MXPA01000655A - Aerothricin analogs, their preparation and use - Google Patents

Abstract

The present invention relates to novel Aerothricins represented by Formula (I), wherein R1, R2, R3, R4, R5, X, Y, Z, and m are as defined in Claim 1;and pharmaceutically acceptable salts thereof. The present invention also relates to a pharmaceutical composition comprising an Aerothricin of Formula (I) and a pharmaceutically acceptable carrier. Furthermore, the present invention relates to the use of such Aerothricins for the preparation of medicaments, as well as to processes and intermediates for the preparation of the Aerothricins of Formula (I).

Description

ANEROTRIC ANALOGS, ITS PREPARATION AND USE DESCRIPTION OF THE INVENTION The present invention relates to new cyclic compounds that have an antifungal activity (hereinafter called aerotricins), to the use of aexotricins in medical therapy, to pharmaceutical compositions containing aerothricins, as well as to the procedures and intermediate products for the preparation of aerotricinos. Azole antifungal agents are commonly used for the treatment of systemic mycoses. However, the long-term prophylactic use of antifungal azoles resulted in the generation of Candi da spp. resistant to azoles, due to its fungistatic action. Therefore, fungicidal agents are particularly important for the treatment of severe systemic mycosis. In addition, the currently available antifungal agents are not effective against Fusarium um spp. , which is one of the pathogens that appear among immunosuppressed patients. Amphotericin B is a highly effective fungicidal agent commonly used clinically, but its therapeutic index (effective dose to toxic dose) is rather low.

Ref: 126191 Certain cyclic compounds such as LY303366 (EP 736 541), WF11243 (EP 584 360) are known to exhibit fungicidal activity through the inhibition of β-1,3-glucan synthase. However, they still have some disadvantages in terms of their antifungal spectrum and / or safety profile. Therefore, it is urgently necessary to develop new fungicidal agents with a better safety profile and efficacy against the main systemic pathogens including the newly emerging pathogens such as Fusarium um spp. In particular, the present invention relates to the new aerotricines, represented by the formula (I), where : R1 is guanidino, tri-lower alkyl-ammonium, N (R ') R 1 -N (R 1150 v) -CO-R, 114 N (R, 1153) -CO-CH [N (Ri) R--] -R * NHCOCH (R ") -NHCOCH (NH; .15, .10, "11. 13 2 'n - N S- CH) -N (R) -CO-CH [N (R) R] -R "10, 13' (CH2) nN (R15) -CO-CH [N (R R11] -R R1"and Rj3 are each, independently of one another, selected from hydrogen, heteroaryl substituted with one or two amines, lower alkyl optionally substituted with one or more, preferably one or two, aminos, amino-lower alkyl, cyano, guanidino, heterocycle (s) containing nitrogen or phenyl group (s) containing an amino, amidino or guanidino group: R13 is a residue derived from natural or unnatural amino acids; Rld is lower alkyl substituted with one or more, preferably one or two, aminos , guanidino, nitrogen-containing heterocycle (s) or phenyl group (s) containing an amino, amidino or guanidino group; R1 'is hydrogen, lower alkyl optionally substituted with one or more, preferably one or two, amino, guanidino, heterocycle ( s) containing nitrogen, or phenyl group (s), containing an amino, amidino or guanidino group; R "is hydrogen, hydroxysulfonyl, lower alkyl or lower alkenyl, wherein lower alkyl and alken lower nyl may be optionally substituted with acyl, carbamoyl, amino, lower monoalkylamino or lower alkylamino; R1 is hydrogen, hydroxyl, nitro, amino, acylamino, lower alkylcarbamoyl amino, carboxyl, lower alkoxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl or lower alkynyl, wherein lower alkyl, lower alkenyl and lower alkynyl may be optionally substituted with hydroxyl, amino, mono-lower alkylamino, lower-alkylamino, lower alkoxycarbonyl or carbamoyl; R 4 is alkyl, alkenyl, alkoxy or alkenyloxy which may be optionally substituted with lower alkyl, aryl, cycloalkyl or fluorine atom (s); R5 is -CONH_, -CN or -CH_NH_; X is a single bond, or an aryl, biphenyl or terphenyl group optionally containing one or more heteroatom (s), and / or being substituted with halogen atom or lower alkyl; Y is a single bond, -CH2-, -CH (lower alkyl) -, -CONH- or -CON (lower alkyl) -; Z is -O-, -NH- or -N (lower alkyl) -; m is an integer from 0 to 4; and n is an integer from 2 to 5; with the proviso that when -Y- (CH_) -XR "is unsubstituted alkyl or aralkyl, then R1 is not amino, R2 and R3 are not hydrogen, R5 is not -CONH, and Z is not -0- or -NH- at the same time, and the pharmaceutically acceptable salts thereof The present invention also relates to a pharmaceutical composition containing an aerothricino of formula (I) and a pharmaceutically acceptable carrier, In addition, the present invention relates to the use of said aerotricines for the preparation of medicaments as well as, to processes and intermediates for the preparation of the aerothricins of formula (I). [).] Additionally, the present invention relates to a method for the prophylactic and / or therapeutic treatment of infectious diseases. caused by pathogenic microorganisms In this specification, the term "lower" is used to indicate a group containing from 1 to 6, preferably from 1 to 4 carbon atom (s), unless Indicate otherwise The term "alkyl" refers to a branched chain or saturated monovalent linear aliphatic hydrocarbon radical, of one to twenty carbon atoms, preferably one to sixteen carbon atoms. The term "lower alkyl" refers to a branched or straight-chain monovalent alkyl radical of one to six carbon atoms, preferably one to four carbon atoms. This term is exemplified below with the methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, tere-butyl radicals and the like. The term "alkenyl" refers to an alkyl group that contains one or more double bond (s) in the alkylene chain. The term "alkynyl" refers to an alkyl group that contains one or more triple bond (s) in the alkylene chain. The term "alkoxy" refers to the group -O-R ', wherein R' is an alkyl. The term "lower alkoxy" refers to the group -O-R ', wherein R' is a lower alkyl. The term "alkenyloxy" refers to an alkoxy group containing one or more double (s) bond (s) in the alkylene chain. The term "acyl" refers to the group -C (0) -R ', wherein R' is a lower alkyl. The term "acylamino" refers to an acyl group attached to an imino radical, i.e., -NH-. The term "mono-lower alkylamino" refers to a lower alkyl group attached to an imino radical, i.e., -NH-. The term "lower di-alkylamino" refers to two selected lower alkyl groups attached to a nitrogen atom, i.e., -N (-lower alkyl) -lower alkyl. The term "tri-lower alkylammonium" means lower trialkylammonium containing three independently selected alkyl groups of 1 to 3 carbon atoms. The term "lower alkoxycarbonyl" refers to the group -C (0) OR ', wherein R' is a lower alkyl. The term "(lower alkylcarbamoyl) amino" refers to the group -NHCONH-R ', wherein Rf is a lower alkyl. The term "halogen atom" refers to fluorine, chlorine, bromine and iodine. The term "aryl" refers to a monovalent carbocyclic aromatic radical (for example phenyl), or two fused carbocyclic rings (for example naphthyl) optionally mono, di or trisubstituted, independently, with lower alkyl, trifluoromethyl, halogen and the like. The term "nitrogen-containing heterocycle" refers to a saturated, unsaturated or aromatic monovalent cyclic radical containing at least one nitrogen atom.

The term "heteroaryl" refers to a monovalent or monovalent aromatic monocarboxylic radical containing at least one heteroatom, namely nitrogen, sulfur or oxygen. Examples of heteroaryl radicals with one or more nitrogen atoms are pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and imidazolyl. The term "cycloalkyl" refers to a monovalent carbocyclic radical of three to ten carbon atoms, preferably three to six carbon atoms. The term "pharmaceutically acceptable salts", comprises the salts of Aerothricis of formula (I) with an inorganic or organic acid such as hydrochloric acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, acid trifluoroacetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, which are not toxic to living organisms. Each substituent of formula (I) above is explained in more detail below. In the definition of R1, the term "tri-lower alkylammonium" preferably means trimethylammonium and triethylammonium.

In the definition of R 10 and R 11, the term "heteroaryl" preferably means 2-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 2-pyridazinyl, 2-triazinyl, 2-imidazolyl and the like, more preferably 2-pyridyl and 2-imidazolyl, and more preferably 2-pyridyl. The term "lower alkyl" preferably means an alkyl chain containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, n-pentyl, neopentyl, tert-pentyl, and n-hexyl; preferably methyl, ethyl, n-propyl or n-butyl, more preferably methyl, ethyl or n-propyl. The term "nitrogen containing heterocycles" preferably means morpholino, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrazinyl and the like, more preferably piperazinyl and morpholino, and more preferably piperazinyl. . The term "phenyl group (s) containing an amino, amidino or guanidino group" preferably means 4-aminophenyl, 4-amidinophenyl, 4-guanidinophenyl and the like. In the definition of R13, the term "a radical derived from natural or non-natural amino acids" preferably means hydrogen or lower alkyl which may be substituted with hydroxyl, amino, guanidino, methylthio, mercapto, carbamoyl, carboxyl, phenyl, hydroxyphenyl, aminophenyl , imidazolyl or iyl and the like. The preferred version of R 13 is lower alkyl substituted with amino or guanidino such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 4-guanidinobutyl. In the definition of R14, the term "lower alkyl" means the same as defined for R1C and R11. Preferably, it means an alkyl chain of 2 to 5 carbon atoms such as ethyl, propyl, butyl and pentyl. The term "heterocycles containing nitrogen" means the same as defined for Rlf1 and R1 1. Preferably, it means morpholino, piperazinyl, N-methylpiperazinyl, pyrrolidino, piperidinyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrazinyl and the like, more preferably piperazinyl and morpholino. The term "phenyl group (s) containing an amino, amidino or guanidino group" preferably means 4-aminophenyl, 4-amidinophenyl, 4-guanidinophenyl and the like. The preferred version for R 14 is 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-guanidinoethyl, 3-guanidinopropyl, 2-piperazinoethyl, 2-morpholinoethyl, 4-aminophenethyl and the like. In the definition of Ri5, the terms "lower alkyl", "nitrogen containing heterocycles" and "phenyl group (s) containing an amino, amidino or guanidino" are the same as defined for RXU. The preferred version of R15 is 2- aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-guanidinoethyl, 3-guanidinopropyl, 2-piperazinoethyl, 2-morpholinoethyl, 4-aminophenethyl and the like. Preferred versions of -N (R? P) -R 11 [wherein R 10 and R 11 are as defined above], are amino, 5-aminopyrid-2-ylamino, methylamino, ethylamino, propylamino, (2-aminoethyl) amino) (3-aminopropyl) amino, [3- [(3-aminopropyl) amino] propyl] amino, (2-piperazinylethyl) amino, (2-morpholinoethyl) amino, N, N-dimethylamino, N, -diethylamino, N, N-dipropylamino, N, -ethylmethylamino , N, N-bis (2-aminoethyl) amino, N, N-bis (3-aminopropyl) amino, N, N-bis (4-aminobutyl) amino, N, N-bis (2-piperazinylethyl) amino, N , N-bis (2- (morpholinoethyl) amino, N, N-bis (2-guanidinoethyl) amino, N, N-bis (3-guanidinopropyl) amino, N, N-bis (2-pyridin-2-ylethyl) amino, N, N-bis (imidazol-2-ylmethyl) amino, N- (2-aminoethyl) -N- (3-aminopropyl) amino, N- (3-aminopropyl) -N- (2-piperazinylethyl) amino, N- (3-aminopropyl) -N- (2-pyridin-2-ylethyl) amino and the like The most preferred versions are amino, 5-aminopyrid-2-ylamino, N, N-dimethylamino, (2-aminoethyl) amino (3-aminopropyl) amino, [3- [(3-aminopropyl) amino] ropil] amino, (2-piperazinylethyl) amino, N, N-bis (2-aminoethyl) amino, N, N-bis (3-aminopropyl) amino, N, N-bis (4-aminobutyl) amino, N, N-bis (2-piperazinylethyl) amino, N , N-bis (2-guanidinoethyl) amino, N, N-bis (3-guanidinopropyl) amino, N- (2-aminoethyl) -N- (3-aminopropyl) amino, N- (3-aminopropyl) -N- (2-piperazinylethyl) amino and the like. The most preferred versions are (3-aminopropyl) amino, N, N-bis (2-aminoethyl) amino, N, N-bis (3-aminopropyl) amino and N, N-bis (2-piperazinylethyl) amino. In the definition of -N (R15) -CO-CH [N (R10) R11] -R13, the group -CO-CH [N (R: R:? -R: [wherein R10 and R11 are hydrogen; R1"" is a radical derived from natural or unnatural amino acids ", preferably means sarcosyl, glycyl, alanyl, ornitinyl, lysyl, valyl, leucyl, isoleucyl, tryptopyl, phenylalanyl, methionyl, seryl, tyrosyl, threonyl, cysteinyl, asparaginyl, glutayl, aspartyl, glutamyl, arginyl, histidyl, 2,3-diaminopropionyl, 2,4-diaminobutyryl, 2-amino-4-triazol-1-ylbutyryl, and the like.

Preferred versions of -N (R ~~) -COCH [N (R10) R11] -R13 are acylamino groups derived from basic amino acids. Examples of said acylamino groups are ornithinylamino, lysilamino, arginylamino, histidylamino, 3-aminopropylamino, 2,3-diaminopropionylamino, 2,4-diaminobutyrylamino, 2-amino-4-triazol-1-ylbutyrylamino, [3-amino-2- [bis] (2-aminoethyl) amino] propionyl] amino, [4-amino-2- [bis (2-aminoethyl) amino] utyryl] amino, [5-amino-2- [bis (2-aminoethyl) amino] valeryl] amino , N- (3-amino ropil) -N- (2,3-diaminopropionyl) amino, N- (3-aminopropyl) -N- (2,4-diaminobutyryl) amino, N- (3-aminopropyl) -N- (2 , 5-diaminovaleryl) amino, N- (3-aminopropyl) -N- (2,6-diaminohexanoyl) amino and the like; more preferably ornithinylamino, lysilamino, arginylamino, histidylamino, 3-aminopropylamino, 2,3-diaminopropionylamino, 2,4-diaminobutyrylamino, 2-amino-4-triazol-l-ylbutyrylamino, [3-amino-2- [bis (2 -aminoethyl) amino] propionyl] amino, [4-amino-2- [bis (2-aminoethyl) amino] butyryl] amino, [5-amino-2- [bis (2-aminoethyl) amino] valeryl] amino, N - (3-aminopropyl) -N- (2, 3-diaminopropionyl) mino, N- (3-aminopropyl) -N- (2, 4-diaminobutyryl) amino, N- (3-aminopropyl) -N- (2, 5-diaminovaleryl) amino and N- (3-aminopropyl) -N- (2,6-diaminohexanoyl) amino and the like; more preferably, ornithinylamino, lysilamino, arginylamino, histidylamino, 2, 3-diaminopropionylamino, 2,4-diaminobutyrylamino, [3-amino-2- [bis (2-aminoethyl) amino] propionyl] amino, [4-amino-2 - [bis (2-aminoethyl) amino] butyryl] amino, [5-amino-2- [bis (2-aminoethyl) amino] valeryl] amino, N- (3-aminopropyl) -N- (2,3-diaminopropionyl) amino), N- (3-aminopropyl) -N- (2, -diaminobutyryl) amino, N- (3-aminopropyl) -N- (2, 5-diaminovaleryl) amino and N- (3-aminopropyl) -N- (2,6-diaminshexanoyl) amino, with higher reference, ornithinylamino, lysilamino, 2,4-diaminobutyrylamino, [4-amino-2- [bis (2-aminoethyl) amino] butyryl] amino, [5-amino-2- [bis (2-aminoethyl) amino] valeryl] amino, N- (3-aminopropyl) -N- (2, 4-diaminobutyl) amino, N- (3-aminopropyl) -N- (2,5-diaminovaleryl) amino and N- (3-aminopropyl) -N- (2,6-diaminohexanoyl) amino. In the definition of R? the preferred version of is bis [2- (ornithylamino) ethyl] amino, bis- [3- (ornithylamino) propyl] amino, [2- (lysylamino) ethyl] amino, bis- [3-lysylamino) propyl] amino and the like. In the definition of R1, the preferred version of is N-ornityl-N- [2- (ornithylamino) ethyl] -amino, N-ornityl-N- [3- (ornithylamino) propyl] -amino, N-ornityl-N- [3- (lysylamino) propyl] amino , N-ornithyl-N- [3- (lysylamino) propyl] amino, N-lysyl-N- [2- (ornithylamino) ethyl] amino, N-lysyl-N- [3- (ornithylamino) propyl] -amino, N-lysyl-N- [2- (lysilamino) ethyl] amino, N-lysyl-N- [3- (lysylamino) propyl] amino, and the like. In the definition of R1, the preferred version of is prolylamino, 3-aminoprolylamino, 4-aminoprolylamino, N- (3-aminopropyl) -N-prolylamino, (2-aminoethyl) prolylamino and the like. The term "-NHCOCH (R13) -NHCOCH (NH) -R 13, [wherein R13 is as defined above], preferably means ornithyl-ornithylamino, lysyl-ornithylamino, ornitylyl-lysilamino, lysyl-lysylamine and the like In the term "-N (R15) -CO-R14" [where R14 and R 15 are as defined above], the term "nitrogen containing heterocycle" and the term "phenyl group (s) containing an amino, amidino or guanidino group, are as defined above." Preferred versions of -N (R15) -CO-R14 are 3-aminopropionylamino, 3-guanidinopropionylamino, 3-piperazinylpropionylamino, (3-pyridin-3-ylpropionyl) amino, [3- (4-aminophenyl) propionyl] amino, N- (3-aminopropionyl) -N- (3-aminopropyl) amino and similar. In a preferred aspect, R1 is -N (R10) R1: L wherein R ~ ° and R11 are as defined above. In another preferred aspect, R1 is -N (R15) -CO-CH [N (R10) R11] -R13, wherein R? N, R *!, R13 and R15 are as defined above. In another preferred aspect R1 is -N (R15) -CO-R1, wherein R14 and R15 are as defined above. In another preferred aspect, R1 is -N (R ') wherein R10 and R1 are as defined above. In another preferred aspect, R1 is -NHCOCH (R-3) -NHCOCH (NH;) -R13 wherein R13 is as defined above. In another preferred aspect, R "is lower trialkylammonium In still another preferred aspect, R1 is amino or guanidino In the definition of R ~, the term" optionally substituted lower alkyl, with acyl, carboxyl, carbamoyl, amino, mono-lower alkylamino or "lower dialkylamino" preferably means methyl, ethyl, n-propyl, isopropyl, butyl, oxo-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, amino-lower alkyl and the like, more preferably, methyl, ethyl, propyl, n-butyl, 2-oxopropyl, carboxymethyl, carbamoylmethyl, 3-aminopropyl and the like The term "lower alkenyl optionally substituted by acyl, carboxyl, carbamoyl, amino, mono-lower alkylamino or lower alkylamino", preferably means allyl, 2-butenyl, 3-butenyl and the like, more preferably, allyl In a preferred aspect, R 2 is hydrogen, hydroxysulfonyl or lower alkyl such as methyl or ethyl.

