EP1524972A2 - Compounds with antiparasitic activity and medicines containing same - Google Patents

Abstract

The invention concerns compounds with antiparasitic, in particular antimalarial, activity, characterized in that they are of general formula (I). The invention is in particular useful as compounds with anti-parasitic activity.

Description

 "Compounds with anti-parasite activity and drugs containing them"

The subject of the invention is compounds with anti-parasitic activity, and more particularly antimalarial and antibabesiosis.

Many works are devoted to the search for active drugs against parasites and especially against Plasmodium, especially Plasmodium falciparum, given the extension of the diseases they cause.

The inventors have found, with certain categories of chemical compounds, a high activity, accompanied by tolerable toxicity and high bioavailability properties. Advantageously, these compounds are administrable orally.

The invention therefore aims to provide new compounds with antiparasitic activity, especially antimalarial.

It also relates to a process for synthesizing such compounds.

The invention is further directed to medicaments containing such compounds as active ingredients and their use and that of derivatives for the manufacture of medicaments having said activities.

The compounds according to the invention are characterized in that they correspond to the general formula (I)

_N - ^R ι II X- (NH) _n - C- NY (I)

R ₂ in which or X represents a group of formula (II)

where Z is - (CH ₂ ) _m , where m = 8 to 21, n = 0 or 1 and Y = R ₃ ,

. R ₁ and R ₁ , identical to or different from each other, being chosen from H, alkyl, OH, O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl, OSO ₂ - alkyl, OSO ₂ -aryl, OSO ₂ -heterocycle, O-CO-O (or S or NH) -alkyl, O-CO-O (or S or NH) -aryl, PO (O-alkyl or O-aryl) ₂ , CO-O-CH ₂ -aryl, cycloalkyl, R ₂ and R ' ₂ , which are identical or different from one another, are chosen from H, alkyl, CO-O-

CH ₂ -aryl, CO-O-alkyl, cycloalkyl,

. R ₃ and R ' ₃ , identical to or different from each other, representing H, alkyl, CO-O-alkyl, CO-O-aryl, COO-CH (R) -O-CO-alkyl, PO ( O-alkyl or O-aryl or ONa) ₂ , CO-O-CH (R) -aryl, R being H or alkyl, or

. R _! and R, and / or R'i and R ', or R and R ₃ and / or R' and R ' ₃ , together form a non-aromatic mono-heterocycle with the nitrogen atoms to which they are respectively attached, or . R and R ₃ and / or R 'and R' ₃ may be the same substituent, doubly bound to nitrogen, cyclized with, respectively, R ₁ or R'i to form a heterocycle, optionally substituted by R _a , which is selected from H, alkyl, alkyl substituted with 1,2 or 3 halogen atoms, aryl, CO-O-alkyl (or aryl), -CO-OH, -CO-NH ₂ , -CN, -CO- N-alkyl (or aryl), -CO-N- (alkyl) ₂ , -CO-heterocycle nitrogen and / or oxygenated, NH (H or alkyl), N (alkyl) ₂ , nitrogenous and / or oxygenated heterocyl, -O -alkyl (or aryl), -O-CH ₂ -aryl, CH ₂ N [H, (H, alkyl), (dialkyl), aryl], -CH-nitrogenous and / or oxygenated heterocycle, CH ₂ -CO-OH ,

or X = R _t and Y represents a group of formula (III) _ _Z -N- R ' ₄ (III) R' ₂ with n and Z as defined above,

. R _\ and R _'ls identical or different from each other, are selected from H, alkyl, OH, O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl, OSO ₂ -alkyl , OSO ₂ -aryl, OSO ₂ -heterocycle, O-CO-O (or S or NH) -alkyl, O-CO-O (or S or NH) -aryl, PO (O-alkyl or O-aryl) ₂ ,

CO-O-CH _2. aryl, cycloalkyl,

. R ₄ and R ' ₄ represent H, alkyl or aryl, these may be substituted by OH, O-alkyl, O-aryl, NH (H or alkyl), nitrogenous and / or oxygenated heterocycle and R and R ' ₂ , identical to or different from each other, being chosen from H, alkyl, CO-O-CH ₂ aryl, CO-O-alkyl, cycloalkyl, or

. R 1 and t and / or R ' ₁ and R' ₄ together form a group - (CH ₂ ) _P , where p is an integer of 1 to 5, one or more hydrogen atoms may be replaced by a lower alkyl, and R and R ' ₂ representing H, or R4 and R ₂ and / or R' ₄ and R ' ₂ together form a group - (CH) _P , 1 or more H may be replaced by a lower alkyl, Ri and R'i representing H, and the pharmacologically acceptable salts of these compounds. Unless otherwise specified,

"aryl" means phenyl or any ring or heterocycle having an aromatic character, such as pyridine, oxazole, thiazole, optionally substituted, in particular chlorine, -NO ₂ , -NH ₂ , N (H, alkyl) rings; ) or (dialkyl);

"nitrogenous and / or oxygenated heterocycle" denotes a ring with 5 or 6 vertices such as the pyrrolidine, piperidine, morpholine, piperazine and methylpiperazine rings;

"alkyl" denotes a C 1 -C 5 alkyl, straight or branched chain, optionally substituted with one or more halogen atoms, amino group NH ₂ , N (H, alkyl) or (dialkyl).

A preferred family of derivatives of the invention, or family A, corresponds to formula (IV) He he

R ' ₃ - N - C - (NH) _n - Z - (NH) _n - C - N - R ₃ (IV)

R _'2 ^{R 2} wherein n, Z, R _l5 R'ι, R2, R'2, R3 and _R'3 are as defined above in relation to formula (II).

Advantageous compounds of this family correspond to the case where n = 0 and correspond to formula (V):

In a preferred group, or group a1, R _1; R and R ₃ and / or R ' ₁ , R' ₂ and R ' ₃ are independent of one another.

In a subgroup, R ₁ and / or R ' ₁ , and R ₂ and / or R' ₂ represent a hydrogen atom, R ₃ and / or R ' ₃ being as defined above, but different from a hydrogen atom.

In another subgroup, R ₁ and / or R ' ₁ are as defined above, but do not represent a hydrogen atom, while R ₃ and / or R' ₃ , R and / or R ' ₂ represent a hydrogen atom.

Another preferred group of compounds of formula (V) corresponds to the case where n = 0 and

Ri and R, and / or R'i and R ', correspond to formula (VI) or group a2

or - R ₂ and R ₃ and / or R ' ₂ and R' ₃ correspond to the formula (Vu) or group a3

(VII)

In a subgroup corresponding to formula (VI), R 1 and R ₂ and / or R ' ₁ and R' ₂ together form a group -O-CO-, O-SO-, O-CS, S-CO or -S-CS, and R ₃ and / or R ' ₃ represent a hydrogen atom.

In another subgroup corresponding to formula (VI), R ₁ and R ₃ and / or R ' ₁ and R' ₂ represent an optionally branched alkylene group and R ₃ and / or R ' ₃ represent -CO-O-alkyl (or aryl), -CO-O-CH ₂ -aryl, CO-O-CH (alkyl) -O-CO-alkyl, PO (O-alkyl or -aryl) ₂ , alkyl or H.

In a subgroup corresponding to formula (VII), R 1 and / or R ' ₁ represent a hydrogen atom, and R ₂ and R ₃ , and / or R' and / or R ' ₃ represent a group - ( Œ ₂ ) _p -.

Another preferred group of the family A, or group a4, corresponds to the case where R ₂ and R ₃ and / or R ' ₂ and R' ₃ form the same substituent and together with R 1 or R ' ₁ form a bis-oxadiazole of formula (VIII).

wherein R _a is as defined above.

In preferred compounds of this group, halogen is suitably F or Cl, alkyl is methyl or ethyl, aryl is phenyl. Another preferred family of the invention, or family B, corresponds to formula (IX)

R'r Ri

He h

R ' ₄ - (NH) _n -CNZNC- (NH) _n -R4 (IX)

R ' ₂ R2 In advantageous compounds of this family, Z = - (CH ₂ ) _m and n = 0, the compounds corresponding to formula (X):

In a preferred group of the B family, or b1 group, the substituents are independent of one another.

In a subgroup, R 1 and R ₁ and / or R ' ₁ and R' ₄ are as defined above and R represent a hydrogen atom.

In another subgroup, R 1 and R ₂ and / or R '1 and R' together represent the oxycarbonyl chain -OCO- and R ₄ and R ' ₄ are as defined above.

In yet another subgroup, R 1 and R 'and / or R' ₁ and R ' ₄ together represent a group - (CH ₂ ) _n - where n is an integer of 3 to 5 and R ₂ and R' represent H.

In yet another subgroup, R ₁ and R ' ₁ represent H and R 1 and R ₂ and / or R' ₄ and R ' ₂ together represent a group - (CH 2) _P - where p is an integer of 3 to 5, one or more hydrogen atoms may be replaced by a lower alkyl. Another subgroup corresponds to formula (XI):

Preferred compounds of families A and B are given in Tables 1 to 3 below. TABLE 1

R '^

N N II II

Series A R'3 ^" -C- - (NH) _n _ - Z- - (NH) n- -c- -N ~ -R ₃

1 RR ₂

TABLE 2

TABLE 3

Series B

The compounds according to the invention are optionally in the form of salts. Examples include hydrochlorides, citrates, tartrates, maleates, lactates, acetates and trifluoroacetates.

According to the invention, the carbamates and N-phosphoryl derivatives of general formula (V) and (VI) defined above can be obtained by a process characterized in that it comprises the reaction in two-phase medium of bisamidine compounds of formula general (V) and (VI) in which R ₃ and R ' ₃ = H with a derivative CI-R ₃ (or R' ₃ ) where R ₃ and R ' ₃ are as defined above and different from H as illustrated in the examples.

The amidoxime derivatives of general formula (V) and (X) defined above can be obtained by a process characterized in that it comprises the reaction in basic medium of bisamidoximes of general formulas (V) and (X) in which R 1 and R '1 = OH and the appropriate reagent as illustrated in the examples.

Advantageously, compounds of general formula (VI) group a2 and (VIII) group a4 defined above can be obtained by intramolecular cyclization of amidoxime or of previously defined amidoxime derivatives of general formula (V) group a1 in the presence appropriate reagent as illustrated in the examples.

The study of the activity of the products of the invention with respect to parasites, and in particular Plasmodium, has shown that they exhibit a strong activity in vitro.

Thus, the values of IC ₅ o (concentration inhibiting 50% of the parasite) are of the order of nM microM vis-à-vis P. falciparum. The invention therefore aims to take advantage of the properties of the compounds for the preparation of pharmaceutical compositions.

The pharmaceutical compositions of the invention are characterized in that they contain an effective amount of at least one compound as defined above, in association with an inert pharmaceutical vehicle.

The invention also relates to the use of at least one of said compounds for the manufacture of medicaments for the treatment of infectious diseases, in particular of malaria.

These compositions contain, if appropriate, active ingredients of other drugs. Their association with other antimalarials (such as lysosomotropic agents, atovaquone, antifolics or antifolinics, or artemisinin or one of its derivatives) for the sake of pharmacological synergy or resistance avoidance.

They will also be used with advantage in combination with compounds facilitating their assimilation.

The pharmaceutical compositions of the invention are administrable in different forms, more especially orally or injectably or rectally.

For oral administration, it is particularly used tablets, pills, tablets, capsules, drops.

Other forms of administration include intravenous, subcutaneous or intramuscular injection solutions made from sterile or sterilizable solutions. It can also be suspensions or emulsions. Suppositories can also be used for other forms of administration.

The compositions of the invention are particularly suitable for the treatment of infectious diseases in humans and animals, in particular malaria or babesiosis.

By way of indication, the dosage that can be used in humans corresponds to the following doses: thus, for example, the patient is administered from 1 to 90 mg / kg in one or more doses.

The invention also relates to biological reagents containing as active ingredients, the compounds defined above.

These reagents can be used as references or standards in studies of possible anti-parasitic activities.

Other characteristics and advantages of the invention will become apparent in the following examples relating to the synthesis of the compounds and to the study of their pest control activity. In these examples, reference will be made to Figure 1, which shows the antimalarial activity of compound 6.0 as a function of drug concentration, according to the Desjardins test (Desjardins RE et al, Antimicrob Agents Chemother, 1979, 16). , 710-718).

Synthetic intermediates

1.12-dicyanododécane:

A stirred suspension of 3.3 g (67.10 mmol) of sodium cyanide in 30 ml of dimethylsulfoxide is heated to 90-95 ° C until complete dissolution. To the solution obtained and cooled to below 50 ° C are added in very small portions and. slowly 10 g (30.49 mmol) of 1,12-dibromododecane. After 2 hours stirring at room temperature the suspension obtained, is dissolved by addition of 90 ml of dichloromethane and washed several times with a saturated aqueous solution of sodium chloride. After which, the organic phase is dried over sodium sulphate and evaporated under reduced pressure. The cold oily residue, taken up in ether and then evaporated to dryness, crystallizes and gives 6.44 g (96%) of white crystals.

Melting point: <40 ° C

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.60 (m, 4H); 2.31 (t, 4H) FT-IR, v (cm- ¹ ): 2246 (CN)

Diethyltetradecanediimidoate dihydrochloride

In a solution cooled to 0 ° C., 20 ml of anhydrous ethanol, 60 ml of anhydrous ether and 5 g (22:73 mmol) of 1,12-dicyanododecane, allow the hydrochloric acid to be bubbled over for 2 hours. then, stirring the reaction mixture overnight. After which, the solvents are evaporated under reduced pressure. The solid residue obtained is crystallized and washed several times with ether and then dried in a desiccator. 7.7 g (82%) of a white powder are obtained. Melting point: 118-120 ° C

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.26 (s, 16H); 1.35 (t, 6H); 1.60 (m, 4H); 2.63 (t, 4H); 4.55 (q, 4H); 11.16 and 12.08 (2s, 4H) FT-IR, v (cm- ¹ ): 1097 (CO), 1651.50 (C = N), 3032 and 3118 (NH ₂ , Cl) -

N, N'-di-benzyloxycarbonyl-S-methylisothiourea:

To a solution of 1 g (3.60 mmol) of S-methylisothiourea sulfate in 40 ml of a diphasic mixture of dichloromethane / saturated aqueous sodium bicarbonate solution (1: 1), with vigorous stirring, are added dropwise 2 ml. (14.4 mol) benzyl chloroformate. Stirring is maintained at ambient temperature for 25 h. After which, the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are then washed with water and then dried over sodium sulphate and evaporated under reduced pressure. The resulting residue was purified by silica column chromatography (DCM) to give 1.06 g (82%) of product as a yellow oil. 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 2.46 (s, 3H); 5.24 (s, 4H); 7.42 (s, 10H);

11.91 (s, 1H)

FT-IR, v (cm): 1022 and 1173 (C-O); 1647 (C≈N); 1751 (NCO); 3169 (NHCO)

N, N'-di-tert-butyloxycarbonyl-S-methylisothiourea:

A two-phase solution (100 ml) of saturated aqueous DCM / NaHCO ₃ containing 5.81 g (26.60 mmol) of di-tert-butyl carbonate and 2.53 g (18.20 mmol) of S-methylisothiourea hemisulfate is stirred vigorously for 48 hours. . After that, the separated aqueous phase is extracted with 2 X 100 ml of DCM. The combined organic phases are then washed with 2 × 200 ml of water and then evaporated under reduced pressure. The residue is then taken up with 100 ml of the saturated aqueous DCM / saturated NaHCO.sub.3 mixture to which 0.55 g (3.85 mmol) of S-methylisothiourea hemisulfate is added. The reaction mixture is further stirred vigorously for 72 hours. The combined organic phases after the same treatment as above, are dried over sodium sulphate and evaporated under reduced pressure.

The residue is finally purified on silica (Hexane / CHCl ₃ 5% then CHCl ₃ ) to yield 3.46 g (90%) of product in the form of a white powder. Melting point: 123-124 ° C 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.49 (s, 18H); 2.38 (s, 3H); 11.60 (s, 1H) FT-IR, v (cm): 1043 and 1252 (CO); 1667 (C = N); 1765 (NCO); 3337 (NHCO)

O-chloromethyl-S-ethyl carbonothioate

To a solution with stirring and cooled between 0 and 5 ° C of 44 ml (500 mmol) of chloromethyl chloroformate in 900 ml of ether is added dropwise for 2 hours, a solution of 37 ml (500 mmol) of ethanethiol and 69.3 ml (500 mmol) of triethylamine in 200 ml of ether. After which, the operating conditions are maintained for 30 minutes. The reaction mixture is then left stirring for 16 hours at room temperature and the precipitate formed is filtered and washed with ether. The combined ether phases are evaporated and the residue purified by distillation to give 57 g (73%) of product as a liquid.

