Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
  • C07C331/16—Isothiocyanates
  • C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
  • C07C331/22—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
  • C07C331/24—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
  • C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
  • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
  • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
  • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
  • C07C331/16—Isothiocyanates
  • C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
  • C07C331/20—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of a saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C333/02—Monothiocarbamic acids; Derivatives thereof
  • C07C333/04—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C333/14—Dithiocarbamic acids; Derivatives thereof
  • C07C333/18—Esters of dithiocarbamic acids
  • C07C333/20—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C335/04—Derivatives of thiourea
  • C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
  • C07C335/08—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of a saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid

Definitions

• the present invention relates to a process for the synthesis of an isothiocyanate of general formula (I)
• R 2 represent, independently of one another, an alkyl, aryl or alkylaryl group
• R represents a carbonyl, sulfinyl, sulphonyl or sulphide group and its derivatives.
• the present invention relates to a process for the synthesis of sulphoraphane, a particular isothiocyanate according to general formula (I) in which R 1 is a butyl group, R 2 is a methyl group and R 4 represents a sulfinyl group and its derivatives.
• R 1 is a butyl group
• R 2 is a methyl group
• the present invention also relates to the manufacture of suiforaphane analogues such as 6-isothiocyanatohexan-2-one which has the formula (B), that is to say a particular isothiocyanate according to the general formula (!
• R 1 represents a butyl group
• R 2 represents a methyl group
• R 4 represents a carbonyl group
• thioureas obtained from sulphoraphane or 6-isothiocyanatohexan-2-one
• coupling products with alcohols or thiols and suiforaphane and / or 6-isothiocyanatohexan-2-one SC - R 1 - C- F3 ⁇ 4
• Sulforaphane is a naturally occurring molecule in crucifers, such as broccoli or Brussels sprouts. This molecule has aroused great interest in the 1990s because it is attributed the origin of beneficial effects on the health of the consumption of these plants, especially as anticancer.
• alkylsulphinylalkylamine in particular 4-methylsulfinylbutylamine and synthetic sulforaphane has been described in WO 02/58664.
• WO 02/058664 4-methylsulphinylibutylamine reacts in the presence of thiophosgene and NaOH to form D, L-sulforaphane.
• the yields of this synthesis route are very low because the steps used often lead to the formation of annoying by-products for the subsequent steps, which requires intermediate purification steps having a negative effect on the overall returns.
• the document WO02 / 058664 describes a yield of 31% for the step of creating the isothiocyanate combined with a distillation step, which leads to an overall yield of 18% over the entire synthesis process described in FIG. WO 02/058664.
• the reagents used in this known synthetic route are all expensive, harmful to the environment or toxic.
• the process according to the invention provides a process as mentioned at the beginning comprising a reaction of an amine having the general formula (11)
• R 4 represents a carbonyl group, sulfinyl, sulfonyl or sulfur, in the presence of carbon sulphide and di-tert-butyl dicarbonate with formation of the corresponding isothiocyanate of the general formula (I).
• isothiocynanate compounds according to general formula (I), such as, for example, sulforaphane or 6-isothiocyanatohexan-2-one are synthesized from their corresponding amine, avoiding the use of thiophosgene, which is a particularly toxic and without using "thiocarbonyl transfer” reactions carried out with "substituents" of thiophosgene such as thiocarbonylditriazole or thiocarbonyldiimidazole or else dipyridyl-thionocarbonate.
• substituents can indeed be effective, but they are not economic in terms of atoms and therefore generate by-products that are not always easy to eliminate at the end of synthesis.
• Such processes will therefore require an additional step such as a distillation or chromatographic purification which adversely affects the yield, the cost of production and does not always give satisfactory purity, especially considering that sulforaphane is degraded by heat.
• the use of CS 2 carbon sulphide and di-tert-butyric dicarbonate (BOC 2 0) generates only simple by-products that are easy to eliminate at a lower cost and therefore without incidence. on the efficiency of the process according to the invention and on the environment. Indeed, the by-products generated by the reaction of the process according to the invention are: C0 2 ; COS; BuOH.