In the definition of R ", the term" acylamino "preferably means lower alkylcarbonylamino such as acetylamino, propionylamino or isobutyrylamino, or an acylamino group derived from natural or non-natural amino acids such as sarcosylamino, glycylamino, alanylamino, ornithylamino, lysylamino, prolylamino , valylamino, leucylamino, isoleucylamino, triptophylamino, phenylalanylamino, methionylamino, serylamino, tyrosylane, threoylamino, cysteinylamino, asparaginylamino, glutamylamino, aspartylamino, glutamylamino, arginylamino, histidylamino and the like, preferably sarcosylamino, glycylamino, alanylamino, lysilamino, prolylamino and the like. The term "(lower alkylcarbamoyl) amino" preferably means methylcarbamoylamino, ethylcarbonylamino, propylcarbamoylamino, butylcarbamoylamino and the like, more preferably methylcarbamoylamino or ethylcarbamoylamino The term "lower alkoxy" preferably means methoxy, ethoxy, propoxy, butoxy and the like, more preferably methoxy and ethoxy. The term "lower alkoxycarbonyl" preferably means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like, more preferably methoxycarbonyl and ethoxycarbonyl.

The term "lower alkyl which may be optionally substituted by hydroxy, amino, mono-lower alkylamino, lower alkylamino, lower alkoxycarbonyl or carbamoyl", preferably means methyl, ethyl, propyl, aminomethyl, aminoethyl, aminopropyl, hydroxymethyl, hydroxyethyl, methylaminomethyl, 2- (methylamino) ethyl, 3- (methylamino) propyl, dimethylaminomethyl, 2- (dimethylamino) ethyl, 3- (dimethylamino) propyl, 2- (methoxycarbonyl) ethyl, 2- (carbamoyl) ethyl and the like. The term "lower alkenyl which may be optionally substituted with hydroxyl, amino, ono-lower alkylamino, lower alkylamino, lower alkoxycarbonyl or carbamoyl", preferably means vinyl, 2- (methoxycarbonyl) vinyl, 2- (carbamoyl) vinyl and Similar. The term "lower alkynyl which may be optionally substituted by hydroxyl, amino, mono-lower alkylamino, lower alkylamino, lower alkoxycarbonyl or carbamoyl", preferably means ethynyl, propynyl, hydroxypropyl, aminopropynyl, diethylaminopropynyl and the like. In a preferred aspect, R3 is hydrogen, hydroxyl, nitro, amino or acylamino. In another preferred aspect R3 is (lower alkylcarbamoyl) amino, carboxyl, lower alkoxy or lower alkoxycarbonyl. In the definition of R 4, the term "alkyl, alkenyl, alkoxy or alkenyloxy" preferably means an alkyl, alkenyl, alkoxy or alkenyloxy group containing from 3 to 16 carbon atoms, such as propyl, butyl, pentyl, hexyl, heptyl, octyl, oct-4-enyl, oct-6-enyl, nonanyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, propoxyl, butoxyl, pentyloxy, hexyloxy, heptyloxy, octyloxy, oct-4-enylyl, oct-6-enyloxy, nonanyloxy, non-5-enyloxy, decyloxy and the like. The term "lower alkyl" preferably means methyl, ethyl, propyl, butyl, pentyl, more preferably methyl or ethyl. The term "aryl" means an aryl group which may be optionally substituted with lower alkyl, trifluoromethyl or halogen atom (s), such as phenyl, naphthyl, 3-fluorophenyl, 3-bromophenyl, 3-chlorophenyl, 4-fluorophenyl, -bromo phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl.

The term "cycloalkyl" preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like. The term "alkyl, alkenyl, alkoxy or alkenyloxy, which may be optionally substituted with lower alkyl, aryl, cycloalkyl or fluorine atom (s)" preferably means 5-methylhexyl, 1-methyltridecyl, 2-ethylbutoxy, 4-methylpentyloxy, 2-propylpentyloxy, 2-ethylhexyloxy, 3,7-dimethyloctyloxy, 2-phenylethoxy, 2- (4-fluorophenyl) ethoxy, 2- (4-chlorophenyl) ethoxy, 2- (3-fluorophenyl) ethoxy, 2- (4- trifluorophenyl) ethoxy, 3-phenylpropoxyl, 2-naphthylethoxy, 3-naphthylpropoxyl, 2-cyclopropylethoxy, 2-cyclobutylethoxy, 2-cyclopentylethoxy, 3-cyclopentylpropoxy, 2-cyclohexyl-ethoxy, 3-cyclohexylpropoxy, 3,3-diphenylpropoxy, 3, 3, 3-trifluoropropoxy, 4,4,4-trifluorobutoxyol, 5, 5, 5-trifluoropentyloxy and the like. In a preferred aspect, R is alkyl or alkoxy which may be optionally substituted with lower alkyl, aryl, cycloalkyl or fluorine atom (s). The preferred versions of R5 are -CONH2 or CHNH ..

In the definition of _X, the term "heteroatom" preferably means nitrogen, sulfur and oxygen. The term "aryl, biphenyl or terphenyl optionally containing one or more heteroatom (s), preferably means, XXX • N ^ = N and the like, which can be subsequently substituted with halogen atom or lower alkyl. The lines with open ends in the above formulas indicate the preferred union in the corresponding position. The most preferred version of X is a simple link, which can be subsequently substituted with halogen atom (s) or lower alkyl, preferably methyl. In the definition of Y, the term "lower alkyl" preferably means an alkyl group containing from 1 to 3 carbon atoms, for example methyl, ethyl or propyl. The preferable version of Y is a single bond, -CH_-, -CH (CHJ-, -CONH- or -C0N (CH3) -, more preferably a single bond, -CH (CH) - or -CONH-. In the definition of Z, the term "-N (lower alkyl) -" preferably means an N-alkyl group consisting of 1 to 3 carbon atoms, for example N-methyl, N-ethyl or N-propyl. A preferred version of Z is -0-, another preferred version of Z is -NH-, m is an integer from 0 to 4, preferably 0 to 2.

Preferred aerotricins according to the present invention are aerotricins 2 and 4 to 131, Coma is exemplified in the following table 1.

Table 1 Formula (I) Fóxula (I) Name Compound R go R "Y- (CH2) m-X-R AeáDotricino 31 HH CH2 H2 O (CH2.12CH3 Aerotricino 32 NH2 HH CN O (CH2) i2CH3 Aerotricino 33 NH2 HH CONH2 NH Aerotricino 34 NH2 HH CONH2 NH Aerotricino 35 NHT HH CONH2 NH Aerotricino 36 NH2 HH CONH2 NH (CH2) j- ^ ^ 0 (CH2) sCH- Aerotricino 37 NH2 H H CONH2 NH lt > .? -} -q? and "CH3 Aerotricino 38 NH2 H H CONH2 NH (CHj) 2- ^ - aCH¿íCH (CH, HCHys.CH (C Aerotricino 39 NH2 H N02 CONH2 NH (CH2 i CHi3 Aerotricino 40 NH2 HH CONH2 NH (C "^: - - (^ - CX8Í Aerotricino 41 NHi HH CONH2 NH (CHJ = - ~" ^^^ Aerotricino 42 N? 2 HH CONH2 NH Aerotricino 43 NH2 H H CONH2 NH Aerotricino 44 NH2 H H CONHT NH < »And» - "O" OICHJ 1.

Aerotricino 45 NH2 H H CONH2 NH (CH ^ .- ^ - ^ H OíCHJ-CHCH ^ - Aerotricino 46 NH2 H H CONH2 NH Aerotricino 47 NH H H CONH2 NH < Oy, - v ^ - (C «ACM, NH2 H H CONH2 NH Aerotricino 48 'OtCH .CH.

Aerotricino 49 NH2 CONHT NH 0 (CH-) 4CH- Aerotricino 50 NH. (CH,). H H CONH. NH x OtCH ^ CH, Formula (i; '(S) configuration Formula (I) Formula (I) Nccrfore Formula (I) Configuration (R) Particularly preferred are aerotricins selected from the group consisting of aerotricins 2, 4 to 32, 63, 96-99, 101 to 131. Aerotricins selected from the group consisting of aerotricins 14, 15, 21 are also particularly preferred. , 26-29, 63, 98, 99, 101-131. The aerotricins represented by the formula (I) can be obtained according to the following methods: Procedure A The aerotricins of formula (II) can be obtained by culturing a microorganism belonging to the Deuteromycocins capable of producing aerotricins 1, 2 and 3 [aerotricin 3 (= F11243) is described in reference example 1] under aerobic conditions in an aqueous or solid medium and isolating aerotricins 1, 2 and 3 from the culture. [where RJ is hydrogen or hydroxyl, Y is -CH (CHj) - or -CH_-] Method B Aerotricins of formula (I) [wherein R 1 is amino; Y is -CONH-, -CON (lower alkyl) -, -CH_ or a single bond; Z is -NH- or -N (lower alkyl) -; R ~, R ~, RU R "X and m are as defined above], and may be obtained by condensation of a compound of formula (III), [wherein R6 is an amino protection group; R :, R5 and R5 are as defined above], with a compound of formula (IV), [wherein R is an amino protection group; R is hydrogen or lower alkyl; R4, X, Y and m are as defined above], employing a carboxyl activating agent for the synthesis of peptides, followed by selective removal of the amino protecting group, R7, from the resulting linear peptide, successive cyclization with a carboxyl activating agent for peptide synthesis, and removal of the amino protecting group, R? Process C The aerotricins of formula (I) [wherein R "is a nitro group; R1, R2, R4, R5, X, Y, Z and m are as defined above], can be obtained by nitration of the aerotricines of formula (I) [wherein RJ is hydrogen; R RU R? R? Y.Z and m are as defined above] Procedure D Aerotricins of formula (I) [wherein RJ is an amino R1, R2, R ", R ', X, Y, Z and m are as defined above], can be obtained by reducing the nitro group of aerotricins of formula (I) [wherein R 3 is a nitro group; RU R R X X. Y, Z and m are as defined above] Process E The aerotricins of formula (I) [wherein R 3 is acylamino or (lower alkylcarbamoyl) amino; R1, R2, R4, R5, X, Y, Z and m are as defined above], can be obtained by acylation of the amino group of the aerothricins of formula (I) [wherein R3 is an amino group; R1, R2, R R? X, Y / Z and m are as defined above], with acid chloride, acid anhydride, carboxylic acid / condensing agent or lower alkylcarbamoyl chloride, followed, if necessary, by removal of the amino protecting group . Process F Aerotricins of formula (I) [wherein R 1 is (3-aminopropyl) amino, (2-cyanoethyl) amino, 3-amino-2- (aminomethyl) propyl] amino or -N (R 15) -COCH [NH (CH;) 5NH:] -R13 [wherein R13 and R15 are as defined above], can be obtained by reacting the amino group of the aerothricins of formula (I) [wherein R1 is an amino group or -N (R15) -COCH (NHJ -R13 [wherein R13 and R15 are as defined above], R, R3, R4, R5, X, Y, Z and m are as defined above], with acrylonitrile, ethoxymethylenemalonitrile or (1-ethoxyethylidene) malononitrile, followed by reduction of the resulting nitrile group (s) to amino group (s), and if necessary, elimination of the group (s) protector (s) Process G Aerotricins of formula (I) [wherein R1 is [wherein R? n and R11 are each independently selected from the group consisting of hydrogen, lower alkyl optionally substituted with one or more amino, guanidi no, nitrogen containing heterocycle group (s) or phenyl (s) containing an amino, amidino or guanidino group] or -N (R15) -CO-CH [N (R1C) R :? -R13 [wherein R1C and R11 are each a lower alkyl optionally substituted with one or more amino group (s), amino-lower alkyl, guanidino, nitrogen or phenyl containing heterocycle (s), containing an amino, amidino or guanidino group; R13 and R15 are as defined above]; R 2, R 3, R 4, R 5, X, Y, Z and m are as defined above], can be obtained by reductive alkylation of the amino group of aerothricins of formula (I) [wherein R 1 is amino, (2-cyanoethyl) amino or -N (R ^) -CO-CH [N (R? n) Rn] -R13 [wherein R10 and R11 are each independently a hydrogen atom or (2-cyanoethyl) amino; R12 and R1 £ are as defined above]; R ~, R3, R4, R5, X, Y, Z and m are as defined above], with an aldehyde of formula (V), RQ-CHO (V) [wherein R9 is hydrogen, lower alkyl which it may be further substituted with one or more protected amino group (s), nitrogen-containing heterocycle (s), or phenyl containing a protected amino group], followed, if necessary, by removal of the group (s) of protection of the amino, or by the reduction of a cyano group. Procedure H Aerotricins of formula (I) [wherein R 1 is -N (R 1X0U) v -R > 11 [wherein R1 11 and R1 are each independently from each other, selected from the group consisting of hydrogen or heteroaryl substituted with one or two amino group (s); R2, R3, R4, R5, X, Y, Z and m are as defined above], can be obtained by reaction of the amino group of the aerothricins of formula (I) [wherein R1 is an amino group; R2, R3, R4, R5, X, Y, Z and m are as defined above], with a compound of formula (VI), R12-Q (VI) [wherein R12 is a heteroaryl containing nitrogen, which may also be substituted with a protected amino group or a nitro group, Q is a halogen atom such as chlorine or bromine], followed, if necessary, by the removal of a protected amino group or by the reduction of a group nitro. Procedure 1-1 Aerotricines of formula (I), [where R1 is, -NHCO-CH (NH2) -R1"[wherein R13 is a radical derived from natural or unnatural amino acids] or -NHCO-R1 '[wherein R14 is as defined above]; R ~, R", R4, RU X, Y, Z and m are as defined above], can be obtained by acl ation of the amino group of the aerot ricines of formula (I) [wherein R. is an amino group; R., R3, R4, R5, X, Y. Z and m are as defined above], with an acid of formula (VII) or (VII '), HO (O =) C-CH (NH-R -R1 (VII) [wherein R1"'is a radical derived from natural or non-natural amino acids whose functional group is suitably protected, R7 is an amino protecting group], or an acid of formula (VIII), HO (0 =) CR I. (VIII- [wherein R 14 is lower alkyl having one or more protected amino group (s), nitrogen containing heterocycle (s) or phenyl group (s) containing the protected amino group], followed, if necessary, by the removal of the protective group (s) Procedure 1-2 Aerotricins of formula (I) wherein R 1 is [where RX? R ", Ri3, R15 and m are as defined above], or [wherein R1", Ru, R13, R15 and m are as defined above] can be prepared by acylation of the amino group of the aerothricins of formula (I), wherein R1 is -N (R10) -R11 [wherein R10 and R11 are both alkyl substituted with an amino] or -N (R15) -CO-CH [N (R1C) R11] R13 [wherein R-1 is lower alkyl substituted with an amino group; R1C, R11, R13 are as defined in claim 1, with the proviso that the amino group (s) present in R? N, R11 and RJ are protected], with an acid of formula ( VII) HO (0 =) C-CH (NH-R7) -R1 (VII) [wherein R * "is a radical derived from natural or non-natural amino acids whose functional group is suitably protected, R" 7 is an amino protecting group]; followed by the elimination of the protective group (s). Procedure J The aerotricins of formula (I) [wherein R1 is N (R, 115D,) -CO-CH [NÍR1) R '? -R [wherein R-1 and R 11 are hydrogen, R, 113J is as defined above and R15 is lower alkyl optionally substituted with one or more amino, guanidino, nitrogen-containing heterocycle (s) or phenyl group (s) containing an amino, amidino or guanidino group], [wherein R 1 C is hydrogen and R 5 is lower alkyl optionally substituted with one or more amino groups, guanidino, nitrogen containing heterocycle (s), or phenyl group (s) containing an amino, amidino or guanidino group], or -N (R15) -CO-R14 [wherein R15 is lower alkyl optionally substituted with one or more amino groups, guanidino, nitrogen-containing heterocycle (s) or phenyl group (s) containing an amino, amidino or guanidino group, R14 is as defined above]; R ~, R3, R4, RX, Y, Z and m are as defined above], can be obtained by mono N-alkylation of the amino group of the aerothricins of formula (I) [wherein R1 is an amino group; R, R 3, R R 5, X, Y. Z and m are as defined above] as described in process F, followed by acylation with the corresponding compound of formula (VII), (VII ') or (VIII), as described in. procedure I, followed, if necessary, by the removal of the protective group (s). Method K Aerotricins of formula (I) [wherein R 1 is a guanidino group, -N (Rlu) -R 11 [wherein R 10 and R 11 are independently selected from the group consisting of lower alkyl substituted with guanidino or group (s) ) phenyl. containing a guanidino group], -N (Ri, J) -CO-CH [N (RiU) R11] -R, 113-5 [where R 1x0u and R ~ x and R, 113 are as defined above and R 15 is lower alkyl optionally substituted with one or more guanidino group (s), nitrogen containing heterocycle (s) or phenyl group (s) containing a guanidino group] or N (R 15) CO-R 14 [wherein R 14 is lower alkyl substituted with one or more guanidino group (s), nitrogen-containing heterocycle (s), or phenyl group (s) containing a guanidino group; R2, R R R? X, Y, Z and m are as defined above], can be obtained by reaction of the aerothricins of formula (I) [wherein R 1 is an amino group, -N (R 10) -R [wherein R 10 and R 11 are independently selected from the group consisting of lower alkyl substituted with amino group (s) or phenyl group (s) containing an amino group], -N (R15) -CO- [wherein RX? R11 and R13 are as defined above and R15 is lower alkyl optionally substituted with one or more amino group (s), nitrogen containing heterocycle (s) or phenyl group (s) containing an amino group]; or -NHCO-R14 [wherein R14 is lower alkyl substituted with one or more amino group (s), nitrogen-containing heterocycle (s) or phenyl group (s) containing an amino group; R2, R3, R4, R5, X, Y.