Boiling point: 99-100 ° C /.18 mbar 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm); 1.30 (t, 3H); 2.89 (q, 2H); 5.73 (s, 2H). FT-IR, ν (cm- ¹ ): 1719 (S-CO-O).

S-ethyl-O-iodomethyl carbonothioate: To a stirred solution of 106.8 g (712 mmol) of sodium iodide and 3 g (35.6 mmol) of sodium bicarbonate in 450 ml of acetone, 55 g are added directly ( 356 mmol) of O-chloromethyl-S-ethyl carbonothioate. The reaction mixture is then stirred and at 40 ° C. for 4 hours. The precipitate formed is filtered and washed with acetone and ether. The organic phase is evaporated and the residue is partitioned between 1100 ml of hexane cooled at 0 ° C. and 500 ml of cold water. The separated organic phase is then washed successively with 200 ml of 5% aqueous sodium bicarbonate, 200 ml of 1% aqueous sodium thiosulfate (until the solution is decolorized) and 2 × 200 ml of water. After drying the hexane phase over sodium sulfate and evaporation under reduced pressure, 81 g (92%) of product are obtained as a yellowish liquid without purification.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm); 1.30 (t, 3H); 2.89 (q, 2H,); 5.96 (s, 2H). FT-IR, ν (cm ^-1 ): 1715 (SCO).

O-acetyloxymethyl-5-ethylcarbonothioate: To a stirred solution and cooled to -20 ° C. of 26.7 g (325.2 mmol) of sodium acetate in 420 ml of anhydrous dimethylformamide, 80 g are added dropwise over 2 hours. (325.2 mmol) S-ethyl-O-iodomethyl carbonothioate. The reaction mixture is then stirred for 16 hours at room temperature and the precipitate formed is filtered and washed with 20 ml of dimethylformamide and 40 ml of ether.

To the organic phase in a separating funnel is added 850 ml of ether and 350 ml of cold water. The aqueous phase is isolated and extracted with 350 ml of water. The combined ethereal phases are then washed successively with 220 ml of 5% aqueous sodium bicarbonate, 220 ml of water, 2 × 220 ml of 0.01 N hydrochloric acid and 220 ml of water. After drying the organic phase over sodium sulphate and evaporation, the residue is purified by distillation to give 35 g (60%) of product as a yellowish liquid.

Boiling point: 82-83 ° C / 0.25 mbar

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.30 (t, 3H); 2.09 (s, 3H); 2.87 (q, 2H); 5.76 (s, 2H).

FT-IR, v (cm- ¹ ): 1717 (S-CO-O); 1767 (CO-O).

acetyloxymethyl chloroformate:

To the solution of 33 g (185.4 mmol) of O-acethyloxymethyl-5-ethylcarbonothioate with stirring and cooled to 0-5 ° C. is added 14.90 ml (185.4 mmol) of sulfuryl chloride. The operating conditions are maintained for 15 minutes and the reaction mixture is stirred for 45 minutes at room temperature. The solution of S-ethyl chloride formed is evaporated at ambient temperature and then at 20 mbar overnight. The resulting residue is then purified by distillation to give 15.50 g (56%) of product as an orange liquid.

Boiling point: 75-76 ° C Al 7 mbar

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 2.12 (s, 3H); 5.76 (s, 2H). FT-IR, ν (cm- ¹ ): 1724 (CO-O); 1773 (Cl-CO).

3,4-dihydro-5-methoxy-2H-pyrrole:

To the solution of 20.03 g (0.235 mol) of pyrrolidin-2-one in 85 ml of benzene, heated to 70 ° C are added dropwise 23 ml (1 equivalent) of dimethylsulfate. This reaction mixture is heated under reflux for 3 hours. After cooling to room temperature, 19 ml of a 15N sodium hydroxide solution are added to the reaction mixture. This is poured into a separatory funnel, and the aqueous phase is extracted 3 times with benzene. The combined organic phases are dried over sodium sulphate and evaporated under reduced pressure. The residue is distilled under vacuum to give the product, colorless liquid, with a yield of 58%. Boiling point: 37 ° C at 10 ^-2 mbar, 1 H NMR (CDCl3, 100 MHz), δ (ppm): 1.97 (m, 2H), 2.41 (t, 2H), 3.61 (m.p. t, 2H); 3.75 (s, 3H); 2-methylsulfanyl-3,4,5,6-tetrahydropyrimidinium iodide

The reaction mixture composed of one equivalent of 3,4,5,6-tetrahydro (1H) pyrimidine-2-thione and 1.2 equivalents of iodomethane in methanol (10 ml / g of thiourea) was heated under reflux. for 5 hours. After cooling, the methanol is evaporated under reduced pressure to give the product quantitatively. The precipitate can then be washed in acetone or petroleum ether. Melting point: 146-148 ° C

1 H NMR (DMSO-d ₆ , 100 MHz): 1.94 (m, 2H); 2.66 (s, 3H); 3.44 (t, 4H); 9.53 (s, 2H) ppm.

5,5-Dimethyl-3,4,5,6-tetrahydro (iH) pyrimidine-2-thione:

In a 250 ml flask, 10 ml (167.2 mmol; 2 eq) of carbon disulfide are added to the solution of 10 ml (83.6 mmol) of 2,2-dimethyl-1,3-diaminopropane in 50 ml of absolute ethanol. Then, 16.02 g (83.6 mmol) of EDC is added to the reaction mixture, which is stirred for 3 hours at room temperature. The ethanol is evaporated, the residue is taken up with water and extracted with dichloromethane. After drying over Na 2 SO 4 and evaporation of the organic phase, 11.2 g (93%) of product (white powder) are obtained, used without additional purification. Melting point: 225-228 ° C

1 H NMR (CDCl ₃ , 100 MHz): 0.91 (s, 6H); 2.88 (d, 4H); 7.46 (s, 2H) ppm.

5,5-dimethyl-2-methylsulfanyl-3,4,5,6-tetrahydropyrimidinium hydroiodide:

The reaction mixture composed of one equivalent of 5,5-dimethyl-3,4,5,6-tetrahydro (1H) pyrimidine-2-thione and 1.2 equivalents of iodomethane in methanol (10 ml / g of thio- urea) is refluxed for 5 hours. After cooling, the methanol is evaporated under reduced pressure to give the product quantitatively. The precipitate can then be washed in acetone or petroleum ether. ¹NMR (CDCl ₃ , 100 MHz): 0.95 (s, 6H); 2.62 (s, 3H); 3.11 (s, 4H), 8.76 (s, 2H) ppm. 1- (N-tert-Butyloxycarbonylamino) dodecane 12-ammonium hydrochloride:

A solution of 4.02 g (18.4 mmol) of di-tert-butyldicarbonate in 60 ml of dioxane is added slowly, dropwise (for about two hours), to a solution of 15.01 g (75 mmol, 4.1 eq.) Of 1,12-dodecanediamine in a dioxane / water mixture (150 / 70ml). The reaction mixture is stirred at room temperature for 24 h, the excess diamine is filtered and the solvents are evaporated under reduced pressure. The residue is taken up with a 1N HCl solution and dichloromethane. The precipitate formed in the aqueous phase is filtered to give the mono-Boc derivative and a little diamine, both in the hydrochloride salt form. This solid is recrystallized with ethanol and ether to give 4.56 g (74% yield) of mono-protected diamine salt as a white powder. Melting point: 153-155 ° C.

1H NMR (CD ₃ OD, 100 MHz), δ (ppm): 1.28 (m, 20H); 1.38 (s, 9H); 2.91 (m, 4H) FAB-MS +: [M + H] ⁺ : 301

[1- [N- (5,5-Dimethyl-3,4,5,6-tetrahydro-pyrimidin-2-yl) amino] -12- (N-tert-butyloxycarbonylamino)] dodecane hydroiodide:

To the suspension of 1.02 g (3 mmol) of 12- (N-tert-butyloxycarbonylamino) dodecane-1-ammonium chloride in 15 ml of acetonitrile is added 0.85 g (3 mmol) of iodide 5, 5-dimethyl-2-methylsulfanyl-3,4,5,6-tetrahydropyrimidinium and 0.85 ml (2 eq) of triethylamine. This reaction mixture is refluxed for 24 hours. After cooling to room temperature, the unreacted amine is filtered. The filtrate is evaporated under reduced pressure and chromatographed on a silica column (eluent: CH ₂ Cl ₂ / CH ₃ OH / OH OH 80: 16: 4) to give 1.36 g (85%) of product.

1 H NMR (CD ₃ OD, 100 MHz), δ (ppm): 1.07 (s, 6H); 1.37 (m, 29H); 3.05 (m, 8H).

1- [N- (5,5-Dimethyl-3,4,5,6-tetrahydropyrimidin-2-yl) amino] dodecane-12-ammonium ditrifluoroacetate: 1.06 g (2 mmol) of sodium iodide hydrochloride; [N- (5,5-dimethyl-3,4,5,6-tetrahydropyrimidin-2-yl) amino] -12- (N'-tert-butyloxycarbonylamino)] dodecane are solubilized in 15 ml. of a solution TFA / CH ₂ C1 ₂ (3/1). This solution is stirred for 3 hours at room temperature; the excess of trifluoroacetic acid are evaporated under reduced pressure to give quantitatively 0.98 g of product.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.0 (s, 6H); 1.3 (m, 20H); 3.0 (m, 8H); 8.0 (si, 2H); 9.0 (s, 3H).

SM-ES ⁺ : [M + H] ⁺ : 311; [M + 2H] ⁺⁺ 2: 156

Syntheses 1,12-bis (amidinyl) dodecane dihydrochloride: 1.0, 2HCl: In a solution cooled by an ice bath at a temperature below 10 ° C,

45 ml of anhydrous ethanol and 5 g (13 mmol) of diethyltetradecanediimidoate hydrochloride, bubbling for 2 hours, ammonia gas. After which, the solvent is evaporated under reduced pressure. The residue obtained is then washed several times with ether and dried in a desiccator. 3.53 g (83%) of product is obtained in the form of a white powder, anointed with melting point: 170-172 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.25 (s, 16H); 1.58 (m, 4H); 2.37 (t, 4H); 8.82 (s, 4H); 9.10 (s, 4H) FT-IR, v (cm- ¹ ): 1688 (C = N); 3081 (NH ₂ , Cl); 3245 (NH ₂ );

1,1-bis [N- (1- (methyloxycarbonyl) amidyl] dodecane: 1.1 To a solution of 1 g (3.06 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 60 ml of a diphasic dioxane / water mixture (3: 1) and cooled with an ice bath, 0.60 ml (7.65 mmol) of methyl chloroformate are added dropwise with vigorous stirring while maintaining the pH of the mixture between 10 and 12 with a 4N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 100 ml of water are added. The precipitate formed is then filtered off, washed several times with water and then with ether to give, after drying in a desiccator, 1.30 g (77%) of product in the form of a white powder.

Melting point: 116-117 ° C. 1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.69 (s, 16H); 1.96 (m, 4H); 2.61 (t, 4H); 3.97 (s, 6H); 9.06 (s, 4H).

FT-IR, v (cm- ¹ ): 1256 (COC), 1633 (C = N), 1670 (NHCO), 3183 (NHCO), 3343 (NH) MS-ES +: [M + H] ⁺ : 371

1,12-bis [IV, N ^f - (ethyloxycarbonyl) amidinyl] dodecane: 1.2

To a solution of 1 g (3.06 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 60 ml of a diphasic dioxane / water mixture (3: 1) and cooled with an ice bath, are added dropwise with vigorous stirring, 0.73 ml (7.65 mmol) of ethyl chloroformate while maintaining the pH of the mixture between 10 and 12 with a 4N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 100 ml of water are added.

The precipitate formed is then drained, washed several times with water and then with ether to conduct, after drying with a desiccator, 0.98 g (80%) of product in the form of a white powder.

Melting point: 95-96 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.63 (t, 6H); 1.71 (m, 16H); 1.93 (m,

4H); 2.63 (t, 4H); 4.49 (q, 4H); 8.95 and 9.12 (2s, 4H). FT-1R, v (cm- ¹ ): 1251 (COC); 1667 (C = N); 1757 (CO); 3186 (NHCO); 3330;

(NH)

MS-ES +: [M + H] ⁺ : 399; [M + 2H] ²⁺ / 2: 200 (100%)

1,2-bis [N, N '- (butyloxycarbonyl) amidinyl] dodecane: 1.3 To a solution of 1 g (3.06 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 60 ml of a mixture Diphasic dioxane / water (3: 1) and cooled with an ice bath are added dropwise and with vigorous stirring, 0.99 ml (7.65 mmol) of butyl chloroformate while maintaining the pH of the mixture between 10 and 12 with 4N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 100 ml of water are added.

The precipitate formed is then drained, washed several times with water and then with ether to after drying in a desiccator, conduct 1.12 g (80%) of product in the form of a white powder. Melting point: 87-88 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 0.88 (t, 6H); 1.21 (s, 16H) 1.48 - 1.70 (m, 8H); 1.88 (m, 4H); 2.24 (t, 4H); 4.03 (t, 4H); 6.21 (s, 2H); 9.24 (s, 2H).

FT-IR, v (cm- ¹ ): 1084 and 1234 (COC), 1594 (C = N), 1660 (CO), 3313 (NHCO);

3441 (NH)

SM-ES +: [M + H] ⁺ : 455

1,12-bis [N, N '- (isobutyloxycarbonyl) amidinyl] dodecane: 1.4

To a solution of 1 g (3.06 mmol) of 1,12-bis (amidmyl) dodecane dihydrochloride in 60 ml of a diphasic dioxane / water mixture (3: 1) and cooled with an ice bath, are added dropwise. drop and with vigorous stirring, 1 ml (7.65 mmol) of isobutyl chloroformate while maintaining the pH of the mixture between 10 and 12 with a 4N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 100 ml of water are added. The precipitate formed is then filtered off, washed several times with water and then with ether to conduct, after drying in a desiccator, 1.27 g (91%) of product in the form of a white powder. Melting point: 102-103 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 0.92 (d, 12H); 1.22 (s, 16H) 1.62 (m, 4H); 1.96 (m, 2H); 2.26 (t, 4H); 3.82 (d, 4H); 6.19 (s, 2H); 9.27 (s, 2H). FT-IR, v (cm- ¹ ): 1069 and 1237 (COC), 1599 (C = N), 1661 (CO), 3314 (NHCO), 3440 (NH) MS-ES +: [M + H] ⁺ : 455

1,12-bis [N, N '- (benzyloxycarbonyl) amidinyl] dodecane: 1.5

To a solution of 1 g (3.06 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 60 ml of a diphasic dioxane / water mixture (3: 1) and cooled with an ice bath are added dropwise. drop and with vigorous stirring, 1.1 ml (7.65 mmol) of benzyl chloroformate while maintaining the pH of the mixture between 10 and 12 with an aqueous solution of 4N sodium hydroxide. The mixture is then left stirring and at room temperature overnight. After which, 100 ml of water are added. The precipitate formed is then filtered off, washed several times with water and then with ether to give, after drying in a desiccator, 1.2 g (75%) of product in the form of a white powder.

Melting point 118-119 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.19 (s, 16H); 1.47 (m, 4H); 2.13 (t, H); 4.96 (s, 4H); 7.30 (s, 10H); 8.29 (s, 2H); 8.50 (s, 2H).

FT-IR, v (cm- ¹ ): 693 and 745 (aromatic CH), 1236 (COC), 1648 (C = N), 1666 (CO), 3311 (NHCO), 3436 (NH);

MS-ES +: [M + H] ⁺ : 523; [M + 2H] ²⁺ / 2: 262 (100%)

1,12-bis [N, N '- (4-nitrobenzyloxycarbonyl) amidinyl] dodecane: 1.6

To a solution of 1 g (3.06 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 60 ml of a diphasic dioxane / water mixture (3: 1) and cooled with an ice bath are added dropwise. drop and with vigorous stirring, 1.65 g (7.65 mmol) of 4-nitrobenzyl chloroformate dissolved in 5 ml of dioxane. The pH of the solution is maintained between 10 and 12 with a 4N aqueous sodium hydroxide solution. The mixture is then left stirring and at room temperature overnight. After which, 100 ml of water are added. The precipitate formed is then filtered off, washed several times with water and then with ether to give, after drying on a desiccator, 1.37 g (74%) of product in the form of a white powder. Melting point: 87-88 ° C.

