.340 g, 8.50 mmol) at 0°C. After 15 min at 0°C and 15 min at room temperature, n-Bu4NI (0.026 g, 0.071 mmol) was added in a portion at 0°C followed by the dropwise addition of allyl bromide (0.735 ml, 8.50 mmol). The reaction mixture was allowed to reach room temperature, stirred overnight, then thoroughly hydrolyzed with water and extracted with ether (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over Na₂SO₄, and concentrated under vacuum. Purification by silica gel chromatography (petroleum ether / ether = 80 / 20 to 70 / 30) yielded pure N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine (0.941 g, 73%) as an oil.

[0211] 1H NMR (300 MHz, DMSO) δ 5.88 (ddt, J = 17.3, 10.5, 5.3 Hz, 1H), 5.24 (ddd, J = 17.3, 3.8, 1.7 Hz, 1H), 5.16 - 5.09 (m, 1H), 3.93 (dt, J = 5.3, 1.6 Hz, 2H), 3.43 (t, J = 6.4 Hz, 2H), 3.12 (s, 1H), 2.55 (t, J = 6.4 Hz, 2H), 2.21 (s, 3H), 1.27 (s, 6H).

[0212] ESLLRMS 182.0 [M + H] +.

[0213] Preparation of S-methyl 4-[2-allyloxyethyl (methyl)amino] - 4-Methylpent-2-ynethioate: The compound is obtained using the same process as described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methylpent-2-ynethioate [Example 1] from N-(2-allyloxyethyl)-N,2-dimethylbut-3-yn-2-amine. Quantity: 2.2 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10 to 80 / 20). Yield: 65%. Nearly colorless oil.

[0214] 1H NMR (300 MHz, DMSO) δ 5.88 (ddt, J = 17.3, 10.5, 5.3 Hz, 1H), 5.24 (ddd, J = 17.3, 3.8, 1.7 Hz, 1H), 5.17 - 5.10 (m, 1H), 3.94 (dt, J = 5.3, 1.5 Hz, 2H), 3.45 (t, J = 6.2 Hz, 2H), 2.58 (t, J = 6.2 Hz, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 1.36 (s, 6H).

[0215] ESLHRMS calculated for C13H22NO2S [M + H] +: 256.1366, found: 256.1364.

[0216] Example 3: 4-[2-benzyloxyethyl(methyl)amino1 4-methyl-pent-2-ynethioate of S-methyl

[0217] Preparation of N-(2-benzyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 1.015 eq of NaH and 1.01 eq of benzyl bromide. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10). Yield: 81%. Colorless oil.

[0218] 1H NMR (300 MHz, DMSO) ô 7.39 - 7.24 (m, 5H), 4.47 (s, 2H), 3.49 (t, J = 6.3 Hz, 2H), 3.12 (s, 1H), 2.58 (t, J = 6.3 Hz, 2H), 2.21 (s, 3H), 1.27 (s, 6H). ESLLRMS 232.0 [M + H] +.

[0219] Preparation of 4-[2-benzyloxyethyl(methyl)amino]-4-methylpent-2-ynethioate of S-methyl: The compound is obtained using the same process as described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate [example 1] from N-(2-benzyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine. Quantity: 2.2 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10). Yield: 79%. Colorless oil.

[0220] 1H NMR (300 MHz, DMSO) ô 7.37 - 7.26 (m, 5H), 4.48 (s, 2H), 3.52 (t, J = 6.1 Hz, 2H), 2.62 (t, J = 6.1 Hz, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.36 (s, 6H).

[0221] ESI-HRMS calculated for C17H24N02S [M + H] +: 306.1522, found: 306.1514.

[0222] Alternative protocol: To N-(2-benzyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine (0.650 g, 2.81 mmol) in THF (8 mL), a 2.28 M solution of n-BuLi in hexane (1.36 mL, 3.09 mmol) was added dropwise at -70°C. After 5 minutes at -70°C, the reaction mixture was heated to 0°C, held at this temperature for 30 minutes, and CO2 was bubbled through the solution for 30 minutes. The mixture was warmed to room temperature in 5 minutes and then cooled again to 0°C. Isobutyl chloroformate (0.40 mL, 3.08 mmol) was added dropwise and the mixture was stirred for 10 minutes before the addition of sodium methylate (0.236 g, 3.37 mmol) in one portion. The mixture was heated to room temperature, stirred for a further 15 minutes at that temperature, then thoroughly hydrolyzed at 0°C with water and extracted with ether.The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. Purification of the crude by silica gel chromatography (petroleum ether / EtOAc = 90 / 10) gave pure 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate (0.307 g, 36%).

[0223] Example 4: 4-methvl-4-rmethvl-[2-(m-tolvlmethoxv)ethvl1amino1 pent-2-vnethioate of S-methvl

[0224] Preparation of N-2-dimethyl-N-[2-(m-tolylmethoxy)ethyl]but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 3-methylbenzyl bromide. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10). Quantity: 4.5 mmol. Yield: 79%. Colorless oil.

[0225] 1H NMR (300 MHz, DMSO) ô 7.26 - 7.19 (m, 1H), 7.16 - 7.05 (m, 3H), 4.43 (s, 2H), 3.48 (t, J = 6.3 Hz, 2H), 3.12 (s, 1H), 2.57 (t, J = 6.3 Hz, 2H), 2.30 (s, 3H), 2.21 (s, 3H), 1.27 (s, 6H).

[0226] ESLLRMS 246.1 [M + H] +.

[0227] Preparation of S-methyl 4-methyl-4-[methyl-[2-(m-tolylmethoxy)ethyl]amino]pent-2-ynethioate: The compound is obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methylpent-2-ynethioate [Example 1] from N-2-dimethyl-N-[2-(m-tolylmethoxy)ethyl]but-3-yn-2-amine. Amount: 1.3 mmol. Purification by silica gel chromatography (ether Petroleum / EtOAc ratio = 90 / 10). Yield: 77%. Colorless oil.

[0228] 1H NMR (300 MHz, DMSO) ô 7.26 - 7.19 (m, 1H), 7.16 - 7.05 (m, 3H), 4.44 (s, 2H), 3.50 (t, J = 6.1 Hz, 2H), 2.62 (t, J = 6.1 Hz, 2H), 2.38 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H), 1.36 (s, 6H).

[0229] ESI-HRMS calculated for C18H26N02S [M + H] +: 320.1679, found: 320.1667.

[0230] lAtdLLUhL^ljtJ.^JjLdi^^dimetlTylphQiylJmelhoxy^ - 4-methyl-pent-2-ynethioate

[0231] Preparation of N-[2-[(3,4-dimethylphenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 3,4-dimethylbenzyl bromide. Purification by silica gel chromatography (petroleum ether / EtOAc = 60 / 40). Quantity: 3.8 mmol. Yield: 60%. Colorless oil.

[0232] 1H NMR (300 MHz, DMSO) ô 7.12 - 7.06 (m, 2H), 7.04 - 6.99 (m, 1H), 4.39 (s, 2H), 3.45 (t, J = 6.3 Hz, 2H), 3.12 (s, 1H), 2.56 (t, J = 6.3 Hz, 2H), 2.20 (s, 6H), 2.19 (s, 3H), 1.27 (s, 6H).

[0233] ESLLRMS 182.0 [M + H] +. ESLLRMS 260.0 [M + H] +.

[0234] Preparation of S-methyl 4-[2-[(3,4-dimethylphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate: The compound is obtained using the same process as described for 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N-[2-[(3,4-dimethylphenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine. Quantity: 1.3 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10). Yield: 77%. Oil almost colorless.

[0235] 1H NMR (300 MHz, DMSO) ô 7.12 - 7.06 (m, 2H), 7.05 - 6.99 (m, 1H), 4.40 (s, 2H), 3.48 (t, J = 6.2 Hz, 2H), 2.60 (t, J = 6.2 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 1.36 (s, 6H).