Z and m are as defined above], with an activated derivative of amidine. Process L The aerotricins of formula (I) [wherein R- is lower alkyl or lower alkenyl optionally substituted with acyl, carboxyl, carbamoyl, hydroxyl, amino, monoalkylamino lower or di-lower alkylamino, R1, R3, R4, R5, X , Y, Z and m are as defined above], can be obtained by O-alkylation of the phenolic hydroxyl group of the aerothricins of formula (I) [wherein R 2 is hydrogen; R1, R3, R, Rs, X, Y, Z and m are as defined above], with an alkylating agent. Process M Aerothricines of formula (I). [Wherein RJ is carboxyl, lower alkoxycarbonyl, lower alkyl, alkenyl or alkynyl, which may be optionally substituted by hydroxyl, amino, mono-lower alkylamino, di-lower alkylamino, alkoxycarbonyl lower or carbamoyl; R "is hydrogen, R1, R4, R5, X, Y, Z and m are as defined above], can be obtained by iodination of formula aerotricins (I) [wherein R2 and R3 are hydrogen; R1, R4, R5, X, Y, Z and m are as defined above], with an iodinating agent, followed by palladium (0) catalyzed coupling of the resulting iodinated derivative of formula (I) [wherein R3 it is an iodine; R1, R2, R4, RX, Y, Z and m are as defined above], with carbon monoxide, methyl acrylate and the like, and, if necessary, by removal of the group (s) protector (is) Procedure N The aerotricins of formula (I) [wherein RE is -CN; R1, R2, R3, R4, X, Y, Z and m are as defined above], can be obtained by dehydration of the carbamoyl group of the aerothricins of formula (I) [wherein R5 is -CONH2; R1, R2, R3, R4, X, Y, Z and m are as defined above], with a dehydrating agent, and if necessary, by elimination of the protecting group (s) of the amino . Procedure O The aerotricins of formula (I) [wherein R5 is -CH; NH;; R1, R2, R ~ R4, X, Y, Z and m are as defined above], can be obtained by reduction of the carbamoyl or cyano group of the aerothricins of formula (I) [wherein R = is -CONH; or -CN; R1, R2, R3, R4, X, Y, Z and m are as defined above], with a reducing agent, and if necessary, by elimination of the protecting group (s) of the amino .

Process P The aerotricins of formula (I) [wherein R 2 is hydroxysulfonyl R 1, R 3, R 3, R 5, XYZ and m are as defined above], can be obtained by hydroxysulfonation of the tyrosine radical of aerothricins of formula (I) [wherein R2 is hydrogen; R1, R3, R3, R5, X, Y, Z and m are as defined above], followed by removal of the protecting group (s). Procedure O The aerotricins of formula (I) [wherein Y- (CH2) m-X-R4 - is n-trideeanyl or 1-methyltrideeanyl, R5 - is -CONH2, Z is an oxygen atom and R1, R2 and R3 are as defined above] can be obtained from the linear peptide of "formula (TX) by the method described in reaction scheme I. The compound of the above formula (III), wherein R2, R3 and R5 are as defined above, and R6 is an amino protecting group, with the proviso that when R5 is -CONH2, then R2 or R3 are other than hydrogen , and the salts thereof are new and are also subject to the present invention In addition, the linear peptides of formula (IX), (X) and (XII) shown in scheme 1 and optionally the salts thereof are new and are also subject to the present invention.

Reaction Scheme 1 The processes A to Q can be illustrated in more detail as follows: Procedure A The microorganism used in the preceding invention can be any strain including mutants and variants belonging to Deuteromicotin capable of producing aerothricins 1, 2 and 3. Especially preferred is the NR strain 7379 that was isolated from the warm leaves collected in Kagoshima pref. in Japan, and identified as a strain belonging to Deuteromicotina. The cultivation and morphological characteristics of strain NR 7379 are as follows: 1. Characteristics of the crop Corn meal agar (CMA): The growth was not extensive. The colonies reached 11 mm in diameter from the inoculum (4.5 mm agar plug diameter) after 14 days at 25 ° C. They were flat and pale cream yellow in color. The reverse side was pale cream yellow. They also speak colorless mucilaginous exudates. Middle of Miura (LCA): The growth was not extensive. The colonies reached 11 mm in diameter from the inoculum after 14 days at 25 ° C. They were flat and pale cream yellow in color. The reverse side was pale cream yellow. There were no exudates. Malt extract agar (MEA): The growth was not extensive. The colonies were pustuliform and reached a diameter of 18 mm from the inoculum after 14 days at 25 ° C. The color of the colonies was light yellowish brown. The reverse side was the same color. The exudates were colorless and mucilaginous. Potato-Dextrose Agar (PDA): Growth was not extensive. The colonies were pustuliform and reached 14 mm in diameter from the inoculum after 14 days at 25 ° C. The color and texture of the colonies was similar to those of MEA. The exudates were colorless and mucilaginous. Germination was observed between 5 ° C and 30 ° C on CMA, LCA, MEA and PDA. 2. Morphological characteristics The mycelia were partially submerged, partially superficial, branched, septated, and light brown to "creamy yellow." The conidiophores were formed from the submerged mycelium, were hyaline, septated, irregularly branched, and the conidiogenic cells were on separate conidiaphors or hyphae. They were enteroblastic, fialidic, terminal or subterminal The terminal or subterminal fialides were variable in length and shape, they were of cylindrical shape to lining and their length and width were of 5.5 to 10 μm and 2.5 to 5 , 5 μm respectively, irregularly filiform conidisfors were often formed with conidiogenic lateral cells of septa immediately below.Conidia were single-celled, hyaline, smooth, globose to subglobose, 2.0 to 5.5 μm in length, and 2.0 at 5.0 μm wide, on the basis of these different cultivation and morphological characteristics, This strain belonged to the Deu teromyco tub, and was designated by the name of Deuteromycotina NR 7379. The strain designated as the Deuteromycotina NR 7379 has been deposited at the National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology , Japan with Nippon Roche KK name, 6-1, Shiba 2-chome, Minato-ku, Tokyo 105 Japan on June 16, 1998, according to the Budapest Treaty, as follows: Deuteromycotina NR 7379 (FERM BP -6391). The culture according to the method provided by the present invention can be carried out in a culture medium containing the customary nutrients customary in the microorganism to be cultivated. Examples of carbon sources which can be mentioned are glucose, sucrose, starch, glycerin, molasses, dextrin and mixtures thereof. Nitrogen sources are for example, soybean meal, flour, cotton seed, meat extract, peptone, dried yeast, yeast extract, extract of corn germ, ammonium sulfate, sodium nitrate and mixtures thereof . Furthermore, it may be added to the culture medium other organic or inorganic substances to promote the growth of the microorganism and for increasing the production of aerotricino 1. Examples of such substances are inorganic salts such as calcium carbonate, sodium chloride, phosphates and Similar . The cultivation is carried out under aerobic conditions preferably in a liquid medium by submerged fermentation or in a solid medium by static fermentation. A temperature of 20 ° C to 30 ° C, with an optimum temperature of 27 ° C is suitable for cultivation. The culture is preferably carried out at pH 3 to 9. The duration of the culture depends on the conditions in which the culture is effected. In general, it is sufficient to carry out the cultivation for 20 to 360 hours. For the collection of aerotricines 1, 2 and 3 of the crops, the separation methods usually used to isolate the metabolites produced by the microbes in their crops can be used correctly. For example, aerotricin 1, which is an amphoteric substance extractable with methanol, is advantageously separated by the following methods: All the solid culture obtained is extracted by fermentation in the solid state, by means of an appropriate solvent to separate the proposed product. Solvents that can be used to extract the subject compound from the total culture include water-soluble solvents or aqueous solutions of water-soluble organic solvents, such as methanol, ethane and hydroalcohols. For the separation of salts, water-soluble substances, etc. from the resulting extract, the method of distribution in a solvent, between water and organic solvents immiscible in water, such as n-butanol, ethyl acetate, etc., is used with advantage. To eliminate the coloring substances, fat-soluble substances or the like, from the extract, the purification of the solvent by methanol, ethanol, a mixture of acetonitrile-0.1% aqueous trifluoroacetic acid, etc. is advantageously used. For the complete purification of the aerotricin, a chromatographic column is preferably used. The supports that can be used in said chromatographic column are for example YMC-GEL ODS (Yamamura Chemical Laboratories, Japan) or Preparative C18 (Waters Millipore Corporation). As the eluent, a solvent system consisting of a mixture of aqueous trifluoroacetic acid and suitable water-soluble organic solvents such as methanol, ethanol, acetonitrile, etc. is employed. The eluate fraction thus purified, which contains each component, can be subjected to concentration or freeze-drying to pulverize aerotricinos 1, 2 and 3. aerotricinos 1, 2 and 3 were isolated as the trifluoroacetic acid salt, but aerotricinos 1 2 and 3 free can be prepared by the following procedure. Trifluoroacetic acid salt of aerothricino 1 is dissolved in water, 2 and 3, one equivalent of sodium hydroxide is added, and the mixture is subjected to chromatography with a Sephadex LH-20 column, followed by elution with a hydroalcohol such as methanol-water, etc. to obtain aerotricines 1, 2 and 3 (free form), respectively. Method B The starting compound of formula (III) can be obtained from aerothricins of formula (I) [which includes aerotricins 1 to 3 as well as those converted from aerotricins 1 to 3, by employing a procedure selected from procedures C to Q] by the method similar to that described in the WO patent 96/30399. This method comprises the alkaline hydrolysis of the lactone ring followed by the enzymatic cleavage of the fatty acid chain. Preferred groups for the protection of the amino for R6 in the formula (III) and R "in the formula (IV) are tert-butoxycarbonyl (Boc) and the 9-fluorenylmethyloxycarbonyl (Fmoc), respectively. III) can also be prepared from the linear peptide of formula (IX), obtained by fermentation of Deuteromycotina, by the conventional synthesis of peptides mentioned below.

The leaving compound of formula (IV) [wherein Y is -CONH-; R4, R8 and X are as defined above] can be obtained by condensation of the compound of formula (XIV), [wherein R is an amino protecting group, such as the Fmoc group, and R8 is as defined above], with a compound of formula (XV), R8NH - (CH) n? - X - R4 (XV) [wherein R4, R X and m are as defined above], followed by removal of the tert -butyl group. The compound of formula (XIV) is commercially available. The starting compounds of formula (XV) [wherein X is a single bond, an aryl, biphenyl or terphenyl group, optionally containing one or more heteroatom (s) and / or being substituted with halogen atom or lower alkyl ], are commercially available or can be prepared by methods similar to those described in patent EP 736 541 and scheme 2: for example, reduction with LiAlH4 of the carboxamide prepared from the intermediate carboxylic acids in scheme 2 mentioned below, followed by protection of the amino group with Fmoc chloride and the like. Representative compounds of formula (IV) [wherein Y is -CONH- or -CON (lower alkyl) -; R4, R ~, Ry and X are as defined above], are HOU-CH.CH (NHFmoc) -CONH- (CH;) 1; CH_, HO-C-CH.CH (NHFmoc) -CONH- (CHJ?; CH?, HO_C-CH; CH (NHFmoc) -CONH- (CHJ 14CH3, HOU-CHiCH (NHFmoc) -CONH- (CH): 1CH (CH3) -, HO.C-CH; CH (NHFmoc) -CONH- (CHJ;; - CH = CH-CH; , HO; C-CH: CH (NHFmoc) -CONH- (CH;) = -CH = CH- (CHJ 3CH3, HO; C-CH; CH (NHFmoc) -CONH (CH3) - (CHJ 1: CH3, H02C-CH2CH (NHFmoc) -CONH (CH3) - (CH2) 14 CH3, and the like The starting compound of formula IV) [in • where Y -is, run 'link - simple - or -CH2--; R4, R8"" and -X "are as defined above], can be prepared by the addition of Michael of (R) - (+) - N-benzyl-1-phenylethylamine to give a compound of formula (XVI) , [wherein R, X and m are as defined above] in the presence of a strong base such as LDA [see Tetrahedron Asymmetry, 2 (3), 183 (1991)], followed by i) N-debenzylation by hydrogenation catalytic, ii) protection of the resulting primary amine with Fmoc chloride and the like, and iii) elimination of the tere-butyl group. The starting compounds of formula (XVI) can be prepared by the method described in the following reaction scheme 2: Re du c i on Reaction Wittig or P 3P = CHC02: Bu -X. OHC '• RJ (XVI) Reaction scheme 2 The compounds of formula (XVI), wherein m is 4, can be prepared by repeating steps 1 to 3 in scheme 2 before the last Wittig reaction. Representative compounds of the formula (IV). [where Y is a simple link or -CH? -; R4, R7, and X are as defined above], are: H02C-CH2CH (NHFmoc) - (Cr ^) 12CH3 _H02C-CH2CH (NHFmoc) - ^^ - 0 (CH2) 8CH3, H02C-CH2CH (NHFmcc) - (CFÍ2) 4- ^ ^? (CH2) 4CH3, H02C -CH2CH (NHFmoc) - (CF2) 2? Q ^? (CH2) sCH3, HO2C-CH2CH (NHFmoc.) - (CF2) 2, HO2C-CH2CH (NHFmoc) - (CB,) 2 -Q -? CH2) pCH3, H02C-CH2CH (NHFm0C) - (Cr ^) 2 ~ ~ ^ 0 (CH2) BCH3, HO2C-CH2CH (HFmoc) - (CH2) 2 - < ^ - { CK2) sCH3.

H02C-CH2CH (NHFmoc) - (Ch2) '2 - = / "0 (C ^)« CH » H02C-CH2CH (NHFmoc) - (CK2.) 2- < ^ J ^ ^ O (CH2) 6CH3, H02C-CH2CH (NHF oc) - (Ch2) 2 - Q ^ - ^ -? (CH2) 3CH (CH3) 2H? 2C-CH2CH (HFmoc) - (CH2) 2- ^ -Q-OCH2CH {C2H5) HO2C-CH2CH (NHFmoc) - (CH2) 2- ^ 3_0"OCH2CH [(CH2) Í H02C-CH2CH (NHFmoc) - (CH2) 2- (~?) "OCH2CHIC2H5) H02C-CH2CH (NHF cjc) - (CH2) 2 - (^^ O { CH2) 3 - ^^, HO2C-CH2CH (NHFmoc) - (CH2) 2- ~ < 0"0 (C 2.}. ^ 3 HO2C-CH2CH (NHFmoc) - (CH2) 2- ^ ~ ^ "0 (CH2) 2 ~ 0 , , HO2C-CH2CH (NHFmocHCH,) 2 0 (CH2) .CH3 H02C-CH2CH (NHFmoc) - (Cr) 2 0 (CH2) .CH3 HO2C-CH2CH (NHFmoc) - (CHj) 2 0 (CH2) sCH3 HO2C-CH2CH (NHFmoc) - (CH2) ^ - ^) - 0Cb \ z) 3CF3 H 2 C-CH 2 CH (N (CH 3) Fmoc) - (CH 2), 4CH 3 The first reaction of formation of the peptide bond as well as the cyclization of the resulting linear peptide can be carried out by the method known to those skilled in the chemistry of peptides [see "The practice of Peptide Synthesis" (? The practice of peptide synthesis "), M. Bodansky and A. Bodansky / 2nd edition, 1994 (Springer editorial).] The preferred agent for condensation is BOP-HOBt , PyBOP ™ -HOBt, PyBroP ™ -HOBt and the like [coupling reagents: commercially available (see "The Combinatorial Chemistry Catalog" { "Catalog of combinatorial chemistry".}, Feb., 1997; Novabiochem. )] The reaction can be carried out in a solvent such as methanol, ethanol, pyridine, N, N-dimethylformamide, N-methylpyrrolidone and the like in the presence or absence of a base such as triethylamine, di-isopropylethylamine, pyridine and the like. temperature between -20 ° C and + 50 ° C, preferably at 0 ° C to + 25 ° C Process C The nitration of the aerotricino of formula (I) can be carried out by the method known to those skilled in the art; typically by sodium nitrite / acetic acid, tetranitromethane / pyridine and the like.