1H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.22 (s, 16H); 1.51 (m, 4H); 2.18 (t, 4H); 5.15 (s, 4H); 7.59 (dd, 4H); 8.23 (dd, 4H); 8.69 (s, 4H).

FT-IR, v (cm- ¹ ): 1248 (COC), 1344 and 1512 (NO ₂ ), 1621 (C =), 1658 (CO), 3316 (NHCO), 3406 (NH) MS-ES +: [M + H] ⁺ : 623

1,12-bis [N, N '- (phenyloxycarbonyl) amidinyl] dodecane: 1.7 To a solution of 1.5 g (4.59 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 80 ml of a biphasic mixture of dioxane / water (3: 1) and cooled with an ice bath, are added dropwise. drop and with vigorous stirring, 1.44 ml (11.47 mmol) of phenyl chloroformate while maintaining the pH of the mixture between 10 and 12 with a 2N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 150 ml of water are added and the solution extracted with 3 X 60 ml of DCM. The organic phase is then washed several times with water and then evaporated under reduced pressure. 1.77 g (78%) of product in liquid form are obtained. 1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.73 (s, 16H); 2.05 (m, 4H); 2.72

(t, 4H); 7.17 - 7.90 (m, 10H); 9.20 (s, 4H). FT-IR, v (cm- ¹ ): 1623 (C = N); 1682 (COO); 3378 (NH and NHCO) MS-ES +: [M + H] ⁺ : 495

1,2-bis [N ^, N - (4-fluorophenyloxycarbonyl) amidinyl] dodecane: 1.8

To a solution of 1.5 g (4.59 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 80 ml of a biphasic mixture of dioxane / water (3: 1) and cooled with an ice bath, are added dropwise. drop and with vigorous stirring, 1.50 ml (11.47 mmol) of 4-flurophenyl chloroformate while maintaining the pH of the mixture between 10 and 12 with a 2N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 150 ml of water are added. The precipitate formed is then filtered off, washed several times with water and then with ether to give, after drying in a desiccator, 1.55 g (64%) of product in the form of a white powder. 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.26 (s, 16H); 1.70 (m, 4H); 2.35 (t, 4H);

6.62 - 7.14 (m, 8H); 6.20 (s, 2H); 9.23 (s, 2H).

FT-IR, v (cm- ¹ ): 1177 (COC), 1253 (CF), 1622 (C = N), 1679 (COO), 3327 (NH and NHCO) MS-ES +: [M + H] ⁺ : 531 Dihydrochloride 1,12-bis [N, N ^r - (4-fluorophenyl ² oxycarbonyl) amidinyl] dodecane: 1.8, 2HC1

In 20 ml of a saturated ethanolic solution of hydrochloric acid gas is added 1 g of 1.8. The reaction mixture with vigorous stirring is then heated at 50 ° C. for 2 hours. To the cold solution are added 150 ml of ether and the mixture is left to stand in the refrigerator overnight. After decantation, the oily layer formed is taken up with 100 ml of distilled water and then filtered. The filtrate is finally lyophilized to give the salt as a white powder. 1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.75 (s, 16H); 2.15 (m, 4H); 3.06 (t, 4H); 7.20 (s, 2H); 7.70 and 7.78 (d, 8H); 7.85 and 8.21 (2s, 4H).

FT-IR, v (cm ^-1 ): 1684 (C = N), 1753 (NCO), 3324 (NH, HCI).

1,12-bis [N, N '- (4-methoxyphenyloxycarbonyl) amidinyl] dodecane: 1.9

To a solution of 1.5 g (4.59 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 80 ml of a biphasic mixture of dioxane / water (3: 1) and cooled with an ice bath, are added dropwise. drop and with vigorous stirring, 1.70 (11.47 mmol) of 4-methoxyphenyl chloroformate while maintaining the pH of the mixture between 10 and 12 with a 2N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 150 ml of water are added and the solution extracted with 3 X 60 ml of DCM. The organic phase is then washed several times with water and then evaporated under reduced pressure. 1.97 g (78%) of product are obtained in liquid form. 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.62 (m, 4H); 2.28 (t, 4H); 3.73 (s, 6H); 6.71 - 7.06 (m, 8H); 6.18 (s, 2H); 9.21 (s, 2H). FT-IR, v (cm- ¹ ): 1176 and 1189 (COC), 1504 (aromatic CH), 1623 (C = N);

1678 (COO); 3374 (NH and NHCO) MS-ES +: [M + H] ⁺ : 555

Diphenyl [1,12-bis (amidmyl) dodecane] -1,12-bis-N, N-phosphonate: 1.12 To a solution of 1.5 g (4.59 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 30 ml of a biphasic mixture dioxane / water (3: 1) and cooled with an ice bath, 2.85 ml (13.76 mmol) of diphenylchlorophosphonate are added dropwise with vigorous stirring while maintaining the pH of the mixture between 10 and 12 with a 4N aqueous sodium hydroxide solution. The mixture is then stirred and at room temperature for 3 hours. After which, 50 ml of water are added. The precipitate formed is then filtered off, washed several times with water and then with ether to give, after drying with a desiccator, 2.70 g (82%) of product in the form of a white powder. Melting point: 100-101 ° C

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.65 (s, 16H); 1.93 (m, 4H); 2.79 (t, 4H); 7.68 - 7.81 (m, 20H); 8.31 (s, 2H); 8.71 (s, 2H)

³¹ P NMR (DMSO-d ₆ , 81 MHz), δ (ppm): -1.64

FT-IR, v (cm- ¹ ): 935 (P = O); 1230 (CO); 1675 (C = N); 3169 (NHPO); 3324 (NH) MS-FAB +: [M + H] ⁺ : 719; [M + 2H] / / 2: 360 (100%)

Diethyl [1,12-bis (amidinyl) dodecane] -1,12-bis-N, N'-phosphonate: 1.13

To a solution of 1 g (3.06 mmol) of 1,12-bis (amidinyl) dodecane dihydrochloride in 40 ml of a diphasic dioxane / water mixture (3: 1) and cooled with an ice bath, are added dropwise. drop and with vigorous stirring, 1.11 ml (7.65 mmol) of diethylchlorophosphonate while maintaining the pH of the mixture between 10 and 12 with a 4N aqueous sodium hydroxide solution. The mixture is then left stirring and at room temperature overnight. After which, the solution is extracted with dichloromethane (3x 30 ml). The organic phase is then washed several times with water and then dried over sodium sulfate. Evaporation under reduced pressure of the solution leads to an oily residue. The latter taken up in a minimum of ether and at -4 ° C overnight, crystallized to give 1.08 g (67%) of product in the form of a white powder. Melting point: 68-69 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.20 (s, 16H); 1.26 (t, 12H); 1.53 (m, 4H); 2.21 (t, 4H); 3.99 (quintuplet, 8H); 6.05 (s, 2H); 7.78 (s, 2H). ³¹ P NMR (CDCl ₃ , 81 MHz), δ (ppm): 8.76 FT-IR, v (cm- ¹ ): 793 and 1031 (PO-CH ₂ CH ₃ ), 958 (P≈O), 1647 (C = N), 3187 (NHPO), 1581 and 3386 (NH). ES +: [M + H] ⁺ : 527

sodium [1,12-bis (amidinyl) dodecane] -1,12-bis-N, N'-phosphonate: 1.14 a) [1,12-bis (amidmyl) dodecane] -1,12-bis-N acid , N ^f -phosphonic

To a solution of 10 ml of anhydrous dichloromethane cooled at 0 ° C. under a nitrogen atmosphere and with stirring of 1 g (1.9 mmol) of 1.13, 1.36 ml (9.51 mmol) of trimethylsilane iodide are added dropwise. The operating conditions are thus maintained for 1 hour. The solution is then evaporated under reduced pressure. The cold residue is taken up in 10 ml of acetone containing 3 ml of water and then stirred for 24 hours. After which, the precipitate formed is filtered off, washed several times with acetone and then recrystallized from ethanol to yield 0.52 g (66%) of product in the form of a white powder. Melting point: 164-165 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.56 (m, 4H); 2.32 (t, 4H);

9.26 and 9.63 (2s, 8H).

³¹ P NMR (CDCl ₃ , 81 MHz), δ (ppm): -5.82

FT-IR, v (cm- ¹ ): 1044 and 1211 (P-OH), 939 (PO), 1667 (C = N), 2324 (POH), 3019 (NHPO), 1557 and 3322 (NH).

SM-ES +: [M + H] ⁺ : 415

b) [1,12-bis (amidinyι) dodecane] -1,12-bis-N, N'-phosphonate sodium: 1.14

To a stirred suspension of 1 g of [1,12-bis (amidinyl) dodecane] -1,12-bis-N, N'-phosphonic acid in 20 ml of water is added dropwise to pH 7.4. , a solution of soda 0.1Ν (about 21 ml). After which, the solution is freeze-dried to yield a white powder. RMΝ ³¹ P (81 MHz), δ (ppm): -3.16

1, 12-bis (Λ ^r , Λ ^r '-hydroxyamidinyl) dodecane: 1.15 To a hydroalcoholic solution of sodium hydroxide [prepared from 8.22 g of sodium hydroxide, 36 ml of water and 138 ml of 95% ethyl alcohol] 13.70 g (196.91 mmol) of hydroxylamine hydrochloride are added. After stirring for 15 minutes, 20 g (90.91 mmol) of 1,12-dicyanododecane are added. The reaction mixture is then refluxed for 72 hours and then evaporated under reduced pressure. The residue obtained is then taken up with water and left stirring and filtered. The precipitate is drained and washed several times with water and with petroleum ether. After recrystallization with ethanol and drying in the desiccator overnight, 25 g (96%) of product in the form of a white powder are obtained. Melting point: 170-171 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.70 (s, 16H); 1.90 (m, 4H); 2.39 (t, 4H);

5.75 (s, 4H); 9.13 (s, 2H).

FT-IR, v (cm- ¹ ): 1661 (C = N), 3244 (N-OH), 3315 and 3400 (NH ₂ )

+ MS TOF: 287 (M + H); 254 (M-32); 144 (M + H / 2)

1,12-bis (N, N'-methoxyamidinyl) dodecane: 1.16

To a suspension cooled with an ice bath and with stirring of 2 g (7 mmol) of 1.15 in 50 ml of a biphasic mixture of dioxane / NaOH 0.7 N, 1.70 ml (17.48 mmol) of dimethylsulphate are added dropwise. . Stirring is maintained overnight at room temperature. The reaction mixture is then extracted

DCM filtered and the filtrate washed with 3 X 100 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The cold residue crystallizes by addition of petroleum ether and after drying on a desiccator, gives 1.05 g (48%) of product in the form of a white powder. Melting point: 85-86 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.23 (s, 16H); 1.50 (m, 4H); 2.10 (t, 4H);

3.74 (s, 6H). 4.44 (s, 4H).

FFTT - IIRR ,, vv ((ccmm - ¹¹ )): 11004488 ((Nb-OC); 1643 (C = N); 3288 and 3433 (NH ₂ ) + TOF MS: 315 (M + H)

1,12-bis (N, N'-ethoxycarbonyloxyamidinyl) dodecane: 1.17 To a stirred suspension of 2 g (7 mmol) of 1.15 and 2.65 ml of triethylamine (18.9 mmol) in 45 ml of chloroform are added dropwise 1.40 ml (14.68 mmol) of ethyl chloroformate in 5 ml of chloroform. Stirring is maintained for 3 hours at room temperature. The reaction mixture is then filtered and the filtrate washed with 3 X 100 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. After crystallization of the cold residue, the crystals are washed with petroleum ether and dried in a desiccator to yield 2.53 g (84.33%) of product as a white powder. Melting point: 100-101 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.29 (t, 6H) 1.53 (m, 4H); 2.19 (t, 4H); 4 = 23 (quartet, 4H). 4.79 (s, 4H).

FT-IR, ν (cm- ¹ ): 1240 (COC); 1620 (C≈N); 1741 (OCOO); 3374 and 3508 (NH ₂ ) + TOF MS: 431 (M + H);

1, 12-bis (N, N'-methoxycarbonyloxyamidinyl) dodecane: 1.18 To a stirring suspension of 2 g (7 mmol) of 1.15 and 2.65 ml of triethylamine (18.9 mmol) in 45 ml of chloroform are added dropwise. drop 1.14 ml (14.68 mmol) of methyl chloroformate in 5 ml of chloroform. Stirring is maintained for 3 hours at room temperature. The reaction mixture is then filtered and the filtrate washed with 3 X 100 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The cold residue is washed with petroleum ether and then drained and dried in a desiccator to yield 2.05 g (73%) of product as a white powder. Melting point: 79-80 ° C.

NMR ^! H (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.53 (m, 4H); 2.19 (t, 4H); 3.81 (s, 6H). 4.81 (s, 4H).

FT-IR, v (cm- ¹ ): 1247 (COC), 1622 (C≈N), 1750 (OCOO), 3380 and 3497 (NH ₂ ) + TOF MS: 403 (M + H)

1,12-bis (N, N'-phenoxycarbonyloxyamidinyl) dodecane: 1.19 To a stirred suspension of 2 g (7 mmol) of 1.15 and 2.65 ml of triethylamine (18.9 mmol) in 30 ml of DMF and cooled with a cold water bath, 1.85 ml (14.68 mmol) are added dropwise. phenyl chloroformate. Stirring is maintained for 4 hours at room temperature then the reaction mixture is filtered and the filtrate diluted with 150 ml of ethyl acetate. The solution is then washed with water (100 ml) and with saturated sodium chloride solution (2 X 100 ml). The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The cold residue is washed with petroleum ether and then drained and dried in a desiccator to yield 3.02 g (82%) of product as a white powder.

Melting point: 108-109 C.

NMR Η (DMSO-d ₆ , 100 MHz), δ (ppm): 1.72 (s, 16H); 1.98 (m, 4H); 2.52 (t, 4H); 6.98 (s, 4H); 7.65 - 7.98 (m, 10H). FT-IR, v (cm- ¹ ): 1197 and 1241 (COC), 1633 (C = N), 1770 (OCOO), 3309 and 3473 (NH ₂ )

+ TOF MS: (M + H)

1,12-bis (N, N-thiomethylcarbonyloxyamidyl) dodecane: 1.20

To a stirred suspension of 2.46 g (8.60 mmol) of 1.15 and 3.26 ml of triethylamine (23.22 mmol) in 45 ml of chloroform are added dropwise.

1.55 ml (18.06 mmol) of thiomethyl chloroformate in 5 ml of chloroform.

Stirring is maintained for 2 hours at room temperature. The reaction mixture is then filtered and the filtrate washed with 3 X 100 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The cold residue is washed with petroleum ether and then drained and dried in a desiccator to yield 3.45 g (92%) of product in the form of a white powder.

Melting point: 89-90 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.56 (m, 4H); 2.20 (t, 4H);

2.31 (s, 6H). 4.79 (s, 4H). FT-IR, n (cm- ¹ ): 1131 (COC), 1605 (C = N), 1719 (OCOS), 3384 and 3496 (NH ₂ )

ES + MS: 435 (M + H) 1,12-bis (N, N-thioethylcarbonyloxyamidinyl) dodecane: 1.21

To a stirred suspension of 2 g (7 mmol) of 1.15 and 2.65 ml of triethylamine (18.9 mmol) in 45 ml of chloroform are added dropwise 1.53 ml (14.68 mmol) of thioethyl chloroformate in 5 ml of chloroform. .

Stirring is maintained for 3 hours at room temperature. The reaction mixture is then filtered and the filtrate washed with 3 X 100 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The cold residue is washed with petroleum ether and then drained and dried in a desiccator to yield 2.70 g (83%) of product as a white powder.