• one of the aims of the invention is to provide clean and inexpensive sulforaphane or 6-isothiocyanatohexan-2-one and their derivatives or analogues such as sulforamate for example. to have a sufficient quantity to study the potential effects of these in cosmetics or cancer treatment.
• R 4 represents a sulfinyl group and said amine is a alkylsulfinylalkylamine. More particularly, said amine of general formula (I) is 4-methylsulfinylbutylamine and said corresponding formed isothiocyanate is sulforaphane.
• said alkylsulfinylalkylamine is obtained by oxidation of alkylthioalkylamine in solution in a solvent based on trifluoroethanol.
• the process according to the invention uses trifluoroethanol as a solvent to effect the oxidation of alkylthioalkylamine to alkylsulfinylalkylamine.
• trifluoroethanol as solvent allows faster kinetics (approximately 30 min at 0 ° C after adding the oxidant and then one hour at room temperature). This time is much shorter than that of WO 02/58664 (overnight at 50 ° C with acetone as solvent).
• the product obtained is pure and shows no traces of sulfonyl, which means that the oxidation is controlled and does not result in the formation of superoxide products mixed with the sulfinyl thus produced.
• the oxidation product is obtained in an isolated manner and is pure at the end of the stage, which allows a certain flexibility residing in linking other steps or storing the product under this shape. In any case, the yield is better since it is not necessary to chain a multitude of purification steps to obtain the product.
• This synthesis step is therefore clean and therefore does not generate overoxidation products, the fluorinated solvent which costs more than The conventional solvent will advantageously be recovered by simple distillation in order to further reduce the costs of the process according to the invention.
• R represents a carbonyl group and said amine comprises a keto group.
• said amine comprising a keto group is 4-methylketobutylamine or 6-aminohexan-2-one and the corresponding isothiocyanate formed is 6-isothiocyanatohexan-2-one.
• the process also comprises a reaction of said corresponding isothiocyanate, such as, for example, sulforaphane or its analog, 6-isothiocyanatohexan-2-one, of general formula (I) with a primary or secondary amine. to form a derivative thiourea, given by way of example, of sufloraphane or 6-isothiocyanatohexan-2-one.
• a reaction of said corresponding isothiocyanate such as, for example, sulforaphane or its analog, 6-isothiocyanatohexan-2-one, of general formula (I)
• a primary or secondary amine to form a derivative thiourea, given by way of example, of sufloraphane or 6-isothiocyanatohexan-2-one.
• isothiocyanates are rapidly absorbed and then conjugated with protein thiols, cysteine or glutathione. In the body, this conjugation reaction is a reversible process and the adduct can dissociate to release the isothiocyanate again.
• sulforaphane can induce the many effects attributed to it (for example: stimulation of phase II enzymes, inhibition of AP1 transcription factor involved in cutaneous cancers by interaction between sulforaphane and thiols of cysteines, ).
• sulforaphane is accumulated in the cells in its conjugated form with glutathione.
• isothiocyanates are dithiocarbamate forms resulting from the reaction of isothiocyanate on glutahione.
• 95% of the product accumulated in the cells is in this form.
• the dithiocarbamate form is the storage form of sulforaphane at the cellular level (rapid accumulation in high concentrations), the cells are not able to directly absorb this form if it is already present to them. preformed instead of the corresponding isothiocyanate. In this case, extracellular hydrolysis of the dithiocarbamate would first be carried out in order to return to free isothiocyanate, a form which can then be integrated by the cell and then converted for storage in the form of dithiocarbamate.
• sulforaphane derivatives and potentially those of 6-isothiocyanatohexan-2-one, such as the glutathione coupling product, can not be stored directly by the cell, but are first cleaved tn-vivo for return to sulforaphane or 6-isothiocyanatohexan-2-one which is phagocytized by the cells, to be stored in form giutathion.
• the amine-sulphonamide or amine-6-isothiocyanatohexan-2-one coupled structures according to the present invention in humans, would also be cleaved during metabolism, which would cause a release of sulforaphane on the one hand depigmenting effect ( or 6-isothiocyanatohexan-2-one) and on the other hand free amine which could also play its role of depigmenting. Therefore, these sulforaphane or 6-isothiocyanatohexan-2-one derivatives allow several possibilities of action: either the thiourea is active in itself, or it is metabolized to release 2 molecules each having a depigmenting effect or potentially a depigmenting effect.