[0236] ESLHRMS calculated for C19H28NO2S [M + H] +: 334.1835, found: 334.1825.

[0237] Example 6: 4-[2-[(4-methoxypheny-1)methoxy]ethyl-methyl-amino]-4-methylpent-2-ynethioate

[0238] Preparation of N-[2-[(4-methoxyphenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 1-(bromomethyl)-4-methoxybenzene. Purification by silica gel chromatography (DCM / MeOH = 99 / 1 to 97.5 / 2.5). Quantity: 4.0 mmol. Yield: 53%. Colorless oil.

[0239] 1H NMR (300 MHz, DMSO) ô 7.27 - 7.20 (m, 2H), 6.93 - 6.86 (m, 2H), 4.39 (s, 2H), 3.74 (s, 3H), 3.45 (t, J = 6.3 Hz, 2H), 3.12 (s, 1 H), 2.55 (t, J = 6.4 Hz, 2 H), 2.20 (s, 3 H), 1.27 (s, 6 H).

[0240] ESI-LRMS 261.9 [M + H] +.

[0241] Preparation of S-methyl 4-[2-[(4-methoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate: The compound is obtained using the same process as described for S-methyl 4-[2-ethoxyethyl (methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N-[2-[(4-methoxyphenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine. Quantity: 1.3 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 80 / 20). Yield: 74%. Oil almost colorless.

[0242] 1H NMR (300 MHz, DMSO) ô 7.27 - 7.21 (m, 2H), 6.93 - 6.87 (m, 2H), 4.40 (s, 2H), 3.74 (s, 3H), 3.48 (t, J = 6.2 Hz, 2H), 2.60 (t, J = 6.2 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.36 (s, 6H).

[0243] ESLHRMS calculated for C18H26N03S [M + H] +: 336.1628, found: 336.1613.

[0244] Example 7: 4- [2-[(3,4-dimethoxyphenyl)methoxy1-ethyl-methylLamino1-4-methyl-pent-2-ynethioate

[0245] Preparation of N-[2-[(3,4-dimethoxyphenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 4-(bromomethyl)-1,2-dimethoxybenzene. Purification by silica gel chromatography (DCM / MeOH = 99 / 1 to 97.5 / 2.5). Quantity: 4.0 mmol. Yield: 67%. Colorless oil.

[0246] 1H NMR (300 MHz, DMSO) ô 6.94 - 6.88 (m, 2H), 6.87 - 6.80 (m, 1H), 4.39 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.46 (t, J = 6.3 Hz, 2H), 3.12 (s, 1H), 2.56 (t, J = 6.3 Hz, 2H), 2.21 (s, 3H), 1.27 (s, 6H).

[0247] ESLLRMS 292.0 [M + H] +.

[0248] Preparation of S-methyl 4-[2-[(3,4-dimethoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate: The compound is obtained using the same process as described for 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N-[2-[(3,4-dimethoxyphenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine. Quantity: 1.0 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10). Yield: 67%. Oil almost colorless.

[0249] 1H NMR (300 MHz, DMSO) ô 6.94 - 6.87 (m, 1H), 6.87 - 6.81 (m, 1H), 4.40 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.48 (t, J = 6.1 Hz, 2H), 2.61 (t, J = 6.2 Hz, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.36 (s, 6H).

[0250] ESLHRMS calculated for C19H28N04S [M + H] +: 366.1734, found: 336.1720.

[0251] Example 8: 4-12-[(3-chlorophenyl)methoxy1-ethylmethyl1-amino1-4-methylpent-2-ynethioate of S-methyl

[0252] Preparation of N-[2-[(3-chlorophenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 3-chlorobenzyl bromide. Purification by silica gel chromatography (petroleum ether / EtOAc = 70 / 30). Quantity: 4.0 mmol. Yield: 71%. Colorless oil.

[0253] 1H NMR (300 MHz, DMSO) ô 7.43 - 7.25 (m, 4H), 4.49 (s, 2H), 3.50 (t, J = 6.2 Hz, 2H), 3.12 (s, 1H), 2.58 (t, J = 6.2 Hz, 2H), 2.22 (s, 3H), 1.28 (s, 6H).

[0254] ESLLRMS 266.0 [M + H] +.

[0255] Preparation of S-methyl 4-[2-[(3-chlorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate: The compound is obtained using the same process as described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N-[2-[(3-chlorophenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine except that the reaction mixture was maintained at -70°C after the addition of n-BuLi for 30 minutes before bubbling with COS. Scale bar: 1.3 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 75 / 25). Yield: 63%. Oil almost colorless.

[0256] 1H NMR (300 MHz, DMSO) ô 7.44 - 7.24 (m, 4H), 4.50 (s, 2H), 3.52 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.27 (s, 3H), 1.37 (s, 6H).

[0257] ESLHRMS calculated for C17H23C1N02S [M + H] +: 340.1133, found: 340.1120.

[0258] Example 9: 4-r2-r(3-fiorophenvl)methoxvlethvl-methvl-aminol-4-methvl-pent-2-vnethioate of S-methvl

[0259] Preparation of N-[2-[(3-fluorophenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 3-fluorobenzyl bromide. Purification by silica gel chromatography (petroleum ether / EtOAc = 80 / 20). Quantity: 4.0 mmol. Yield: 71%. Colorless oil.

[0260] Preparation of S-methyl 4-[2-[(3-fluorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate: The compound is obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N-[2-[(3-fluorophenyl)methoxy]ethyl]-N,2-dimethyl-but-3-yn-2-amine, except that the reaction mixture was maintained at -70°C after the addition of n-BuLi for 30 minutes before bubbling with COS. Quantity: 1.3 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 70 / 30). Yield: 87%. Oil almost colorless.

[0261] 1H NMR (300 MHz, DMSO) ô 7.44 - 7.34 (m, 1H), 7.20 - 7.05 (m, 3H), 4.51 (s, 2H), 3.53 (t, J = 6.1 Hz, 2H), 2.63 (t, J = 6.1 Hz, 2H), 2.38 (s, 3H), 2.27 (s, 3H), 1.37 (s, 6H).

[0262] ESI-HRMS calculated for C17H23FNO2S [M + H] +: 324.1428, found: 324.1415

[0263] Example 10: 4-methvl-4-rmethvl-[2-(2-Dvridvlmethoxv)ethvl1 aminol pent-2-vnethioate of S-methvl

[0264] Preparation of N-2-dimethyl-N-[2-(2-pyridylmethoxy)ethyl]but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] from 2-(bromomethyl)pyridine hydrobromide and using 4 eq of NaH. Purification by silica gel chromatography (DCM / MeOH = 99:1 to 95:5). Quantity: 2.1 mmol. Yield: 71%. Yellow oil.

[0265] 1H NMR (300 MHz, DMSO) ô 8.50 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.32 - 7.24 (m, 1H), 4.55 (s, 2H), 3.56 (t, J = 6.2 Hz, 2H), 3.13 (s, 1H), 2.61 (t, J = 6.2 Hz, 2H), 2.23 (s, 3H), 1.28 (s, 6H).

[0266] ESLLRMS 233.1 [M + H] +.

[0267] Preparation of S-methyl 4-methyl-4-[methyl-[2-(2-pyridylmethoxy)ethyl]amino] pent-2-ynethioate: The compound is obtained using the same process as described for S-methyl 4-[2-ethoxyethyl (methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N-2-dimethyl-N-[2-(2-pyridylmethoxy)ethyl]but-3-yn-2-amine and using 1.5 eq of n-BuLi, 1.5 eq of Mel and DCM extractions. Scale bar: 0.9 mmol. Purification by silica gel chromatography (DC / MeOH = 99 / 1 to 90 / 10). Yield: 18%. Yellow oil.