Melting point: 59-60 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.23 (s, 16H); 1.30 (t, 6H) 1.56 (m, 4H); 2.20 (t, 4H); 2.86 (quartet, 4H). 4.80 (s, 4H). FT-IR, n (cm- ¹ ): 1127 (COC); 1608 (C = N); 1718 (OCOS); 3386 and 3496 (NH ₂ ) ES + MS: 462 (M + H);

1,12-bis (N, N'-acetoxyamidinyl) dodecane: 1.22

To 26 ml (280 mmol) of acetic anhydride under stirring and cooled with an ice-water bath, 2 g (7 mmol) of 1.15 are added portion by portion. Stirring is maintained for 2 hours at room temperature. To the reaction mixture are added 100 ml of chloroform. The solution is then washed successively with 2 × 100 ml of a saturated aqueous solution of sodium chloride, 3 × 100 ml of a 3N sodium hydroxide solution and 100 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. After crystallization of the cold residue, the crystals are washed with petroleum ether and dried in a desiccator to lead to

2.33 g (90%) of product in the form of a white powder. Melting point: 128-129 ° C.

1H NMR (CDCl3, 100 MHz), δ (ppm): 1.23 (s, 16H); 1.55 (m, 4H); 2.12 (s, 6H); 2.23 (t, 4H); 5.74 (s, 4H). FT-1R, v (cm- ¹ ): 1232 (COC), 1633 (C = N), 1736 (OCO), 3319 and 3425 (NH ₂ )

+ MS TOF: 371 (M + H) 1, 12-bis (1H, 7y ^, -benzoyloxyamidyl) dodecane: 1.23

To a stirred suspension of 1.5 g (5.24 mmol) of 1.15 and 2 ml of triethylamine (14.16 mmol) in 30 ml of DMF and cooled with a cold water bath, 1.28 ml (14.68 mmol) are added dropwise. benzoyl chloride. Stirring is maintained for 3 hours at room temperature then the reaction mixture is filtered and the filtrate precipitated in 200 ml of cold water. The precipitate is then drained, washed with water and with petroleum ether and then dried in a desiccator to yield 2.25 g (87%) of product in the form of a white powder. Melting point: 158-159 C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.73 (s, 16H); 2.01 (m, 4H); 2.56

(t, 4H); 6.94 (s, 4H); 7.96 - 8.11 (m, 6H); 8.54 - 8.61 (m, 4H).

FT-1R, v (cm- ¹ ): 684 and 699 (aromatic CH); 1266 (COC); 1625 (C = N);

(OCO); 3315 and 3452 (NH ₂ )

1,12-bis (N, 7'-ethylcarbamoyloxyamidyl) dodecane: 1.24 To a stirred suspension of 2 g (7 mmol) of 1.15 and 1.01 g of potassium carbonate (7.34 mmol) in 80 ml of chloroform are added dropwise 1.16 ml (14.68 mmol) of ethyl isocyanate. Stirring is maintained overnight at room temperature. The reaction mixture is then filtered and the filtrate washed with 2 X 100 ml of water. The organic phase is then dried over sodium sulfate and evaporated under reduced pressure to yield 2.22 g (74%) of product as a colored oil. 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.14 (t, 6H); 1.22 (s, 16H); 1.51 (m, 4H); 2.12 (t, 4H); 3.26 (quintuplet, 4H). 5.00 (s, 4H); 6.44 (t, 2H).

FT-IR, v (cm- ¹ ): 1650 (C = N); 1701 (OCONH); 3335 (NH); 3374 and 3490 (NH ₂ ) + TOF MS: 429 (M + H);

1,12-bis (N, N '-phenylcarbamoyloxyamidinyl) dodecane: 1.25 To a stirred suspension cooled to 0 ° C with a cold water bath, 2 g (7 mmol) of 1.15 and 1.01 g of sodium carbonate. potassium (7.34 mmol) in 40 ml of DMF is added dropwise 1.6 ml (14.68 mmol) of phenyl isocyanate. Stirring is maintained for 2H30 at room temperature. The reaction mixture is then filtered and the filtrate precipitated in 150 ml of cold water. The precipitate is subsequently washed successively with water, acetone and ether. After drying with a desiccator, 2.95 g (80%) of product are obtained in the form of a white powder. Melting point: 134-135 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.72 (s, 16H); 2.0 (m, 4H); 2.55 (t, 4H); 6.83 (s, 4H); 7.54 (t, 2H); 7.76 (t, 4H); 7.93 (t, 4H); 9.65 (s, 2H). FT-IR, v (cm- ¹ ): 1018 and 1220 (COC); 1628 (C = N); 1708 (CON);

(OCONH); 3345 and 3455 (NH ₂ ) ES + MS: 525- (M + H); 263 (M + H / 2)

[1,12-bis (amidinyl) dodecane] -1,1,2-bis-N, N'-diethyl phosphate: 1.26 To a stirred suspension cooled to 0 ° C. with a cold water bath, 2 g ( 7 mmol) of 1.15 and 2.06 ml of triethylamine (14.68 mmol) in 30 ml of DMF are added dropwise 2.08 ml (14.33 mmol) of diethylchlorophosphonate.

Stirring is maintained for 16 hours at room temperature. The reaction mixture is then filtered and the filtrate is taken up with 150 ml of ethyl acetate. The organic phase is subsequently washed with 3 × 200 ml of water and then dried over sodium sulfate and evaporated under reduced pressure to yield 2.88 g (74%) of product in the form of a colored oil.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.31 (t, 12H); 1.51 (m, 4H);

2.15 (t, 4H); 4.15 (quintuplet, 8H); 4.30 (s, 4H). FT-IR, v (cm- ¹ ): 837 and 1027 (OP-O-CH ₂ CH ₃ ), 969 (OP = O), 1648 (C = N), 3323 and

3487 (NH ₂ ).

ES + MS: 559 (M + H)

1,12-Bis [(1,2,4-oxadiazol-5 (4H) -one) -3-yl] dodecane: 1.27 A stirred suspension of 4 g (9.30 mmol) of 1.17 in 70 ml of xylene is heated at 150 ° C for 2 hours (until the formation of an oily layer colored). The reaction mixture is then evaporated under reduced pressure. The solid residue obtained is then dissolved in 50 ml of DMSO and then precipitated in 200 ml of cold water. The precipitate formed is filtered off and then redissolved in acetone and filtered. The filtrate was dried over sodium sulfate and evaporated under reduced pressure, after drying on a desiccator, 2.97 g (94%) of product in the form of colored crystals. Melting point: 150-151 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.71 (s, 16H); 2.03 (m, 4H); 2.93 (t, 4H). FT-IR, n (cm- ¹ ): 1718 (C = N), 1783 (OCONH), 3163 (NHCO).

ES + MS: 339 (M + H)

1,12-bis [(1,2,3,5-oxathiadiazol-2 (3H) -oxide) -4-yl] dodecane: 1.28

To a suspension with stirring and cooled to 0 ° C, 2 g (7 mmol) of 1.15 and 2.82 ml of pyridine (34.96 mmol) in 30 ml of DMF are added dropwise.

1.1 ml (15.03 mmol) of thionyl chloride. Stirring is maintained for 45 minutes under cold conditions and then the reaction solution is precipitated in 150 ml of cold water. The precipitate filtered and dried on a desiccator gave 1.65 g (62%) of product as a colored powder. Melting point: 94-95 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.71 (s, 16H); 2.05 (m, 4H); 2.99 (t, 4H).

FT-IR n (cm ^-1 ): 1146 (NSOC) 1615 (CN) 1655 (C = N) 3219 and 3323 (NHSO) ES + MS 379 (M + H)

1,12-bis [(1,2,4-oxadiazol-5 (4H) -thione) -3-yl] dodecane: 1.29 To a suspension with stirring and cooled to 0 ° C of 2 g (5.4 mmol) of 1.22 and 2.5 ml (34.96 mmol) of this carbon sulfide in 50 ml of DMF are slowly added 1.32 g (32.97 mmol) of 60% sodium hydride. Stirring is maintained for 45 minutes in the cold and then for 2 hours at room temperature. The reaction solution is then precipitated in 150 ml of cold water, acidified to pH 5 with 2N HCl and then extracted with 3 X 50 ml of ethyl acetate. The organic phase washed with water then dried over sodium sulphate and evaporated under reduced pressure gives a solid residue. The latter is then washed with ether to give after drying in the desiccator to 1.45 g (72%) of product in the form of colored powder. 1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.71 (s, 16H); 2.06 (m, 4H); 3.02

(t, 4H); 9.25 (s, 2H)

FT-IR, v (cm- ¹ ): 1644 (C = N), 1737 (SCONH), 3090 (NHCO), ES + MS: 371 (M + H), 313 [M + 2H-60 (SCO)]

1,12-bis [(1,2,4-thiadiazol-5 (4H) -one) -3-yl] dodecane: 1.30

A suspension of 2 g (7 mmol) of 1.15 and 3.74 g (21 mmol) of 1,1-thiocarbonyl diimidazole in 70 ml of THF is left stirring and at room temperature for 16 hours. The reaction mixture is diluted with 150 ml of water and extracted with 3 X 70 ml of ethyl acetate. The organic phase is then washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is taken up with 50 ml of THF to which are added 5.32 ml (41.96 mmol) of BF ₃ and ₂ O. The reaction mixture obtained is then left stirring overnight at room temperature. The solution is diluted with water, extracted with ethyl acetate, washed with water, dried and then evaporated under reduced pressure. The cold residue obtained is then taken up in 50 ml of ethanol and precipitated in 200 ml of cold water.

The isolated precipitate is finally washed with water and dried to give 1.62 g (62.55%) of product as an orange powder.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.70 (s, 16H); 2.04 (m, 4H); 2.93 (t, 4H); 9.30 (s, 2H) FT-IR, v (cm- ¹ ): 1666 (C = N), 1707 (SCONH), 3129 (NHCO).

+ TOF MS: 313 [M + 2H - 60 (SCO)]

1,14-Di (pyrrolidin-1-yl) tetradecane-1,14-diimine: 2.0, 2HCl

A mixture consisting of 1.16 g (3 mmol) of diethyl tetradecanediimidate dihydrochloride, 0.51 ml of pyrrolidine and 15 ml of ethanol is heated at reflux for 24 hours. After evaporation, the residue obtained is recrystallized from methanol-ether to give 0.97 g (75%) of beige powder. Melting point: 171 ° C

¹ H NMR (CD ₃ OD, 250 MHz), δ (ppm): 1.35 (m, 16H); 1.68 (m, 4H); 2.08 (m, 8H); 2.55 (t, 4H); 3.42 (t, 4H); 3.70 (t, 4H); 9.12 (s, 4H)

1,14-Di (piperidin-1-yl) tetradecane-1,14-diimine: 3.0

2.2 g (10 mmol) of 1,12-dicyanododecane and 1.98 g (20 mmol) of CuCl are added,

1.68 ml (20 mmol) of anhydrous piperidine. The mixture, initially green, turns blue. The mixture is then heated at 80 ° C. for 20 hours and the resulting red solution is poured into 125 ml of ether and stirred for 2 minutes with 12 ml of NaOH (30% aqueous). The organic phase is isolated and dried over SO ₄ Na 2, filtered and evaporated. The residue obtained is recrystallized from ether (yield 50%).

Melting point: 149 ° -150 ° C. 1H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.3 (m, 20H); 1.4-1.6 (m, 12H); 2.2 (t, 4H);

3.3 (m, 8H); 6.5 (m, 2H).

N ¹ , N ¹ , N ¹⁴ , N ¹⁴ -tetramethyltetradecanediimidamide: 4.0, 2HCl

1.16 g (3 mmol) of diethyl tetradecanediimidoate dihydrochloride and 1.1 ml of a solution of dimethylamine in ethanol (5.6 M) are mixed with 15 ml of ethanol and heated at reflux for 26 hours. After that, the solvent is evaporated and the resulting residue is recrystallized from a methanol-ether mixture to yield 0.98 g (85%) of greenish powder.

Melting point: 209 ° C 1 H NMR (CD ₃ OD, 250 MHz), δ (ppm): 1.35 (m, 16H); 1.68 (m, 4H); 2.59

(t, 4H); 3.12 (s, 6H); 3.25 (s, 6H); 9.10 (s, 4H)

N, N-N, N-tetramethyloctadecanediimidamide, S.O.

A mixture of 0.46 g (1.2 mmol) of diethyl octadecanediimidoate dihydrochloride in 5.3 ml of a solution of ammonia in methanol

(2M) is cooled to -10 ° C for 1 hour, then left at room temperature hours. After evaporation of the solvent, the residue obtained is recrystallized using a methanol-ether mixture, filtered and dried in a desiccator, to give 0.25 g (54%) of product. Melting point: 196-198 ° C. 1 H NMR (DMSO-d ₆ , 250 MHz), δ (ppm): 1.24 (m, 24H); 1.60 (m, 4H); 2.37

(t, 4H); 8.82 (s, 4H); 9.10 (s, 4H)

1, 12-bis (imidazolin-2-yl) dodecane: 6.0 a) 1,12-bis (imidazolin-2-yl) dodecane dihydrochloride: 6.0, 2HCl To a solution of 4.5 g (11.69 mmol) of hydrochloride of 1 , 14-diéthoxytétradécane-

1,14-diimine in 100 ml of absolute ethanol are slowly and coldly added 1.64 ml (24.55 mmol) of ethylene diamine. The reaction mixture is then refluxed for 4 hours. After evaporation under reduced pressure to the minimum of solvent, the cold residue obtained is crystallized by adding ether with stirring. The precipitate isolated by filtration is then washed with ether and dried with a desiccator to give 3.9 g (88%) of product in the form of a white powder. Melting point: 191-192 ° C

1H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.22 (s, 16H); 1.57 (m, 4H); 2.45 (t, 4H); 3.75 (s, 8H); 9.28 (s, 4H). FT-IR, v (cm- ¹ ): 1600 (C≈N); 3031 (C = NH, HCl); 3200 (NH);

(b) 1,12-bis (imidazolin-2-yl) dodecane: 6.0

To an aqueous solution (20 ml) of 2 g (5.28 mmol) of 6.0, 2 HCl is added dropwise with stirring, triethylamine to pH 14. The precipitate formed is drained, washed with water , with acetone and then with ether and dried in a desiccator to give 1.4 g (86.4%) of free base in the form of a white powder. This powder is then recrystallized from methanol and gives 1.26 g (90%) of product in the form of white crystals.

Melting point: 176-178 ° C 1 H NMR (CD ₃ OD, 100 MHz), δ (ppm): 1.29 (s, 16H); 1.55 (m, 4H); 2.20 (t, 4H);

3.52 (s, 8H). FT-IR, v (cm- ¹ ): 1611 (C = N); 3177 (NH);

1,12-bis [N, N '- (methyloxycarbonyl) imidazolin-2-yl] dodecane: 6.1

To a suspension of 1.5 g (4.90 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 1.5 ml (10.78 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. 0.80 ml (10.29 mmol) of methyl chloroformate dissolved in 5 ml of chloroform are added dropwise with stirring. After which, the stirring is maintained at ambient temperature overnight. The reaction mixture is then filtered and the filtrate washed successively with 120 ml of water, 120 ml of a saturated aqueous sodium chloride solution and 2 × 120 ml of water. 'water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure to give an oily residue. The latter taken up in petroleum ether and left at -4 ° C. gives 1.51 g (73%) of product in the form of a white liquid. 1H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.20 (s, 16H); 1.58 (m, 4H); 2.64 (t, 4H); 3.70 (s, 8H); 3.76 (s, 6H).

FT-IR, v (cm- ¹ ): 1142 and 1194 (COC), 1642 (C = Ν), 1723 (NCO).

1,12-bis [N, N '- (ethyloxycarbonyl) imidazolin-2-yl] dodecane: 6.2

To a suspension of 1.5 g (4.90 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 1.5 ml (10.78 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. 0.98 ml (10.29 mmol) of ethyl chloroformate dissolved in 5 ml of chloroform are added dropwise with stirring. After that, stirring is maintained at room temperature overnight. The reaction mixture is then filtered and the filtrate washed successively with 120 ml of water, 120 ml of a saturated aqueous sodium chloride solution and 2 x 120 ml of water. After drying over sodium sulfate, the organic phase is evaporated under reduced pressure to yield 1.78 g _(81%>) of product as an oil. 1H NMR (CDCl3, 100 MHz), δ (ppm): 1.22 (s, 16H); 1.30 (t, 6H); 1.59 (m, 4H); 2.65 (t, 4H); 3.72 (s, 8H); 4.16 (q, 4H). FT-IR, v (cm- ¹ ): 1073 and 1099 (COC), 1644 (ON), 1720 (NCO). 1,12-bis [7Y, N- (butyloxycarbonyl) imidazol-2-yl] dodecane: 6.3

To a suspension of 1.5 g (4.90 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 1.5 ml (10.78 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. 1.33 ml (10.29 mmol) of butyl chloroformate dissolved in 5 ml of chloroform are added dropwise with stirring. After that, stirring is maintained at room temperature overnight. The reaction mixture is then filtered and the filtrate washed successively with 120 ml of water, 120 ml of a saturated aqueous sodium chloride solution and 2 x 120 ml of water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure to yield 2.05 g (82%) of product in the form of an oil.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 0.88 (t, 6H); 1.20 (s, 16H); 1.36 -1.64

(m, 12H); 2.63 (t, 4H); 3.71 (s, 8H); 4.08 (t, 4H).

