Title of Invention

"THE ECHINOCANDIN COMPOUND"

Abstract

A subject of the invention is the compounds of formula (I) :either Rl and R2 , H, OH, alkyl optionally substituted, - or NR1 form with the carbon carrying NR1R2 a double bond and R2 is Xra, X being 0, NH OR N-alkyl and Ra being H, alkyl optionally substituted, - R = chain containing up to 30 carbon atoms, optionally containing one or more heteroatoms, one or more heterocycles, - T = H, CH3, CH2CONH2, CH2C=N, (CH2)2NH2, - Y = H, OH, Halogen, - W = H, OH - Z = H or CH3. - The products have anti-fungal proprieties.

Full Text

The present invention relates to the enchinocandin compound. A subject of the invention is, in all possible isomer forms as well as their mixtures, the compounds of formula (I).in which (Formula Removed) either Rl and R2 identical to or different from one another, represent a hydrogen atom, a hydroxyl radical, a linear, branched or cyclic alkyl radical containing up to 8 carbon atoms, optionally interupted by an oxygen atom optionally substituted by a halogen atom, an OH radical, an(Formula Removed) radical, a and b representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, a and b optionally being able to form with the nitrogen atom a heterocycle optionally containing one or more additional heteroatoms, - or Rl forms with the endocyclic carbon carrying the (Formula Removed) radical, a double bond and either R2 represents an XRa radical, X representing an oxygen atom or an NH radical, or N-alkyl containing up to 8 carbon atoms, and Ra represents a hydrogen atom, a linear, branched or cyclic alkyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms, by one or more OH, CO22H, C02alk radicals, by an (Formula Removed) radical, a' and b' representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, a' and b' being able to form a heterocycle optionally containing one or more additional heteroatoms and/or by a heterocycle containing one or more heteroatoms or R2 representing an(Formula Removed) radical in which d, e, f and g represent a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, in addition f and g being able to represent an acyl radical containing up to 8 carbon atoms, e and f also being able to form a ring optionally containing one or more heteroatoms, R3 represents a hydrogen atom, a methyl or hydroxyl radical R4 represents a hydrogen atom or a hydroxyl radical R represents a linear or branched or cyclic chain containing up to 30 carbon atoms, optionally containing, one or more heteroatoms, one or more heterocycles, or a linear, branched or cyclic acyl radical containing up to 30 carbon atoms optionally containing one or more heteroatoms and/or one or more heterocycles, T represents a hydrogen atom, a methyl radical, a CH2CONH2, CH2CsN radical, a (CH2)2NH2 or (CH2) 2Nalk+X-~ radical, X being a halogen atom and alk an alkyl radical containing up to 8 carbon atoms, Y represents a hydrogen atom, a hydroxyl radical or a halogen atom, or an OS03H radical or one of the salts of this radical W represents a hydrogen atom or an OH radical, - Z represents a hydrogen atom or a methyl radical, as well as the addition salts with the acids of the products of formula (I). Among the addition salts with acids, there can be mentioned those formed with the mineral acids, such as the following acids: hydrochloric, hydrobromic, sulphuric or phosphoric or with organic acids such as the following acids: formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxilic, aspartic, alkanesulphonics, such as methane or ethane sulphonics, arylsulphonics such as benzene or paratoluenesulphonic acids. In the definition of substituents, - the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclo-hexyl radical, - halogen is preferably fluorine or chlorine, or bromine, - the aryl radical is preferably the phenyl radical, - the heterocyclic radical is preferably the pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl radical. As the salt of the S03H radical, there can be mentioned the salts of sodium, of potassium or also the amine salts. Among the preferred compounds of the invention, there can be mentioned quite particularly the compounds of formula (I), in which -/ T represents a hydrogen atom, - ,/Y represents a hydrogen atom, W represents a hydrogen atom, - Z represents a methyl radical, - R3 represents a methyl radical, - R4 represents a hydroxyl radical - R represents a radical (Formula Removed) and quite particularly those in which