[0268] 1H NMR (300 MHz, DMSO) ô 8.54 - 8.48 (m, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 6.7, 5.1 Hz, 1H), 4.56 (s, 2H), 3.59 (t, J = 6.1 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 1.37 (s, 6H).

[0269] ESLHRMS calculated for C16H23N202S [M + H] +: 3071475, found: 307,1471.

[0270] Example 11: 4-methyl-4-rmethyl-[2-(3-pyridylmethoxy)ethyl1 aminol pent-2-ynethioate of S-methyl

[0271] Preparation of N-2-dimethyl-N-[2-(3-pyridylmethoxy)ethyl]but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] from 3-(bromomethyl)pyridine hydrobromide and using 4 eq of NaH. Purification by silica gel chromatography (DCM / MeOH = 99 / 1 to 95 / 5). Quantity: 2.1 mmol. Yield: 67%. Yellow oil.

[0272] 1H NMR (300 MHz, DMSO) ô 8.56 - 8.52 (m, 1H), 8.49 (dd, J = 4.8, 1.7 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.38 (ddd, J = 7.8, 4.8, 0.8 Hz, 1H), 4.52 (s, 2H), 3.52 (t, J = 6.2 Hz, 2H), 3.12 (s, 1H), 2.58 (t, J = 6.2 Hz, 2H), 2.21 (s, 3H), 1.27 (s, 6H).

[0273] ESI-LRMS 233.1 [M + H] +.

[0274] Preparation of S-methyl 4-methyl-4-[methyl-[2-(3-pyridylmethoxy)ethyl]amino] pent-2-ynethioate: The compound is obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl (methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N-2-dimethyl-N-[2-(3-pyridylmethoxy)ethyl]but-3-yn-2-amine and using 1.5 eq of n-BuLi, 1.5 eq of Mel and DCM extractions. Quantity: 0.4 mmol. Purification by silica gel chromatography (DCM / MeOH = 99 / 1 to 95 / 5). Yield: 15%. Yellow oil.

[0275] 1H NMR (300 MHz, DMSO) ô 8.54 (d, J = 1.5 Hz, 1H), 8.49 (dd, J = 4.8, 1.7 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.38 (ddd, J = 7.8, 4.8, 0.8 Hz, 1H), 4.53 (s, 2H), 3.54 (t, J = 6.1 Hz, 2H), 2.63 (t, J = 6.1 Hz, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.36 (s, 6H)).

[0276] ESLHRMS calculated for C16H23N202S [M + H] +: 3071475, found: 307,1474.

[0277] Example 12: S-methyl 4-methyl-4-r-methyl-[2-(4-pyridylmethoxy)ethyl1-amino]pent-2-ynethioate

[0278] Preparation of N-2-dimethyl-N-[2-(4-pyridylmethoxy)ethyl]but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] from 4-(bromomethyl)pyridine hydrobromide and using 4 eq of NaH. Purification by silica gel chromatography (DCM / MeOH = 99 / 1 to 95 / 5). Quantity: 2.1 mmol. Yield: 95%. Yellow oil.

[0279] 1H NMR (300 MHz, DMSO) ô 8.56 - 8.49 (m, 2H), 7.38 - 7.27 (m, 2H), 4.54 (s, 2H), 3.53 (t, J = 6.2 Hz, 2H), 3.13 (s, 1H), 2.61 (t, J = 6.2 Hz, 2H), 2.23 (s, 3H), 1.28 (s, 6H).

[0280] ESLLRMS 233.1 [M + H] +.

[0281] Preparation of S-methyl 4-methyl-4-[methyl-[2-(4-pyridylmethoxy)ethyl]amino]pent-2-ynethioate: The compound is obtained using the same process as described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methylpent-2-ynethioate [Example 1] from N-2-dimethyl-N-[2-(4-pyridylmethoxy)ethyl]but-3-yn-2-amine and using 1.5 eq of n-BuLi, 1.5 eq of Mel and DCM extractions. Quantity: 1.0 mmol. Purification by silica gel chromatography (DCM / MeOH = 99 / 1 to 95 / 15). Yield: 24%. Yellow oil.

[0282] 1H NMR (300 MHz, DMSO) ô 8.60 - 8.45 (m, 2H), 7.37 - 7.26 (m, 2H), 4.55 (s, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 1.37 (s, 6H).

[0283] ESLHRMS calculated for C16H23N202S [M + H] +: 3071475, found: 307,1470.

[0284] Example 13: S-methyl 4-((4-(benzyloxy)butyl)(methyl)amino)-4-methylpent-2-ynethioate

[0285] Preparation of 4-(methyl (2-methylbut-3-yn-2-yl)amino)butan-l-ol: Ce The compound was prepared by previously described standard protocols for the synthesis of N-methyl-N-(2'-hydroxyethyl)-3-amino-3-methyl-l-butyne (Easton, Nelson R.; Hennion, George FUS (1967), US 3337625 19670822) from commercially available 4-(methylamino)butan-ol. The 4-(meth(2-methylbut-3-yn-2-yl)amino)butan-l-ol was obtained as a bright yellow oil. Quantity: 3 mmol. Yield: 99%.

[0286] 1H NMR (300 MHz, DMSO) ô 4.41 (t, J = 5.2 Hz, 1H), 3.42 - 3.33 (m, 2H), 3.09 (s, 1H), 2.38 - 2.29 (m, 2H), 2.14 (s, 3H)), 1.45 - 1.36 (m, 4H), 1.27 (s, 6H).

[0287] ESI - LRMS: 170.1 [M + H] +

[0288] Preparation of N-(4-(benzyloxy)butyl)-N,2-dimethylbut-3-yn-2-amine: The The compound was obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] from 4-(methyl (2-methylbut-3-yn-2-yl)amino)butan-l-ol and using 1.015 eq of NaH and 1.01 eq of benzyl bromide. Purification by silica gel chromatography (cyclohexane / EtOAc = 80 / 20). Quantity: 2.4 mmol. Yield: 55%. Yellow oil.

[0289] 1H NMR (300 MHz, DMSO) ô 7.39 - 7.22 (m, 5H), 4.44 (s, 2H), 3.42 (t, J = 6.3 Hz, 2H), 3.08 (s, 1H), 2.34 (t, J = 6.9 Hz, 2H), 2.13 (s, 3H), 1.60 - 1.37 (m, 4H), 1.26 (s, 6H).

[0290] ESI - LRMS: 260.2 [M + H] +

[0291] Preparation of S-methyl 4-((4-(benzyloxy)butyl)(methyl)amino) - 4-Methylpent-2-ynethioate: The compound was obtained using the same process as described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methylpent-2-ynethioate [Example 1] from N-(4-benzyloxybutyl)-N,2-dimethylbut-3-yn-2-amine. Purification by silica gel chromatography (cyclohexane / EtOAc = 90 / 10). Amount: 0.77 mmol. Yield: 80%. Yellow oil.

[0292] 1H NMR (300MHz, CDC13) ô 7.38 - 7.19 (m, 5H), 4.48 (s, 2H), 3.47 (t, J = 6.1 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 1.73 - 1.48 (m, 4H), 1.39 (s, 6H).

[0293] ESI - HRMS: calculated for C19H28NO2S [M + H] + 334.1835, found 334.1840.