FT-1R, v (cm- ¹ ): 1073 and 1152 (COC), 1644 (C = N), 1722 (NCO).

1,12-bis [7V, N- (isobutyloxycarbonyl) imidazolin-2-yl] dodecane: 6.4

To a suspension of 1.5 g (4.90 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 1.5 ml (10.78 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. 1.35 ml (10.29 mmol) of isobutyl chloroformate dissolved in 5 ml of chloroform are added dropwise with stirring. After that, stirring is maintained at room temperature overnight. The reaction mixture is then filtered and the filtrate washed successively with 120 ml of water, 120 ml of a saturated aqueous sodium chloride solution and 2 x 120 ml of water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure to give an oily residue. The latter taken up in petroleum ether and left at -4 ° C. gives 2.26 g (91%) of product in the form of a white solid.

Melting point: <40 ° C

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 0.87 (d, 12H); 1.17 (s, 16H); 1.55 (m, 4H); 1.89 (quint., 2H); 2.62 (t, 4H); 3.70 (s, 8H); 3.84 (d, 4H). FT-IR, v (cm- ¹ ): 1072 and 1142 (COC), 1642 (C = N), 1722 (NCO).

1,2-bis [N, N '- (benzyloxycarbonyl) imidazolin-2-yl] dodecane: 6.5 To a suspension of 1 g (3.27 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 0.85 ml (6.54 mmol) of triethylamine in 30 ml of chloroform cooled by an ice bath, are added dropwise. 0.94 ml (6.54 mmol) of benzyl chloroformate in 5 ml of chloroform are added dropwise with stirring. After that, stirring is maintained at room temperature overnight. The solution obtained is evaporated under reduced pressure. The isolated precipitate is subsequently extracted several times with ether. Evaporation under reduced pressure from the ether phase gives 1.02 g (54%) of product in the form of an oil crystallizing to a white powder at -4 ° C. in ether. Melting point: 75-76 ° C

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.23 (s, 16H); 1.60 (m, 4H); 2.68 (t, 4H);

3.77 (s, 8H); 5: 16 (s, 4H); 7.35 (s, 10H).

FT-IR, v (cm- ¹ ): 1142 and 1299 (COC); 1646 (C = N); 1714 (NCO)

SM-ES +: [M + H] ⁺ : 575

1,1-bis [N, N - (4-nitrobenzyloxycarbonyl) imidazolin-2-yl] dodecane: 6.6 To a suspension of 1 g (3.27 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 0.87 ml (6.70 mmol) of triethylamine in 20 ml of chloroform cooled with an ice bath are added dropwise with stirring 1.44 g (6.70 mmol) of 4-nitrobenzyl chloroformate dissolved in 10 ml of chloroform. After that, stirring is maintained at room temperature overnight. The reaction mixture is then diluted with 30 ml of chloroform and then washed successively with 120 ml of water, 120 ml of a saturated aqueous solution of sodium chloride and 2 x 120 ml of water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure. The residue cooled and taken up in a minimum of chloroform is finally crystallized at -4 ° C. with hexane to yield 2.08 g (96%) of product in the form of a white powder. Melting point: 115-116 ° C. 1H RMΝ (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.60 (m, 4H); 2.67 (t, 4H); 3.80 (s, 8H); 5.24 (s, 4H); 7.46 and 7.55 (dd, 4H); 8.17 and 8.25 (dd, 4H). FT-IR, v (cm- ¹ ): 1005 and 1154 (COC), 1343 and 1517 (N0 ₂ ), 1645 (C = N), 1724;

(NCO).

SM-ES +: [M + H] ⁺ : 665

1,12-bis [N, N '- (phenyloxycarbonyl) imidazolm-2-yl] dodecane: 6.7

To a suspension of 1.5 g (4.90 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 1.3 ml (10.05 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath, are added dropwise. dropwise and with stirring 1.26 (10.05 mmol) of phenyl chloroformate dissolved in 5 ml of chloroform. After that, stirring is maintained at room temperature overnight. The reaction mixture is then diluted with 30 ml of chloroform and then washed successively with 120 ml of water, 120 ml of a saturated aqueous solution of sodium chloride and 2 x 120 ml of water. After drying over sodium sulfate, the organic phase is evaporated under reduced pressure to yield 2.42 g (90%) of product in the form of an oil.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.64 (m, 4H); 2.72 (t, 4H);

3.89 (s, 8H); 7.06 - 7.43 (m, 10H)

FT-IR, v (cm- ¹ ): 1162 and 1188 (COC), 1646 (C = N), 1737 (NCO).

MS-ES +: [M + H] ⁺ : 547; [M + 2H] ²⁺ / 2: 274 (100%)

1,2-bis [N, N '- (4-fluorophenyl) oxycarbonyl) imidazolin-2-yl] dodecane: 6.8 To a suspension of 1 g (3.27 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 0.89 ml (6.86 mmol) of triethylamine in 20 ml of chloroform cooled with an ice bath are added dropwise with stirring 0.89 ml (6.70 mmol) of 4-fluorophenyl chloroformate in solution in 5 ml of chloroform. After that, stirring is maintained at room temperature overnight. The reaction mixture is then diluted with 20 ml of chloroform and then washed successively with 60 ml of water, 60 ml of a saturated aqueous sodium chloride solution and 2 x 60 ml of water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure. The cooled residue is finally crystallized at -4 ° C with hexane to yield 1.70 g (85%) of product as a white powder. Melting point: 95-96 ° C

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.64 (m, 4H); 2.71 (t, 4H);

3.90 (s, 8H); 7.03 and 7.36 (d, 8H).

FT-IR, v (cm- ¹ ): 1100 (CF); 1179 (COC); 1655 (C≈N); 1733 (NCO). SM-ES +: [M + H] ⁺ : 583; [M + 2H] ] ²⁺ / 2: 292 (100%)

1,12-bis [N, N '- (4-fluorophenyl) oxycarbonyl) imidazolin-2-yl] dodecane dihydrochloride: 6.8, 2 HCl.

In 20 ml of a saturated ethanolic solution of hydrochloric acid gas is added 1 g of 6.8. The reaction mixture with vigorous stirring is then heated at 50 ° C. for 4 hours. To the cold solution are added 150 ml of ether and the mixture is left to stand in the refrigerator overnight. After decantation, the oily layer formed is taken up with 100 ml of distilled water and then filtered. The filtrate is finally lyophilized to give the salt as a white powder.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.70 (s, 16H); 2.13 (m, 4H); 3.46 (t, 4H); 4.55 (t, 4H); 4.80 (t, 4H); 7.78 and 7.85 (d, 8H); 8.71 (s, 2H).

FT-IR, v (cm- ¹ ): 1692 (C = N), 1760 (NCO), 3350 (N, HCl).

1,12-bis [N, N '- (4-methoxyphenyl) oxycarbonyl) imidazolin-2-yl] dodecane: 6.9

To a suspension of 1 g (3.27 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 0.89 ml (6.86 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. dropwise and with stirring 1.02 ml (6.86 mmol) of 4-methoxyphenyl chloroformate dissolved in 5 ml of chloroform.

After that, stirring is maintained at room temperature overnight. The isolated precipitate (triethylamine hydrochloride) is subsequently extracted several times with ether. Evaporation under reduced pressure of the ether phase leads to

1.31 g (66%) of product as an oil.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.63 (s, 4H); 2.71 (t, 4H); 3.75

(s, 8H); 3.88 (s 2H); 6.61 to 7.10 (m, 8H).

FT-IR, v (cm- ¹ ): 1177 and 1248 (COC), 1646 (C = N), 1735 (NCO), MS-ES +: [M + H] ⁺ : 607, [M + 2H] ²⁺ / 2: 304 (100%) 1,12-bis [7Y, N '- (4-nitrophenyloxycarbonyl) imidazolin-2-yl] dodecane: 6.10

To a suspension of 1 g (3.27 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 0.89 ml (6.86 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. 1.38 g (6.86 mmol) of 4-nitrophenyl chloroformate dissolved in 5 ml of chloroform are added dropwise with stirring. After which, stirring is maintained at room temperature for 5 hours. After evaporation under reduced pressure of the solution, the precipitate formed is then washed with water and then with acetone. The yellow solid obtained is then crystallized by dissolution in a minimum of dichloromethane and by slow addition of acetone. The product is isolated as 74% white crystals (1.54 g). Melting point: 121-122 ° C

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.23 (s, 16H); 1.67 (m, 4H); 2.73 (t, 4H); 3.95 (s, 8H); 7.25 and 7.36 (dd, 4H), 8.24 and 8.32 (dd, 4H). FT-IR, v (cm- ¹ ): 1185 and 1196 (COC); 1349 and 1524 (NO ₂ ); 1656 (C = N); 1748;

(NCO). MS-ES +: [M + H] ⁺ : 637; [M + 2H] ²⁺ / 2: 319 (100%)

1, 12-bis [V, N '- (acetoxymethoxycarbonyl) imidazolin-2-yl] dodecane: 6.11 to a suspension of 1 g (3.27 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and

0.92 ml (6.54 mmol) of triethylamine in 20 ml of chloroform cooled with an ice bath are added dropwise with stirring 1 g (6.54 mmol) of acetoxymethyl chloroformate in solution in 5 ml of chloroform. After that, stirring is maintained at room temperature overnight. The reaction mixture is then washed successively with 20 ml of water, 20 ml of a 5% aqueous sodium bicarbonate solution and then 20 ml of a saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic phase is evaporated under reduced pressure to yield 2.95 g (84%) of product as an oil. 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.21 (s, 16H); 1.58 (m, 4H); 2.08 (s, 6H);

2.65 (t, 4H); 3.74 (s, 8H); 5.74 (s, 4H). FT-IR, v (cm- ¹ ): 1643 (C = N), 1682 (NCO), 1736 (OCO), MS-ES +: [M + H] ⁺ : 539

1,12-bis [N, N '- ((1-acetoxyethoxy) carbonyl) imidazolin-2-yl] dodecane: 6.12 a) 1,12-bis [N, N' - ((1-chloroethoxy) dihydrochloride) carbonyl) imidazolin-2-yl] dodecane

To a suspension of 2.50 g (8.17 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 2.16 ml (16.75 mmol) of triethylamine in 40 ml of chloroform cooled by an ice bath, are added dropwise. 1.8 ml (16.75 mmol) of 1-chloroethyl chloroformate dissolved in 10 ml of chloroform are added dropwise with stirring. After that, stirring is maintained at room temperature overnight. The reaction mixture is then filtered and the filtrate washed successively with 100 ml of water, 100 ml of a saturated aqueous sodium chloride solution and 3 x 100 ml of water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure. The cooled residue is then crystallized at -4 ° C with hexane to yield 3.91 g (92%) of product as a white powder. RMΝ 1 H (CDC1 _3, 100 MHz), δ (ppm): 1.19 (s, 16H); 1.58 (m, 4H); 1.77 (d, 6H); 2.64 (t, 4H); 3.74 (s, 8H); 6.49 (q, 2H). FT-1R, v (cm- ¹ ): 1087 (COC), 1377 (CH ₃ , CH), 1648 (C = Ν), 1737 (NCO).

b) 1,12-bis [7N, N ^, - ((1-acetoxyethoxy) carbonyl) imidazolin-2-yl] dodecane: 6.12 A solution of acetic acid containing 3.20 g (6.17 mmol) of dihydrochloride of 1.12 g. bis [N, N '- ((1-chloroethoxy) carbonyl) imidazolin-2-yl] dodecane and 5.9 g (18.50 mmol) of mercuric acetate is left stirring and at room temperature for 72 hours. After evaporation of the solvent under reduced pressure, the reaction residue is diluted in 150 ml of chloroform and then filtered. The filtrate is then washed with 3 × 300 ml of a saturated aqueous sodium chloride solution. Drying over sodium sulfate and evaporating the organic phase under reduced pressure gave 2.40 g (68%) of product as a colored oil. 1H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.44 (d, 6H); 1.52

(m, 4H); 2.03 (s, 6H); 2.61 (t, 4H); 3.79 (s, 8H); 6.69 (q, 2H). FT-IR, v (cm- ¹ ): 1072 and 1224 (COC), 1645 (C = N), 1684 (NCO), 1733 (CO) MS-ES +: [M + H] ⁺ : 567

[l, 12-bis (imidazolin-2-yl) dodecane] -l, 12-bis-N, Λ ^r 'diphenyl phosphonate: 6.13

To a suspension of 1 g (3.26 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 0.96 ml (6.86 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. 1.40 (6.70 mmol) of diphenylchlorophosphonate dissolved in 5 ml of chloroform are added dropwise with stirring. After that, stirring is maintained at room temperature overnight. The reaction mixture is then filtered and the filtrate washed successively with 100 ml of water, 100 ml of a saturated aqueous sodium chloride solution and 2 x 100 ml of water. After drying over sodium sulphate, the organic phase is evaporated under reduced pressure to yield 2.37 g (94%) of product in the form of an oil. NMR ^! H (CDCl ₃ , 100 MHz), δ (ppm): 1.20 (s, 16H); 1.62 (m, 4H); 2.58 (t, 4H);

3.79 (s, 8H); 7.17 - 7.34 (m, 20H). FT-IR, v (cm ^-1 ): 925 (P = O), 1160 and 1184 (CO), 1646 (C = N).

[l, 12-bis (imidazolin-2-yl) dodecane] -l, 12-bis-N, Λ ^r 'diethyl phosphonate: 6.14

To a suspension of 1.5 g (4.90 mmol) of 1,12-bis (imidazolin-2-yl) dodecane and 1.5 ml (10.78 mmol) of triethylamine in 25 ml of chloroform cooled by an ice bath are added dropwise. 1.49 ml (10.29 mmol) of diethylchlorophosphonate dissolved in 5 ml of chloroform are added dropwise with stirring. After that, stirring is maintained at room temperature overnight. The reaction mixture is then filtered and the filtrate washed successively with 100 ml of water, 100 ml of a saturated aqueous sodium chloride solution and 2 x 100 ml of water. After drying over sodium sulfate, the organic phase is evaporated under reduced pressure to yield 2.38 g (84%) of product as an oil. 1 H NMR (CDCl _3, 100 MHz), δ (ppm): 1.15 (s, 16H); 1.23 (t, 12H); 1.54 (m, 4H);

2.37 (t, 4H); 3.60 (t, 8H); 4.00 (quintuple !, 8H). FT-IR, v (cm- ¹ ): 963 (P = O), 1016 and 1268 (CO), 1640 (C = N) MS-ES +: [M + H] ⁺ : 579, [M + H] ²⁺ / 2: 290 (100%)

1,1,2-bis (1-methylimidazolin-2-yl) dodecane dihydrochloride: 7.0.2HCl 3.9 g (10 mmol) of diethyltetradecanediimidoate dihydrochloride are refluxed with an excess of N-methylethylenediamine for 24 hours. After cooling the solution, ethyl ether is added to the solution. The crystals obtained are isolated by filtration, washed with ether and dried in a desiccator, to yield 2.9 g (71%) of white crystals. Melting point: 166-170 ° C

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.38 (m, 16H); 1.67 (m, 4H); 2.47

(t, 4H); 2.90 (s, 6H); 3.35 (s, 8H); 9.28 (m, 2H).