The reaction can be carried out at a temperature between 20 ° C and 0 ° C, preferably at 0 ° C. Method D The reduction of the nitro group (s) can be carried out by the method known to those skilled in the art; typically by catalytic hydrogenation using a catalyst such as palladium-C, platinum oxide and the like. The reaction can be carried out at room temperature in a solvent such as methanol, ethanol, acetic acid, and the like. Methods E The N-acylation of an amino group present in Rl 6 R3 of formula (I) can be carried out with an anhydride or carbamoyl chloride by the method known to those skilled in the art or with carboxylic acid using condensing agents such as dicyclohexylcarbodiimide, BOP, HBTU, TNTU, PyBroP ™, PyBOP ™, TBTU, TSTU, HOBt and the like, or the combination of two of them. The reaction can be carried out in a solvent such as methanol, ethanol, pyridine, N, N-dimethylformamide, N-methylpyrrolidone and the like, in the presence or absence of a base such as triethylamine, di-isopropylethylamine, pyridine and the like, at a temperature between -20 ° C and + 50 ° C, preferably from 0 ° C to + 25 ° C. The removal of the amino protecting group, when an N-protected amino acid is used for the condensation reaction, can be carried out by the method known to those skilled in the art, for example treatment with trifluoroacetic acid for the Boc group, or with piperidine for the Fmoc group. Process F The N-monoalkylation of an amino group present in R1 of formula (I) can be carried out using acrylonitrile, ethoxymethylene-malononitrile or (1-ethoxyethylidene) alononitrile according to the method described in Organic Synthesis col. vol. III page 93, followed by reduction of the resulting nitrile group by catalytic hydrogenation or reduction with sodium borohydride / cobalt chloride, borane-methyl sulfide complex, and the like [see J. Med. Chem., 37, 222 (1994)] . Process G The N-alkylation of the primary or secondary amino group in the R: of the formula (I) can be carried out by the conventional reductive alkylation with aldehyde derivatives of the formula (V), using a reducing agent such as sodium cyanoborohydride. in the presence or absence of a weak acid such as acetic acid. The reaction can be carried out at room temperature in a solvent such as methanol, ethanol, acetic acid and the like. Process H Examples of the compound (R12 -Q) of formula (VI) for the substitution reaction are 2-bromo-5-nitropyridine, 2-chloropyrimidine, chloropyrazine and the like. The substitution reaction can be carried out at a temperature between -20 ° C and + 50 ° C, preferably from 0 ° C to +25 ° C, in a solvent such as acetonitrile, N, N-dimethylformamide and the like, in the presence or absence of an acid binder such as potassium carbonate, triethylamine, di-isopropylethylamine and the like. Process I The first mono-N-alkylation of an amino group existing in the R: of the formula (I) can be carried out by the method described in process F. The subsequent N-acylation can be carried out by the method described in process E Process K The conversion of an existing amino group in the R 1 of the formula (I) to a guanidino group can be carried out by an activated amidine derivative such as 3, 5-dimethyl-lH-pyrazole-1-carboxamidine, acid formamidinesulfonic, benzatriazole-1-carboxamidinium tosylate and the like. The reaction can be carried out in a solvent such as methanol, ethanol, water, N, N-dimethylformamide and the like at a temperature between 0 ° C and ~ 50 ° C, preferably from 20 ° C to ~ 30 ° C. Process L The O-alkylation of a hydroxyl group of the tyrosine radical of the formula (I) can be carried out by the method known to those skilled in the art, in the presence of an acid fixative such as sodium carbonate, diisopropylethylamine and similar [Can. J. Chem., 36, 1521 (1958)]. The reaction can be carried out in a solvent such as methanol, ethanol, acetone, N, N-dimethylformamide and the like at a temperature between 0 ° C and + 50 ° C, preferably from 0 ° C to + 25 ° C. Method M The iodination in the ortho position of the phenol group in a tyrosine residue can be effected by treatment of the aerothricins of formula (I) wherein R2 is hydrogen, with iodine monochloride or sodium iodide / aqueous sodium hypochlorite in a solvent such as methanol, ethanol and the like at room temperature. The coupling reaction catalysed with palladium (0) with carbon monoxide, methyl acrylate and the like, can be carried out using a palladium (O) catalyst such as Pd (OAc) L, Pd (OAc); (dppp) 2 in a solvent such as methanol, ethanol, N, N-dimethylformamide, acetonitrile and the like in the presence of a base such as triethylamine at a temperature between 20 ° C and + 100 ° C, preferably 20 ° C at + 70 ° C [Bioorg. Med. Chem. Lett., 7 (22), 2897 (1997)]. Process N The dehydrogenation of the carbamoyl group (R5) of formula (I) can be carried out by the Burgess reagent [available from Aldrich], cyanuric chloride, oxalyl chloride and the like [see J. Med. Chem., 37, 222 ( 1994)]. The reaction can be carried out in a solvent such as N, N-dimethylformamide, N-methylpyrrolidone and the like at room temperature.

Process O The reduction of the carbamoyl or cyano group (R5) of the formula (I) can be effected by sodium borohydride / cobalt chloride, borane-methyl sulfide complex, and the like [see J. Med. Chem., 37 , 222 (1994)]. The reaction can be carried out in a solvent such as methanol, ethanol and the like, at room temperature. Process P The hydroxysulfonation of the tyrosine radical of formula (I) can be carried out by the sulfur trioxide-DMF complex, sulfur trioxide / pyridine complex, or sulfur trioxide-triethylamine complex, in a solvent such as N, N-dimethylformamide, N-methylpyrrolidone / 1,4-dioxane, tetrahydrofuran and the like, at a temperature between -30 and + 70 ° C, preferably at room temperature [see J. Chem. Soc. Perkin Trans, (6) 1739 (1990)]. Process 0 The reactions involved in this process can be carried out by methods similar to those described in the B-O process. The starting material, a linear peptide of formula (IX), can be obtained by culturing a microorganism belonging to the Deuteromicotin in aerobic conditions in an aqueous or solid medium and isolating a linear peptide of formula (IX) from the culture. The microorganism employed in the present invention can be any strain including mutants and variants belonging to Deuteromycotina capable of producing a linear peptide of formula (IX). Especially preferred is strain NR 7379 which was isolated from the fallen leaves collected in Kagoshima pref. in Japan, and identified as a strain belonging to the Deuteromycotina. The strain indicated as Deuteromycotina NR 7379 has been deposited with the National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology ("National Institute of Biological Sciences and Human Technology, Agency for Industrial Science and Technology"), Japan 16 June 1998, in accordance with the Budapest Treaty, as follows: Deuteromycotina NR 7379 (FERM BP-6391). The culture according to the method provided by the present invention can be carried out in a culture medium containing the customary nutrients employed by the microorganism that is grown. Examples of carbon sources which can be mentioned are glucose, sucrose, starch, glycerin, molasses, dextrin and mixtures thereof. Nitrogen sources are for example, soybean meal, flour, cotton seed, meat extract, peptone, dried yeast, yeast extract, extract of corn germ, ammonium sulfate, sodium nitrate and mixtures thereof . In addition, other organic or inorganic substances may be added to the culture medium to enhance the growth of the microorganism and to increase the production of a linear peptide of formula (IX). Examples of such substances are inorganic salts-S such as calcium carbonate, sodium chloride, phosphates and the like. The cultivation is carried out under aerobic conditions preferably in a liquid medium by submerged fermentation or in a solid medium by static fermentation. A temperature of 20 ° C to 30 ° C, with an optimum temperature of 27 ° C is- suitable for cultivation. The culture is preferably carried out at pH 3 to 9. The duration of the culture depends on the conditions in which the culture is carried out. In general, it is sufficient to carry out the cultivation for 120 to 672 hours. For the collection of the linear peptides in question, of formula (IX) of the cultures, the separation methods usually employed to isolate the metabolites produced by the microbes in their crops can be used correctly. For example, a linear peptide of formula (IX), which is an amphoteric substance extractable with methanol, is advantageously separated by the following procedures. All the culture broth obtained by the liquid fermentation is extracted with an appropriate solvent to separate the product in question. Solvents that can be used to extract the subject compound from the culture broth include water-soluble solvents or aqueous solutions of water-soluble organic solvents., such as methanol, ethanol and hydroalcohols, or an organic solvent immiscible with water, such as n-BuOH. For the separation of salts, water-soluble substances, etc. from the resulting extract, the method of distribution between water and organic solvents immiscible in water, such as n-butanol, ethyl acetate, etc., is used to advantage. To remove the coloring substances, substances soluble in fats or the like, from the extract, the purification of the solvent by methanol, ethanol, a mixture of acetonitrile-0.1% aqueous trifluoroacetic acid, etc. is advantageously used.

For the complete purification of a linear peptide of formula (IX), a chromatographic column is preferably used. The supports that can be used in said chromatographic column are for example Capcel Pak C18 UG80 (Shiseido Co., LTD, Japan). As the eluent, a solvent system consisting of a mixture of aqueous trifluoroacetic acid and suitable water-soluble organic solvents such as methanol, ethanol, acetonitrile, etc., is employed. The fraction of eluate thus purified, containing a linear peptide of formula (IX), can be subjected to a concentration or lysylation to spray a linear peptide of formula (IX). A linear peptide of formula (IX) was isolated as the trifluoroacetic acid salt, but the free linear peptide of formula (IX) can be prepared by the following procedure: The trifluoroacetic acid salt of the linear peptide of formula is dissolved in water (IX), to which an equivalent of sodium hydroxide has been added, and the mixture is subjected to column chromatography with Sephadex LH-20, followed by elution with a hydroalcohol such as methanol-water, etc., with what is obtained a linear peptide of formula (IX). The linear peptide of formula (IX) provided by the present invention does not exhibit any fungicidal activity against several fungi, however, it can be an intermediate key to produce a potent antifungal agent such as aerothricins. The present invention also relates to the acid addition salts of aerothricins. The acid addition salt can be obtained as the trifluoroacetic acid salt after a normal isolation process. The salt thus obtained can be dissolved in water and passed through an anion exchange column carrying the desired anion. The eluate containing the desired salt can be concentrated to recover the salt as a solid product. The aerotricins of formula (I) can be converted into a corresponding salt, by virtue of the presence of tertiary nitrogen atoms. The acid addition salt of aerotricins of formula (I) can be obtained by treating the free base of the aerotricins with at least a stoichiometric amount of an appropriate acid, such as mineral acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids, for example acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as ethanol, methanol and the like, and the acid is added in a similar solvent. The temperature is maintained around 40 ° C. The resulting salt precipitates spontaneously or can be converted into a solution with a less polar solvent. The acid addition salts of the aerotricins of formula (I) can be converted to the corresponding free base by treatment with at least a stoichiometric amount of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate. , ammonia, and the like.

The aerotricins provided by the present invention have a broad fungal activity against several fungi and can be used as agents for the treatment and prophylaxis of infectious fungal diseases. The antifungal activity in vi tro and the vi (see tables 2 and 3) as well as the toxicity to hepatocytes (see table 4) of the aerotricins of formula (I), can be seen as follows: 1. Antifungal activity in vi The antifungal activity in vi tro of the representative aerotricines of the present study was evaluated by determining the inhibitory concentration of 50% (IC50). which was calculated as the lowest concentration of an antifungal to inhibit the growth of the fungus up to 20% turbidity compared spectrophotometrically with the control growth without the drug. The IC5 values; were determined by the procedure of .micro dilution of the broth based on the NCCLS Approved Standard with the following minor modifications (National Committee for Clinical Laboratory Standards (1997).) Reference method for the analysis of antifungal susceptibility, for yeasts. Document M27-A). The Yeast Nitrogen Base ("Yeast Nitrogen Base") (YNB, Difco Lab.) Supplemented with glucose 1% and K, HP0 0.25%, was used as a means of analysis for yeast, the same medium solidified with agarose 0 , 2% low melting point (BRL), was used for filamentous fungi. The inoculum size was 1-3 x 104 cells / ml, and the incubation was carried out for 1-2 days at 35 ° C.

Table 2: Antifungal activity in vi tro, IC50 (Ug / ml) Candida Aspergillus Fusarium albicans fumigatus solani CY1002 CF1003 CF1088 • Aerotricino 1 0.03 Q.06 0.21 Aerotricino 5 0.03 0.07 0.19 Aerotricino 12 0.09 0.10 2.20 Aerotricino 31 0.07 0.49 0.70 Aerotricino 36 0.08 0.05 1.00 Aerotricino 39 Q.09 0.17 0.70 Aerotricino 41 0.08 0.03 2.40 Aerotricino 43 0.05 Q.04 0.07 Aerotricino 45 0.07 0.08 2.30 Aerotricino 46 0.09 0.08 1.80 Aerotricino 47 0.09 0.11 1.40 Aerotricino 53 0.11 0.09 2.30 Aerotricino 54 0.15 0.17 0.74 Aerotricino 55 0.04 0.04 0.39 Aerotricino 57 0.14 0.05 1.30 Aerotricino 75 0.15 0.10 1.40 Aerotricino 77 0.13 0.10 0.67 Aerotricino 95 0.14 0.10 0.74 2. In Vivo Antifungal Efficacy The in vivo antifungal efficacy of the aerotricins of the present invention is shown in the following table 3. Mice of a conventional immunocompetent mouse strain, Crj: CD-1 (ICR) were used for experimental models of infection of systemic candidiasis. Four-week-old Crj: CD-1 (ICR) mice were used for sitchemic candidiasis by injection of Candi da albi cans 5xl06 conidia / mouse via caudal vein. The treatments were given twice (0.4 hours after infection) on the first day and once daily the next 2 days for the sitémic candidiasis (b.i.d x 1 day followed by q.d. x 2 days), intravenously (i.v.). The effective dose of 50% (EDsJ from the number of survivors, at each dose, on day 14 was calculated. Table 3: Antifungal activity in vi vo against sitémic candidiasis, in mice, ED5 ((mg / kg) day 14: Aerotricino 5 0.3 Aerotricino 16 0.3 Aerotricino 18 0.6 Aerotricino 36 0.6 Aerotricino 41 0.3 Aerotricino 42 0.6 Aerotricino 45 0.3 Aerotricino 46 0.4 Aerotricino 50 < 0.3 Aerotricino 55 < 0.3 Aerotricino 65 0.6 3. Analysis of hepatoxicity in vi tro Hepatocytes were isolated of mice by digestion with collagenase and cultured on microanalysis plates The monolayers of hepatocytes were subjected to aerotricin assay in the culture system for 1 day.After the culture period, the hepatocytes were observed under a microscope and evaluated Morphologically, the degree of morphological alteration (degeneration) of the hepatocytes by aerotricin assay was compared with WF11243 and LY3Q3366 Table 4: I quote Hepatocyte toxicity (Mg / ml) Aerotricino 14 > 100 Aerotricino 15 > 100 Aerotricino 21 > 100 Aerotricino 34 > 100 Aerotricino 38 > 100 Aerotricino 45 > 100 Aerotricino 47 > 100 Aerotricino 48 > 100 Aerotricino 53 > 100 Aerotricino 65 > 100 Aerotricino 67 > 100 Aerotricino 72 > 1Q0 Aerotricino 81 > 100 WF11243 > 100 (= aerotricino 3) LY303366 10 mg / kg and 30 mg / kg of 1 administration of aerotricin to mice for 4 weeks did not show any acute toxicity. Therefore the new aerotricins of formula (I) as well as the pharmaceutically acceptable salts thereof, have a potent antifungal activity against different fungal infections, including aspergillosis, in mice in a wide range of dosages, and are useful as agents antifungal In addition, the aerotricins provided by this invention are much less cytotoxic to hepatocytes than the known cyclic peptide derivatives (WF11243 and LY303366). The aerothricins of the present invention may also be useful for the inhibition or alleviation of Pneumocystis carinii infections in immunodeficient patients. The present invention also relates to pharmaceutical compositions containing the new aerotricins of formula (I) as well as the pharmaceutically acceptable salts thereof. The new aerotricins of formula (I) as well as the pharmaceutically acceptable salts thereof are highly active fungicidal agents. They are active against different species of fungi including Candida spp., Aspergillus spp., Fusarium spp., Mucor spp., And Absidia spp. Thus, the aerotricins of the present invention are useful for the topical and systemic treatment of mycoses in animals as well as in humans. For example, they are useful in the treatment of topical fungal infections and mucous infections caused by Candida spp., Trichophyton spp., And Microsporum spp.

They can also be used in the treatment of sitic fungal infections caused for example, by Candida spp., Aspergillus spp., Or Fusarium spp. For clinical use, the new aerotricins of formula (I) as well as pharmaceutically acceptable salts thereof can be administered alone, but are generally administered in a pharmaceutical formulation formulated in a manner suitable for the particular intended use and purpose, by mixing an excipient, binder, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and / or ointment base. The mixture can be used for oral administration, such as injectable, nasal, rectal or topical. The pharmaceutical formulations of aerothricins for oral administration can be granules, tablets, sugar-coated tablets, capsules, pills, suspension or emulsion. For parenteral injection, for example, intravenously, intramuscularly or subcutaneously, the aerothricins of formula (I) may be used in the form of a sterile aqueous solution which may contain substances, for example, salts or glucose to convert the solution to isotonic . These compositions can be presented in the form of a dosage unit in ampoules or in multi-dose containers, preferably with additive preservatives. Alternatively, the active ingredients may be in powder form, for reconstitution with an appropriate vehicle prior to administration. The aerotricins can therefore be administered in the form of a suppository or pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment or fine powder. The daily dosage level of aerotricins of formula (I) ranges from 0.1 to 50 mg / kg (in divided doses) when administered either orally or parenterally. Thus, aerotricin tablets or capsules may be expected to contain 5 mg to 0.5 g of active compound for administration individually or two or more at a time. In any case, the effective dosage can be determined by the physician, and may vary depending on the age, weight and response of the particular patient. When aerotricins are used as antifungals, any method of administration can be used. For the treatment of fungal infections, oral or intravenous administration is usually employed. When aerotricins should be used to control pneumocidal infections, it is desirable to treat the lungs and bronchi directly. For this reason, inhalation methods are preferred. For administration by inhalation or nasal administration, the aerothricins of the present invention are mainly provided in the form of a spray aerosol presentation from pressurized containers or nebulizers. The preferred delivery system for inhalation or nasal is an inhalation aerosol of a metered dose, which can be formulated in the form of a powder, suspension or solution of a compound of formula (I) in suitable propellants, such as fluorocarbons or hydrocarbons. Although the aerotricins of the present invention can be employed as tablets, capsules, topical compositions, blowing powders, suppositories, and the like, the solubility of the aerothricins of the present invention in water and aqueous media makes them suitable for use in injectable formulations and also in liquid compositions suitable for sprayable aerosols. The following examples illustrate the preferred methods for the preparation of the aerothricins of the present invention, which are not intended to limit the scope of the invention thereof. In the following examples, the products were analyzed and purified by HPLC using an inverted phase column selected from the group listed below. The mixing solvent consisted of 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile, in the appropriate proportion described in each working example.