[0294] Exempt e 14: S-methyl 4-((2-hydroxyethyl) (methyl) amino) - 4-methylpent-2-ynethioate 5 "COSMe

[0296] a) See Easton, Nelson R. Hennion, George F., US (1966), US 3285913 b) 3,4-DHP, pTSA, DCM (70%) c) nBuLi, THF, -70°C, carbonyl sulfide then Mel 0°C (59%) d) pTSA, MeOH, room temperature (90%)

[0297] Preparation of Compound 3: N,2-Dimethyl-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)but-3-yn-2-amine: To 2-(methyl(2-methylbut-3-yn-2-yl)amino)ethanol 2 (3.00 g, 21.2 mmol) and 3,4-dihydro-2H-pyran (5.0 eq) in anhydrous DCM (135 mL), p-Toluenesulfonic acid (0.1 eq) was added at room temperature. The reaction mixture was stirred overnight, washed with saturated aqueous NaHCO3 (30 mL) and then with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was first purified by short path distillation using a Kugelrohr apparatus (10-12 Torrs, oven 155°C) and then by flash chromatography on silica gel (petroleum ether / ethyl acetate 95 / 5 to 60 / 40) to give compound 3 in oil form (yield 70%).

[0298] 1H NMR (300 MHz, DMSO) ô 4.60 - 4.50 (m, 1H), 3.82-3.70 (m, 1H), 3.59-3.56 (m, 1H), 3.49 - 3.35 (m, 2H), 3.12 (s, 1H)), 2.55 (t, J = 6.5 Hz, 2H), 2.21 (s, 3H), 1.77 -1.35 (m, 6H), 1.27 (s, 6H).

[0299] Preparation of compound 4: S-methyl 4-Methyl-4-(methyl(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)amino)pent-2-ynethioate: To acetylenic amine 3 (1.00 g, 4.44 mmol) in anhydrous THF (22 mL), a solution of n-butyllithium (2.2 M in hexanes, 1.5 eq) was added dropwise. The mixture was allowed to reach 0°C in 10 minutes and then cooled again to -70°C before bubbling carbonyl sulfide. After 30 minutes, the bright yellow solution was carefully heated to 0°C, stirred for 30 minutes at this temperature, and methyl iodide (1.2 eq) was added dropwise. The reaction mixture was stirred for 2 hours at 0°C before hydrolysis with water. A DCM extraction treatment (washing with brine, drying with sodium sulfate and concentration under reduced pressure) gave a crude which was purified by silica gel chromatography (petroleum ether / ethyl acetate 90 / 10 to 60 / 40) to give compound 4 as oil (yield 59%).

[0300] 1H NMR (300 MHz, DMSO) ô 4.58 (t, J = 3.2 Hz, 1H), 3.75 (ddd, J = 11.4, 7.9, 3.3 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.49 - 3.38 (m, 2H), 2.59 (t, J = 6.3 Hz, 2H), 2.39 (s, 3H), 2.27 (s, 3H), 1.77 - 1.39 (m, 6H), 1.36 (s, 6H). 13C NMR (75 MHz, CDC13) ô 176.62 (C = O), 98.94 (CH), 96.46 (C), 80.97 (C), 66.55 (CH2), 62.37 (CH2), 55.19 (C), 52.43 (CH2), 37.92 (CH3), 30.75 (CH2), 28.01 (2xCH3), 25.59 (CH2), 19.63 (CH2), 12.61 (CH3).

[0301] Preparation of compound 5: S-methyl 4- ((2-hydroxyethyl)(methyl)amino)-4-methylpent-2-ynethioate: to aminothiolester 4 (1.00 g, 3.34 mmol) in methanol (15 mL) was mixed with p-toluenesulfonic acid (1.1 eq) at room temperature. The reaction mixture was stirred overnight, washed with saturated aqueous NaHCO3 (30 mL) and then brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography (petroleum ether / ethyl acetate 80 / 20 to 20 / 80) to give compound 5 as an oil (90% yield).

[0302] 1H NMR (300 MHz, DMSO) δ 4.42 (t, J = 5.6 Hz, 1H), 3.44 (td, J = 6.7, 5.6 Hz, 2H), 2.46 (, J = 6.7 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.36 (s, 6H). 13C NMR (75 MHz, CDC13) ô 176.46 (C = O), 95.56 (C), 80.89 (C), 58.92 (CH2), 54.99 (C), 53.52 (CH2), 36.12 (CH3), 27.88 (2xCH3), 12.53 (CH3). ESLHRMS: Cale, for Ci0Hi8NO2S [M + H] + 216,1053 found 216,1043.

[0303] Example 15.4-methyl-4-[methyl-[2- (2-naphthylmethoxy)ethyl1amino1 pent-2-ynethioate of S-methyl

[0304] Preparation of N,2-Dimethyl-N-[2-(2-naphthylmethoxy)ethyl]but-3-yn-2-amine: The compound is obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] using 1.015 eq of NaH and 1.01 eq of 2-naphthyl bromide. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10). Yield: 61%. Orange oil.

[0305] 1H NMR (300 MHz, DMSO) ô 7.91 - 7.88 (m, 4H), 7.50 - 7.48 (m, 3H), 4.65 (s, 2H), 3.55 (t, 6.1 Hz, 2H), 3.13 (s, 1H), 2.62 (t, 6.2 Hz, 2H), 2.23 (s, 3H), 1.28 (s, 6H).

[0306] Preparation of S-methyl 4-methyl-4-[methyl-[2-(2-naphthylmethoxy)ethyl]amino]pent-2-ynethioate: The compound is obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate [Example 1] from N,2-dimethyl-N-[2-(2-naphthylmethoxy)ethyl]but-3-yn-2-amine. Quantity: 0.65 mmol. Purification by silica gel chromatography (petroleum ether / EtOAc = 85 / 15). Yield: 28%. Yellow oil.

[0307] 1H NMR (300 MHz, DMSO) δ7.95 - 7.82 (m, 4H), 7.55 - 7.41 (m, 3H), 4.66 (s, 2H), 3.57 (t, J = 6.2 Hz, 2H), 2.66 (t, J = 6.1 Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 1.37 (s, 6H).

[0308] ESI - HRMS: wedge, for C21H26NO2S 356.1683, found 356.1679 [M + H] +

[0309] Example 16: S-methyl 4-methyl-4-[methyl-[2- [(2,6,6-trimethylcyclohexen-l-yl) methoxyethyll amino] pent-2-ynethioate

[0310] Preparation of N,2-dimethyl-N-[2-[(2,6,6-trimethylcyclohexen-l-yl)methoxy]ethyl]but-3-yn-2-amine: The compound is obtained using the same process as that described for N-(2-allyloxyethyl)-N, 2-Dimethyl-but-3-yn-2-amine [Example 2] using 1.015 eq of NaH and 1.01 eq of 2-(bromomethyl)-1,3,3-trimethyl-1-cyclohexene (prepared from [3-cyclocitral] by known protocols (WO 2015048363)). Purification by silica gel chromatography (petroleum ether / EtOAc = 95 / 05). Yield: 67%. Pale yellow oil.

[0311] 3.86 (s, 2H), 3.41 (t, J = 6.5 Hz, 2H), 3.12 (s, 1H), 2.53 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H), 1.90 (t, J = 5.9 Hz, 2H), 1.62 (s, 3H), 1.57 - 1.49 (m, 2H), 1.41 - 1.33 (s, 2H), 1.27 (s, 6H), 0.97 (s, 6H).

[0312] Preparation of S-methyl 4-methyl-4-[methyl-[2-[(2,6,6-trimethylcyclohexen-l-yl) methoxy]ethyl]amino]pent-2-ynethioate: The compound is obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate (Example 15) from N,2-dimethyl-N-[2-[(2,6,6-trimethylcyclohexen-l-yl) methoxy]ethyl]but-3-yn-2-amine. Purification by silica gel chromatography (petroleum ether / EtOAc = 90 / 10). Yield: 63%. Yellow oil.