FT-IR, v (cm- ¹ ): 1600 (C = N); 3031 (C = NH, HCl); 3200 (NH);

1,12-bis (1,4,5,6-tetrahydropyrimidin-2-yl) dodecane dihydrochloride: 8.0,

2HC1

To a solution of 1.16 g (3 mmol) of diethyltetradecanediimidoate dihydrochloride in 15 ml of absolute ethanol is added 0.51 ml (6.12 mmol) of 1,3-diaminopropane. The reaction mixture is then refluxed for 6 hours. After addition of 4.5 ml of water, the temperature of the reaction mixture is raised to 95 ° C for 4 hours. After evaporation to dryness, the residue obtained is crystallized by addition of ether and stirring for 48 hours. The precipitate isolated by filtration is then washed several times with vigorous stirring in ether and dried in a desiccator to give 0.83 g (68%) of white crystals. Melting point: 117-119 ° C

1 H NMR (DMSO-d ₆ , 250 MHz), δ (ppm): 1.22 (s, 16H); 1.55 (m, 4H); 1.80 (m, 4H); 2.45 (t, 4H); 3.25 (s, 8H); 9.28 (m, 2H).

1,12-bis (4-methylimidazolin-2-yl) dodecane dihydrochloride: 9.0.2HCl To a solution of diethyl tetradecanediimidate diethyl dihydrochloride (0.96 g, 2.5 mmol) in 12 ml of anhydrous ethanol is added with stirring, 0.44 ml (5.1 mmol) of 1,2-diaminopropane. The mixture is then heated at a temperature of 90 ° C for 48 hours. After evaporation of the solvent, the residue obtained is solubilized in ethanol and then filtered. The filtrate is evaporated and then ether is added and removed under reduced pressure to entrain solvent residues. 0.71 g (70%) of product are then obtained in the form of a white powder.

1 H NMR (DMSO-d ₆ , 250 MHz), δ (ppm): 1.30 (m, 22H); 1.64 (m, 4H); 2.52 (t, 4H); 3.40 (t, 2H); 3.95 (t, 2H); 3.95 (m, 2H); 9.32 (m, 2H).

1,12-bis (4,4-dimethylimidazolin-2-yl) dodecane dihydrochloride: 10.0.2HCl The reaction mixture composed of diethyl tetradecanediimidate diethyl dihydrochloride (0.96 g, 2.5 mmol) in 12 ml of ethanol anhydrous and 0.54 ml (5.1 mmol) of 1,2-diamino-2-methylpropane is heated at 90 ° C for 48 hours. The solvent is evaporated, and the residue is solubilized in hot ethanol. After cooling to room temperature, the solid formed is filtered and then treated with ether as the compound 9.0, 2HC1 to yield 0.76 g (70%) of product in the form of a beige powder.

1 H NMR (DMSO-d ₆ , 250 MHz), δ (ppm): 1.24 (s, 12H); 1.32 (s, 16H); 1.62 (m, 4H); 2.50 (t, 4H); 3.54 (s, 4H); 9.30 (m, 2H).

1,12-di (3α, 4,5,6,7,7a-hexahydro-1H-benzimidazo-2-yl) dodecane dihydrochloride: 11.0, 2HCl

0.96 g (2.5 mmol) of diethyltetradecanediimidoate dihydrochloride in 12 ml of anhydrous ethanol and 0.63 ml of 1,2-diaminocyclohexane are refluxed (90 ° C) for 48 hours. After evaporation of the mixture, ethanol is added to the solution, filtered and the evaporated filtrate is treated as described for compound 9.0,

2HC1. 0.82 g (67%) of crystals are obtained.

1 H NMR (DMSO-d ₆ , 250 MHz), δ (ppm): 1.25 (s, 16H); 1.30-1.65 (m, 16H); 1.70 (m, 4H); 2.50 (t, 4H); 3.34 (m, 2H); 4.10 (m, 2H); 9.32 (m, 2H).

1,12-Bis [(1,2,4-oxadiazolo) -3-yl] dodecane: 18.0 To a stirred suspension of 2 g (7 mmol) of bis-amidoxime 1.15 in 23.26 ml (139.86 mmol) of ethyl orthoformate are added 0.6 ml (4.9 mmol) of diethyltrifluoroborane. The reaction mixture is stirred at room temperature for 15 minutes and then refluxed for 1 hour. 150 ml of ethyl acetate are added to the solution obtained, and the mixture is washed successively with water (100 ml), saturated sodium bicarbonate solution (100 ml) and with a saturated solution of sodium chloride. sodium (100 ml). The organic phase is then dried over sodium sulfate and evaporated under reduced pressure. The residue obtained is washed with cold ether and then dried to yield 1.50 g (70%) of product in the form of a white powder.

Melting point: 92-93 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.73 (m, 4H); 2.77 (t, 4H); 8.61 (s, 2H). FT-IR, v (cm- ¹ ): 1111 (CO); 1558 (C = N); 3123 (CH).

1,12-Bis [(5-methyl-1,2,4-oxadiazol) -3-yl] dodecane: 18.1

A stirred suspension of 1.5 g (4.05 mmol) of 1.22 in 30 ml of xylene is heated at 150 ° C for 2 hours. The reaction mixture is then evaporated under reduced pressure. The solid residue obtained is subsequently recrystallized with petroleum ether to give, after drying on a desiccator, 1.10 g (81%) of product in the form of a white powder. Melting point: 63-64 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.23 (s, 16H); 1.69 (m, 4H); 2.53 (s, 6H); 2.66 (t, 4H). FT-IR, v (cm- ¹ ): 1581 (CN); 1640 (C = N)

1,12-Bis [(5-trifluoromethyl-1,2,4-oxadiazole) -3-yl] dodecane: 18.4

In 20 ml (139.86 mmol) of trifluoroacetic anhydride with stirring and cooled with an ice-water bath, 1 g (3.50 mmol) of bis-amidoxime 1.15 are added portion by portion. Stirring is maintained for 30 minutes cold until complete dissolution of 1.15. To the reaction mixture are added 50 ml of ether and very slowly, 100 ml of cold water (exothermic reaction). The ethereal phase is then washed successively with 2 × 100 ml of water, 2 × 50 ml of 1N sodium hydroxide solution and 100 ml of water. The organic phase is then dried over sodium sulfate and evaporated under reduced pressure. After cooling, the residue crystallizes to give 1.39 g (90%) of product as white crystals.

Melting point: <40 ° C.

NMR Η (CDCl ₃ , 100 MHz), δ (ppm): 1.26 (s, 16H); 1.75 (m, 4H); 2.81 (t, 4H). FT-IR, v (cm- ¹ ): 766 and 1150 (CF ₃ ); 1519 (CN); 1608 (C = N);

1,12-Bis [(5-trichloromethyl-1,2,4-oxadiazole) -3-yl] dodecane: 18.5

A stirred suspension of 3 g (10.49 mmol) bis-amidoxime 1.15 and 13.71 g (83.92 mmol) of trichloroacetic acid in 10 ml of chloroform is heated at 85 ° C until a solution is obtained. To the solution, 4.70 ml (41.96 mmol) of trichloroacetyl chloride is added in three equal portions. The reaction mixture is then heated at 94 ° C for 45 minutes. After cooling, 200 ml of ethyl acetate are added and the mixture is then washed successively with a saturated solution of sodium carbonate (2 × 100 ml), a saturated solution of sodium chloride (2 × 100 ml) and with 100 ml of ethyl acetate. ml of water. The organic phase is then dried over sodium sulfate and evaporated under reduced pressure. The resulting residue is dried to yield 5.19 g (91%) of product as a yellow powder.

Melting point: 55-56 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.26 (s, 16H); 1.76 (t, 4H); 2.78 (t, 4H). FT-IR, ν (cm ^-1 ): 798 and 830 (CCl ₃ ), 1573 (C = N).

1,12-Bis [(5-phenyl-1,2,4-oxadiazole) -3-yl] dodecane: 18.6

A stirred suspension of 1.5 g (3.04 mmol) of 1.23 in 30 ml of xylene is heated at 150 ° C for 2 hours. The reaction solution is then decanted and then evaporated under reduced pressure. The solid residue obtained is then recrystallized with petroleum ether to conduct after drying in a desiccator,

1.12 g (80%>) of product in the form of a colored powder Melting point: 97-98 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.25 (s, 16H); 1.78 (m, 4H); 2.77 (t, 4H); 7.48 - 7.54 (m, 6H); 8.06 - 8.14 (m, 4H). FT-IR, ν (cm- ¹ ): 1581 (CN); 1640 (C≈N)

1,12-Bis [(5-ethyloxycarbonyl-1,2,4-oxadiazol) -3-yl] dodecane: 18.7 To a stirred suspension of 2 g (7 mmol) bis-amidoxime 1.15, 4 ml (49.50 mmol). ) pyridine and 4 g of 4 A molecular sieve in 50 ml of chloroform are added 2.35 ml (21 mmol) of oxalyl ethyl chloride. The reaction mixture is then heated at 80 ° C. for 16 hours, then filtered and evaporated under reduced pressure. To the residue, 100 ml of ethyl acetate are added and the solution is then washed successively with a saturated solution of sodium carbonate (2 × 50 ml), saturated solution of sodium chloride (2 X 50 ml) and with 50 ml of water. The organic phase is then dried over sodium sulfate and evaporated under reduced pressure. The cold residue obtained is washed with cold ethanol and then dried to yield 1.96 g (62%) of product in powder form. Melting point: 70-71 ° C.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.44 (t, 6H) 1.77 (m, 4H); 2.80 (t, 4H); 4.51 (quartet, 4H). FT-IR, v (cm- ¹ ): 1029 and 1197 (COC); 1584 (C = N); 1760 (COO)

1,12-Bis [(5-carbamoyl-1,2,4-oxadiazole) -3-yl] dodecane: 18.9

10 g (4.44 mmol) of 2 g (4.44 mmol) are added to 10% ammonia ethanol solution (90 ml).

18.7. The sealed reaction mixture is stirred at room temperature for 24 hours. The suspension is then filtered and washed with cold ethanol and dried. 1.58 g (91%) of product are thus isolated in the form of a yellow powder.

Melting point 196-197 ° C.

1 H NMR (DMSO-d ₆ , 100 MHz), δ (ppm): 1.71 (s, 16H); 2.14 (m, 4H); 3.23 (t, 4H); 8.98 (s, 2H).

FT-IR, v (cm- ¹ ): 1573 (CN); 1604 (C = N); 1673 (CON); 3233 and 3432 (NH ₂ ) 1,12-Bis [(5-cyano-1,2,4-oxadiazol) -3-yl] dodecane: 18.10

To a suspension cooled at 0 ° C. of 1.5 g (3.83 mmol) of 18.9 and 1.55 ml (19.13 mmol) of pyridine in 60 ml of dioxane are added 1.3 ml (9.18 mmol) of trifluoroacetic anhydride. The reaction mixture is stirred at room temperature for 16 hours. The solution obtained is then diluted with 150 ml of ethyl acetate and then washed successively with water (100 ml) and with saturated sodium chloride solution (2 X 100 ml). The organic phase dried over sodium sulphate and evaporated under reduced pressure gives 0.83 g (61%) of product in the form of a colored oil.

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.73 (m, 4H); 2.81 (t, 4H). FT-IR, v (cm- ¹ ): 1561 (C = N); 2260 (CN)

1,12-bis (N, N'-dibenzyloxycarbonylguanidino) dodecane: 12.1 A solution of 1 g (5 mmol) of 1,12-diaminododecane and 3.76 g (10.5 mmol) of

N, N'-di-benzyloxycarbonyl-S-methylisothiourea in 70 ml of tetrahydrofuran is heated at 60 to 70 ° C for 24 h. After which the solvent is evaporated under reduced pressure. The residue obtained is then taken up with dichloromethane and washed successively with a 5% aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride and water. The organic phase is then dried over sodium sulfate, evaporated under reduced pressure, and purified by silica column chromatography (DCM). The various fractions combined and evaporated under reduced pressure gave a yellow oil which crystallized in ether to give 2.4 g (58%) of product in the form of a white powder. Melting point: 97-98 ° C

1H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.54 (s, 4H); 3.40 (q, 4H);

5.11 (s, 4H); 5.16 (s, 4H); 7.15-7.54 (m, 20H); 8.28 (t, 2H); 11.73 (s, 2H)

FT-IR, v (cm- ¹ ): 1054 and 1130 (CO), 1651 (C = Ν), 1736 (NCO), 3130 (NHCO);

3333 (NH)

FAB-MS ⁺ : [M + H] ⁺ : 821; [M + 2H] ⁺⁺ / 2: 412 1,12-Bis (N, N'-di-tert-butyloxycarbonylguanidino) dodecane: 12.2

A mixture of 1 g (5 mmol) of 1,12-diaminododecane and 3.19 g (11 mmol) of N, N'-di-tert-butyloxycarbonyl-5-methylisothiourea in 100 ml of methanol is heated to between 50 and 60 ° C. during 48 hours. After evaporation under reduced pressure of the solution, the residue obtained is taken up in 100 ml of DCM and washed successively with a 5% aqueous solution of ΝaHCO ₃ (2 × 100 ml), water (2 × 100 ml) and with 100 ml of a saturated solution of NaCl. The organic phase is then dried over sodium sulphate, evaporated under reduced pressure and purified on silica (DCM / MeOH 98%) to yield 2.50 g (73%) of product crystallizing in cold petroleum ether under powder form.

Melting point: 114-116 ° C

1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.24 (s, 16H); 1.47 (s, 36H); 1.61 (m, 4H) 3.35 (q, 4H); 8.27 (t, 2H); 11.48 (s, 2H) FT-IR, v (cm- ¹ ): 1028 and 1138 (CO), 1670 (CN), 1740 (NCO), 3132 (NHCO), 3314 (NH);

SM-ES +: [M + H] ⁺ : 685

Dihydroiodide of l, 12-bis [N, N ^r - (2-amino-3,4,5,6 tétrahydropyrimidyl)] dodecane: 16.0, 2HI The reaction mixture composed of 0.72 g (3.6 mmol) of 1,12-dodecanediamine,

1.86 g (7.2 mmol) of 2-methylsulfanyl-3,4,5,6-tetrahydropyrimidinium iodide and 0.5 ml (3.6 mmol) of triethylamine in 20 ml of acetonitrile is heated to room temperature. reflux for 22h. After cooling to room temperature, the reaction solvent is evaporated and the residue is chromatographed on a silica column (CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 89: 10: 1). 0.91 g of guanidinium salt are obtained, ie a yield of 41%.

1 H NMR (CD ₃ OD, 100 MHz), δ (ppm): 1.49 (m, 20H); 2.13 (m, 4H); 3.33 (m, 4H); 3.56 (m, 8H). FAB-MS +: [M + H] ⁺ : 365; [M + H + HI] ⁺ : 493

1,12-bis [N ^, -, 5,5-dimethyl-3,4,5,6-tetrahydropyrimidin-2-diiodohydrate yl) amino] dodecane: 17.0, 2Hi

The reaction mixture composed of 0.72 g (3.6 mmol) of 1,12-dodecanediamine, 2.06 g (7.2 mmol) of 5.5-dimethyl-2-methylsulfanyl-3,4 hydrate, 5,6-tetrahydropyrimidinium and 0.5 ml (3.6 mmol) of triethylamine in 20 ml of acetonitrile is refluxed for 22 h. After cooling to room temperature, the reaction solvent is evaporated and the residue is chromatographed on a silica column (CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 89: 10: 1). 0.91 g of salt are obtained, ie a yield of 36%.

1 H NMR (CD ₃ OD, 100 MHz), δ (ppm): 1.17 (s, 12H); 1.49 (m, 20H); 3.07 (s, 8H); 3.23 (m, 4H).

[1- [N- (5,5-Dimethyl-3,4,5,6-tetrahydropyrimidin-2-yl) amino] -12- [A] - (3,4-dihydro-2H-pyrrol-5) ditrifluoroacetate -yl) amino]] dodecane: 25.0, 2 TFA

The reaction mixture composed of 1 mmol of 1- [N- (5,5-dimethyl-3,4,5,6-tetrahydropyrimidinium-2-yl) amino] dodecane-12-ammonium ditrifluoroacetate, 1 mmol (leq) of 3,4-dihydro-5-methoxy-2H-pyrrole and 0.5 ml of triethylamine in 10 ml of absolute ethanol is heated at reflux for 20 h. After cooling to room temperature, the reaction mixture is evaporated to dryness and chromatographed on a silica column (CΗ ₂ Cl ₂ / CΗ ₃ OΗ / ΝΗ ₄ or 85: 13: 2) to give the product, in the form of an oil, with a yield of 65%.