• the starvation chosen will be a function of the desired effect for the coupling compound.
• amines known to have a UV filter effect for example: para-amino benzoic acid or anthranilate
• diamines such as piperazine
• the amine is a primary amine having the general formula HNR 5 R 6 in which R 5 represents a hydrogen atom and R 6 a methylsulfinylbutyl group. This makes it possible to reach 1,3-bis (4- (methylsulfinyl) butyl) thiourea.
• This sulforaphane derivative is among others described in the patent application WO 02/58664.
• the synthesis of this thiourea uses the process of sulforaphane degradation in water (degradation of su! foraphane to 4-methylsulfinylbutylamine and it is the latter which reacts on the sulforaphane still present to form thiourea).
• the goal is to achieve this thiourea in a controlled and high yield manner, for example from the 2 pure reactants in a suitable solvent.
• the reaction is carried out at a lower temperature (45 ° C. instead of 100 ° C. and in a shorter time (1 hour instead of 24 hours)) and the yield obtained is approximately 97%, which allows obtain a pure product that can be used for further analysis.
• the amine is a primary amine having the general formula HNR 5 R 6 in which R 5 represents a hydrogen atom and R 6 represents an alkyl, alkenyl, alkylaryl, aryl or aicynyl group, linear, cyclic or branched optionally comprising one or more heteroatoms.
• the amine is a secondary amine having the general formula HNR 5 R 6 in which R 5 and R 6 represent, independently of one another, an alkyl, alkenyl or alkylaryl group, aryl, aicynyl, linear, cyclic or branched optionally having one or more heteroatoms.
• the sulforaphane or 6-isothiocyanatohexan-2-one analog is a derivative thereof formed by a reaction between sulforaphane or 6-isothiocyanatohexan-2-one and a nucleophilic agent, in particular an alcohol or a thiol and preferably ethyl alcohol.
• the process according to the invention comprises an oxidation of the sulfinyl radical to the sulphonyl radical, by the addition of an oxidizing agent, in particular a perbenzoic acid or a halogenated derivative thereof, in especially meta-chloroperbenzoic acid.
• an oxidizing agent in particular a perbenzoic acid or a halogenated derivative thereof, in especially meta-chloroperbenzoic acid.
• This oxidation can take place either on sulforaphane directly before the addition reaction of an amine or a nucleophilic agent, or directly on the analog formed.
• the subject of the invention is also a synthetic and isolated compound of general formula (III) obtained by the process according to the invention,
• the invention relates to the particular compounds:
• thioureas obtained by coupling primary or secondary amines with oxidized sulforaphane (for example 1- (4- (methylsulfinyl) butyl) -3- (4-methylsulfonyl) butylthiourea and 1,3-bis ( 4-methylsulfonyl) butyl) thiourea), coupling products between an alcohol (or thiol) and oxidized sulforaphane and precursors such as 4-methylsulfonybutylamine.
• oxidized sulforaphane for example 1- (4- (methylsulfinyl) butyl) -3- (4-methylsulfonyl) butylthiourea and 1,3-bis ( 4-methylsulfonyl) butyl) thiourea
• thiourea obtained by coupling primary or secondary amines on 6-isothiocyanatohexan-2-one, as mentioned below.
• the present invention also relates to a use of the compounds according to the invention as a depigmenting agent, in the treatment of hyperpigmentation, as inducer of the enzymes of phase II, as an inhibitor or moderator of phase i enzymes in anti-cancer treatment, in the protection of the skin against radiation (UV and others), in the treatment of canities, in the protection of the skin against UV radiation and effects thereof, for example in phototherapies, radiotherapies, erythema solar exposures, DNA damage, induction, repair, signaling, cancerization, in the treatment of inflammation, atopic dermatitis, in protection of the skin against the effects of pollution, and in the treatment of lucite.
• the groups R 1, R 2, R 3, R 5, R 6, R 7, R 1 R “and R '" advantageously each have, independently of one another, from 1 to 20 carbon atoms, preferably from 1 to 18 carbon atoms, for example from 1 to 12 carbon atoms.