R represents a chain(Formula Removed) and those in which R represents a chain (Formula Removed) the compounds of formula (I) in which NRl forms with the endocyclic carbon atom carrying the NR1R2 radical, a double bond, and in particular those in which R2 represents the radical 0(CH2)nNY'2 in which n represents an integer comprised between 1 and 8 and quite especially those in which n represents the number 2 and Y' represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, and those in which R2 represents a radical (Formula Removed) A quite particular subject of the invention is also the compounds of formula (I) in which R2 represents a radical (Formula Removed) in which Y" represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms and p represents an integer varying from 1 to 8, and quite especially the compounds in which p represents the number 2. A quite particular subject of the invention is the compounds in which Rl represents a hydrogen atom. Among the preferred compounds of the invention, there can be mentioned the products of Exemples 8, 9, 11, 13 and 14. The compounds of formula (I) have useful anti-fungal proprieties; in particular they are active against Candida albicans and other Candida such as Candida glabrata, krusei tropicalis, pseudotropicalis, parapsilosis and Aspergillus fumigatus, Aspergillus flavus, Cryptococcus neoformans. The compounds of formula (I) can be used as medicaments in man or animals, in particular to combat digestive, urinary, vaginal or cutaneous candidosis, cryptococcosis, for example neuromeningeal, pulmonary or cutaneous cryptococcosis, bronchopulmonary and pulmonary aspergillosis and invasive aspergillosis of the immunosuppressed. The compounds of the invention can also be used in the prevention of mycotic illnesses in sufferers of congenital or acquired immunodepression. The compounds of the invention are not limited to a pharmaceutical use, they can also be used as fungicides in field other than pharmaceutics. Therefore a subject of the invention is as anti-fungal compounds, the compounds of formula (I). A subject of the invention is also the compounds of formula (I), as medicaments and their addition salts with acids. A quite particular subject of the invention is the pharmaceutical compositions containing as active ingredient at least one compound of formula (I) or one of its addition salts with pharmaceutical acceptable salts. These compositions can be administered by buccal, rectal, parenteral route or by local route as a topical application on the skin and mucous membranes,but the preferred route is the buccal route. They can be solid or liquid and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives. These compositions can also be presented in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example apyrogenic sterile water. The dose administered is variable according to the illness treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 50 mg and 300 mg per day by oral route, in an adult for the products of Examples 8, 9, 11, 13 and 14. A subject of the invention is also a preparation process for the compounds of formula (I), characterized in that a compound Of formula (Formula Removed) in which R, R3, R4, T, W, Y and Z retain their previous meaning, is subjected to the action of an amine or of an amine derivative capable of introducing the(Formula Removed) radical in which Rl and R2 retain their previous meaning and if desired to the action of a reducing agent and/or of a functionalization agent of the amine, and/or of an acid in order to form the salt of the product obtained, and/or of a separation agent of the different isomers obtained, and in this way the sought compound of formula (I) is obtained(Formula Removed) in which Rl, R2, T, W, Y, R and Z retain their previous meaning then, if desired the different isomers obtained are subjected. The compounds of formula (II) used as starting compounds of the process of the invention are new products and are themselves a subject of the present invention, their preparation which is given in the experimental part can be schematized as follows: (Formula Removed) ISI-(CH3)3 or any other Lewis acid can be used. A detailed example of the preparation of the compound of formula (II) is given in the experimental part and a more particular subject of the invention is as a new chemical product 1-4-OXO-N2-(12-methyl-l-oxotetradecyl) L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B. product A corresponding