1 H NMR (CD ₃ OD, 360 MHz), δ (ppm): 1.12 (s, 6H); 1.36 (m, 16H); 1.60

(m, 2H); 1.69 (m, 2H); 2.28 (m, 2H); 2.93 (m, 2H); 3.09 (s, 4H); 3.22 (m, 2H);

3.31 (m, 2H); 3.75 (m, 2H).

MS-ES ⁺ : [M + H] ⁺ : 378; [M + H + TFA] ⁺ : 492; [M + 2H] ⁺⁺ / 2: 189.5

1,12-bis [N, N '- (3,4-dihydro-2H-pyrrol-5-yl) amino] dodecane: 21.0 To a solution of 2.76 g (10.1 mmol) of 1,12-diaminododecane hydrochloride in 70 ml of absolute ethanol are added 2.5 g (25.25 mmol) of 2-methoxypyrroline. The reaction mixture is left stirring at room temperature for 24 h. The solution is then evaporated under reduced pressure and the residue after cooling is taken up with 100 ml of water and then made alkaline with water. 0.1 N sodium hydroxide solution. After which the precipitate formed is drained, washed with water and then with ether and dried in a desiccator. 3.27 g (97%) of the expected product are obtained in the form of a white powder. Melting point: 155 ° -156 ° C. 1 H NMR (CDCl ₃ , 100 MHz), δ (ppm): 1.23 (s, 16H); 1.49 (m, 4H); 1.89 (quint,

4H); 2.38 (t, 4H); 3.21 (t, 4H); 3.43 (s, 2H); 3.62 (t 4H) FT-IR, v (cm- ¹ ): 1630 (C = N); 3049 and 3221 (NH);

l, 12-bis (N, Λ ^ _ace tamidinyl) dodecane: 20.0 A mixture of 2 g (10 mmol) of 1,12-diaminododecane and 2.47 g

(20 mmol) of ethylacetimidate hydrochloride in 25 ml of anhydrous dioxane is refluxed for 24 hours. After cooling to room temperature, an aqueous solution of 1N KOH is added which causes the formation of a precipitate. This precipitate is washed with hot methanol and filtered. After passing through the desiccator for several hours, 2.06 g (7.3 mmol) of product are obtained, ie a yield of

73%.

Melting point: 92-97 ° C

1 H NMR (DMSOd ₆ , 250 MHz), δ (ppm): 1.3 (m, 16H); 1.5 (m, 4H); 1.8 (s, 6H); 2.9 (t, 4H); 5.5 (m, 2H)

1,12-bis (N, N'-hydroxyacetamidinyl) dodecane, 20.1 and its dihydrochloride, 20.1,

2HC1.

To a solution of 12.9 g (125 mmol) of ethyl N-hydroxyacetimidate in 125 ml of ethanol is added 10 g (50 mmol) of 1,12-diaminododecane. The reaction mixture is heated at 80 ° C for 4 days. After cooling, the precipitate formed is filtered off and washed several times with ethanol and with ether, dried with a desiccator and recrystallized in ethanol, to yield 7.26 g (46%) of hydroxyacetamidinyl 20.1 in the form of a white powder. (Melting point: 150-15 CP). 1 g of hydroxyacetamidinyl 20.1 is dissolved in 20 ml of a solution of anhydrous ethanol saturated with hydrochloric acid gas. The mixture with vigorous stirring is heated at 50 ° C for 2 hours. To the cold solution are added 100 ml of anhydrous ether and the mixture is left to stand. The solid formed is drained, dried, dissolved in 100 ml of distilled water and then filtered. The aqueous filtrate is lyophilized to yield the product as a white powder. 1H NMR (DMSO-d _6, 100 MHz): 1.72 (s, 16H, H3-H1 _0); 1.96 (s, 4H, H ₂ and H _n ); 2.62

(s, 6H, 2H ₂ ; 3.68 (q, 4H, Hi and Hι ₂ ); 9.30 (t, 2H, 2NH); 11.40 (s, 2H, 2NOH); 12.92 (s, 2H, 2C = NOH, HCl); FT-IR: 1683 (C = N); 3002; 3142 and 3202 (NH; C-NOH, HCl and NOH).

1,12-bis (N, N'-methoxyacetamidinyl) dodecane, 20.2.

To a hydroalcoholic solution of sodium hydroxide [prepared from 0.45 g (11.15 mmol) of sodium hydroxide and 25 ml of ethanol / water (4: 1)] is added 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1. After stirring for 30 minutes, 0.42 ml (6.68 mmol) of methyl iodide are added dropwise to the reaction suspension. The mixture is stirred at ambient temperature for 24 hours. The cloudy solution is then filtered and the filtrate evaporated under reduced pressure. The residue obtained is taken up in 50 ml of chloroform and then washed with a saturated aqueous solution of NaCl (2 × 100 ml). The organic phase is dried over sodium sulfate and evaporated under reduced pressure to yield 1.05 g (96%) of methoxyacetamidinyl in colored oil form. 1 H NMR (CDCl ₃ , 100 MHz): 1.24 (s, 16H, H ₃ -H ₁₀ ); 1.45 (m, 4H, H ₂ and Hn); 1.83 (s, 6H, 2H ₂ -); 3.05 (q, 4H, Hi and Hι ₂ ); 3.70 (s, 6H, 2H ₃ ^' ); 5.03 (t, 2H, 2NH). ES ⁺ MS: 343 [M + H ⁺ ]; 172 (100%) [(M + 2H ⁺ ) / 2]. FT-IR: 1637 (C = N); 3264 (NH).

1,12-bis (N, N'-acetoxyacetamidinyl) dodecane: 20.8

In 12 ml (127.4 mmol) of acetic anhydride with stirring and cooled to 0 ° C is added in small portions 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1. Stirring is maintained for 2 hours at room temperature. To the reaction mixture are added 100 ml of chloroform. The solution is washed successively with 2 × 100 ml of a saturated aqueous solution of sodium chloride, 3 × 100 ml of a 2N sodium hydroxide solution and 2 × 100 ml of water. The organic phase is subsequently dried over sodium sulphate sodium and evaporated under reduced pressure. 30 ml of ether are added to the cold oily residue, and the solution is left in the refrigerator for 16 hours. The solid formed is then triturated in ether and then wrung. The resulting powder was finally washed with ether and dried to yield 1.12 g (89%) of acetoxyacetamidinyl as a white powder. Melting point: 68-69 ° C.

1 H NMR (CDCl ₃ , 100 MHz): 1.24 (s, 16H, H ₃ -H, _O ); 1.44 (m, 4H, H ₂ and Hn); 1.92 (s, 6H, 2H ₂ , 2.11 (s, 6H, 2H ₄ , 3.10 (q, 4H, Hi and H ₁₂ ), 5.04 (t, 2H, 2NH) ES ⁺ MS: 399 (100%) [M + H ⁺ ]; 200 [(M + 2H ⁺ ) / 2. FT-IR: 1623 (C = N); 1742 (OCO); 3333 (NH).

1,12-bis (N, N'-benzoyloxyacetamidinyl) dodecane, 20.9.

A suspension with stirring and cooled to 0 ° C of 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1 and 0.94 (6.68 mmol) ml of triethylamine in 30 ml of chloroform, is added dropwise 0.78 ml (6.68 mmol) of benzoyl chloride in 5 ml of chloroform. Stirring is maintained for 3 hours at room temperature. The reaction mixture is then washed with 2 × 100 ml of water and then with 100 ml of a saturated solution of NaCl. The organic phase is then dried over sodium sulfate and evaporated under reduced pressure. The oily residue is allowed to stand overnight in the refrigerator. The solid formed is triturated in cold ether, washed with ether and then drained and dried to give 1.27 g (77%) of benzoyloxyacetamidinyl as a white powder. Melting point: 95-96 ° C. 1 H NMR (CDCl ₃ , 100 MHz): 1.23 (s, 16H, H ₃ -H _[0 ]; 1.51 (m, 4H, H ₂ and Hn); 2.02 (s, 6H, 2H ₂ -); 3.15 (q, 4H, H _! And Hι ₂ ); 5.19 (t, 2H, 2NH); 7.34-7.54 [m, 6H, 2 (H ₆ > - H _8. )]; 7.93-8.03 [dd, 4H, 2 (H ₅ - and H ₉ >)]. FT-IR: 1279 (COC); 1622 (C = N); 1714 (OCO); 3385 (NH). ES ⁺ MS: 523 (100%) [M + H ^{1 '];} 262 [(M + 2H ⁺⁾ / 2.

1,12-bis (N, N'-ethylcarbamoyloxyacetamidinyl) dodecane: 20.10

To a stirred suspension of 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1 and 0.45 g (3.18 mmol) of potassium carbonate in 40 ml of chloroform is added dropwise 0.53 ml (6.69 mmol) of ethylisocyanate. The agitation is kept overnight at room temperature. The reaction mixture is filtered and the filtrate washed with 3 x 100 ml of water. The organic phase is then dried over sodium sulphate and evaporated under reduced pressure to give 1.32 g (91%) of ethylcarbamoyloxyacetamidinyl in the form of colored oil. 1 H NMR (CDCl ₃ , 100 MHz): 1.14 (t, 6H, 2H ₅ ); 1-22 (s, 16H, H ₃ -H ₁₀ ); 1.44 (m, 4H,

H ₂ and Hn); 1.84 (s, 6H, 2H ₂ ); 3.07 (q, 4H, Hi and Hι ₂ ); 3.26 (quintuple, 4H, 2H ₄ >); 5.33 (t, 2H, 2NH); 6.49 (t, 2H, 2NHCO). FT-IR: 1215 (CO); 1641 (C = N); 1705 (OCON); 3345 (NHCO); 3398 (NH).

1,12-bis (N, N-phenylcarbamoyloxyacetamidinyl) dodecane: 20.11

To a stirred suspension of 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1 and 0.45 g (3.18 mmol) of potassium carbonate in 40 ml of chloroform is added dropwise 0.73 ml (6.69 mmol) of phenylisocyanate. Stirring is maintained overnight at room temperature. The reaction mixture is then filtered and the filtrate washed with 3 × 100 ml of water. The organic phase is then dried over sodium sulfate and evaporated under reduced pressure. The solid residue obtained is washed several times with ether and then dried in a desiccator to give 1.53 g (87%) of phenylcarbamoyloxyacetamidinyl in the form of a white powder. Melting point: 103-104 ° C. 1 H NMR (CDCl ₃ , 100 MHz): 1.26 (s, 16H, H ₃ -H ₂ O); 1.51 (m, 4H, H ₂ and Hn); 1.94 (s,

6H, 2H ₂ ); 3.13 (q, 4H, Hi and H ₁₂ ); 5.46 (t, 2H, 2NH); 7.0-7.52 (m, 10H, aromatic H); 8.61 (s, 2H, 2NHCO).

FT-IR: 1663 (C = N); 1717 (OCON); 3291 (NHCO); 3443 (NH). ES ⁺ MS: 457 (100%) [M + H ^4]; 229 [(M + 2H ⁺ ) / 2.

1,12-bis (N, N'-methylsulfonyloxyacetamidinyl) dodecane: 20.12 To a suspension with stirring and cooled to 0-5 ° C with an ice bath of 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1 and 0.55 ml ( 6.68 mmol) of pyridine in 30 ml of chloroform is added dropwise 0.52 ml (6.68 mmol) of methylsulfonyl chloride in 5 ml of chloroform. Stirring is maintained for 4 hours at 10-15 ° C. The reaction mixture is then washed with 3 x 100 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The oily residue is left overnight in the refrigerator. The solid formed is triturated in cold ether, washed with ether and then drained and dried to give 1.33 (89%) g of methylsulfonyloxyacetamidinyl as a white powder. Melting point: 67-68 ° C.

1 H NMR (CDCl ₃ , 100 MHz): 1.25 (s, 16H, H ₃ -H ₁₀ ); 1.50 (m, 4H, H ₂ and Hn); 1.91 (s, 6H, 2H ₂ -); 3.11 (s, 6H, 2H _3; 3.15 (q, 4H, Hi and H _12); 5.23 (t, 2H, 2NH) FT-IR: 1637 (C = N); 3302 (NH) ES ⁺ MS.:. 471 (100%) [M + H ^4].

[1,12-bis (acétamidinyl) dodecane] -l, 12-bis-N, N ^f diethyl phosphate, 20.13.

To a suspension with stirring and cooled between 0 and 5 ° C 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1 and 0.94 ml (6.68 mmol) of triethylamine in 30 ml of DMF is added dropwise 0.97 ml (6.68 mmol ) of diethylchlorophosphonate in 5 ml of chloroform. Stirring is maintained overnight. The reaction mixture is filtered and the filtrate is taken up with 100 ml of ethyl acetate. The organic phase is washed with 3 x 100 ml of water and then dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up with 100 ml of chloroform and again washed with 3 x 100 ml of water, dried over sodium sulphate and evaporated under reduced pressure to give 1.13 g (61%) of 20.13 in the form of a colored oil.

1H NMR (CDCl ₃ , 100 MHz): 1.25 (s, 16H, H ₃ -H ₁₀ ); 1.33 (t, 12H, 4Hψ); 1.43 (m, 4H, H ₂ and Hn); 1.87 (s, 6H, 2H ₂ -); 3.08 (q, 4H, Hi and H _{! 2} ); 4.18 (quint, 8H, 4H ₃ -); 5.28 (t, 2H, 2NH). FT-IR: 1634 (C = N); 3316 (NH).

1,12-bis [N, N '(3-methyl-1,2,4-oxadiazol-5 (4H) -one) -3-yl] dodecane: 20.14 To a stirred suspension of 1 g (3.18 mmol) of hydroxyacetamidinyl 20.1 and 0.45 g (3.18 mmol) of potassium carbonate in 30 ml of chloroform is added dropwise 0.50 ml (6.68 mmol) of methylchloroformate in 5 ml of chloroform. Stirring is maintained for 1Η at room temperature and the suspension is heated around 50 ° C for 45 minutes. The reaction mixture cold is then filtered, washed with 3 x 100 ml of water. The organic phase is then dried over sodium sulfate and evaporated under reduced pressure. The residue is left overnight in the refrigerator. The solid formed is finally triturated in cold ether, washed with ether and then drained and dried to yield 0.92 g (79%) of oxadiazolone as a white powder. Melting point: 53-54 ° C.

1 H NMR (CDCl ₃ , 00 MHz): 1.24 (s, 16H, H 3 -H _{1 O} ); 1.64 (s, 4H, H ₂ and Hn); 2.24 (s, 6H, 2H ₂ -); 3.52 (t, 4H, Hi and H12). FT-IR: 1599 (C = N); 1754 (OCO).

1,12-bis [N, N '2-hydroxyacetamidmyl]] dodecane, 26.0. a) Hydroxyacetonitrile or Glycolonitrile

To an aqueous solution (60 ml) cooled to 0 ° C. of 15 g (306 mmol) of sodium cyanide, 22.73 g (303 mmol) of a formaldehyde solution (40% in water) are added dropwise. ). Stirring is maintained for 30 minutes at this temperature. The pH of the solution is successively adjusted to 2 with H SO ₄ 7.5N

(45 ml) and at 5 with Na ₂ CO ₃ . The sodium sulphate possibly formed is dissolved by addition of water and the solution is then extracted with ether (4 × 200 ml). The organic phase is dried over anhydrous sodium sulphate and evaporated under reduced pressure to give 13.13 g (76%) of hydroxyacetonitrile as a colored oil. This oil, unpurified, is used directly. It decomposes at room temperature after 24 hours.

1H NMR (CDCl3, 100 MHz): 2.30 (s, 1H, OH); 4.34 (s, 2H, CH ₂ ). FT-IR: 2259 (C≡N); 3425 (OH). b) Ethyl hydroxyacetimidate hydrochloride HCl gas is bubbled into a solution cooled to 0 ° C of 20 ml of anhydrous ethanol, 40 ml of anhydrous ether and 9 g (158 mmol) of hydroxyacetonitrile, for 1H30. The reaction mixture is allowed to stir overnight at room temperature. The formed precipitate is then drained and washed several times with ether and then dried in a desiccator to yield 19.52 g (89%) of ethyl hydroxyacetimidate hydrochloride in the form of a white powder. 1 H NMR (DMSO-d ₆ , 100 MHz): 1.80 (t, 3H, CH ₃ ); 4.80 (s, 2H, CH ₂ ); 4.85 (q, 2H,

CH ₂ ); 11.73 (si, 2H, NH, HC1).