HPLC Columns: Column A: CAPCELL PAK C18, UG-120, 4.6 X 250 mm Column B: CAPCELL PAK C18, UG-120, 10 X 250 mm Column C: CAPCELL PAK C18, UG-80, 20 X 250 mm Column D: CAPCELL PAK C18, SG-120, 4.6 X 250 mm Column E: CAPCELL PAK C18, SG-120, 10 X 250 mm Column F: TSK GEL ODS-80TS, 20 X 250 mm In the following working examples, aerotricins were obtained as trifluoroacetic acid salts unless otherwise indicated. Reference Example 1 Preparation of (R) -3- (9-Fluorenylmethoxycarbonylamino) -5- (4'-heptyloxybiphenyl-4-yl) -pentanoic acid a) Preparation of 4-bromo-4'-heptyloxybiphenyl To a stirring solution of 4-bromo-4'-hydroxybiphenyl (5.05 g, 20.2 mmol) in DMF (100 ml) were added K_COj (4.20 g, 30.4 mmol) and 1-bromoheptane ( 4.14 mL, 26.4 mmol), and then the mixture was heated to 80 ° C. After stirring at 80 ° C for 20 hours, the mixture was cooled to room temperature. The mixture was diluted with Et_0 (250 ml) and then the solution was washed with saturated brine (150 ml x 2). The organic layer was dried with anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was recrystallized with CH2Cl2-petroleum ether to obtain 4-bromo-4'-heptyloxybiphenyl (6.21 g, 88%) as a white solid; EM-BAR: m / z 347 [MH +]. b) Preparation of 4-formyl-4'-heptyloxybiphenyl To a stirred (0 ° C) stirred solution of 4-bromo-4'-heptyloxybiphenyl (6.21 g, 17.9 mmol) in THF (120 ml) was added n-BuLi (1.66 M solution in hexane, 32.3 ml, 53.6 mmol). After the mixture was stirred at 0 ° C for 20 minutes, DMF (4.85 mL, 62.6 mmol) was added at -78 ° C. The mixture was stirred at -78 ° C for an additional 20 minutes, and then quenched with saturated NH 4 Cl solution. The mixture was diluted with EtOAc (220 ml), and then washed successively with saturated aqueous solution of NH 4 Cl (125 ml) and saturated brine solution (100 ml). The organic layer was dried with anhydrous NaSO 4 and concentrated in vacuo. The residue was purified by a chromatographic column on silica gel (EtOAc / hexane, 1:20) to obtain 4-formyl-4'-heptyloxybiphenyl (2.21 g, 42%) as an amorphous powder) c) Preparation of the 3- (4'-heptyloxybiphenyl-4-yl) acrylic acid ethyl ester To a stirred solution of 4-formyl-4'-heptyloxybiphenyl (2.21 g, 7.46 mmol) in benzene (40 ml) was added Ph3P = CHCOOEt (5.19 g, 14.9 mmol) and then the mixture was heated to 60 ° C. After stirring at 60 ° C for 3 hours, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CH2Cl2 / hexane, 1: 2), obtaining 3- (4'-heptyloxybiphenyl-4-yl) acrylic acid ethyl ester (2.66 g, 97%). , in the form of a white amorphous powder. MS-BAR: m / z 367 [MH +], XH NMR: d 0.90 (t, J = 6.8 Hz, 3H), 1.25-1.55 (m, 8H), 1.35 (t, J = 7.1 Hz, 3H), 1.81 (quint, J = 6, 6 Hz, 2H), 4.00 (t, J = 6, 4 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 6.46 (d, J = 16.0 Hz, 1H), 6.94-7.00 (m, 2H), 7.50-7.60 (m, 6H), 7.72 (d , J = 16.0 Hz, 1H). d) Preparation of the 3- (4'-heptyloxybiphenyl-4-yl) propionic acid ethyl ester To a stirred solution of the 3- (4'-heptyloxybiphenyl-4-yl) acrylic acid ethyl ester (2.65 g, 7.23 mmole) in CH2C1; (60 ml) palladium on activated charcoal (Pd approx 10% by weight, 1.07 g) was added, and then the mixture was placed under an atmosphere of H2. After being stirred for 2 hours, the mixture was filtered through a pad of Celite and washed with CH2C1. The filtrate and the washings were combined and concentrated in vacuo to obtain the 3- (4'-heptyloxybiphenyl-4-yl) propionic acid ethyl ester (crude 2.74 g), which was used for the next step without further purification. X H NMR: d 0.90 (t, J = 6.6 Hz, 3 H), 1.25 (t, J = 7.3 Hz, 3 H), 1.29-1.56 (m, 8 H), 1 , 75-1.86 (m, 2H), 2.65 (t, J = 7.8 Hz, 2H), 2.98 (t, J = 7.8 Hz, 2H), 3.99 (t, J = 6, 6 Hz, 2H), 4.14 (q, J = 7.3 Hz, 2H), 6.93-6.98 (m, 2H), 7.25 (d, J = 8.6 Hz, 2H 7.43-7.52 (m, 4H). e) Preparation of 3- ('-heptyloxybiphenyl-4-yl) propan-1-ol to a cooled (0 ° C) suspension, under stirring, of LIA1H4 (0.47 g, 12.4 mmol) in THF (20 g). ml) was added a solution of 3- (4'-heptyloxybiphenyl-4-yl) propionic acid ethyl ester (crude, 2.74 g) in THF (30 ml). After stirring for 30 minutes at room temperat the mixtwas quenched with H20 at 0 ° C. The mixtwas filtered through a pad of Celite and washed with CH: C1; . The filtrate and washings were combined and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc / hexane, 2: 3) to obtain 3- (4'-heptyloxy-bi-phenyl-4-yl) propan-1-ol (2.27 g, 96% for 2 steps) in the form of a white amorphous powder. MS-MS: m / z 326 [MJ, XH NMR: d 0.90 (t, J = 6.8 Hz, 3H), 1.21-1.55 (m, 8H), 1.81 (quint, J = 6, 6Hz, 2H), 1.86-2.00 (m, 2H), 2.75 (t, J = 7.3 Hz, 2H), 3.71 (t, J = 6.6 Hz, 2H), 3.99 (t, J = 6.6 Hz, 2H), 6.92-7.00 (m, 2H), 7.25 (d, J = 7.9 Hz, 2H), 7.44-7.55 (m, 4H). f) Preparation of 3- (4'-heptyloxybiphenyl-4-yl) propionaldehyde To a stirred solution (0 ° C) of 3- (4'-heptyloxybiphenyl-4-yl) ropan-1-ol (2.26 g, 6.92 mmoles) in CH2C12 (60 ml) were added 4A molecular sieves in powder (5.17 g) and PCC (5.25 g, 24.4 mmoles). After stirring for 2 hours at room temperature, Et was added; (20 ml) to the mixture. The reaction mixture was transferred to a short column of silica gel and eluted with CH2C1;. The eluate was concentrated in vacuo or the 3- (4'-heptyloxybiphenyl-4-yl) propionic aldehyde (crude, 2.45 g) was obtained, which was used for the next step without further purification. g) Preparation of tert-butyl ester of 3 (4'-heptyloxybiphenyl-4-yl) pent-2-enoic acid To a stirred solution of 3- (4'-heptyloxybiphenyl-4-yl) propionic aldehyde (in crude form) , 45 g) in benzene (150 ml), Ph3P = CHC00t-Bu (5.21 g, 13.8 mmol) was added, and then the mixture was heated to 60 ° C. After stirring for 30 minutes at 60 ° C, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc / hexane, 1:30) to obtain 3- (4'-heptyloxybiphenyl-4-yl) pent-2-enoic acid tert -butyl ester (1.95). g, 67% for 2 steps) in the form of a white amorphous powder. MSI: m / z 422 [MU, XH NMR: d 0.90 (t, J = 6.6 Hz, 3H), 1.21-1.51 (m, 8H), 1.49 (s, 9H), 1.74-1.87 (m, 2H), 2.47-2.58 (m, 2H), 2.79 (t, J = 7.3 Hz, 2H), 3.99 (t , J = 6.6 Hz, 2H), 5.81 (dt, J = 1.5 Hz, 15.5 Hz, 1H), 6.87-7.01 (m, 3H), 7.23 (d , J = 7.9 Hz, 2H), 7.44-7.53 (m, 4H). h) Preparation of (R) -3- [benzyl- ((R) -1-phenylethyl) amino] -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid tert-butyl ester To a cold-stirred suspension (0 ° C) of (R) -N-benzyl-1-phenylethylamine hydrochloride (3.28 g, 13.2 mmol) in THF (40 ml), n-BuLi (1.61 M solution in hexane) was added. , 15.0 ml, 24.2 mmol). After stirring the mixture for 25 minutes at 0 ° C, a solution of the 3- (4'-heptyloxybiphenyl-4-yl) pent-2-enoic acid tert -butyl ester (1.94 g, 4.38 g. mmoles) in THF (30 ml), at -78 ° C. After stirring the mixture for an additional 20 minutes at -78 ° C, the reaction mixture was quenched with saturated aqueous NH 4 Cl and concentrated in vacuo. The residue was diluted with saturated aqueous NH4C1 (200 ml) and then extracted with CH2C12 (200 ml x 2). The combined extracts were dried with Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc / hexane, 1:40), yielding the (R) -3- [benzyl- ((R) -1-phenylethyl) amino) tert-butyl ester] -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid (2.83 g,? Uant.), In the form of a colorless oil. MS-IE: m / z 633 [Mj, XH NMR: d 0.91 (t, J = 6.6 Hz, 3H), 1.24-1.55 (m, 13H), 1.38 (s, 9H), 1.57-2.04 (m, 6H), 2.52-2.69 (m, 1H), 2.97-3.10 (, 1H), 3.37-3.49 (m , 1H), 3.55 (ABq, J = 15.0 Hz, 1H), 3.85 (ABq, J = 15.0 Hz, 1H), 3.88 (q, J = 6.9 Hz, 1H ), 4.00 (t, J = 6.6 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.21-7.53 (m, 16H). i) Preparation of (R) -3-amino-5- ('-heptyloxybiphenyl-4-yl) pentanoic acid tert-butyl ester To a stirred solution of the (R) -3- [benzyl- ((R) -1-phenylethyl) amino] -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid tert-butyl ester (2.82 g) 4.45 mmoles) in EtOAc (50 ml), AcOH (2.5 ml) and Pd (OH) 2 on carbon (Pd (OH) 2 approximately 20% by weight, 1.07 g) were added, then the mixture was treated with H atmosphere; . After stirring for 15 minutes, the mixture was filtered through a plug of Celite and washed with MeOH. The filtrate and the washings were combined and concentrated in vacuo to obtain the (R) -3-amino-5- ('-heptyloxybiphenyl-4-yl) pentanoic acid tert-butyl ester (crude, 3.14 g ) which was used for the next step without further purification. j) Preparation of tert-butyl ester of (R) -3- (9-fluorenylmethoxycarbonylamino) -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid ester To a stirred suspension of tert-butyl ester of (R) - 3-amino-5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid (crude, 3.14 g) in 50% aqueous 1,4-dioxane (40 ml), Na 2 CO 3 (1.19 g, 11.2 mmol) and FmocCl (1.28 g, 4.95 mmoles). After stirring for 1 hour, the mixture was diluted with saturated brine (100 ml) and extracted with CH2C12 (100 ml x 3). The combined extracts were dried with anhydrous Na 2 SO 4 and concentrated in vacuo to obtain (R) -3- (9-fluorenylmethoxycarbonylamino) -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid tert-butyl ester (crude , 3.34 g), which was used for the next step without further purification. MS-BAR: m / z 668 [M? Li], XH NMR: d 0.81 (t, J = 6.6 Hz, 3H), 1.15-1.44 (m, 8H), 1.35 (s, 9H), 1.62-1.93 (m, 4H), 2.29-2.68 (m, 4H), 3.84-4.02 (m, 1H), 3.88 (t , J = 6.6 Hz, 2H), 4.13 (t, J = 6.8 Hz, 1H); 4.25-4.41 (m, 2H), 5.27 (d, J = 9.2 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.06-7 , 42 (m, 10H), 7.51 (d, J = 7.3 Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H). k) Preparation of the acid (R) -3- (9-fluorenylmethoxycarbonylamine) -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid To a stirred solution of the tert-butyl ester of the acid (R) -3- (9-) fluorenylmethoxycarbonylamino) -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid (crude, 3.34 g), in CH_C1; (20 ml) TFA (20 ml) was added dropwise. After stirring for 1 hour at room temperature, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH / CH2Cl2, 1:20) to obtain (R) -3- (9-fluorenylmethoxycarbonylamino) -5- (4'-heptyloxybiphenyl-4-yl) pentanoic acid ( 2.07 g, 77% in 3 steps) in the form of a white amorphous powder. MS-BAR: m / z 606 [MH "], XH NMR: d 0.88 (t, J = 6.6 Hz, 3H), 1.21-1.51 (m, 8H), 1.64- 2.04 (m, 2H), 1.78 (q, J = 6, 6 Hz, 2H), 2.27-2.78 (m, 4H), 3.91-4.07 (m, 1H) , 3.96 (t, J = 6.6 Hz, 2H), 4.20 (t, J = 6.6 Hz, 1H), 4.34-4.56 (, 2H), 5.09-5 , 28 (m, 1H), 6.92 (d, J = 8.9 Hz, 2H), 7.10-7.49 (, 10H), 7.57 (d, J = 7.3 Hz, 2H ), 7.73 (d, J = 7.3 Hz, 2H) The starting compounds of formula (IV) [wherein Y - is a single bond or -CH2-] used in process B, were prepared from according to the method similar to that described above Reference example 2 Preparation of (S) -3- (9H-fluorenylmethoxycarbonylamino) -N-undecylsuccinnamic acid a) To a solution of (S) -2- (9H-fluoren- 9-ylmethoxycarbonyl-amino) -succinic acid (150 mg, 0.36 mmol), BOP reagent (162 mg, 0.36 mmol) and HOBT hydrate (56 mg, 0.36 mmol) in N, N-dimethylformamide. , 2 ml), N, N-diisopropylethylamine (64 μl, 0.36 mmol) was added, after stirring for 30 minutes at room temperature. At room temperature, 1-aminoundecane (79 μL, 0.37 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with Et20. The combined extracts were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography on silica gel (using n-hexane: ethyl acetate = 3: 1 as eluent) afforded the (S) -3- (9H-fluoren-9-ylmethoxycarbonylamino) tert-butyl ester ) -N-undecylsuccinnamic (169 mg, 82% yield) as a colorless amorphous solid. MS-BAR (m / z): 565 [MH +], LH NMR: (CDCl 3) d: 0.88 (3H, t, J = 7 Hz), 1.24 (16H, m), 1.45 (11H , m), 2.58 (1H, dd, Ji = 17 Hz, J = 7 Hz), 2.91 (1H, dd, J; = 17 Hz, J2 = 4 Hz), 3.23 (2H, q, J = 7 Hz), 4.22 (1H, t, J = 7 Hz), 4.42-4.45 (3H, m) 5.94 (1H, broad d, J = 8 Hz), 6.43 (1H, broad s), 7.31 (2H, t, J = 7 Hz), 7.41 (2H, t, J = 7 Hz), 7.58 (2H, d, J = 7 Hz), 7.77 (2H, d, J = 7 Hz). b) A solution of tert-butyl ester of (S) 3- (9H-fluoren-9-ylmethoxycarbonylamino) -N-undecylsuccinnamic acid ester (113 mg, 0.2 mmol) in TFA (2 ml) was stirred at room temperature. environment for 30 minutes. After the reaction was finished, the TFA was removed by evaporation at room temperature. The purification of the residue by silica gel column chromatography (using dichloromethane: methanol = 9: 1 as eluent) provided the acid (s) -3- (9H-fluoren-9-ylmethoxycarbonylamino) -N-undecylsuccinnamic acid (101 mg, yield 99%) in the form of a colorless amorphous solid. MS-BAR (m / z): 507 [MH +], XH NMR: (CDC13) d: 0.87 (3H, t, J = 7 Hz), 1.23 (16H, m), 1.46 (2H , m), 2.62-2.80 (1H, m), 2.90-3.05 (1H, m), 3.21 (2H, m), 4.20 (1H, t, J = 7 Hz) 4.44 (2H, d, J = 6 Hz), 4.53 (1H, broad s), 5.98 (1H, m), 6.52 (1H, broad s), 7.30 (2H , t, J = 7 Hz), 7.40 (2H, t, J = 7 Hz), 7.56 (2H, d, J = 7 Hz), 7.76 (2H, d, J = 7 Hz) . The starting compounds of general formula (IV) [wherein Y is -CONH- or -CON (CH3) -], used in process B, were prepared according to the method described above. Reference Example 3 Preparation of N-Boc-Aerothricin 3 (Compound A) To a solution of aerothricin 3 (10.0 g, 6.07 mmol) in MeOH (1500 mL) was added triethylamine (2.54 mL, 18%). 2 mmole), di-tert-butyl dicarbonate (13.9 ml, 60.7 mmoles) successively. After stirring the mixture at room temperature for 18 hours, the solvent was evaporated in vacuo. The residue was dissolved in MeOH (ca. 10 ml) and the solution was added to diethyl ether (1500 ml). The resulting precipitate was filtered and washed with diethyl ether to obtain 9.9 g of N-Boc-aerothricino-3 (compound A) in the form of a pale yellow amorphous solid, which was used for a subsequent structural modification in the examples of work described later without further purification. Example 4 Preparation of aerotricins 1, 2 and 3 a) Fermentation in the solid state A 0.1 ml portion of the frozen culture of Deuteromycotina NR 7379 (FERM BP-6391) in 10% (v / v) of glycerin solution, thawed and inoculated in a 500 ml Erlenmeyer flask containing 100 ml of a medium consisting of 2% glucose, potato starch 1 %, glycerin 1.5%, roasted soybeans 1%; (Nissin Seiyu), yeast extract 0.35 (Nippon Seiyaku), polypeptone 0.25% (Nihon Seiyaku), NaCl 0.3%, CaC03 0.5%, ZnS04 • 7H20 0.005%, CuS0 .5H, 0 0.0005%, and MnS0 • 4H20 0.0005%. The pH of the medium was not adjusted. The seed culture was incubated on a rotary shaker at 27 ° C for 7 days at 220 rpm. 2 ml of the seed culture was transferred to a 3-liter Erlenmeyer flask containing a solid medium consisting of 200 g of pressed barley, 0.12 g of yeast extract (Difco), 0.06 g of sodium tartrate, 0, 06 g of KH.P0 and 120 ml of water. The fermentation was carried out at 27 ° C under static conditions. The production reached a maximum around 240 hours of fermentation, and the crop was subjected to the isolation procedure of aerotricinos 1, 2 and 3. To the cultivated solid (10 kg) obtained was added methanol (40 liters) and the mixture was stirred, followed by removal by filtration to obtain the methanol extract (39 liters). The methanol extract thus obtained was concentrated to dryness under reduced pressure, and to the residue (64.8 g) was added ethyl acetate (1 liter) and water (1 liter), and the mixture was stirred, followed by the elimination of the ethyl acetate layer. In addition, the aqueous layer was washed in a similar manner with ethyl acetate (1 liter) twice. The remaining aqueous layer was extracted with n-butanol (1 liter) three times. The extracts thus obtained were combined and concentrated to dryness under reduced pressure; and the residue (28.5 g) was dissolved in a mixture (250 ml) of acetonitrile-0.1% aqueous trifluoroacetic acid (1: 1).