to the starting product of Preparation liis a known product described and claimed in European Patent 438813. The following examples illustrate the invention without however limiting it. A subject of the invention is also a preparation process characterized in that a compound of formula (III) (Formula Removed) in which the different substituents retain their previous meaning is subjected to the action of an agent which is capable of replacing NH2 with NHR, R retaining its previous meaning in order to obtain the compound of formula (IV) (Formula Removed) in which the different substituents retain their previous meaning which is subjected to the action of trimethyl silyl iodide in order to obtain the compound of formula (II). The compounds of formula (III) used as starting product are new products, an example of the preparation of the compound of formula (III) is given hereafter in the experimental part. A more particular subject of the invention is the deoxymulundocandin nucleus (compound of formula (III) the preparation of which is given hereafter in the experimental part). Compounds of formula (IV) except mulundandin and deoxymulundocandin are new products and are one subject of this invention. A quite particular subject of this invention is compounds of formula (IV) prepared hereafter in the experimental part. PREPARATION 1: 1-[N2-(12-methyl-l-oxotetradecyl)-4-oxo-L-ornithine] 4-[4-(4-hydroxypheny1)-L-threonine]-5-L-serine echinocandine B. 1 g of 1-[(4R,5R)-4,5-dihydroxy-N2-(12-methyl-l-oxotetradecyl) -L-ornithine] 4-[4-(4-hydroxyphenyl)-L- threonine]-5-L-serine echinocandine B is introduced into 25 ml of acetonitrile under magnetic stirring and under a nitrogen atmosphere. 455 µl trimethylsilyl iodide is added. Heating is carried out at 55°C for 40 minutes. Hydrolyzation is carried with a 3% solution of sodium thiosulphate. After 10 minutes under agitation, the reaction medium is taken to dryness under reduced pressure and purified by chromatography on silica. 62% of sought product is obtained. TLC: rf = 0.25 (eluent: CH2Cl2-MeOH-H20 86-13-1). EXAMPLE 1: 1-[4-amino-N2-(12-methyl-l-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate (isomer B). 50 mg of the product of Preparation 1 is introduced into 2.5 ml of methanol in the presence of activated 4A siliporite. 158 mg of ammonium acetate is added at 20°C. The solution obtained is heated at 50°C and 5.5 mg of NaBH3CN is added. Agitation is carried out for 3 hours 15 minutes. 1 ml of demineralized water is added and the solution is concentrated to dryness. 166 mg of product is obtained which is purified by HPLC (C18) eluting with a CH3CN-H20-TFA mixture (50-50-0.02). 17 mg of sought product is obtained. MH+ = 975. EXAMPLE 2; 1-[4-[2-dimethylaminoethyl-amino-N2-(12-methyl-l-oxotetradecyl) -L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate (isomers A and B). 80 mg of the product of Preparation 1 is introduced, at 20°C, into a solution containing 1 ml of methanol, 160 µl of 2-dimethyl-aminoethylamine, 8 ml of a 1M solution of hydrochloric acid in methanol in the presence of 4 A siliporite. 35 mg of sodium cyanoborohydride is introduced and agitation is carried out for 20 hours at 20°C, followed by filtering, washing with methanol and concentration to dryness. 325 mg of product is obtained which is purified by HPLC (C18) (eluent: CH3CN-H20-TFA 45-55-0.02 then CH3CN-H20-TFA 42-58-0.02). 8.1 mg of sought product isomer A and 9.4 mg of sought product isomer B are obtained. Mass spectrum: MH+ = 1046 MNa+ = 1068. EXAMPLE 3; l-[4-[(3-aminopropyl)-amino]-N2-(12-methyl-l- oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L- threonine]-5-L-serine echinocandine B trifluoroacetate (isomers A and B). 30 cm3 of a 1M solution of hydrochloric acid in methanol is added at 0°C to a solution containing 200 mg of the product of Preparation 1, 2 ml of methanol and 300 µl of diaminopropane. The reaction medium is agitated for 15 minutes at 0°C and 84 mg of 95% sodium cyanoborohydride is added. The reaction medium is left for 6 hours under agitation at ambient temperature and brought to dryness under reduced pressure. The residue obtained is impasted in acetonitrile, separated and dried under reduced pressure. 