• the present invention therefore relates to a sulforaphane synthesis process mainly comprising the successive steps of synthesis of 4-methylthiobutyronitrile (A), synthesis of 4-methylthiobutylamine (B), synthesis of 4-methylsulfinylbutylamine (C) and synthesis of sulforaphane (4-methylisulphinylbutyl isothiocyanate) (D). These steps are shown below.
• Another sulforaphane derivative which can be produced according to the invention is N- (4 - (methylsulfinyl) butyl) piperidine-1-carbothioamide by the addition of an amine, piperidine, which has the formula V).
• sufloraphane which can be produced according to the invention is Ay- (4- (methylsulfinyl) butyl) morpholine-4-carbothioamide by the addition of an amine, morpholine.
• This compound has the formula (VI).
• sufloraphane which can be produced according to the invention is 1 - (1-benzylpiperidin-4-yl) -3- (4- (methylsulfonyl) butyl) thiou rated by the addition of an amine, benzylpiperidine.
• This compound has the formula (VII).
• the invention also provides for the manufacture of certain sulforaphane derivatives, for example the oxidized form thereof according to reaction (G).
• oxidized forms of sulforaphane derivatives are also obtained according to the invention in a manner analogous to that described above.
• Thioureas derived from oxidized sulforaphane in the two possible cases 1 - (4- (methylsulfinyl) butyl) -3- (4-methylsulfonyl) butyl) thiourea having the following formula (VIII) and 1,3-bis (4- (methylsulfonyl) butyl) thiourea having the following formula (IX).
• other thioureas can be obtained by coupling cyclic or non-cyclic primary or secondary amines on oxidized sufloraphane.
• the present invention therefore also relates to a process for the synthesis of 6-isothiocyanatohexan-2-one comprising the synthesis step (H) mentioned below.
• 6-isothiocyanatohexan-2-one which can be produced according to the invention are mentioned below.
• one of the derivatives which can be obtained according to the invention is 1,3-bis (5-oxohexyl) thiourea by the degradation of 6-isothiocyanatohexan-2-one in water.
• This compound has the formula (XII).
• one of the derivatives which can be obtained according to the invention is 1- (4- (methylsulfinyl) butyl) -3- (5-oxohexyl) thiourea by the addition of 4-methylsulfinylbutylamine.
• This compound has the formula (XIII).
• one of the derivatives that can be obtained according to the invention is 1- (4- (methylsulfonyl) butyl) -3- (5-oxohexyl) thiourea by the addition of a 4-methylsulfonylbutyiamine amine.
• This compound has the formula (XIV).
• one of the derivatives that can be obtained according to the invention is W- (5-oxohexyl) morpholine-4-carbothioamide by the addition of morpholine.
• This compound has the formula (XV).
• one of the derivatives that can be obtained according to the invention is O-ethyl-N-5-oxohexylcarbamothioate by the addition of an alcohol (ethanol).
• This compound has the formula (XVI).
• the flask is cooled by means of an ice-water bath and the system is degassed, then placed under nitrogen and kept stirring.
• the solution containing the nitrile is then poured into the reactor in about an hour (fast dripping).
• the assembly is degassed, then placed under nitrogen and kept stirring at room temperature.
• the 4-methylthiobutyronitrile is then slowly poured.
• the addition causes a heating of the medium, the rate of addition is then controlled so as to control the reflux that takes place.
• the reactor is cooled with a water-giace bath, then 100 ml of distilled water are slowly poured through the dropping funnel in order to neutralize the excess LiAlH 4 .
• the mixture is then sintered and the filter washed several times with ether.
• the filtrate is then decanted, the organic phase is filtered on charcoal, the filter is rinsed and the combined organic phases are dried over sodium sulfate.
• n D 20 1, 4831
• reaction mixture is brought back to ambient temperature and kept stirring at this temperature for 1 hour.
• the filtrate is recovered and concentrated on a rotary evaporator at a bath temperature of 50 ° C.
• the product is taken up in 60 ml of dichloromethane and dried over MgSO, then the solvent is removed on a rotary evaporator.
• reaction medium is then stirred and at 0 ° C for 15 min, then the ice bath is removed and the reaction is continued for 2 hours at room temperature.