»After removing the insoluble materials by centrifugation, the solution thus obtained was evaporated to dryness under reduced pressure, and methanol was added to the residue (300 ml), and the mixture was stirred, followed by removal by filtration to obtain the solution in methanol (280 ml). The methanol-soluble materials thus obtained (9.3 g) were then subjected to column chromatography with an inverted phase of silica gel C18 (1 liter). The column was eluted stepwise using a mixture of 0.1% aqueous methanol, trifluoroacetic acid (2: 8, 4: 6, 5: 5, 6: 4, 7: 3, and 8: 2). Aerotricins 1, 2 and 3 eluted in this order with 0.1% aqueous methanol trifluoroacetic acid (7: 3), concentrated to dryness under vacuum or obtaining aerotricine salt 3 of trifluoroacetic acid in the form of a white powder (731 mg ) and aerotric acid salt 1 of trifluoroacetic acid (747 mg), respectively. Fractions containing Aerotricin 2 were concentrated under reduced pressure and subsequently purified by HPLC under the following conditions: column: Capcell Pak C18 (d.i. 30 x 250 mm, Shiseido Co., LTD); mobile phase: acetonitrile-0.1% aqueous trifluoroacetic acid (45:55); flow rate: 40 ml / min .; Detection: UV 220 nm. The appropriate eluates obtained with the aforesaid conditions were concentrated to dryness by evaporation or to obtain the aerotric acid salt 2 of trifluoroacetic acid in the form of a white powder (42 mg). b) Bottle fermentation A 2 ml portion of frozen culture of Deuteromycotina NR 7379 (FERM BP-6391) in 10% glycerin solution (v / v) was thawed and inoculated into a 500 ml Erlenmeyer flask containing 100 ml of a medium consisting of 1% glucose, 1% oatmeal, 4% tomato paste, 0.5% wheat germ extract (Ando kasei), 0.001% FeS04.7H20, 0.001% MnS04 .4H20, 0.0001% CaCl2, 0.0002% ZnSO- .7H20, 0.00002% (NH4) 6Mo02.4H20, and 0.00006% H3B03. The pH of the medium was adjusted to 6.8 before sterilization. The seed culture was incubated on a rotary shaker at 27 ° C for 3 days at 220 rpm. 2 ml of the first seed culture was transferred to 500 ml Erlenmeyer flasks containing 100 ml of the same medium and incubated on a rotary shaker under the same conditions for 3 days. 2 ml of the second seed culture were inoculated into 500 ml Erlen eyer flasks containing 100 ml of the medium constituted by 8 ml., 5% glycerin, 1% citrus pectin, 0.4% peanut powder, 0.4% milk casein free of vitamins, 0.4% tomato paste, 0.4% extract corn germ (Ando kasei), 0.2% of. glycine and 0.2% KH2P04. The pH of the medium was adjusted to 7.0 before sterilization. The fermentation was carried out at 27 ° C with stirring at 220 rpm. After 10 days of cultivation, the production reached a maximum and the whole crop was submitted to the isolation procedure of aerotricinos 1, 2 and 3. c) Fermentation in jars A 2 ml portion of the frozen culture of Deuteromycotina NR 7379 (FERM BP-6391) in 10% glycerin solution (v / v) was thawed and inoculated into a 500 ml Erlenmeyer flask containing 100 ml. ml of the same planting medium described above. The flask was stirred at 27 ° C at 220 rpm for 3 days. 2 ml of the first seed culture was transferred to 500 ml Erlenmeyer flasks containing 100 ml of the same seed medium and incubated on a rotary shaker under the same conditions for 3 days. Six hundred ml of the second seed culture was inoculated into a 50 liter fermentation vessel containing 30 liters of the same production medium as described above and 0.4% of "disfoam" (Nissan Disfoam CA-123). The fermentation was carried out at 27 ° C with aeration of 30 liters / minute and agitation of 400 r.p.m. The production reached a maximum at approximately 168 hours of fermentation, and the whole crop was subjected to the isolation procedure of aerotricinos 1, 2 and 3. Aerotricino 1 1) Appearance: White solid 2) Molecular weight (EM-BAR method) : m / z 1547 (M + H) + 3) Empirical formula: C72Hne? 40; 3 4) High resolution mass spectroscopy (for M + H) "1: Found: 1547.8568 Calculated for C72H119N14? 23 1547.8572 5) UV spectrum (figure 1): in methanol:? (e) max. (in MeOH): 225 ± 5 (10600 sh), 270 ± 5 (2000), 278 ± 5 (2100)? (e) max. (in NaOH N / 10 - MeOH): 240 ± 5 (7700), 268 ± 5 (1800), 298 ± 5 (1800) 6) IR spectrum (KBr) (figure 2): Wave numbers of the main absorption (cm ~ J are as follows: 3379, 2927, 2855, 1740, 1660 , 1535, 1453, 1203, 1139, 837 7) H-NMR spectrum (figure 3): 400 MHz, in CD ^ OD 8) 13C-NMR spectrum (figure 4): 100 MHz, in CD30D 9) Solubility: Soluble in : water, methanol, dimethyl sulfoxide 10) Color reaction: Positive: ninhydrin, anisic aldehyde - sulfuric acid, iodine vapors, vanillin - sulfuric acid, Rydon-Smith reagent, molybdenophosphoric acid Negative: Sakaguchi reagent, bromocresol green, 2,4-dinitrophenylhydrazine - sulfuric acid 11) Thin layer chromatography (CCF): Solvent Support Rf Silica gel F254 ~~: n-BuOH: acetone: AcOH: H20 (4: 5: 1: 1) 0.74 MeOH: H; 0 (95: 5) 0.12 ~~ E. Merck AG. , Germany 12) High resolution liquid chromatography: Support: Capcell Pak C18 gel S120A, 4.6x250 mm (manufactured by Shiseido, Co., LTD). Mobile phase: acetonitrile: trifluoroacetic acid 0.05% = 1: 1 Flow rate: 1 ml / minute Rt = 12, 1 ± 0.5, 13) analysis of amino acids: Aerotricin 1 was heated at 120 ° C in 6N HCl for 24 hours, and then subjected to the analysis of amins acids to detect threonine, 3 units of alltreonine, glycine, alanine, valine, tyrosine, ornithine, 3-hydroxyproline, 4-hydroxyproline, 3-hydroxyglutamine. Aerotricino 2 1) Appearance: White solid 2) Molecular weight (EM-BAR method): m / z 1549 (M + H) + 3) Empirical formula: C7lHn6N140; 4 4) High resolution mass spectroscopy (for M + H )? Found: 1549.8384 Calculated for C-71Hn-N14024: 1549.8365 5) UV spectrum (Figure 5): in methanol? . (e) max. (in MeOH): 225 + 5 (10200 sh), 270 + 5 (1900), 278 ± 5 (2000)? (e) max. (in NaOH N / 10 - MeOH): 240 + 5 (7700), 293 + 5 (2000) 6) IR spectrum (KBr) (figure 6): The wave numbers of the main absorption (cm-1) are as follows: 3323, 2928, 2856, 1740, 1670, 1531, 1450, 1203, 1137, 837 Spectrum ^? - NMR (Figure 1 400 MHz, in CD30D Spectrum 13, C-NMR (figure 8) 100 MHz, in CD30D Solubility: Soluble in: water, methanol, dimethyl sulfoxide ) Color reaction: Positive: ninhydrin, anisic aldehyde - sulfuric acid, iodine vapors, vanillin - sulfuric acid, Rydon-Smith reagent, molybdenophosphoric acid Negative: Sakaguchi reagent, bromocresol green, 2-dinitrophenylhydrazine - sulfuric acid 1) Thin layer chromatography (TLC): Solvent support Rf Silica gel F254 * 1 n-BuOH: acetone: AcOH: H20 (4: 5: 1: 1) 0.29 MeOH: H20 (95: 5) 0.15 +1 E. Merck AG. , Germany 2) High resolution liquid chromatography: Support: Capcell Pak C18 gel S120A, 4.6x250 mm (manufactured by Shiseido, Co., LTD). Mobile phase: acetonitrile: trifluoroacetic acid 0.05% = 1: 1 Flow rate: 1 ml / minute Rt = 9, 9 + 0.5 Rt = 9, 9 + 0.5 3) analysis of amins acids: The aerotricino 2 at 120 ° C in 6N HCl for 24 hours, and then subjected to amino acid analysis to detect threonine, 3 units of allo-threonine, glycine, alanine, valine, 3-hydroxytyrosine (DOPA), ornithine, 3-hydroxyproline , 4-hydroxyproline, 3-hydroxyglutamine. Aerotricino 3) Appearance: White solid) Molecular weight (EM-BAR method): m / z 1533 (M + H) +) Empirical formula: C7iHnN1 4023) UV spectrum: in methanol? (e) max. (in MeOH): 225 + 5 (11,000 sh), 275 ± 5 (2000), 280 ± 5 (1900)? (e) max. (in NaOH N / 10 - MeOH): 243 ± 5 (7800), 295 ± 5 (1800) IR spectrum (KBr): Wave numbers of the main absorption cm "1) are as follows: 3334, 2928, 2852, 1742, 1662, 1520, 1449, 1202, 1136, 836 1 H-NMR spectrum: 400 MHz, in CDjOD 13 C-NMR spectrum: 100 MHz, in CD3OD Solubility: Soluble in: water, methanol, dimethyl sulfoxide Color reaction »: Positive: ninhydrin, anisoic aldehyde - sulfuric acid, iodine vapors, vanillin - sulfuric acid, Rydon-Smith reagent, molybdenophosphoric acid Negative: Sakaguchi reagent, bromocresol green, 2,4-dinitrophenylhydrazine - sulfuric acid Thin-layer chromatography (TLC): Support Solvent Rf Silica gel F254 * 1 n-BuOH: acetone: AcOH: H20 (4: 5: 1: 1) 0.26 MeOH: H20 (95: 5) 0.09 * 1 E. Merck AG. , Germany 11) High resolution liquid chromatography: Support: Capcell Pak C18 gel S120A, 4.6x250 mm (manufactured by Shiseido, Co., LTD). Mobile phase: acetonitrile: trifluoroacetic acid 0.05% = 1: 1 Flow rate: 1 ml / minute Rt = 9.1 + 0.5 12) amino acid analysis: Aerotricin 3 was heated at 120 ° C in 6N HCl for 24 hours, and then subjected to the analysis of amins acids to detect threonine, 3 units of allo-threonine, glycine, alanine, valine, tyrosine, ornithine, 3-hydroxyproline, 4-hydroxyproline, 3-hydroxyglutamine.

Example 5 Preparation of compound (IX) 1) Fermentation in flask A 1 ml portion of frozen culture of Deuteromycotina NR 7379 (FERM BP-6391) in 10% glycerin solution (v / v), was thawed and inoculated in a 500 ml Erlenmeyer flask containing 100 ml of a medium consisting of 1% glucose, 1% oatmeal, 4% tomato paste, 0.5% wheat germ extract (Ando kasei), 0.001% FeS04.7H2 ?, 0.001% of MnS04.4H20, 0.0001% of CaCl2, 0.0002% of ZnS04.7H O, 0.00002% of '(NH4) 6MoO.4H, 0, and 0.00006% of H3B03. The pH of the medium was adjusted to 6.8 before sterilization. The seed culture was incubated on a rotary shaker at 27 ° C for 4 days at 220 rpm. 2 ml of the seed culture were inoculated in 500 ml Erlenmeyer flasks containing 100 ml of the medium constituted by 8.5% glycerin, 1% citrus pectin, 2% peanut powder, 0.4% casein milk free of vitamin, 0.4% tomato paste, 0.4% glycine and 0.2% KH2P04. The pH of the medium was adjusted to 7.0 before sterilization. The fermentation was carried out at 27 ° C with stirring at 220 rpm. After 14 days of cultivation, the production reached a maximum and the whole culture was subjected to the isolation procedure. To all the cultivated broth (1.9 liters) obtained, n-butanol (2 liters) was added and the mixture was stirred. The extracts thus obtained were concentrated to dryness under reduced pressure. And to the residue was added hexane (500 ml) and methanol (500 ml) and the mixture thus obtained was stirred, and then the hexane layer was removed.

After removing the methanol under reduced pressure, the residue thus obtained was washed with a mixture of hexane and ethyl acetate (1: 1, 200 ml, twice), and dried under reduced pressure. To the residue (3.9 g) was added water (20 ml) and the mixture was stirred and then centrifuged to obtain the solution in water. The solution thus obtained was then subjected to an inverted phase column chromatography of silica gel C18 (200 liters). The column was eluted first with aqueous trifluoroacetic acid., 1% and then stepwise eluted using a mixture of methanol-0.1% aqueous trifluoroacetic acid (1: 9, 3: 7, 5: 5, 6: 4, 7: 3 and 8: 2). Compound (IX) eluted with methanol-0.1% aqueous trifluoroacetic acid (7: 3), and the solution was neutralized with IN aqueous sodium hydroxide and then concentrated to dryness in vacuo. To the residue thus obtained was added water (10 ml) and n-butanol (10 ml), and the mixture was stirred. The extract thus obtained was concentrated under reduced pressure to obtain the compound (IX) (96.9 mg) as a white powder. Subsequent purification to obtain the compound (IX) by spectroscopy was achieved by HPLC under the following conditions: column: Capcell Pak C18 UG80 (d.i. 20 x 250 mm, Shiseido Co., LTD.); mobile phase: 0.05% trifluoroacetic acid / acetonitrile - 0.05% trifluoroacetic acid / water (38:62); flow rate 22.86 ml / min; Detection: UV 210 nm. The appropriate eluates obtained under the above conditions were concentrated to dryness in vacuo or to obtain the compound as a white powder (IX), trifluoroacetic acid salt. c) Jar fermentation A 1 ml portion of the frozen culture of Deuteromycotina NR 7379 (FERM BP-6391) in 10% glycerin solution (v / v) was thawed and inoculated into a 500 ml Erlenmeyer flask containing 100 ml. ml of the same planting medium described above. The flask was stirred at 27 ° C at 220 rpm for 4 days. Two ml of the first seed culture was transferred to 500 ml Erlenmeyer flasks containing 100 ml of the same seed medium and incubated on a rotary shaker under the same conditions for 3 days. 600 ml of the second seed culture was inoculated in a 50 liter fermentation vessel containing 30 liters of the same production medium as described above and 0.4% of "disfoam" (Nissan Disfoam CA-123). The fermentation was carried out at 27 ° C with an aeration of 30 liters / minute and agitation of 400 r.p.m. The production peaked at approximately 278 hours of fermentation, and the entire culture was subjected to the isolation procedure of the compound (IX). Compound (IX) 1) Appearance: White solid 2) Molecular weight (EM-BAR method): m / z 1317 (M + H) + 3) Empirical formula :} 4) High resolution mass spectroscopy (for M + H)? Found: 1317, 7555 Calculated for C59H? O5N? 20; 1317, 7517 5) UV spectrum: in methanol:? (e) max. (in MeOH): final absorption 6) IR spectrum (KBr) (figure 9): The wave numbers of the main absorption (cm-1) are as follows: 3450, 2928, 1665, 1520, 1450, 1225, 1135 7 ) XH-NMR spectrum (figure 10): 500 MHz, in DMS0-do 8) 13C-NMR spectrum (figure 11): 125 MHz, in DMSO-db 9) Solubility: Soluble in: water, methanol, dimethyl sulfoxide 10 ) Color reaction: Positive: ninhydrin, anisic aldehyde - sulfuric acid, iodine vapors, vanillin - sulfuric acid, Rydon-Smith reagent, molybdenophosphoric acid Negative: Sakaguchi reagent, bromocresol green, 2,4-dinitrophenylhydrazine - sulfuric acid 11) High resolution liquid chromatography: Support: Capcell Pak C18 UG80A, 4.6x250 mm (manufactured by Shiseido, Co., LTD). Mobile phase: 0.05% trifluoroacetic acid / acetonitrile = 0.05% trifluoroacetic acid / water = 38, 62 Flow rate: 1 ml / minute Rt = 7.7 ± 0.5 Example 6 Preparation of the N-Boc derivative (N (orn) -Boc-IX) of the ornithine radical of the compound (IX): The compound of the formula (XII: R '"= Boc) To a solution of the compound (IX) obtained in example 5 (10.4 mg, 0.0073 mmol) in dioxane-H20 (0/43 ml-0.5 ml), triethylamine (3 μl) and 0.1 M solution of tert-butyl N-succinimidyl carbonate (0.0073 μl) were added. 0.0073 mmole) in dioxane at room temperature After stirring for 1.5 hours, the mixture was acidified with acetic acid and evaporated under reduced pressure, purification of the residue by HPLC gave the N (orn) -Boc- IX in the form of a colorless amorphous (4.8 mg, yield 45%); HPLC (Rt) 18.0 min. (Column: Soken-ODS, 20x250 mm, flow rate: 9 ml / min., Eluent: H; 0: CH3CN = acetic acid gradient 1%); EM-BAR [M + Na] + 1440. Example 7 Preparation of the N-Boc derivative (N (val) -Boc-IX) of the valine radical of the compound (IX): the compound of the formula (X: R '= Boc) A mixture of the compound (IX) obtained in example 5 (15.0 mg, 0.0105 mmol), di-tert-butyl dicarbonate (0.703 M solution in methanol, 0.20 ml, 0.015 mmol) and triethylamine (7.8 μl) in MeOH (3 ml ) was stirred at 0 ° C for 24 hours. The mixture was washed with n-hexane and evaporated under reduced pressure. Purification of the residue by inverted-phase HPLC gave N (val) -Boc-IX) as a colorless amorphous (1.0 mg, 6% yield); HPLC (Rt) 16.0 min. (column: Soken-ODS, 20x250 mm, flow rate: 9 ml / min., eluent: H20: CH CN = acetic acid gradient 1%); MS-BAR [M + H] + 1418.