[0313] H NMR (300 MHz, DMSO) δ 3.87 (s, 2H), 3.44 (t, J = 6.3 Hz, 2H), 2.57 (t, J = 6.3 Hz, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.91 (t, J = 6.2 Hz, 2H), 1.62 (s, 3H), 1.57 - 1.49 (m, 2H), 1.36 (s, 6H), 1.39 - 1.34 (m, 2H), 0.97 (s, 6H).

[0314] ESI - HRMS calculated for C20H34N02S [M + H] +: 352.2305, found: 352.2289.

[0315] Example 17: S-methyl 2.5.10.11.11-pentamethyl-6-oxo-7-oxa-2.5.10-triazatetradec-12-yne-14-thioate

[0316] Preparation of compound 6: A p-nitrochloroformate solution (140 mg, 0.70 mmol, 1.5 eq) in dichloromethane (DCM) (2.5 mL) is added dropwise to a solution of compound 5 from Example 14 (100 mg; 0.46 mmol) with triethylamine (TEA) (1.5 eq) in DCM (1.5 mL) at 0°C. After 10 minutes at 0°C, the reaction mixture is heated to room temperature with stirring until complete conversion (verified by TLC, 1h). The mixture is then diluted in DCM (30 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (petroleum ether / ethyl acetate 100 / to 70 / 30) to give compound 6 in the form of an amorphous solid (yield 82%).

[0317] 1H NMR (300MHz, DMSO): ô(ppm) 8.35-8.30 (m, 2H), 7.59-7.53 (m, 2H), 4.30 (t, 7= 5.7 Hz, 2H), 2.75 (t, J= 5.7 Hz, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 1.39 (s, 6H).

[0318] Preparation of S-methyl 2,5,10,11,H-pentamethyl-6-oxo-7-oxa-2,5,10-triazatetradec-12-yne-14-thioate: To compound 6 (200 mg, 0.53 mmol) in 3 mL of DCM (3 mL), TEA (1.2 eq) is added at room temperature. A solution of N,N,N'-trimethylethylenediamine (1.2 eq) in dichloromethane (2.3 mL) is added to the reaction mixture at 0°C. The bright yellow reaction mixture is heated to temperature room temperature and stir overnight. The bright yellow reaction mixture was stirred overnight at room temperature, diluted with dichloromethane (40 mL), and then washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. Purification was performed by silica gel chromatography (petroleum ether / ethyl acetate 75 / 25 to 20 / 80). Yield: 70%. Oil.

[0319] 1H NMR (300MHz, DMSO): ô(ppm) 3.99 (t, J = 5.7Hz, 2H), 3.30 (s, 3H), 2.85-2.70 (m, 7H), 2.66-2.58 (m, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.37 (s, 9H), 1.36 (s, 6H). ESI - LRMS: Cale, for C20H36N3O5S [M+H]+: 430.2; found: 430.2.

[0320] Purification by silica gel chromatography DCM / MeOH (85 / 15). Yield: 34%. Yellow oil.

[0321] 1H NMR (300 MHz, DMSO) ô 4.01 (t, J = 5.9 Hz, 2H), 3.32-3.25 (m, 2H), 2.83 (large s, 3H), 2.62 (t, J = 5.8 Hz, 2H), 2.6-2.5 (m partially masked by solvent peak, 2H), 2.39 (s, 3H), 2.27 (s, 3H), 2.17 (large s, 6H), 1.36 (s, 6H).

[0322] ESLHRMS calculated for C16H30N303S [M + H] +: 344,1992, found: 344,1993.

[0323] Example 18: S-methyl 4-((( 1 R. 2R)-2-(benzyloxy)cyclopentyl)fmethyl)amino)-4-methylpent-2-ynethioate

[0324] Preparation of (IR, 2R)-2-benzyloxy-N-(l,l-dimethylprop-2-ynyl)cyclopentamine:

[0325] To a commercial solution of (IR, 2R)-2-(benzyloxy)cyclopentanamine (0.93 g, 4.86 mmol), 3-chloro-3-methylbutylyne (1.3 eq), and triethylamine (1.3 eq) in THF (20 mL), Cul (8 mol%) was added at room temperature. The mixture was left under stirring overnight. The solvent was evaporated under reduced pressure, and the crude material was then diluted in a saturated aqueous solution of NaHCO3, extracted with ethyl acetate. The combined organic layers were washed with a 2% aqueous solution of NH4OH followed by brine, dried over Na2SO4, and the solvent evaporated under reduced pressure. (1R,2R)-2-benzyloxy-N-(1,1-dimethylprop-2-ynyl)cyclopentanamine was obtained as a brown oil. Yield: 99%.

[0326] 1H NMR (300 MHz, DMSO) ô 7.37 - 7.16 (m, 5H), 4.56 - 4.36 (m, 2H), 3.72 - 3.58 (m, 1H), 3.28 - 3.19 (m, 1H), 3.08 (s, 1H)), 2.00 - 1.88 (m, 1H), 1.86 - 1.67 (m, 2H), 1.65 - 1.49 (m, 3H), 1.40 - 1.28 (m, 1H), 1.25 (s, 3H), 1.25 (s, 3H) ).

[0327] Preparation of (1R,2R)-2-(benzyloxy)-N-methyl-N-(2-methylbut-3-yn-2-yl)cyclopentanamine: To (1R,2R)-2-(benzyloxy)-N-(2-methylbut-3-yn-2-yl)cyclopentanamine (0.25 g, 0.97 mmol) 5 eq of formic acid and 1.5 eq of formaldehyde (37% in water) were added. The mixture was heated under reflux overnight, then 2N HCl was added until pH 1 was reached and washed with ether. The aqueous layer was basified with NaOH₂IN and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, and the solvents evaporated. under reduced pressure. The crude oil is then purified by silica gel chromatography (petroleum ether / EtOAc = 80 / 20), yielding a yellow oil. Yield: 68%.

[0328] 1H NMR (300 MHz, DMSO) ô 7.43 - 7.17 (m, 5H), 4.52 (m, 2H), 3.94 - 3.78 (m, 1H), 3.62 - 3.49 (m, 1H), 3.11 (s, 1H), 2.20 (s, 3H), 1.78 - 1.45 (m, 6H), 1.37 (s, 3H), 1.34 (s, 3H).

[0329] ESI - LRMS: 272.1 [M + H] +.

[0330] Preparation of S-methyl 4-(((1R, 2R)-2-(benzyloxy)cyclopentyl)(methyl)amino)-4-methylpent-2-ynethioate: The compound was obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methylpent-2-ynethioate [Example 1] from (1R, 2R)-2-(benzyloxy-N-methyl-N-(2-methylbut-3-yn-2-yl)cyclopentanamine. Purification by silica gel chromatography (petroleum ether / EtOAc = 80 / 20 then DCM = 100). Quantity: 0.64 mmol. Yield: 47%. Yellow oil.

[0331] 1H NMR (300 MHz, DMSO) ô 7.35 - 7.20 (m, 5H), 4.51 (s, 2H), 3.92 - 3.80 (m, 1H), 3.59 - 3.45 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 1.78 - 1.49 (m, 6H), 1.45 (s, 3H), 1.42 (s, 3H).

[0332] ESI - HRMS calculated for C20H28NO2S [M + H] +: 346.1835, found: 346.1824.

[0333] Example 19: 4-(2-((benzyloxy)methyl)pyrrolidin-l-yl)-4-methylpent-2-ynethioate of IS)-S-methyl:

[0334] Preparation of (S)-2-((benzyloxy)methyl)-l-(2-methylbut-3-yn-2-yl)pyrrolidine: The compound was obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethyl-but-3-yn-2-amine [Example 2] from (S)-(l-(2-methylbut-3-yn-2-yl)pyrrolidine-2-yl)methanol, 1.015 eq. of NaH, and 1.01 eq. of benzyl bromide. Purification by silica gel chromatography (dichloromethane / methanol = 95 / 5). Quantity: 3.0 mmol. Yield: 60%. Orange oil.