• the crude reaction product is transferred to a single neck flask and concentrated on a rotary evaporator, then taken up in 30 ml of dichloromethane to be filtered on charcoal. The filter is rinsed with dichloromethane and the combined filtrates are again placed on a rotary evaporator. 23.1 g of an orange oil are thus obtained.
• the crude product essentially contains traces of residual DMAP. Purification on a chromatographic column was initially envisaged, but we can advantageously replace it with a simple washing.
• Amax 242 nm.
• n D 20 1, 3516
• This isothiocyanate is synthesized according to the same process as the sulforaphane of Example 4, by reaction of the corresponding amine (4- (ethylsulfinyl) butanamine) in the presence of carbon disulfide and di-tert-butyl dicarbonate.
• the amine is obtained by following the first 3 steps of sulforaphane synthesis described in this patent, simply replacing CH 3 SNa by EtSNa in the first step.
• the overall yield of the reaction, including amine synthesis, is 87%.
• This isothiocyanate is synthesized by the same method as sulforaphane by reaction of the corresponding amine (4- (phenylsulfinyl) butanamine) in the presence of carbon disulfide and di-tert-butyl dicarbonate.
• the amine is obtained by following the first 3 steps of sulforaphane synthesis described in this patent, simply replacing CH 3 SNa by PhSNa in the first step.
• the overall yield of the reaction, including amine synthesis, is 57%.
• This isothiocyanate is synthesized by the same method as sulforaphane, by reaction of the corresponding amine (5- (methylsulfinyl) pentanamine) in the presence of carbon disulfide and di-tert-butyl dicarbonate.
• the amine is obtained by following the first 3 steps of sulforaphane synthesis described in this patent, simply replacing the nitrile by its homologue.
• 5- (Methylsulfonyl) pentanamine reacts in ethanol in the presence of 1 equivalent of triethylamine and 10 equivalents of carbon disulfide. After reaction, the mixture is cooled to 0 ° C. before adding 0.99 equivalents of di-tert-butyl dicarbonate and 3 mol% of DMAP dissolved in ethanol. After returning to ambient temperature and additional 2 hours of reaction, the reaction medium can be treated: removal of the solvent, washing with a hydrochloric acid solution, decantation and removal of the solvent. The isothiocyanate is obtained in the form of a yellow liquid with a yield of 88% for this step.
• the overall yield of the reaction, including amine synthesis, is 86%.
• UV SPECTRUM A max 245 nm
• the mixture is refluxed and thus maintained, with stirring, for 1 hour.
• the solvent is then removed on a rotary evaporator, and then the crude is taken up in dichloromethane added with hexane in order to obtain the precipitation of the thiourea.
• the solid thus obtained is milled, then washed successively with diethyl ether and hexane before being dried. 7.6 g of a white powder are finally obtained, a yield of 97%.
• Crystallization / recrystallization from ethyl acetate of 4-methyl-N- (4- (methylsulfinyl) butyl) piperazine-1-carbothioamide is advantageous and allows the compound to be contained in a solid state in which the melting at 72 ° C.
• N- (4- (methylsulfinyl) butyl) morpholine-4-carbothioamide was synthesized by heating under reflux for 1 hour in dichloromethane 1.1 equivalents of morpholine in the presence of 1 equivalent of sulforaphane obtained in Example 4. In at the end of the reaction, the solvent is evaporated. The thiourea was then crystallized as a white solid and the excess amine removed in the wash water of the solid. The yield is 95% for the final coupling step of the amine on sulforaphane.
• Example 4 The sulforaphane obtained in Example 4 is solubilized in absolute ethanol. After degassing and putting under nitrogen, the mixture is refluxed until complete conversion. The ethanol is finally removed on a rotary evaporator. A yellow viscous liquid is obtained, it is purified on a chromatographic column to provide a beige solid with a yield of 84%.
• the reactor is cooled to -20 oC and maintained 1 hour at this temperature before performing filtration.
• the filtrate and the solid are analyzed by NMR.
• the solid contains the MCPBA derivatives, while the filtrate contains the oxidized product, as well as some traces of aromatic residues and residual sulforaphane.