Example 8 Aerotricin preparation 33 To a stirred solution of (R) -3- (9-fluorenylmethoxycarbonylamino) -7- (4-pentyloxyphenyl) heptanoic acid (25.5 mg, 0.048 mmol) in DMF (0.5 ml) BOP reagent (21.3 mg, 0.048 mmol), HOBT hydrate (7.5 mg, 0.049 mmol) and N, N-diisopropylethylamine (0.0095 mL, 0.055 mmol) were added. After stirring the mixture at room temperature for 1 hour, a solution of compound B [= the linear peptide of formula (III), wherein R "and R" - are hydrogen, R 5 is added to the reaction mixture. Carbamoyl group and R 'is tert-butoxycarbonyl which was prepared from aerotricin 1 or 3 according to the procedure described in WO 96/30399] (50.7 mg, 0.036 mmol) and N, N-diisopropylethylamine ( 0.0095 ml, 0.055 mmol) in DMF (0.6 ml). After stirring the mixture for 2.5 hours at room temperature, piperidine (0.20 ml) was added, and the mixture was stirred for a further 2 hours at room temperature. The solvent was evaporated in vacuo. The residue was purified by preparative reverse phase HPLC (column C, flow rate 9 ml / min., Gradient: eluent: 1% AcOH-H20: 1% AcOH-CH, CN = 80:20, 2.98) . Appropriate fractions were pooled, frozen and lyophilized to yield 49.5 mg of linear peptide C, a precursor for cyclization, in the form of a white amorphous solid. To a stirred solution of the linear peptide C (49.5 mg, 0.029 mmol) obtained above, in DMF (27 ml), HOBT hydrate (11.3 mg, 0.074 mmol) was added, N, N-diisopropylethylamine (0.018 ml, 0.105 mmol) and a solution of BOP reagent (33.1 mg, 0.075 mmol) in DMF (4 ml). After stirring the mixture for 3 hours at room temperature, the solvent was evaporated in vacuo. The residue obtained above was dissolved in TFA (6 ml) and stirred at 0 ° C for 30 minutes. The TFA was then evaporated in vacuo. The residue was purified by reverse phase preparative HPLC, under the conditions detailed below. Appropriate fractions were pooled, frozen and lyophilized to obtain 19.4 mg of aerothricin 33 as a white amorphous solid. HPLC (Rt): 12.4 min. (column C, flow rate: 9 ml / min; eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% - acetonitrile = 61:39); EM-BAR (m / z): 1568 [MH]? The following aerotricins 34-38, 40-53, 64-73 and 89-95, 97-99 and 123, were prepared according to the method similar to that described in this example 8, using the corresponding constitutive block represented as formula (IV ). EM-BAR HPLC Analytical condition Name of the M / z: [MH +] Time of (column) (flow rate: compound restriction (min.) Proportion of eluent *) Aerotricino 34 1568 14.1 (C) (9 ml / min; 60/40) Aerotricino 35 1568 13.2 (C) (9 ml / min; 57/43) Aerotricino 36 1610 21.9 (C) (9 ml / min; 55/45) Aerotricino 37 1638 44.1 (C) (9 ml / min; 54/46) Aerotricino 38 1610 28.1 (C) (9 ml / min; 58/42) Aerotricino 40 1602 16.8 (F) (10 ml / min; 57/43) Aerotricino 41 1616 20.6 (C) (9 ml / min; 60/40) Aerotricino 42 1630 16.8 (F) (10 ml / min; 62/38) Aerotricino 43 1644 29.2 (C) (9 ml / min; 57/43) Aerotricino 44 1658 35.5 (F) (10 ml / min; 50/50) Aerotricino 45 1630 24.7 (C) (9 ml / min; 59/41) Aerotricino 46 1664 18.7 (C) (9 ml / min; 59/41) Aerotricino 47 1594 22.9 (C) (9 ml / min; 54/46) Aerotricino 48 1576 24.4 (F) (10 ml / min; 58/42) Aerotricino 49 1590 24.2 (C) (9 ml / min; 65/35) Aerotricino 50 1604 48.9 (F) (10 ml / min; 55/45) Aerotricino 51 1618 40.4 (F) (9 ml / min; 60/40) Aerotricino 52 1632 32.5 (F) (10 ml / min; 50/50) Aerotricino 53 1646 27.0 (C) (9 ml / min; 54/46) Aerotricino 64 1547 15.5 (B) (4 ml / min; 65/35) Aerotricino 65 1575 15.5 (C) (9 ml / min; 55/45) Aerotricino 66 1603 16.6 (C) (9 ml / min; 52/48) Aerotricino 67 1587 19.9 (C) (9 ml / min; 59/41) Aerotricino 68 1587 19.6 (C) (9 ml / min; 59/41) Aerotricino 69 1589 21.8 (C) (9 ml / min; 58/42) Aerotricino 70 1617 21.6 (C) (9 ml / min; 53/47) Aerotricino 71 1746 30.0 (C) (9 ml / min; 64/36) Aerotricino 72 1673 22.6 (C) (9 ml / min; 57/43) Aerotricino 73 1721 20.2 (C) (9 ml / min; 55/45) Aerotricino 89 1630 22.1 (F) (10 ml / min; 55/45) Aerotricino 90 1658 24.9 (F) (10 ml / min; 50/50) Aerotricino 91 1670 -26.7 JF) (10.ml_p_i __: _ 50_50) Aerotricino 92 1642 26.0 (F) (10 iñl / min; 55/45) Aerotricino 93 1650 21.4 (F) (10 ml / min; 57/43) Aerotricino 94 1658 30.8 (F) (10 ml / min; 52/48) "Aerotricity" 95 -1574 -28.3 • (C) (9-ml mip; 57/43) Aerotricino 97 1740 44.07 (F) (10 ml / min; 57/43) Aerotricino 98 1656 30.0 (F) (10 ml / min; 62/38) Aerotricino 99 1644 16.9 (F) (10 ml / min; 53/47) Aerotricino 100 1630 20J (F) (10 ml / min; 56/44) * proportion of tri-fluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% -acetoni tri l o Example 9 Preparation of aerotricin 16 (a) To a stirred solution of compound A (described in reference example 3) (1 g, 0.61 mmol) in pyridine (2.5 ml) was added tetranitromethane (0.365 ml, , 05 mmoles). After stirring for 4 hours at room temperature the reaction mixture was concentrated in vacuo. The dark brown residue was purified by inverted phase HPLC (Lobar RP18, 10 ml / min., 0.05% trifluoroacetic acid - water: 0.05% trifluoroacetic acid - acetonitrile = 50:50 - 33:66 TFA 0 , 05%). Appropriate fractions were pooled, frozen and lyophilized to obtain 711 mg of the crude nitro derivative of compound A as a pale yellow amorphous solid. (b) A mixture of the crude product obtained above (12 mg, 0.0071 mmol) and TFA (0.5 ml) was stirred at 0 ° C for 30 minutes. The TFA was evaporated under a dry nitrogen atmosphere. The yellow residue was purified by preparative inverted phase HPLC. The appropriate fractions were pooled, frozen and lyophilized to obtain 8 mg of aerotricino TFA salt 16, in the form of a pale yellow amorphous solid. HPLC (Rt): 15.5 min. (column B. flow rate: 4 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% - acetonitrile = 55:45); EMBAR (m / z): 1578 [MHj. The following aerotricins 39, 54, 55 and 77 were prepared according to the method similar to that described in example 9, using the aerotricins obtained in example 8 as starting material. EM-BAR HPLC Analytical condition Name of m / z: [MIF] time of (column) (flow rate: composite restriction (min.) Proportion of eluent *) Aerotricino 39 1577 13.2 (C) (9 ml / min; 55/45) Aerotricino 54 1661 14.2 (C) (9 ml / min; 57/43) Aerotricin 55 1689 2J8 (C) (9 ml / min; 55/45) Aerotricino 77 1648 25.0 (C) (9 ml / min; 53/47) * proportion of trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% acetonitrile Example 10 Preparation of aerotricin 17 (a) To the solution of the crude nitro derivative of compound A, obtained in example 9 (a), (55 mg, 0.033 mmol) in MeOH (5 ml), 10% palladium was added carbon (20 mg), and the reaction vessel was filled with hydrogen. After stirring for 13.5 hours at room temperature, the mixture was filtered through a membrane filter (pore size: 0.2 μm) and the solvent was evaporated to obtain 52 mg of the crude amino derivative of aerotricin 3 in form of a brown amorphous, which was used in the next step without further purification. (b) A mixture of the crude amino derivative of compound A (described in reference example 3), obtained above, (3.4 mg, 0.0021 mmol) and TFA (0.2 ml) was stirred at 0 ° C. ° C for 30 minutes. The TFA was evaporated in a stream of dry nitrogens. The brown residue was purified by preparative reverse phase HPLC. Appropriate fractions were pooled, frozen and lyophilized to obtain 1.3 mg aerotricin 17 as a colorless amorphous solid. HPLC (Rt): 12.8 min. (column A, flow rate: 1 ml / min., eluent: trifluoroacetic acid 0.05% - water •: 0.05% trifluoroacetic acid - acetonitrile = 59:41); EMBAR (m / z): 1548 [MH *]. The following aerotricins 29, 56, and 78 were prepared according to the method similar to that described in example 10, using the aerotricins obtained in example 9 as starting material.

EM-BAR HPLC Analytical condition Name of m / z: [MFT] time of (column) (flow rate: composite restriction (min.) Proportion of eluent *) Aerotricino 29 1606 31.0 (C) (9 ml / min; 60/40) Aerotricino 56 1659 15.1 (C) (9 ml / min; 57/43) Aerotricino 78 1618 16.8 (C) (9 ml / min; 57/43) * proportion of trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% acetonitrile Example 11 Preparation of aerotricin 18 (a) To the solution of the crude amino derivative of compound A, obtained in example 10 (a), (1.7 mg, 0.001 mmol in methanol (0.05 ml) and pyridine (0.025) ml), Boc-Gly-OH (18 mg, 0.10 mmol), WSCI (30 mg, 0.15 mmol, and HOBT hydrate (24 mg, 0.15 mmol) were added in succession. for 15 hours at room temperature, the solvent was removed by a stream of dry nitrogen (b) The crude residue obtained above was dissolved in TFA (0.1 ml) and stirred at 0 ° C for 30 minutes. TFA was removed with a stream of dry nitrogen, the residue was purified by reverse phase preparative HPLC, the appropriate fractions were pooled, frozen and lyophilized to obtain 0.54 mg of aerotricino 18 as a colorless amorphous solid. Rt): 8.9 minutes (column B. flow rate: 4 ml / min., Eluent: trifluoroacetic acid 0.5% - water: trifluoroac acid ethic 0.05% - acetonitrile = 57:43); EMBAR (m / z): 1605 [MH? - The following aerotricins 12-23, 30, 57-62, 79 and 81, were prepared according to the method similar to that described in example 11, using the corresponding acylating agent and the aerotricins obtained in Example 10 as starting material.

EM-BAR HPLC Analytical condition Name of the M / z: [MH ~] Time of (column) (flow rate: composite restriction (min.) Proportion of eluent *) Aerotrícino 19 1590 17.5 (A) (1 ml / min; 57/43) Aerotricino 20 1619 6.0 (B) (4 ml / min; 55/45) Aerotricino 21 1663 18.0 (C) (9 ml / min; 60/40) Aerotricino 22 1605 12.5 (A) (1 ml / min; 55/45) Aerotricino 23 1620 23.9 (C) (9 ml / min; 55/45) Aerotricin 30 1676 24.6 (C) (9 ml / min; 61/39) Aerotricino 57 1701 21.2 (C) (9 ml / min; 56/44) Aerotricino 58 1730 23.4 (C) (9 ml / min; 55/45) Aerotricino 59 1716 13.7 (C) (9 ml / min; 58/42) Aerotricino 60 1730 16.3 (C) (9 ml / min; 55/45) Aerotricino 61 1730 39.1 (C) (9 ml / min; 47/53) Aerotricino 62 1730 15.8 (C) (9 ml / min; 55/45) Aerotricino 79 1689 36.1 (C) (9 ml / min; 57/43) Aerotricino 81 1675 24.4 (C) (9 ml / min; 60/40) * proportion of trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% acetonitrile.

Example 12 Preparation of aerotricin 12, To a solution of aerotricin 5 (7.5 mg, 0.0048 mmol), 37% formalin (150 μl) and acetic acid (50 μl) in MeOH (1.0 ml) were added cyanoborohydride of sodium (7.5 mg, 0.119 mmol) in MeOH (100 μl) at room temperature, and the mixture was stirred for 7 hours at room temperature. After evaporating the solvent to the vat, the residue was dissolved in n-butanol and washed with dilute hydrochloric acid and water successively. The organic layer was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC, and the detailed conditions thereof are shown below. The appropriate fractions were pooled, frozen and cyclized to obtain 5.4 mg of aerotricin 12 as a colorless amorphous solid. HPLC (Rt): 7.1 minutes (column B. flow rate: 4 ml / min., Eluent: trifluoroacetic acid 0.05 - water: trifluoroacetic acid 0.05% - acetonitrile = 50:50); MS-BAR (m / z): 1575 [MH +]. The following aerotricins 13, 25, 30 and 75 were prepared according to the method similar to that described in example 12.

EM-BAR HPLC Analytical condition Name of m / z: [_ vffiT] time of (column) (flow rate: compound restriction (min.) Proportion of eluent *) Aerotricino 13 1561 13.7 (B) (4 ml / min; 55/45) Aerotricino 25 1607 23.5 (C) (4 ml / min; 55/45) Aerotricin 30 1676 24.6 (C) (9 ml / min; 61/39) Aerotricino 75 1631 24.2 (C) (9 ml / min; 55/45) * proportion of trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% acetonitrile Example 13 Preparation of aerotricin 111 (a) To a solution of aerotricin 3 (500 mg, 0.326 mmol), (2-oxoethyl) carbamic acid tert-butyl ester (1.66 g, 10.4 mmol) and acid acetic acid (5 ml) in MeOH (45 ml) was added sodium cyanoborohydride (410 mg, 6.52 mmol) in MeOH (5 ml) at room temperature. The mixture was stirred for 18 hours at room temperature. After evaporating the solvent in vacuo, the residue was dissolved in n-butanol and washed with dilute hydrochloric acid and water successively. The organic layer was evaporated in vacuo. The crude residue was used in the next step without further purification. * CAS No. 89711-08-0 (b) A solution of the crude residue obtained above in TFA (20 ml) was stirred at 0 ° C for 30 minutes. The TFA was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC, the detailed condition of which is shown below. Appropriate fractions were pooled, frozen and lyophilized to obtain 253 mg aerotricino 111 as a colorless amorphous solid. HPLC (Rt): 18.6 minutes (column F. flow rate: 10 ml / min., Eluent: trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% - acetonitrile = 57:43); ES-B7AR (m / z): 1619 [M + H]? The following aerotricins 100, 112, 114 and 115 were prepared according to the method similar to that described in example 13.

EM-BAR HPLC Analytical condition Name of m / z: [MHT] time of (column) (flow rate: compound restriction (min.) Proportion of eluent *) Aerotricino 100 1730 14.8 (F) (10 ml / min; 56/44) Aerotricino 112 1647 11.8 (F) (10 ml / min; 57/43) Aerotricin 1 14 1759 23.1 (C) (10 ml / min; 60/40) Aerotricino 115 1633 19.6 (F) (10 ml / min; 59/41) * proportion of trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% acetonitrile Example 14 Preparation of Aerotricin 120 To a mixture of aerothricin .3 (500 mg, 0.326 mmol), and triethylamine (682 μL, 4.89 mmol) in MeOH (10 mL) was added acrylonitrile (214 μL, 3.27 mmol) at room temperature. The mixture was stirred for 20 hours at room temperature. After evaporating the solvent in vacuo, the residue was dissolved in n-butanol and washed with dilute hydrochloric acid and water successively. The organic layer was evaporated in vacuo.

The crude residue was purified by reverse phase preparative HPLC, under the conditions detailed below. Appropriate fractions were pooled, frozen and lyophilized to obtain 207 mg aerotricin 120 in the form of a colorless amorphous solid. HPLC (Rt): 27.5 minutes (column F. flow rate: 10 ml / min., Eluent: trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% - acetonitrile = 53:47); MS-BAR (m / z): 1586 [M + H] U Example 15 Preparation of Aerotricin 113 To a mixture of aerothricin 120 (100 mg, 0.063 mmol), in MeOH (5 mL) was added 10% palladium on carbon (20 mg) and the reaction vessel was filled with hydrogen. After stirring for 20 hours at room temperature, the mixture was filtered through a membrane filter (pore size 0.2 μm) and the solvent was evaporated in vacuo. The crude residue was purified by reverse phase preparative HPLC, the conditions of which are detailed below. Appropriate fractions were pooled, frozen and lyophilized to obtain 87.2 mg aerotricin 113 as a colorless amorphous solid.

HPLC (Rt): 23.0 minutes (column F. flow rate: 10 ml / min., Mobile phase: trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% - acetonitrile = 57:43); EM-BAR (m / z): 1590 [M + H] Aerotricin 129 was prepared according to the method similar to that described in example 14-15 followed by removal of the Boc group from the ornithine radical with trifluoroacetic acid. The starting material, in this case, was the N-Boc derivative of part (D) -ornithine of aerotricin 106 obtained in the process similar to Example 16.