312 mg of product is obtained which is purified by HPLC (C18) (eluent: CH3CN-H20-TFA 45-55-0.02) and 15 mg of isomer A and 10 mg of isomer B are obtained. Mass spectrum: MH+ = 1032. EXAMPLE 4: (Z + E) 1-[4-[(4,5-dihydro-lH-imidazol-2-yl)-hydrazono-N2-(12-methyl-l-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate. 350 mg of product of Preparation 1, 12 ml of methanol and 130 mg of 2-hydrazino, 2-imidazoline hydrobromide is maintained for 2 hours, under agitation, under reflux. After evaporation to dryness, 510 mg of product is obtained which is purified by chromatography on silica eluting with a CH2Cl2-MeOH-H20 mixture (86-13-1) then by semi-preparative HPLC (C18) eluting with a CH3CN-H20-TFA mixture (55-45-0.02). In this way 133 mg of sought product is obtained. Mass spectrum: MH+ = 1056 MNa+ = 1078. EXAMPLE 5: (Z) 1-[4-[(2-hydroxyethoxy) imino]-N2-(12-methyl-l-oxotetradecyl) -L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B and corresponding isomer E. A mixture of 36 mg of 0-(2-hydroxyethyl) hydroxylamine, 5 ml of ethanol, 12 µl of pyridine, 4 µl pure acetic acid and 150 mg of the product of Preparation 1 is maintained for 4 hours under reflux. 205 mg of product is obtained which is purified by chromatography on silica eluting with a methylene chloride-methanol-water mixture (86-13-1) . 2 products of rf = 0.2 and 0.25 (isomer Z and isomer E) are isolated. Mass spectrum: MH+ = 1033 MNa+ = 1055. EXAMPLE 6; (E) 1-[4-(hydroxyimino]-N2-(12-methyl-l-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B and corresponding isomer Z. A mixture containing 200 mg of the product of Preparation 1, 8 ml of ethanol, 36 mg of hydroxylamine hydrochloride is left for 1 hour under agitation under reflux. After bringing to dryness and purifying by HPLC chromatography (C18) (eluent CH3CN-H20 60-40) 72 mg of isomer Z and 60 mg of isomer E are obtained. Mass spectrum: MH+ =989 MNa+ = 1011 EXAMPLE 7: 1-[4-(hydroxyamino)-N2-(12-methyl-l-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate (isomer A and isomer B). 70 mg of a mixture of E + Z oximes obtained in the preceding example, I cm3 trifluoroacetic acid, 12 mg of sodium cyanoborohydride at 95% are left for 3 hours under agitation. After bringing to dryness under reduced pressure and purifying by HPLC (C18), the sought products are obtained. Mass spectrum: MH+ = 991 MNa+ = 1013 EXAMPLE 8: (Z) 1-[(S)-N2-(12-methyl-l-oxotetradecyl) 4-[[(3-piperidinyl) oxy] imino]-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B hydrochloride. Stage A: 146 mg of the product of Preparation 1 and 60 µl of acetic acid are added to a solution containing 45 mg of phenylmethyl R-3-(aminooxy)-1-piperidine carboxylate and 2 ml of methanol. Agitation is carried out for 2 hours at ambient temperature, followed by concentration and purifying by chromatography on silica eluting with a methylene chloride-methanol mixture 98-2. In this way the sought product is obtained. Mass spectrum: MH+ = 1206 MNa+ = 1228 Stage B: A mixture containing 61 mg of the product prepared in Stage A, 20 mg of palladium on carbon and 1 ml acetic acid are placed under a hydrogen atmosphere and vigorous agitation for 5 hours. After filtering and concentrating 65% of sought product is obtained. Mass spectrum: MH+ = 1072. EXAMPLE 9; 1-[4-[(2-aminoethyl) amino]-N2-(12-methyl-l-oxotetradecyl) -L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate (isomer A and isomer B). 63 ml of a 1M solution of hydrochloric acid in methanol is added to a solution of 300 mg of Preparation 1 in 6 ml of methanol in the presence of 375 µ1 of ethylenediamine. After agitation for 15 minutes, 126 mg of sodium cyanoborohydride (NaBHsCN) is added. The reaction medium is maintained under agitation for 5 hours. Filtration and bringing to dryness are carried out, the products being purified by HPLC (C18) eluting with a CH3CN - H20 - TFA mixture (40-60-0. 02). In this way the sought products are obtained. Mass spectrum: MH+ = 1018 MNa+ = 1040. EXAMPLE 10: (E) 1-[4-[(2-bromoethoxy) imino]-N2-(12-methyl-l-oxotetradecyl) -L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B and corresponding isomer Z. 402 mg of bromo-2-ethoxyamine hydrobromide is added to a solution containing 710 mg of product of Preparation 1 and 28 ml of absolute ethanol. The mixture is taken to reflux for 55 minutes and concentrated under reduced pressure. The product obtained is purified by flash chromatography on silica eluting with a methylene chloride-methanol mixture (9-1). The sought products are obtained isomer A: Rf = 0.54, isomer B: Rf = 0.47. Mass spectrum: MH+ = 1095 MNa+ = 1117 EXAMPLE 11; (±)1-[4-[(aminoiminomethyl) hydrazono]-N2-(12-methyl-l-oxotetradecyl) -L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate. 