[0335] 1H NMR (300 MHz, DMSO) ô 7.41 - 7.19 (m, 5H), 4.46 (s, 2H), 3.24 (dd, J = 8.3, 2.7 Hz, 1H), 3.14 (dd, J = 7.6, 3.2 Hz, 1H), 3.11 - 3.02 (m, 2H), 2.86 (dd, J = 8.4, 6.0 Hz, 1H), 2.65 - 2.54 (m, 1H), 1.81 - 1.51 (m, 4H), 1.25 (s, 3H), 1.23 (s, 3H).

[0336] ESLLRMS: 258.1 [M + H] +.

[0337] Preparation of (S)-S-methyl 4-(2-((benzyloxy)methyl)pyrrolidin-l-yl)-4-methylpent-2-ynethioate: The compound was obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methylpent-2-ynethioate [Example 1] from (S)-2-((benzyloxy)methyl)-l-(2-methylbut-3-yn-2-yl)pyrrolidine. Purification by silica gel chromatography (petroleum ether / EtOAc = 80 / 20). Quantity: 1.2 mmol. Yield: 50%. Orange oil.

[0338] 1H NMR (300 MHz, DMSO) ô 7.46 - 7.18 (m, 5H), 4.47 (s, 2H), 3.29 - 3.23 (m, 1H), 3.17 - 3.03 (m, 2H), 2.94 (dd, J = 8.5.5.7 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.38 (s, 3H), 1.85 - 1.58 (m, 4H), 1.34 (s, 3H), 1.32 (s, 3H).

[0339] Example 20: 4-(R)-S-methvl 4-(3-(benzvloxv)pyrrolidin-l-vl) -4-methvlpent-2-vnethioate:

[0340] Preparation of (R)-3-(benzyloxy)-1-(2-methylbut-3-yn-2-yl)pyrrolidine: The compound was obtained using the same process as described for N-(2-allyloxyethyl)-N,2-dimethylbut-3-yn-2-amine [Example 2] from (R)-1-(2-methylbut-3-yn-2-yl)pyrrolidin-3-ol using 1.01 eq of NaH and 1.01 eq of benzyl bromide. Purification by silica gel chromatography (dichloromethane / methanol = 98 / 2). Amount of 3.3 mmol. Yield: 69%. Orange oil.

[0341] 1H NMR (300 MHz, DMSO) ô 7.40 - 7.17 (m, 5H), 4.42 (s, 2H), 4.07 (tt, J = 7.3, 3.7 Hz, 1H) 3.13 (s, 1H), 2.86 (dd, J = 9.6, 6.7 Hz, 1H), 2.75 - 2.65 (m, 2H), 2.60 - 2.53 (m, 1H), 2.06 - 1.95 (m, 1H), 1.75 - 1.65 (m, 1H), 1.29 (s, 6H)).

[0342] ESI - LRMS 244.1 [M + H] +.

[0343] Preparation of (R)-S-methyl 4-(3-(benzyloxy)pyrrolidin-l-yl)-4-methylpent-2-ynethioate: The compound was obtained using the same process as that described for S-methyl 4-[2-ethoxyethyl (methyl)amino]-4-methylpent-2-ynethioate [Example 1] from (R)-3-(benzyloxy)-l-(2-methylbut-3-yn-2-yl)pyrrolidine. Purification by silica gel chromatography (dichloromethane / methanol = 98 / 2). Amount of 1.2 mmol. Yield: 69%. Orange oil.

[0344] 1H NMR (300 MHz, DMSO) ô 7.32 (m, 5H), 4.44 (s, 2H), 4.09 (dq, J = 10.2, 3.5 Hz, 1H), 2.97 - 2.83 (m, 1H), 2.80 - 2.65 (m, 2H), 2.65 - 2.55 (m, 1H), 2.37 (s, 3H), 2.11-1.90 (m, 1H), 1.83 - 1.67 (m, 1H), 1.37 (s, 6H).

[0345] ESI - HRMS calculated for C18H24NO2S [M + H] +: 318.1522, found: 318.1518.

[0346] Example 21: preparation of 4-dimethylamino-4-methylpent-2-ynethioate S-methyl To a solution of 0.855 g of 3-dimethylamino-3-methylbutylyne [HENNION, GF, NELSON, KW (1957) J. Am. Chem. Soc., 79, 2142-2144] (2.80 mmol) in 14 mL of tetrahydrofuran, 4.07 mL (9.24 mmol) of a 2.27 M denbutyllithium in hexane solution is added over 5 minutes at -70°C. After 5 minutes, the reaction mixture is cooled to 0°C and stirred for another 30 minutes at this temperature. After returning to -70°C, 2 mL of previously condensed carbon oxysulfide is cannulated and the mixture is stirred for 30 minutes at -70°C. The reaction mixture is then brought to 0°C for 30 minutes, and 0.575 mL (9.24 mmol) of methyl iodide is added. Stirring is continued for 2 hours at 0°C. The mixture is diluted in 250 mL of ether, washed with a saturated sodium chloride solution (3 x 30 mL), and dried over sodium sulfate. After evaporation under vacuum and purification... Deposition by silica gel chromatography (elution with a petroleum ether / ethyl acetate mixture = 70 / 30) isolates 1.16g of the compound as a colorless oil (yield: 81%) 1H NMR (300 MHz, CDC13): v= 1.42 (s, 6H, (CH3)2C), 2.31 (s, 6H, (CH3)2N), 2.39 (s, 3H, CH3S).

[0347] Example 22: preparation of S-methyl 4-methvl-4-morDholin-4-vl-Dent-2-vnethioate The preparation is identical to that described in Example 21, using 3-di-n-propylamino-3-methyl-but-l-yne [HENNION, GF, HANZEL, RF, J. Am. Chem. Soc., 82,4908-4912, (1960)] instead of 3-methyl-3-morpholin-4-yl-but-l-yne. Quantity: 1.5 mmol, purification by silica gel chromatography (petroleum ether / ethyl acetate eluent = 60 / 40), yield: 77%. White solid.

[0348] 1H NMR (300 MHz, CDC13): v = 1.43 (s, 6H, (CH3)2C), 2.40 (s, 3H, CH3S), 2.65 (m, 4H, CH2O), 3.97 (m, 4H, CH2N).

[0349] Example 23: S-methyl 4-methyl-4-1-methyl(octyl)amino1pent-2-ynethioate

[0350] To N-methyl-N-(2-methylbu-3-yn-2-yl)hetan-l-amine (511 mg, 2.62 mmol) in anhydrous THF (5 mL), a 2.28 M nBuLi solution in hexane (1.26 mL, 1.1 eq) is added dropwise at -70°C. The reaction mixture is cooled to 0°C and CO2 gas is introduced into the solution by bubbling through a needle for 30 min. Bubbling is continued for a further 5-10 min while the solution returns to room temperature. After returning to 0°C, isobutyl chloroformate (1.1 eq) is added dropwise. Stirring is continued for 15 min before the addition of MeSNa (1.2 eq) in a single portion. The reaction mixture is brought to room temperature and stirred for 15 minutes before hydrolysis with water. The treatment consists of an extraction with ethyl acetate (x3) followed by washing the combined organic phases with a saturated aqueous solution of sodium chloride.After drying over Na2SO4 and concentration by rotary evaporator, the crude reaction product is purified by silica gel chromatography (petroleum ether / EtOAc = 95 / 5) to give the thiolester (445 mg). Yield: 63%. White solid.