FT-IR: 1645 (C = N); 3119 (OH); 3229 (NH, HCI).

1,12-bis (N, N '2-hydroxyacetamidinyl) dodecane: 26.0

To a methanolic solution (50 ml) of 3.07 g (22 mmol) of ethyl hydroxyacetimidate hydrochloride are added 2 g (10 mmol) of 1,12-diaminododecane. The reaction mixture is stirred at room temperature for 24 hours. The solution is then evaporated under reduced pressure. The cold residue is taken up with 100 ml of water and basified cold with 0.5N NaOH. The precipitate formed is filtered off and then washed with water, with acetone and then several times with ether and drained, to conduct after drying to 2.55 g (81%) of 2-hydroxyacetamidinyl 26.0 in the form of a white powder. Melting point: 99-100 ° C. 1H NMR (CD ₃ OD, 250MHz): 1.00 (s, 16H, H3-H10); 1.27 (m, 4H, H ₂ and H _n ); 2.84 (t, 4H, H, and H ₁₂ ); 2.98 (s, 2H, 2 OH); 3.70 (s, 4H, 2H ₂ -). FT-IR: 1605 (C = N); 3072 (OH); 3290 and 3388 (2NH). ES ⁺ MS: 315 [M + H ⁺ ]

1,12-bis [N, N '- (2-iminopyrrolidinyl)] dodecane: 24.0 To a mixture of 2.21 g (26 mmol) of pyrrolidin-2-one and 0.23 g (10 mmol) of sodium heated to 90 ° C under nitrogen are added in small portions 1.64 g (5 mmol) of 1,12-dibromododecane. This reaction mixture is then heated with stirring at 120 ° C. for 4 hours. After cooling to room temperature, 40 ml of water are added and the solution is extracted with 40 ml of DCM. The organic phase is then washed with a saturated aqueous solution of NaCl, dried over

MgSO ₄ then evaporated under reduced pressure. Purification on a silica column (eluent DCM-methanol, [18-1]) followed by co-evaporation at room temperature with an ether-hexane mixture gives 0.655 g of 1,12-bis [NN '- (pyrrolidine) -2-one-1-yl)] dodecane, with a yield of 39%. To a mixture of 0.336 g (lmmol) of this product in 3 ml of chloroform under nitrogen are added dropwise 0.18 ml (2 mmol) of isocyanate sulfonyl chloride in 3 ml of chloroform. The reaction is heated at 77 ° C for 6 hours. After addition of 4.5 ml of water, the temperature of the reaction mixture is then raised to 95 ° C for 4 hours. After which, 5 ml of water are added and the solution is washed with 2 X 5 ml of DCM. The aqueous phase is then neutralized with an aqueous solution of 1N KOH and the solid is filtered, washed with ether and then dried for 1 hour at the desiccator to give 0.135 g (40%) of product.

Melting point: 53-55 ° C

1 H NMR (DMSOd ₆ , 250 MHz), δ (ppm): 1.3 (m, 16H); 1.5 (m, 4H); 1.8

(q, 4H); 2.3 (t, 4H); 3.2 (t, 4H); 3.3 (t, 4H); 8.0 (s, 2H)

Study of the pharmacological activities of the compounds according to the invention.

A. In vitro antimalarial activity against P. falciparum and in vivo in P. vinckei-infected mice

The results of IC ₅₀ values in μM and DE ₅₀ (mg / kg) obtained with compounds of the invention are reported in Tables 4 and 5 below.

TABLE 4 Series A

* tested after 2 administrations of the compound per day for 4 days TABLE 5

Series B

tested after 2 administrations of the compound per day for 4 days

The IC ₅₀ is the concentration that inhibits the in vitro growth of P. falciparum by 50% (IC ₅₀ measurements were determined according to the Desjardins method in which the incorporation of [ ³ H] hypoxanthine into the nucleic acids of cell viability) (Figure 1), the ED ₅₀ is the effective dose to inhibit in vivo growth of P. vinckei by 50% in a 4-day suppressive test IT corresponds to the therapeutic index, IT = LD ₅₀ (semi chronic) / DE ₅ o; ip intraperitoneal administration; po: per os. These results show that the compounds of the invention possess a strong antimalarial activity in vitro and in vivo as well as good tolerance and good absorption.

B. Pharmacokinetic parameters in mice

The results of pharmacokinetic parameters after intraperitoneal or oral administration in mice for compound 6.0 are reported below. For serum level determination, ex vivo bioassays are used: briefly, the drug is administered to the animal, followed by repeated blood sampling. The will be decomplemented for 30 minutes at

56 ° C. The content of active metabolite is then determined by incubation of different concentrations (dichotonic dilution) of each serum, in the presence of suspensions of erythrocytes infected with P. falciparum, according to the DESJARDINS method with [ ³ H] hypoxanthine.

The results are expressed in SI ₅₀ , which corresponds to the percentage of serum

(containing an active metabolite) capable of inhibiting the growth of P. falciparum by 50

%.

This value is then converted to serum concentration (usually expressed in ng / ml) by testing the active compound directly (without passage in the animal), on the same suspension infected with P. falciparum and determining its IC ₅₀ value ( in ng / ml) [serum = CI ₅ 0] (in ng / ml) x IOO / SI50 (in%)].

The results are expressed in log (serum drug level), as a function of time, which allows evaluation of the half-time for distribution to the tι _/ 2 (d) serum compartment; half-time for the elimination of the serum compartment (fy ₂ ( _e) ); of C ₀ , corresponding to the serum level originally extrapolated in the elimination phase; AUC (which indicates the amount of drugs circulating in the bloodstream); and the relative bioavailability in the oral route versus the intraperitoneal mode [AUC (po) / AUC (ip)] which is indicative of the degree of oral uptake. Pharmacokinetics 6.0

Mice are dosed at 17 and 300 mg per kg of 6.0, intraperitoneally and orally, corresponding to LD _50/3 . The compound is solubilized in 10% DMSO. The results are given in Table 4.

The semi-logarithmic representation makes it possible to determine the main pharmacokinetic parameters of the active metabolite for the two routes of administration. The pharmacokinetic parameters are C ₀ = 50 ng / ml, ty ₂ = 16 hours, AUC = 310 ng · h / ml after administration ip to 17 mg / kg, and Co = 80 ng / ml, fc _{/ 2}

= 17h, AUC = 170 ng.h / ml after oral administration at 300 mg / kg.

Pharmacokinetics of 21.0

The compound 21.0 was administered to mice at doses of 15 and 100 mg / kg, respectively, intraperitoneally and orally LD _50/3 and the IP LD _50/4 in.

After intraperitoneal administration at 15 mg / kg, Co is obtained of 24 ng / ml with t1 ₂ of approximately 35 hours.

Orally at 100 mg / kg, C ₀ is 16 ng / ml. The apparent tj _{/ 2} is 36 hours.

C. Antibiotic activities of the compounds

Products 6.0, 22.0, and 2.0 were also evaluated in vitro for their activities against

Babesia divergens and B. canis. In both cases, compounds 6.0, 22.0, and 2.0 were particularly active (IC 50 <50 nM). These results indicate a potent antibabesia activity for this type of compounds.

Claims

1 / Compounds having an anti-parasitic activity, especially an antimalarial activity, characterized in that they correspond to the general formula (I) II X- (NH) _n -C-NY (I) R ₂ in which - is X represents a group of formula (II) II -Z- (NH) _n - C- N-R _'3 (II) R' 2 where Z is a group - (CH.2) _m, where m = 8-21, n = 0 or 1 and Y = R _3, . Ri and R'i, identical or different from each other, being chosen from H, alkyl, OH, O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl, OSO ₂ -alkyl, OSO ₂ -aryl, OSO ₂ -heterocycle, O-CO-O (or S or NH) -alkyl, O-CO-O (or S or NH) -aryl, PO (O-alkyl or O-aryl) ₂ , CO-O-CH ₂ -aryl, cycloalkyl, . R ₂ and R ' ₂ , which are identical or different from one another, are chosen from H, alkyl, CO-O-CH ₂ -aryl, CO-O-alkyl, cycloalkyl, . R ₃ and R ' ₃ , identical to or different from each other, representing H, alkyl, CO-O-alkyl, CO-O-aryl, COO-CH (R) -O-CO-alkyl, PO (O-alkyl or O-aryl or ONa) ₂ , CO-O- CH (R) -aryl, . R being H or alkyl, or . R 1 and R ₃ and / or R ' ₁ and R' ₂ , or R and R ₃ and / or R ' ₂ and R' ₃ , together form a mono-heterocycle with the nitrogen atom (s) to which they are respectively attached, or, . R ₂ and R ₃ and / or R ' ₂ and R' ₃ may be the same substituent, doubly bound to nitrogen, cyclized with, respectively, Ri or R'i to form a heterocycle, where appropriate substituted by R _a which is selected from H, alkyl, alkyl substituted with 1,2 or 3 halogen atoms, aryl, CO-O-alkyl (or aryl), -CO-OH, -CO-NH ₂ , -CN, -CO -NH-alkyl (or aryl), -CO-N- (alkyl) ₂ , -CO-heterocycle nitrogen and / or oxygenated, NH (H or alkyl), N (alkyl), nitrogenous and / or oxygenated heterocyl, -O-alkyl (or aryl), -O-CH ₂ -aryl, CH ₂ N [H, (H, alkyl), (dialkyl), aryl], -CH _2- nitrogenous and / or oxygenated heterocycle, CH ₂ -CO-OH, - X = 1 and Y represents a group of formula (HI) R ' N ^ II _Z-NC- (NH) _n -R _'4 (III) R' ₂ where n and Z as defined above, . Ri and R'i, which are identical to or different from each other, are chosen from H, alkyl, OH, O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl and OSO ₂ -alkyl; , OSO ₂ -aryl, OSO ₂ -heterocycle, O-CO-O (or S or NH) -alkyl, O-CO-O (or S or NH) -aryl, PO (O-alkyl or O-aryl) ₂ , CO-O-CH ₂ -aryl, cycloalkyl, P and R ' ₄ represent an H, alkyl or aryl, these may be substituted by OH, - O-alkyl, -O-aryl, NH (H or alkyl), nitrogenous and / or oxygenated heterocycle and R ₂ and R ' ₂ , which are identical or different from each other, are chosen from H, alkyl, CO-O-CH ₂ -aryl, CO-O-alkyl cycloalkyl, or. R 1 and R ₄ and / or R '1 and R' together form a group - (CH ₂ ) _P , where p is an integer of 1 to 5, one or more hydrogen atoms may be replaced by a lower alkyl, and R ₂ and R ' ₂ representing H, or i and R and / or R' ₄ and R ' ₂ together form a group - (CH ₂ ) _P , one or more H may be replaced by a lower alkyl, Ri and R' representing H, and the pharmacologically acceptable salts of these compounds. 2 / Compounds according to claim 1, characterized in that they correspond to formula (IV) wherein n, Z, R ₁ , R ₁ , R ₂ , R ', R 3 and R' 3 are as defined in claim 1. 3 / Compounds according to claim 2, characterized in that they correspond to the formula (V) in which Z, R 1, R 1, R 2, R '2, R 3 and R' 3 are as defined in claim 1. 4 / compounds according to claim 3, characterized in that Ri, R'i, R ₂ , R ' ₂ , R ₃ and R' ₃ are independent of each other. 5 / Compounds according to claim 4, characterized in that R ₁ and / or R ' ₁ are as defined above, but do not represent a hydrogen atom, whereas R ₃ and / or R' ₃ , R ₂ and / or R ' ₂ , represent a hydrogen atom, Ri, R ₂ and R ₃ . Compounds according to claim 5, characterized in that R 1 and / or R 1, and R and / or R ' ₂ represent a hydrogen atom, while R ₃ and / or R' ₃ are as defined above. above, but different from a hydrogen atom. Compounds according to claim 3, characterized in that - R _! and R ₂ , and / or R'i and R ' ₂ , or R ₂ and R ₃ and / or R ' ₂ and R' ₃ , or - Ri, R ₂ and R ₃ and / or R'j, R ' ₂ and R' ₃ together form a heterocycle. 8 / Compounds according to claim 7, characterized in that R 1 and R _{2 as} well as K and R ' ₂ form a heterocycle and correspond to formula (VI) 'NN ^' He II R ' ₂ -NC-ZCN-R ₂ (VI) II ^ ^J R'3 R ₃ 9 / Compounds according to claim 7, characterized in that they correspond to the formula (VII) (VII) 10 / Compounds according to claim 8, characterized in that the formula (VI) R 1 and R ₂ and / or R ' ₁ and R' ₂ together form a group -O-CO-, O-SO-, O-CS, S-CO or -S- CS, and R ₃ and / or R ' ₃ represent a hydrogen atom. 11 / Compounds according to claim 8, characterized in that R 1 and R ₂ , and / or R '1 and R' represent an optionally branched alkylene group and R ₃ and / or R ' ₃ represent -CO-O-alkyl (or aryl), -CO-O-CH ₂ -aryl, CO-O-CH (alkyl) -O-CO-alkyl, PO (O-alkyl or -aryl) ₂ , alkyl or H. 12 / Compounds according to claim 9, characterized in that R1 and / or R'1 represent a hydrogen atom, and R ₂ and R ₃ , and / or R ' ₂ and / or R' ₃ represent a group - ( CH ₂ ) _P -. 13 / Compounds according to claim 2, characterized in that R ₂ and R ₃ and / or R ' ₂ and R' ₃ form a same substituent and together with R 1 or R 'i form a bis-oxadiazole of formula (VIII. ) wherein R _a is as defined above. 14 / Compounds according to claim 1, characterized in that they correspond to formula (IX) 15 / Compounds according to claim 14, characterized in that Z = - (CH ₂ ) _m and n = 0, the compounds corresponding to formula (X) 16 / Compounds according to claim 15, characterized in that the substituents are independent of each other. 17 / Compounds according to claim 16, characterized in that R 1 and R ₄ and / or R '1 and R' are as defined above and R ₂ and R ' ₂ represent a hydrogen atom. 18 / compounds according to claim 16, characterized in that Ri and R ₂ and / or R'i and R ' ₂ together represent the oxycarbonyl-OCO- sequence and R ₄ and R' are as defined above. 19 / Compounds according to claim 16, characterized in that R 1 and R ₄ and / or R ' ₁ and R' ₄ together represent a group - (CH ₂ ) _P - where p is an integer of 3 to 5 and R ₂ and R ' ₂ represent H. 20 / Compounds according to claim 16, characterized in that Ri and R'i represent H and R ₄ and R ₂ and / or R ' ₄ and R' ₂ together represent a group - (CH ₂ ) _P - where p is a integer of 3 to 5, one or more hydrogen atoms may be replaced by a lower alkyl. 21 / A compound according to claim 16, characterized in that it corresponds to formula (XI) 22 / Process for obtaining carbamates and N-phosphoryl derivatives of general formula (V), characterized in that it comprises the reaction in two-phase medium of bisamidines compounds of general formula (V) in which R ₃ and R ' ₃ = H with a derivative CI-R ₃ (or R ' ₃ ) where R ₃ and R' ₃ are as defined above and different from H. 23 / Process for obtaining amidoxime derivatives of general formula (X), characterized in that it comprises the reaction in basic medium of bisamidoximes of general formulas (X) in which R 1 and R '1 = OH and of the reagent appropriate. 24 / A method according to claim 23, characterized in that to obtain compounds of general formula (VI) group a2 and (VIII) group a4 defined above, there is carried out an intramolecular cyclization of amidoxime or amidoxime derivatives previously defined of general formula (V) group a1 in the presence of the appropriate reagent. 25 / Pharmaceutical compositions, characterized in that they contain an effective amount of at least one compound as defined in any one of claims 1 to 21 in combination with an inert pharmaceutical vehicle. 26 / Pharmaceutical compositions according to claim 25, characterized in that they are administrable orally, by injection, or rectally. 27 / Compositions according to claim 25 or 26 for the treatment of infectious diseases, in particular malaria, characterized in that they comprise an effective amount of the compounds according to any one of claims 1 to 21. 28 / Use of at least one compound according to any one of claims 1 to 21 to manufacture drugs for the treatment of anti-parasitic diseases, in particular malaria. 29 / Use of at least one compound according to any one of claims 1 to 21 for the manufacture of medicaments for the treatment of anti-parasitic diseases, in particular of malaria and babesiosis.