162 mg of aminoguanidine hydrochloride is added to a solution containing 260 mg of the product of Preparation 1 and 10 ml of n-butanol. The reaction medium is taken to reflux for 2 hours 30 minutes, followed by concentration under reduced pressure. The product obtained is purified by semi-preparative HPLC. 225 mg of product is obtained as a 50/50 mixture of isomers. Mass spectrum: MH+ = 1030 MNa+ = 1052. EXAMPLE 12: (Z) 1-[4-[[2-(dimethylamino) ethoxy) imino]-N2-(12-methyl-l-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxy¬phenyl) -L-threonine]-5-L-serine echinocandine B trifluoro¬acetate and corresponding isomer E. 80.5 mg of the product of Example 10 is introduced into 32 ml of an ethanolic solution of dimethylamine. The reaction medium is taken to reflux for 45 minutes, followed by concentration. The product obtained is purified by HPLC (CH3CN - H20 - TFA 60-40-0.02). In this way the sought products are obtained. Mass spectrum: MH+ = 1060 EXAMPLE 13: (E) 1-[4-[(2-aminoethoxy) imino]-N2-(12-methyl-l-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate and corresponding isomer Z. 50 mg of the product of Example 10 is introduced into ammonia. Agitation is carried out under pressure during 16 hours while leaving the reaction medium to return to ambient temperature. The reaction medium is taken up in a CHsCN-H2O (45-55) mixture in order to be purified by HPLC (C18) . The sought products are obtained. Mass spectrum: MH+ = 1032. Preparation 2: deoxymulundocandine nucleus 2 g of deoxymulundocandine is dissolved in 20 ml of DMSO. This solution is poured into a suspension containing 120 g of Actinoplanes utahensis FH2264 in 870 ml of a KH2P04, K2HP04 buffer (pH: 6.8). The reaction mixture is maintained under agitation for 70 hours at 30°C. After filtering, the mycelium is washed with the phosphate buffer (pH: 6.8). The washing liquids and the filtrate are combined. The product obtained is chromatographed on a DIAION HP 20 resin and a product is obtained which is used hereafter as it is. EXAMPLE 14 ; 1-[4-[(2-(aminoethyl) amino]-N2-[[4'-(octyloxy) [1,1'-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxy¬phenyl) -L-threonine]-5-L-serine echinocandine B trifluoro¬acetate (isomer A) St-.agfi A : 1- [ (4R, 5R) -4 , 5-dihydroxy-N2- [ [4 '- (octyloxy) [1,1-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B. 1) Preparation of the ester. 632 mg of 2,3,4,5,6-pentafluorophenol in 695 mg of N,N'-dicyclohexylcarbodiimide are added to 1 g of 4'-octyloxy [I,1'-biphenyl] 4-carboxylic acid in 22 ml of tetrahydrofuran. The reaction medium is maintained under agitation during 2e hours at ambiant temperature. After filtering elimination of solvents under reduced pressure, taking up the residu in diethyl ether, maintaining under agitation, filtering, evaporing the solvents and drying. 1,46 g of the sought product is obtained which is used hereafter as its. 2) Coupling 677 mg of deoxymulundocandin nucleus obtained in preparation 2 is introduced into 16 ml of DMF. The solution obtained is agitated for 5 minutes and pentafluorophenyl 4'-(octyloxy)-[ 1,1'-biphenyl]-4-carboxylate is added. The reaction mixture is maintained under agitation and a nitrogen atmosphere for 24 hours. After filtering and concentrating, the residue is taken up in ether, triturated, maintained for 25 minutes under agitation, separated, washed with ethyl ether, chromatographed on silica eluting with a methylene chloride, methanol, water mixture (86/13/1) then (80/20/1). In this way the sought product is obtained. Yield 73%. Stage B: 1-[N2-[[4'-(octyloxy)-[1,1'-biphenyl]-4-yl] carbonyl]-4-oxo-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B 311 µl of trimethylsilyl iodide is added to a suspension containing 809 mg of the product of Stage A and 19 ml of acetonitrile. The reaction mixture is maintained under agitation for 15 minutes at 60°C and under a nitrogen atmosphere. The mixture is poured into a saturated solution of sodium thiosulphate. After evaporation and chromatography on silica, the residue obtained is eluted with a methylene chloride methanol water mixture 86/13/1. The sought product is obtained yield 55%. Stage C : 1-[4-[(2-(arainoethyl) amino]-N2-[[4'-(octyloxy) [1,1'-biphenyl]-4-yl]carbonyl]-L-ornithine] -4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B trifluoroacetate (isomer A) 560 pi of acetic acid is added to a solution containing 900 mg of the product of the previous stage, 16 ml of methanol and 250 µl diamine ethylene. Agitation is carried out for 15 minutes and 64 mg of sodium cyanoborohydride is added. Agitation is carried out for 18 hours, followed by filtering and concentrating. The residue is taken up in the minimum amount of water, triturated, separated and purified by preparative HPLC eluting with a CH3CN/H20/TFA/ mixture (55-45-0.2). 