[0351] 1H NMR (300 MHz, DMSO) ô 2.38 (s, 3H), 2.37 (t, J = 7.0 Hz, 2H), 2.18 (s, 3H), 1.35 (s, 6H), 1.42-1.20 (m, 10H), 0.86 (t, J = 6.7 Hz, 3H).NMR 13C (75 MHz, CDC1 3) ô 176.38 (C), 96.50 (C), 81.03 (C), 54.98 (C), 52.39 (CH2), 36.39, 31.85 (CH2), 29.25 (CH2), 28.79 (CH2), 27.81 (2CH3), 27.41 (CH2), 22.62 (CH2), 14.09 (CH3), 12.41 (CH3). ESLLRMS 270.2 [M+H]+.

[0352] Part 2: Preparation of lipid nanocapsules according to the invention Materials and methods Materials

[0353] Labrafac® was obtained from Gattefosse SA (Saint-Priest, France), Lipoid® S100 was obtained from Lipoïd GmbH (Ludwigshafen, Germany) and BASF (Ludwigshafen, Germany). NaCl, methanol, acetonitrile and deionized water were obtained from VWR International LLC. Preparation of nanocapsules

[0354] Lipid nanocapsules are obtained according to the following process. First, the oil phase is prepared by mixing Labrafac® and the compound of formula (I) for 15 minutes. The aqueous phase, in which Lipoid®S100, Kolliphor®HS15, NaCl, and water are mixed, is then added to the oil phase under magnetic stirring and heated to 85°C. Three progressive heating and cooling cycles between 85 and 60°C are carried out, followed by a thermal shock at 70°C by diluting the reaction mixture with water at 0°C. The mixture is then stirred at room temperature for 15 minutes. Analysis of physicochemical properties

[0355] The nanocapsules are analyzed to determine their diameter and charge distribution with a Malvern Zetasizer® Nano (Malvern Instrument SA, Worcestershire, UK) after dilution in deionized water at 1 / 10. Each reported value is derived from an average of 3 measurements ± their standard deviation.

[0356] Quantification by liquid chromatography of compounds No. 3, 5 and 21

[0357] The compounds are extracted from the nanocapsules by adding 800 pL of methanol to 200 pL of the solution to be analyzed. After vortexing, the solution is centrifuged for 10 minutes at 14,000 g. 25 pL of the supernatant is then collected and diluted with 975 pL of acetonitrile. 5 pL of the solution thus prepared is injected into a liquid chromatography system with a Symmetry C8, 3 Ipm, 2.1 x 150 mm column (Waters, ref#WATI06011) with a 0.1 M ammonium acetate:acetonitrile gradient (95 / 5) to (5 / 95) over 21 minutes. Flow rate 0.5 mL / min, UV detection at 270 nm, column temperature 40°C. Results

[0358] Table 2 below shows different nanocapsule formulations made to encapsulate compound No. 21. The physicochemical data and the encapsulation yield (final concentration of compound No. 21) are obtained as a function of the concentrations of the different components of the nanocapsule, namely medium-chain triglycerides, hydrophilic surfactant and lipophilic surfactant.

[0359] [Tables 2] Formulation % Labrafac® % Kolliph or® HS15 % Lipoid S100 Ratio TCM:Compound 21 [LNC] (mg / mL) Diameter (nm) PDI [Compound 21] (mg / mL) A 50% 43% 6% 5 122 45.5 0.04 10.6 B 60% 35% 5% 5 104 65.0 0.05 10.7 C 40% 48% 12% 5 156 30.0 0.08 10.3 D 50% 40% 10% 5 122 39.8 0.03 10.1 E 60% 32% 8% 5 104 54.1 0.02 10.6 F 56% 29% 19.6% 5 125 40.1 0.05 11.4 G 70% 20% 10% 5 87 71.8 0.04 10.3

[0360]

[0361]

[0362]

[0363]

[0364] Formation of nanocapsules allowing the encapsulation of compound no. 21 depending on the quantities of the different components of the nanocapsule. Table 3 below shows other examples of nanocapsules according to the invention formed with compounds of formula (I) which are other than compound No. 21. Indeed, compounds No. 5 and 23 were for example encapsulated with a composition of 51.9% Labrafac®, 44.2% Kolliphor® HS15 and 3.9% Lipoïd S100. Formula Compound (I) Diameter (nm) PDI Potential Zeta Compound Concentration (mg / ml) Compound #28 57 0.05 -1.4 11.095+ / - 0.27 Compound #5 55.7 0.05 -1 11.13+ / - 0.38 Encapsulation of formula (I) compounds with a composition of 51.9% Labrafac®, 44.2% Kolliphor®HS15 and 3.9% Lipoïd S100. Part 3: Use of lipid nanocapsules according to the invention Materials and methods Materials

[0365] Ammonium formate, formic acid, trifluoroacetic acid (TFA) and water were obtained from VWR International LLC. Quantification of compound #21 in blood

[0366] 10 mL of blood to be tested are diluted with a stabilizing solution (water + TFA) 10%). The solution is vortexed and then centrifuged at 3500 g for 5 minutes at +4°C. The supernatant is collected, and the proteins are precipitated with an acetonitrile / TFA solution (96 / 4, v / v) and then diluted, according to concentration, in 10 mM ammonium formate. 5 µL of this solution is injected into the liquid chromatography system using a gradient of 10 mM ammonium formate + 0.1% formic acid and acetonitrile + 0.1% formic acid for 5 minutes with a Luna 3 µm, Phenyl-Hexyl 100A 100*3 mm column (ref#00-4256-YO, Phenomenex Inc., USA). Detection is performed by tandem mass spectrometry with an API 6500 triple quadrupole mass spectrometer (Sciex).

[0367] Efficacy of compounds encapsulated in lipid nanocapsules

[0368] The in vivo efficacy of compound No. 21, encapsulated or unencapsulated, was evaluated using a human acute myeloid leukemia xenograft model, HL-60 (DSMZ, Braunschweig, Germany), developed in SCIB CB 17 mice (Charles Rivers Laboratories, USA) (n=24) via subcutaneous injection. The mice were allowed to allow tumors to grow to a volume of 100 mm³ (measured with calipers). They were then randomized into four groups (n=6): the vehicle group (control), the unencapsulated compound No. 21 group at 40 mg / kg and 20 mg / kg, and the encapsulated compound No. 21 group at 20 mg / kg. The different treatments were administered by intraperitoneal injection every two days, and tumor development was monitored with calipers on the days of administration. After 18 days of the protocol, treatments are stopped and the animals are euthanized. Results

[0369] Table 4 below shows the effect of the nanocapsules on the residual activity of compound No. 21 after 5 minutes of incubation in blood. The results obtained show that the encapsulated compound retains full reactivity, while the unencapsulated compound has already lost 32.72% of its initial activity.

[0370] [Tables4] Percentage of compound remaining: Compound #21 unencapsulated -32.72; Compound #21 encapsulated +10.25

[0371] Assay of compound no. 21 after 5 minutes of incubation in blood.

[0372] Figure 2 shows the anticancer efficacy of compound no. 21, encapsulated or unencapsulated, on an acute myeloid leukemia (HL-60) cell xenograft. After 18 days of treatment, better inhibition of tumor progression was recorded with the encapsulated compound formulation at 41.5 ± 8.2% compared with the unencapsulated compound at 20 mg / kg at 35 ± 5% (t-test; p<0.0001) and the unencapsulated compound at 40 mg / kg at 25.7 ± 10% (t-test; p<0.001).

