Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the subject of the invention is compounds with anti-parasitic activity, and more particularly antimalarial and antibabesiosis.
• the inventors have found, with certain categories of chemical compounds, a high activity, accompanied by tolerable toxicity and high bioavailability properties.
• these compounds are administrable orally.
• the invention therefore aims to provide new compounds with antiparasitic activity, especially antimalarial.
• 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.
• 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-
• 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
• 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 ,
• 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 '2 R 2 wherein n, Z, R l5 R' ⁇ , R2, R'2, R3 and R'3 are as defined above in relation to formula (II).
• R 1; R and R 3 and / or R ' 1 , R' 2 and R ' 3 are independent of one another.
• 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.
• 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.
• Ri and R, and / or R'i and R ' correspond to formula (VI) or group a2
• 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.
• 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.
• R 1 and / or R ' 1 represent a hydrogen atom
• R 2 and R 3 , and / or R' and / or R ' 3 represent a group - ( ⁇ 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).
• R a is as defined above.
• 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)
• the substituents are independent of one another.
• R 1 and R 1 and / or R ' 1 and R' 4 are as defined above and R represent a hydrogen atom.
• 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.
• 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.
• 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):
• the compounds according to the invention are optionally in the form of salts.
• examples include hydrochlorides, citrates, tartrates, maleates, lactates, acetates and trifluoroacetates.
• 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 values of IC 5 o 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.
• 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.
• compositions contain, if appropriate, active ingredients of other drugs.
• active ingredients of other drugs such as lysosomotropic agents, atovaquone, antifolics or antifolinics, or artemisinin or one of its derivatives.
• compositions of the invention are administrable in different forms, more especially orally or injectably or rectally.
• 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.
• compositions of the invention are particularly suitable for the treatment of infectious diseases in humans and animals, in particular malaria or babesiosis.
• 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.
• Figure 1 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).
• 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 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.
• 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.
• 1,1-bis [N- (1- (methyloxycarbonyl) amidyl] dodecane 1.1
• 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.
• 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.
• 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.
• 1,12-bis [N, N '- (phenyloxycarbonyl) amidinyl] dodecane 1.7
• Diphenyl [1,12-bis (amidmyl) dodecane] -1,12-bis-N, N-phosphonate 1.12
• 1, 12-bis ( ⁇ r , ⁇ r '-hydroxyamidinyl) dodecane 1.15
• 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.
• 1,12-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, 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.
• 1,12-bis (N, N'-phenoxycarbonyloxyamidinyl) dodecane 1.19
• 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.
• 1,12-bis (N, N '-phenylcarbamoyloxyamidinyl) dodecane 1.25
• 2 g (7 mmol) of 1.15 and 1.01 g of sodium carbonate 2 g
• 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.
• 1,12-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.
• 1,12-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.
• 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.
• 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
• 1,1-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.
• 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.
• 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.
• 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
• 1,1,2-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
• 1,12-bis (4-methylimidazolin-2-yl) dodecane dihydrochloride 9.0.2HCl
• diethyl tetradecanediimidate diethyl dihydrochloride 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.
• 1,12-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.
• 1,12-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.
• 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.
• 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
• 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%.
• 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 (C ⁇ 2 Cl 2 / C ⁇ 3 O ⁇ / ⁇ 4 or 85: 13: 2) to give the product, in the form of an oil, with a yield of 65%.
• 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.
• 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.
• 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 1 ⁇ 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.
• 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
• 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.
• results are expressed in log (serum drug level), as a function of time, which allows evaluation of the half-time for distribution to the t ⁇ / 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.
• 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.
• Table 4 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 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.
• Co is obtained of 24 ng / ml with t1 2 of approximately 35 hours.
• C 0 is 16 ng / ml.
• the apparent tj / 2 is 36 hours.

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