57% of sought product is obtained yield 26%. NMR spectrum CDC13 9.07 (broad m) 1H; 8.48 (bd, J=8) 1H; 8.00 (bd, J=8) 2H; 7.96 (bd, J=8.5) 2H; 7.71 (bd, J=8.5) 2H; 7.64 (bd, J=8.5) 2H; 7.60 (bd, J=9) 1H; 7.37 (bd, J=9.5) 1H; 7.02 (bd, J=8.5) 2H; 6.97 (bd, J=8.5) 2H; 6.65 (bd, J=8.5) 2H; 4.90 (m) 1H; 4.77 (m) 1H; 4.66 (m) 1H; 4.45 (m) 1H; 4.42 (m) 1H; 4.39 (m) 1H; 4.34 (bl) 1H; 4.26 (m) 1H; 4.22 (m) 1H; 4.08 (m) 1H; 4.01 (t,J=6.5) 2H; 3.88 (m) 3H; 3.70 (m) 2H; 3.51 (m) 2H; 3.48 (m) 1H; 3.31 (m) 2H; 3.28 (m) 1H; 3.16 (m) 2H; 2.53 (dd, J=6 and 13.5) 1H; 2.44 (dd, J=7.5 and 13.5) 1H; 2.27 (m) 1H; 2.25 (m) 1H; 2.15 (m) 2H; 1.94 (m) 1H; 1.74 (m) 2H; 1.44 (m) 2H; 1.22 to 1.40 (m) 8H; 1.13 (d, J=6) 3H; 0.99 (d, J=6.5) 3H; 0.88 (t, J=7) 3H. EXAMPLE 15 : 1-[4-[[(aminoiminomethyl)hydrano]-N2-[[4-[4-[4-(pentyloxy)-phenyl]-1-piperazinyl]phenyl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B Stage A : 1-[(4R,5R)-4,5-dihydroxy-N2-[[4-[4-[4-(pentyloxy) phenyl]-1-piperazinyl] carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B 1- Preparation of the ester 55 mg of pentafluorophenol and 61 mg of N,N' dicyclohexyl carbodiimide are added to a mixture of 100 mg of [4-[4-[4-(pentyloxy)phenyl]-1-piperazinyl]phenyl]carboxylic acid and 3 ml of tetrahydrofuran. The reaction mixture is agitated at 20°C for 16 hours, filtered, washed with THF and concentrated to dryness, followed by taking up in diethy ether, filtering, washing and concentrating. 71 mg of product is obtained. 2- Coupling A suspension containing 71 mg of the above ester, 70 mg of deoxymulundocandine nucleus, 2.5 ml of DMF is agitated at 20°C overnight in the presence of activated 4A siliporite. After concentrating, the product obtained is taken up in ether and filtered. A product is obtained which is chromatographed on silica eluting with an acetonitrile/water/trifluoroacetic acid mixture (60-40-0,02). In this way 30 mg of sought product is obtained. Stage B : 1-[N2-[[4-[4-[4-(pentyloxy) phenyl]-1-piperazinyl]- phenyl] carbonyl]4-oxo-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B A mixture of 1 g of the product of Stage A and 25 ml of acetonitrile is heated at 55°C in the presence of activated 4A siliporite. 430 ml of trimethylsilane iodide is added. Agitation is carried out for 45 minutes then 150 ul of sodium thiosulphate aqueous solution at 30% is added. Agitation is carried out for 40 minutes at 20°C followed by concentration. The dry extract is taken up in water. Agitation is carried out for 1 hour at 20°C followed by separation and washing. A product is obtained which is chromatographed on silica eluting with a methylene chloride-methanol-water mixture (86/13/1). 497 mg of the sought product is obtained. Yield 42%. Stage C : 1-[4-[(aminoiminomethyl)hydrazono]-N2-[[4-[4-[4-(pentyloxy)-phenyl]-1-piperazinyl]phenyl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B A suspension containing 400 mg of the product of Stage B, 4.8 ml of n-butanol and 221 mg of aminoguanidine hydrochloride is heated at 130°C for 3 hours. After concentrating 705 mg of a product is obtained which is chromatographed on silica eluting with a methylene chloride methanol mixture 85/15, then by semi-preparative HPLC (kromasil CIS) with an acetonitrile/water/trifluoroacetic acid mixture (40/60/0.02). In this way 64 mg of sought product is obtained. NMR Spectrum CDC13 10.75 (s ) 0.66H; 10.45 ( s ) 0.33H; 8.39 ( d, J=8 ) 0.33H; 8.34 ( m ) 1H; 8.10 ( d, J=7.5 ) 0.66H; 8.08 ( d, J=8 ) 0.33H; 7.99 ( d, J=8.5 ) 0.66H; 7.74 ( d, J=8.5 ) 1.33H; 7.71 ( d, J=8.5 ) 0.66H; 7.60 ( d, J=8.5 ) 0.66H; 7.50 ( m ) 1.33H; 7.00 ( m ) 6H;6.86 ( d, J=8.5) 2H; 6.65 ( d, J=8 ) 2H; 5.08 ( dt, J=2 and 11.5 ) 0.66H; 4.94 ( m ) 1H; 4.88 ( m ) 0.33H; 4.75 ( dm, J=8 ) 0.33H;4.67 ( dd, J=3 and 7.5 ) 0.66H;4.43 ( m ) 1H; 4.38 ( m ) 1.66H;4.33 ( m ) 0.66H/4.26 a 4.20 (massive) 2.33H; 4.12 ( d, J=9 ) 0.66H;4.00 a 3.68 ( massive ) 7.33H; 3.90 ( t,J=7 ) 2H;3.62 ( d,J=12 ) 0.33H;3.43 (broad s) 2H;3.30 a 3.20 (m ) 1H; 3.20 (broad s) 2H;2.91 ( d,J=14 )0.66H;2.86 ( m ) 0.33H; 2.76 ( m ) 0.33H; 2.63 ( dd, J=14 and 12.5 ) 0.66H;2.52 ( dt, J=6 and 13 ) 1H; 2.44 ( dd, J=8 and 13 ) 1H;2.35 ( m ) 0.33H; 2.25 ( m ) 1.66H;1.93 (broad t,J=13 ) 1H; 1.69 ( m ) 2H; 1.42 a 1.30 (massive) 4H;1.15 ( d, J=6 ) 1.98H;1.10 ( , J=6 ) 0.99H; 0.98 ( d, J=6.5 ) 3H; 0.90 ( t, J=7 ) 3H. EXAMPLE 16 : 1-[4-[(2-aminoethyl)amino]-N2-[4-[4" -(pentyl-oxy) [1,1': 4',1" -terphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B (isomer A and isomer B). By operating as previously, starting with the deoxy-mulundocandine nucleus by obtaining as intermediate product 1-[(4R,5R)-4,5-dihydroxy-N2-[[4' '-(pentyloxy) [1,11 :4g -terphenyl]-4-yl]carbonyl]-L-ornithine] -4-[4-(4-hydroxy¬phenyl) -L-threonine]-5-L-serine-echinocandine B and the corresponding 4-oxo derivative, the sought product was obtained. NMR spectrum CDC13 ppm 9.00 (broad) 1H; 8.37 (bd, J=8.5) 1H; 8.28 (m) 1H; 8.10 (bd, J=6) 1H; 8.02 (bd, J=8) 2H; 7.82 (m) 4H; 7.73 (bd, J=8) 2H; 7.66 (bd, J=8) 2H; 7.38 (bd, J=9) 1H; 7.32 (bd, J=9) 1H; 7.03 (bd, J=8.5) 2H; 6.96 (bd, J=8) 2H; 6.66 (bd, J=8) 2H; 5.03 (m) 1H; 4.84 (m) 1H; 4.67 (m) 1H; 4.45 (m) 2H; 4.36 (dd, J=7.5 and 10.5) 1H; 4.23 (m) 2H; 4.18 (bl) 1H; 4.04 (m) 1H; 4.02 (t, J=6.5) 2H; 4.00 (m) 1H; 3.87 (bd, J=9.5) 1H; 3.76 (m) 1H; 3.72 (m) 2H; 3.55 (m) 1H; 3.44 (m) 1H; 3.35 (m) 2H; 3.30 (m) 1H; 3.19 (m) 2H; 3.12 (m) 1H; 2.53 (m) 1H; 2.45 (m) 1H; 2.12 a 2.30 (m) 3H; 1.90 a 2.05 (m) 2H; 1.74 (m) 2H; 1.30 a 1.55 (m) 4H; 1.20 (d, J=5.5) 3H; 0.96 (d, J=6.5) 3H; 0.91 (t, J=7) 3H. EXAMPLE: Pharmaceutical composition: Tablets were prepared containing: - Product of Example 14 150 mg - Excipient s.q.f 1 g (Detail of excipient: starch, talc, magnesium stearate). PHARMACOLOGICAL STUDY A - Inhibition of the glucane synthase of Candida albicans. Candida albicans membranes were purified according to the process described by Tang et al Antimicrob. Agents Chemother 35, 99-103, 1991. 22.5 ug of the membrane proteins are incubated in a mixture of 2Mm of 14C-UDP glucose (specific activity = 0.34 mCi./mmol, 50 ug of α-amylase, 1Mm of dithiotreitol (DTT), IMm EDTA, lOOMm NaF, 7µM of GTP-y-S, 1M of sucrose and 50Mm of Tris-HCL (pH 7.8) in a volume of lOOµl. The medium is incubated at 25°C for 1 hour and the reaction is terminated by the addition of TCA at a final concentration of 5%. The reaction mixture is transferred onto a pre-wetted glass fibre filter. The filter is washed, dried and its radioactivity is counted. The mulundocandine is used as a positive control. Checking the vehicle is carried out with the same quantity of DMSO 1%. The results obtained show that the products of the invention have a good activity in this test in particular the products of Examples 9, 11 and 14. B - activity on the enzyme of Aspergillus fumigatus. The enzyme is prepared according to the process of Beaulieu et al.(Antimicrob. Agents Chenother 38, 937-944, 1994. The protocol used is identical to the protocol described above for the enzyme of Candida albicans except that dithiotreitol is not used in the reaction mixture. The products show a good activity in this test. We Claim: 1. The echinocandin compound of general formula (I): (Formula Removed) in which R1 and R2 can be identical to or different from one another, represent a hydrogen atom, a hydroxyl radical, a linear, branched or cyclic alkyl radical containing up to 8 carbon atoms, optionally interupted by an oxygen atom optionally substituted by a halogen atom, an OH radical, an(Formula Removed) radical, a and b representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, a and b optionally being able to form with the nitrogen atom a heterocycle optionally containing one or more additional heteroatoms, or R1 forms with the endocyclic carbon carrying the (Formula Removed) radical, a double bond and either R2 represents an XR2 radical, X representing an oxygen atom or an NH radical, or N-alkyl containing up to 8 carbon atoms, and Ra represents a hydrogen atom, a linear, branched or cyclic alkyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms, by one or more OH, CO2H, CO2alk radicals, by an(Formula Removed) radical, a' and b' representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, a' and b' being able to form a heterocycle optionally containing one or more additional heteroatoms and/or by a heterocycle containing one or more heteroatoms or R2 representing a radical in which d, (Formula Removed) e, f and g represent a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, in addition f and g being able to represent an acyl radical containing up to 8 carbon