Claims

Claims

1. Lipid nanocapsule comprising: - an oily core comprising between 25 and 90% by weight of medium-chain triglycerides, preferably between 60 and 80%, relative to the total weight of the nanocapsule; and - an envelope surrounding the oily core comprising between 3 and 25% by weight relative to the total weight of the nanocapsule of at least one lipid surfactant, and at least one hydrophilic surfactant; • in which the oily core further comprises at least one compound of formula (I): Ri R 2 ® XN / \_ “ s-r3 in which: - Ri and R2, identical or different, are chosen from CrC io alkyl, phenyl, benzyl, CHR5CHR6OR4 and (CHR5)VOR4, or Ri and R2 together with the nitrogen atom to which they are linked form a heterocycle, in particular a piperidine or a morpholine; said phenyl and benzyl being optionally substituted by one or more substituents chosen from: a linear or branched C1-C7 alkyl, halogen, NO2 and CONH2; - R3 is a linear or branched C1-C7 alkyl, - R4 is chosen from: H, a linear or branched C2-C7 alkyl, a linear or branched C2-C7 alkenyl group, -CONR7R8, aryl, heteroaryl, a (C2-C7)cycloalkyl, -(CrC7)linear or branched alkyl-aryl and -(Ci-C7)linear or branched alkyl-heteroaryl; said aryl, (C2-C7)cycloalkyl and heteroaryl being optionally substituted by one or more substituents chosen from: halogen, linear or branched CrC7 alkyl optionally substituted by one or more halogen atoms, linear or branched CrC7 alkoxy optionally substituted by one or more halogen atoms, -COOH, aryl, -NRR', -NO2, or said aryl and heteroaryl are fused to form a heterocycloalkyl; - R5 and R6, identical or different, are independently chosen from: • H and linear or branched C1-C7 alkyl, or • R5 and R6 are linked together to form, with the carbon atoms to which they are linked, a cycloalkyl, aryl or heteroaryl, or • R5 is H and R1 and R6 are linked together to form, with the nitrogen atom linked to R1, a heterocycloalkyl or heteroaryl, or • R6 is H and R1 and R5 are linked together to R1 to form, with the nitrogen atom linked to R1, a heterocycloalkyl; - v is chosen from 2 to 4; - R7 is a (C1-C3) alkyl; - R8 is -(C1-C3)alkylNRR'; - R and R', identical or different, are independently chosen from H and a linear or branched CrC7 alkyl, or its pharmaceutically acceptable salts or optical isomers, racemates, diastereoisomers, enantiomers or tautomers; and • in which the weight ratio relative to the total weight of the nanocapsule between the medium-chain triglycerides and said at least one compound of formula (I) is at least 4.

2. Lipid nanocapsule according to claim 1, wherein said at least one compound of formula (I) is present in a concentration of between 5 and 15 mg / mL.

3. Lipid nanocapsule according to one of claims 1 or 2, said nanocapsule having a diameter between 25 and 115 nm.

4. Lipid nanocapsule according to any one of claims 1 to 3, wherein the medium-chain triglycerides are chosen from mixtures of triglycerides of saturated fatty acids, in particular caprylic acid and capric acid, more particularly Kollisolv® MCT 70, MIGLYOL® 810 N, MIGLYOL® 812 N Excipient and Labrafac ® , preferably Labrafac ®.

5. Lipid nanocapsule according to any one of claims 1 to 4, wherein said at least one lipid surfactant is chosen from lecithins derived from soybean oil having a percentage of phosphati-dylcholine greater than 90%, in particular, Lipoïd ®, preferably Lipoïd ® S100.

6. A lipid nanocapsule according to any one of claims 1 to 5, wherein said at least one hydrophilic surfactant is chosen from non-ionic solubilizing and / or emulsifying agents, in particular Macrogol 15 Hydroxy stearate, more particularly Kolliphor®, preferably Kolliphor® HS 15.

7. Lipid nanocapsule according to any one of the preceding claims, wherein said at least one compound of formula (I) is characterized in that R3 is a linear or branched (CrC7) alkyl, preferably a methyl, R1 is a linear or branched (CrC7) alkyl, preferably a methyl, R2 is a (Ci-Ci0) alkyl, preferably a methyl or an octyl, CHR5CHR6OR4, (CHR5)VOR4 or R1 and R2 together with the nitrogen atom to which they are attached form a heterocycle, in particular a morpholine, and R5 and R6 are H.

8. Lipid nanocapsule according to any one of the preceding claims, wherein said at least one compound of formula (I) is characterized in that R5 and R6 are H and R4 is selected from (C2-C7) cycloalkyl, linear or branched, -(C1-C7) alkyl-heteroaryl, or benzyl; preferably benzyl, said (C2-C7)cycloalkyl being substituted by one or more substituents selected from: (C1-C7) linear or branched alkyl, said benzyl being optionally substituted by one or more substituents selected from: (C1-C7) linear or branched alkyl optionally substituted by one or more halogen atoms, (C1-C7) linear or branched alkoxy optionally substituted by one or more halogen atoms, halogen.

9. Lipid nanocapsule according to any one of the preceding claims, wherein said at least one compound of formula (I) is selected from: - S-methyl 4-[2-ethoxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate; - S-methyl 4-[2-allyloxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate; - S-methyl 4-[2-benzyloxyethyl(methyl)amino]-4-methyl-pent-2-ynethioate; - S-methyl 4-methyl-4- [methyl- [2-(m-tolylmethoxy)ethyl]amino]pent-2-ynethioate; - S-methyl 4-[2-[(3,4-dimethylphenyl)methoxy]ethyl-methyl-amino]-4-m ethyl-pent-2-ynethioate; S-methyl 4-[2-[(4-methoxyphenyl)methoxy]ethyl-methyl-amino]-4-me thy l-pent-2- y nethioate; S-methyl 4-[2-[(3,4-dimethoxyphenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-yl nethioate; S-methyl 4-[2-[(3-chlorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate; S-methyl 4-[2-[(3-fluorophenyl)methoxy]ethyl-methyl-amino]-4-methyl-pent-2-ynethioate; S-methyl 4-methyl-4-[methyl-[2-(2-pyridylmethoxy)ethyl]amino]pent-2 -ynethioate; S-methyl 4-methyl-4- [methyl- [2-(3-pyridyhnethoxy)ethyl]ammo]pent-2 -ynethioate; S-methyl 4-methyl-4-[methyl-[2-(4-pyridylmethoxy)ethyl]amino]pent-2 -ynethioate; S-methyl 4-((4-(benzyloxy)butyl)(methyl)amino)-4-methylpent-2-ynethi oate; S-methyl 4-((2-hydroxyethyl)(methyl)amino)-4-methylpent-2-ynethioat e; S-methyl 4-methyl-4-[methyl-[2-(2-naphthylmethoxy)ethyl]amino]pent-2-ynethioate; S-methyl 4-methyl-4-[methyl-[2-[(2,6,6-trimethylcyclohexen-l-yl)methoxy]ethyl]amino]pent-2-ynethioate; S-methyl 2,5,10,11,1 l-pentamethyl-6-oxo-7-oxa-2,5,10-triazatetradec-l 2-yne-14-thioate; - S-methyl 4-methyl-4-[methyl(2-phenoxycyclopentyl)amino]pent-2-ynet hioate; - (S)-S-methyl 4-(2-((benzyloxy)methyl)pyrrolidin-l-yl)-4-methylpent-2-ynet hioate; - S-methyl 4-[3(benzyloxy)-lpyrrolidinyl])-4-methylpent-2-ynethioate; - S-methyl 1- 4-Dimethylamino-4-methyl-pent-2-ynethioate; - S-methyl 5- 4-Methyl-4-morpholin-4-yl-pent-2-ynethioate; - S-methyl 4-methyl-4-[methyl(octyl)amino]pent-2-ynethioate; or its pharmaceutically acceptable salts or optical isomers, racemates, diastereoisomers, enantiomers or tautomers.

10. A pharmaceutical composition comprising a lipid nanocapsule according to any one of the preceding claims.

11. Pharmaceutical composition according to claim 10, comprising between 80 and 250 mg / ml of lipid nanocapsule.

12. Lipid nanocapsule according to any one of claims 1 to 9 or pharmaceutical composition according to claim 10 or 11, for use as a medicament.

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