• the 1-isothiocyanato-4- (methylsulfonyl) butane is placed in a reactor in the presence of dichloromethane and 1, 2 equivalents of morpholine, then the mixture is refluxed and maintained at this temperature for 1 h. After removal of the solvent, the crude reacts! is purified by crystallization in ethyl acetate.
• the thiourea is thus obtained pure in the form of a white solid with a yield of 92% and has the following formula
• 6-Isothiocyanatohexan-2-one is placed in a reactor in the presence of water, then the mixture is refluxed and maintained at this temperature for 24 hours. After removal of the solvent, the crude mixture reacts! is purified on a chromatographic column of silica gel (CH 2 Cl 2 / MeOH). The thiourea is thus obtained pure in the form of a white solid with a yield of 72% and has the following formula
• 6-isothiocyanatohexan-2-one is placed in a reactor in the presence of dichloromethane and 2 equivalents of 4-methylsulfinyibutanamine, the amine precursor of the sulforaphane obtained in Example 3, and the mixture is refluxed and maintained at this temperature during 3h. After removal of the solvent, the reaction crude is chromatographically purified on silica gel (CH 2 Cl 2 / eOH). The thiourea is thus obtained pure in the form of a pale yellow oil and viscous with a yield of 74%.
• 6-Isothiocyanatohexan-2-one is placed in a reactor in the presence of dichloromethane and 1.2 equivalents of piperidine, and the mixture is refluxed and maintained at this temperature for 1 hour. After removal of the solvent, the crude reaction product is purified on a chromatographic column of silica gel (CH 2 Cl 2 / MeOH). The thiourea is thus obtained pure in the form of a viscous oil with a yield of 93% and has the following formula:
• Amax 222 nm; 253 nm; 270 nm
• Example 1 was reproduced and then Example 4 was directly carried out.
• This means that this isothiocyanate is synthesized according to the same process as sulforaphane, by reaction of the corresponding amine (4-methylthiobutanamine) in the presence of carbon disulfide and di-tert-butyl dicarbonate.
• the amine is obtained by following the first sulphate synthesis steps described in this patent, except for the oxidation step.
• 4-Methylthiobutanamine reacts in ethanol in the presence of 1 equivalent of triethylamine and 10 equivalents of carbon disulfide. After reaction, the mixture is cooled to 0 ° C. before adding 0.99 equivalents of di-tert-butyl dicarbonate and 3 mol% of DMAP dissolved in ethanol. After returning to ambient temperature and an additional 2 hours of reaction, the reaction medium can be treated: removal of the solvent, washing with a hydrochloric acid solution, decantation and removal of the solvent. Further purification on a chromatographic column of silica gel may optionally be carried out.
• the isothiocyanate is obtained in the form of a yellow liquid with a yield of 92% for this stage and has the following formula:
• the overall yield of the reaction, including amine synthesis, is 92%.
• n D 20 1, 5278
• EXAMPLE 24 Effectiveness of depigmentation of the synthesized compounds.
• the melanin content was determined spectrophotometrically after 3 days of incubation in the presence of the test molecule and cell lysis.
• Kojic acid a well-known depigmenting agent, is used as a reference for the ranking of results.
• the results are presented in Table 2, which shows, on the one hand, the percentage of residual pigmentation which is calculated as the ratio of the amount of melanin produced in the presence of the active ingredient to the amount of melanin produced in a control culture (cells alone). and on the other hand, the relative activity of the asset in relation to that of kojic acid at the same concentration.
• the analyzes were repeated.
• the indicated value corresponds to the calculated average.
• the average coefficient of variation of the percentage of residual pigmentation is of the order of 3% (between 1.5% and 6% / for 3 tests).
• Table 2 presents the results obtained on the SKMel human igneous for a set of standard molecules making it possible to cover all the families and the chemical modifications proposed in the patent starting from the base molecule (sulforaphane, other isothiocyanates derived, forms oxidized, symmetrical thioureas, other thioureas, derivatives derived from the addition of nucleophiies to the isothiocyanate function of sulforaphane, etc. This list is neither exhaustive nor limiting and the same type of results was obtained for the other molecules. .
• the basic amines, constitutive of thioureas have also been evaluated, which shows that our structures provide an added value, in terms of depigmenting power, compared to the simple amines that constitute them.

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