atoms, e and f also being able to form a ring optionally containing one or more heteroatoms, R3 represents a hydrogen atom, a methyl or hydroxyl radical R4 represents a hydrogen atom or a hydroxyl radical R represents a linear or branched or cyclic chain containing up to 30 carbon atoms, optionally containing, one or more heteroatoms, one or more heterocycles, or a linear, branched or cyclic acyl radical containing up to 30 carbon atoms optionally containing one or more heteroatoms and/or one or more heterocycles, T represents a hydrogen atom, a methyl radical, a CH2CONH2, CH2C=N radical, a (CHa)aNHa or (CH2)2Nalk+X' radical, X being a halogen atom and alk an alkyl radical containing up to 8 carbon atoms, Y represents a hydrogen atom, a hydroxyl radical or a halogen atom, or an OSO3H radical or one of the salts of this radical W represents a hydrogen atom or an OH radical, - Z represents a hydrogen atom or a methyl radical, as well as the addition salts with the acids of the products of formula (I) 2. The compounds of formula (I) as claimed in claim 1 in which T represents a hydrogen atom. 3. The compounds of formula (I) as claimed in claim 1 or 2 in which W represents a hydrogen atom. 4. The compounds of formula (I) as claimed in any one of claims 1 to 3, in which Z represents a methyl radical. 5. The compounds in which Y represents a hydrogen atom. 6. The compounds of formula (I) as claimed in any one of claims 1 to 5 in which R3 represents a methyl radical. 7. The compounds of formula as claimed in any one of claims 1 to 6 in which R4 represents a hydroxyl radical. 8. The compounds of formula (I) as claimed in any one of claims 1 to 7 in which R represents a radical 9. The compounds of formula (I) as claimed in claim 8, in which R represents a chain (Formula Removed) 10. The compounds of formula (I) as claimed in claim 8 in which R represents a chain (Formula Removed) 11. The compounds of formula (I) as claimed in any one of claims 1 to 10, in which R1 forms with the endocyclic carbon atom carrying the NR1R2 radical, a double bond. 12. The compounds of formula (I) as claimed in claim 11, in which R2 represents the radical O(CH2) nNY'2 in which n represents an integer comprised between 1 and 8 and Y' represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms. 13. The compounds of formula (I) as claimed in claim 11, in which n represents the number 2. The compounds of formula (I) as claimed in claim 11, in which R2 represents a radical(Formula Removed) 14. The compounds of formula (I) as claimed in any one of claims 1 to 10, in which Ra represents a radical (CH2)PNY" in which Y" represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms and p represents an integer varying from 1 to 8. 16. The compounds of formula (I) as claimed in any one of claims 1 to 10 and 15, in which R1 represents a hydrogen atom. 17. The compounds of formula (I) as claimed in claim 15, in which p represents the number 2. 18. The compounds of formula (I) as claimed in claim 1, the names of which follow: - 1 - [(S) - N2 - (12-methyl- 1 - oxotetradecyl) 4- [[(3- piperidinyl) oxy] imino]-L- ornithine] 4-[4- (4-hydroxyphenyl)-L-threoninej- 5-L-serine echinocandin. - 1 - [4-[(2-aminoethyl) amino]-N2-(12-methyl-l-oxotetra- decyl) - L- ornithine] 4- [4-(4-hydroxyphenyl)-L-threonine]-5-L- serine echinocandine. - l-[4-[(aminoiminomethyl) hydrazono]-N2-(12-methyl - 1-oxotetradecyl) -L- ornithine] 4-[4- (4-hydroxyphenyl)-L- threonine] -5-L-serine echinocandine. - 1- [4- [[2-(aminoethoxy) imino] -N2- (12-methyl-l-oxotetradecyl) -L- ornithine] 4- [4- (4-hydroxyphenyl) -L- threonine] -5- L-serine echinocandine. l-[4-[ (2-aminoethyl)amino]-N2-[ [4'-(octyloxy) [1, l'-biphenyl]4-yl] carbonyl] -L-omithine] -4- [4- (4-hydroxyphenyl) - L- threonine ]-5-L-serine-echinocandine B trifluoroacetate. as well as their addition salts with acids. 19. The echinocandin compound of formula I substantially as hereinbefore described with reference to the foregoing examples.

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3668-del-1998-abstract.pdf

3668-del-1998-assignment.pdf

3668-del-1998-claims.pdf

3668-del-1998-correspondence-others.pdf

3668-del-1998-correspondence-po.pdf

3668-del-1998-description (complete).pdf

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3668-del-1998-form-13.pdf

3668-del-1998-form-18.pdf

3668-del-1998-form-2.pdf

3668-del-1998-form-3.pdf

3668-del-1998-form-4.pdf

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