EM-BAR HPLC Analytical condition Name of m / z: [MlT] time of (column) (flow rate: compound restriction (min.) Proportion of eluent *) Aerotricin 129 1705 33.8 (F) (10 ml / min; 62/38) ratio of trifluoroacetic acid 0.05! Water: 0.05% trifluoroacetic acid acetonitrile Example 16 Preparation of Aerotricin 14 To a solution of N-Boc-sarcosine (123 mg, 0.65 mmol), WSC-HC1 (240 mg, 1.25 mmol) and DMAP (150 mg, 1.23 mmol) in CH3CN (10 ml) was added a solution of aerothricin 3 (100 mg, 0.065 mmol) in CH30H (3 ml).

The mixture was stirred for 15 hours at room temperature and then evaporated to va cy. The residue was dissolved in n-BuOH (10 ml) and washed with HO (5 ml x 2, the pH was adjusted to 3 ~ 4 with 1 N HCl). The n-BuOH layer was concentrated in vacuo and the residue was dissolved in TFA (5 ml) at 0 ° C. After stirring the solution at room temperature for 1 hour, the TFA was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC to obtain 40.8 mg (39% yield) of aerothricin 14 in the form of a white amorphous HPLC (Rt): 23.1 min. (column C, flow rate: 9 ml / min., trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% - acetonitrile = 60:40); EM-BAR (m / z): 1605 [MH *]. The following aerotricins 15, 21, 26-29 and 101-107, 109, 110, 118, 130 and 131 were prepared according to the method similar to that described in example 16 using the corresponding acid as the starting material.

EM-BAR HPLC Analytical condition Name of m / z: [MHT] time of (column) (flow rate: composite restriction (min.) Proportion of eluent *) Aerotricin 15 1631 24.0 (C) (9 ml / min; 57/43) Aerotricino 21 1663 18.0 (C) (9 ml / min; 60/40) Aerotricino 26 1650 19.9 (C) (9 ml / min; 50/50) Aerotricin 27 1676 22.5 (C) (9 ml / min; 55/45) Aerotricino 28 1636 20.5 (C) (9 ml / min; 50/50) Aerotricino 29 1606 31.0 (C) (9 ml / min; 60/40) Aerotricino 101 1647 16.5 (F) (10 ml / min; 56/44) Aerotricin 102 1661 16.3 (F) (10 ml / min; 56/44) Aerotricin 103 1689 13.4 (F) (10 ml / min; 54/46) Aerotricino 104 1633 22.6 (F) (10 ml / min; 58/42) Aerotricino 105 1615 29.2 (F) (10 ml / mir, 52/38) Aerotricino 106 1647 17.3 (F) (10 ml / min; 56/44) Aerotricino 107 1661 36.5 (F) (10 ml / min; 60/40) Aerotricin 109 1633 26, 1 (F) (10 ml / min; 58/42) Aerotricin 1 10 1619 28.8 (F) (9 ml / min: 58/42) Aerotricin 1 18 1685 15.2 (F) (10 ml / min; 51/49) Aerotricin 130 1847 16.0 (F) (10 ml / min; 63/37) Aerotricin 131 1818 21, 1 1 (F) (10 ml / min; 63/37) * proportion of trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% acetonitrile Example 17 Preparation of aerotricin 74 A mixture of aerothricin 66 (20 mg, 0.012 mmol), 3,5-dimethylpyrazole-1-carboxamidine nitrate (13 mg, 0.064 mmol) and triethylamine (18 ml, 0.13 mmol) in MeOH (1 ml) was stirred for 15 hours at room temperature. After evaporating the solvent, the crude residue was purified by reverse phase preparative HPLC, the conditions of which are detailed below. The appropriate fractions were pooled, frozen, lyophilized to obtain 10.2 mg of aerotricin 74 in the form of a colorless amorphous solid. HPLC (Rt): 21.2 min. (column C, flow rate: 9 ml / min., 0.05% trifluoroacetic acid - water: 0.05% trifluoroacetic acid - acetonitrile = 54:46); EM-BAR (m / z): 1645 [MH? The following aerotricins 4 and 116 were prepared according to the method similar to that described in example 17 using aerotricino 3 and 111 as starting material, respectively.

EM-BAR HPLC Analytical condition Name of m / z: [MÍT] time of (column) (flow rate: compound restriction (min.) Proportion of eluent *) Aerotricino 4 1576 6.6 (D) (1 ml / min; 50/50) Aerotricin 116 1703 14.9 (F) (10 ml / min; 57/43) * ratio of trifluoroacetic acid 0.05% water: trifluoroacetic acid 0.05% acetonitrile Example 18 Preparation of aerotricin 5 (a) To a solution of compound A, obtained in reference example 3 (10 mg, 0.0061 mmol), and potassium carbonate (10 mg, 0.072 mmol) and DMF (1 ml) was added methyl iodide (8 μl, 0.129 mmol) at room temperature , and the mixture was stirred for 43 hours at room temperature. Then, the mixture was filtered through a Celite cartridge and the filtrate evaporated in vacuo. The residue was dissolved in n-butanol and washed with dilute hydrochloric acid and water successively. The organic layer was evaporated to the vacoo.-The crude residue was used in the next step without further purification. (b) A solution of the crude residue obtained above, in TFA (1.0 ml), was stirred at 0 ° C for 30 minutes. The TFA was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC, the conditions of which are given below. Appropriate fractions were pooled, frozen and lyophilized to obtain 3.8 mg aerotricin 5 as a colorless amorphous solid. HPLC (Rt): 14.5 min. (column B, flow rate: 4 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% - acetonitrile = 55:45); MS-BAR (m / z): 1547 [MH +]. The following aerotricins 6-10 and 76 were prepared according to the method similar to that described in -example 18 using the corresponding alkylating agent.

EM-BAR HPLC Analytical condition Name of _? / Z: [Míf] time of (column) (flow rate: composite restriction (min.) Ratio of eluent *) Aerotricino 6 1561 16.0 (A) (1 ml / min; 55/45) Aerotricino 7 1573 8.4 (A) (1 ml / min; 50/50) Aerotricino 8 1589 26.1 (B) (4.7 ml / min; 58/42) Aerotricino 9 1591 38.5 (B) (4 ml / min; 60/40) Aerotricino 10 1590 6J (A) (1 ml / min; 53/47) Aerotricino 76 1617 26.0 (C) (9 ml / min; 53/47) proportion of trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05 * -acetonitrile Example 19 Preparation of aerotricin 24 (a). a cold mixture of compound A, obtained in reference example 3 (100 mg), sodium iodide (29.5 mg, 0.197 mmol) and sodium hypochlorite solution (250 μl) in methanol (2 ml), was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate saturated solution, acidified with 1N HCl and extracted with n-butanol. The organic extracts together were evaporated in vacuo. At this time, there was still material left unreacted. To complete the iodination reaction, the same experimental procedure was repeated. After repeating the same operations, the residue was purified by reverse phase preparative HPLC, obtaining the iodinated derivative of compound A in the form of a colorless amorphous solid (54 mg, 50% yield). (b) A mixture of the iodinated derivative of compound A obtained above (23.8 mg), methyl acrylate (16 μl triethylamine (40 μl) and palladium acetate (2.1 mg) in acetonitrile (250 μl) and N, N. dimethylformamide (750 μl) was heated at 70 ° C. for 28 hours, the resulting mixture was passed with trifluoroacetic acid (1 ml) at 0 ° C. for 1 hour, the resulting mixture was evaporated in vacuo. Preparative inverted-phase HPLC gave aerothricin 24 as a colorless solid (8.8 mg, 40% yield) HPLC (Rt): 86.3 min (column F. flow rate: 9 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% - acetonitrile = 58:42); MS-BAR (m / z): 1617 [MH +].

Example 20 Preparation of aerotricin 96 A mixture of the iodinated derivative of compound A (30 mg), obtained in example 19 (a), potassium acetate (6.9 mg) and tetrakis (triphenylphosphine) palladium (4.6 mg) in degassed dimethyl sulfoxide (2 ml), was heated to 60 ° C. C for 20 hours in a carbon monoxide atmosphere. The resulting mixture was passed through a short inverted phase C-18 column, and the residue was treated with trifluoroacetic acid at 0 ° C for 1 hour. The resulting mixture was evaporated under reduced pressure. Purification of the residue by preparative reverse phase HPLC provided the aerotricino 96 in the form of a colorless solid (2.3 mg, yield 8%). HPLC (Rt): 23.2 min. (column F. flow rate: 10 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% acetonitrile = 52.2: 47.8); MS-BAR (m / z): 1677 [MH +]. Example 21 Preparation of aerotricin 32 (a). A mixture of compound A, obtained in reference example 3 (20 mg), and hydroxide of (methoxycarbonylsulfa oil) triethylammonium (26.5 mg, 0.108 mmol) in acetonitrile (3 ml) was stirred at room temperature for 8 hours. The reaction mixture was acidified with 1 N HCl and evaporated in vacuo. The residue was extracted with n-butanol and the extracts were evaporated in vacuo. (b) The crude product was treated with trifluoroacetic acid at 0 ° C for 1 hour. The TFA was evaporated in vacuo. Purification of the residue by preparative reversed-phase HPLC gave aerothricin 32 as a colorless solid (2.0 mg, 10% yield). HPLC (Rt): 42.9 min. (column B. flow rate: 4 ml / min, eluent: trifluoroacetic acid 0.05% - water: 0.05% trifluoroacetic acid - acetonitrile = 55:45); MS-BAR (m / z): 1516 [MH "] Example 22 Preparation of Aerotricin 31 (a) To a cooled solution of compound A, obtained in reference example 3 (25.7 mg), in tetrahydrofuran (5 ml), the dimethyl borane-sulfoxide complex (25 ml) was added at -10 ° C. After stirring at -10 ° C for 5 hours, the reaction mixture was quenched with 2N HCl and extracted with n-butanol. The extracts were combined and evaporated in vacuo. (b) The crude product was treated with trifluoroacetic acid at 0 ° C for 1 hour. The TFA was evaporated under reduced pressure. Purification of the residue by preparative reverse phase HPLC gave aerothricin 31 as a colorless solid (3.7 mg, 15% yield). HPLC (Rt): 25.1 min. (column B. flow rate: 4 ml / min., eluent: trifluoroacetic acid 0.05% - water: 0.05% trifluoroacetic acid - acetonitrile = 62:38); EM-BAR (m / z): 1519 [MH? . Example 23 Preparation of aerotricin 121 To a solution of aerothricin 3 (50 mg) in DMF (1 ml) and triethylamine (0.025 ml), methyl iodide (0.010 ml) was added. After stirring for 16 hours at room temperature, triethylamine (0.025 ml) and methyl iodide (0.05 ml) were again added to the mixture and stirred for 24 hours at room temperature. The LCMS analysis of the mixture indicated a transformation > 90% of the desired compound. The solvent was purged with a stream of nitrogen and the residue was purified by reverse phase preparative HPLC, the conditions of which are detailed below. Appropriate fractions were pooled, frozen and lyophilized to obtain 23 mg aerotricino 121 in the form of a colorless amorphous solid.

HPLC (Rt): 20.5 min. (column B. flow rate: 4 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% - acetonitrile = 52:48); EM-BAR (m / z): 1576 [MH *]. Example 24 Preparation of Aerotricin 122 To a solution of aerothricin 3 (50 mg) in pyridine (1 ml), the sulfur trioxide complex N, N-dimethyl formamide (23 mg) was added. After stirring for 2 hours at room temperature the solvent was purged with a stream of dry nitrogen. A solution of the crude residue obtained above in TFA (1 ml) was stirred at 0 ° C for 30 minutes. The TFA was purged with a stream of dry nitrogen and the residue was purified by reverse phase preparative HPLC, the conditions of which are detailed below. The appropriate fractions were pooled, frozen and lyophilized to obtain 5 mg aerotricino 122 as a colorless amorphous solid. HPLC (Rt): 24.6 min. (column F. flow rate: 10 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% acetonitrile = 52:48); MS-BAR (m / z): 1613 [MH +].

Example 25 Preparation of aerotricin 63 (a). To a stirred solution of Na-Fmoc-N ^ -Boc (S) -2, 3-diaminopropionic acid (343 mg, 0.80 mmol) in DMF (10 ml) were added BOP reagent (355 mg, 0.80 mmol) ), HOBT hydrate (124 mg, 0.81 mmol) and N, N-diisopropylethylamine (0.174 ml, 1.00 mmol). After stirring the mixture for 1.5 hours at room temperature, a solution of aerothricin 3 (1.10 g, 0.67 mmol) and N, N-diisopropylethylamine (0.174 ml, 1.00 mmol) was added to the mixture. in DMF (9.5 ml). After stirring for an additional 1 hour at room temperature, the mixture was concentrated in vacuo. (b) To a stirred solution of the residue obtained above in DMF (20 ml) was added polyamine resin of piperidine-4-carboxylic acid (200-400 mesh), HL (1.50 mmol / g, 2.66 g), and the The reaction mixture was irradiated with ultrasound for 6 hours. The resin was removed by filtration through a Celite cartridge, washed with MeOH and the filtrate together with the wash were frozen and lyophilized providing 1.08 g of the crude derivative of aerothricin 3 as a white amorphous solid. , which was used in the next step without further purification. (c). To a stirred solution of the crude derivative of aerothricin 3, obtained above (25.6 mg, 0.015 mmol) in MeOH (1 ml) were added the (2-oxo-ethyl) carbamic acid tert-butyl ester (crude, 207 mg), AcOH (0.1 ml) and NaBH 3 CN (19.1 mg). After stirring the mixture for 2 hours at room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with n-BuOB (4 ml) and washed with H20 (1 ml x 2, pH adjusted to 3-4 with 0.1 N HCl. The n-BuOH layer was concentrated in vacuo. crude was used for the next step without further purification. (d) A solution of the crude residue obtained above in TFA (2 ml) was stirred at 0 ° C for 2 hours.TFA was evaporated in vacuo and the residue it was purified by reverse phase preparative HPLC chromatography under the conditions detailed below Pure fractions were pooled, frozen and lyophilized to obtain 8.8 mg of aerothricino 63 as a white amorphous solid. Rt): 24.8 min (column F. flow rate: 9 ml / min., Eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% - acetonitrile = 54:36); EM-BAR (m / z): 1706 [MH +].

Example 26 Preparation of Aerotricin 127 Aerotricin 127 was prepared by the same method as has been previously described. described for aerotricino 63, using N-Fmoc-Nd-Boc- (D) -ornithine. The aerotricino 127 was obtained in the form of a white amorphous solid. HPLC (Rt): 23.9 min. (column F. flow rate: 9 ml / min., eluent: trifluoroacetic acid 0.05%; - water: trifluoroacetic acid 0.05% acetonitrile = 54:36); MS-BAR (m / z): 1734 [MH +]. Example 27 Preparation of aerotricin 124 (a). To a stirred solution of Boc-D-Orn (Boc) -OH (46 mg, 0.138 mmol) in DMF (2 ml) were added BOP reagent (62 mg, 0.14 mmol), HOBT hydrate (22 mg, 0.144). mmoles) and N, N-diisopropylethylamine (24 μl, 0.138 mmol). After stirring for 30 minutes at room temperature, a solution of aerothricin 120 (100 mg, 0.063 mmol) and N-diisopropylethylamine (24 μL, 0.138 mmol) in DMF (2 mL) was added to the reaction mixture. After stirring for 18 hours at room temperature, the solvent was evaporated in vacuo. The residue was dissolved in TFA (4 ml) and the solution was stirred at 0 ° C for 30 minutes. After eliminating the TFA. With a stream of dry nitrogen, the residue was purified by reverse phase preparative HPLC, under the conditions detailed below. The pure fractions were pooled, frozen freeze dried obtaining 48.6 mg of the nitrile derivative as a white amorphous solid. HPLC (Rt): 20.2 min. (column F. flow rate: 10 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% acetonitrile = 57:43); MS-BAR (m / z): 1700 [M + H]? (b) To a mixture of the nitrile derivative obtained above (48.6 mg, 0.0286 mmol) in dioxane (1 ml) and water (1 ml), 10% palladium on carbon (10 mg) was added, and the Mix in hydrogen atmosphere for 14 hours at room temperature. The mixture was then filtered through a membrane filter (pore size: 0.2 μm) and the solvent was evaporated in vacuo. The crude residue was purified by reverse phase preparative HPLC, under the conditions detailed below. The pure fractions were pooled, frozen and lyophilized to obtain 26.5 mg of Aerotricin 124 in the form of a colorless amorphous solid.

HPLC (Rt): 18.2 min. (column F. flow rate: 10 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% acetonitrile = 60:40); MS-BAR (m / z): 1704 [M + H]? Example 28 Preparation of aerotricin 125 (a). To a solution of the TFA mono salt of aerotricin 3 (natural product: 50 mg) in DMF (1 ml) and triethylamine (0.126 ml), 2-bromo-5-nitropyridine (185 mg) was added. After stirring for 25 hours at room temperature, the solvent was purged with a stream of dry nitrogen. The residue was purified by reverse phase preparative HPLC chromatography. Appropriate fractions were pooled, frozen and lyophilized to obtain 25 mg of the 5-nitropyrid-2-yl derivative of aerotricin 3 as a light yellow amorphous solid. HPLC (Rt): 29.9 min .. (column F. flow rate: 10 ml / min., Eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% acetonitrile = 47:53); MS-BAR (m / z): 1655 [M + H]? (b) The 5-nitropyrid-2-yl derivative of aerothricin 3 obtained above (10 mg) was dissolved in dioxane-H20 (1 ml-5 ml), 5% palladium on carbon (20 mg), and the reaction vessel were added. It was filled with hydrogen. After stirring for 3 hours at room temperature it was filtered through a membrane filter (pore size: 0.2 μm) and the solvent was evaporated obtaining 14 mg of crude product which was purified by preparative HPLC inverted phase , under the conditions detailed below. Pure fractions were pooled, frozen and lyophilized to obtain 2.5 mg of Aerotricin 125 in the form of a colorless amorphous solid. HPLC (Rt): 18.7 min. (column F. flow rate: 10 ml / min., eluent: trifluoroacetic acid 0.05% - water: trifluoroacetic acid 0.05% acetonitrile = 52:48); MS-BAR (m / z): 1625 [M + H] *. Example 29 Preparation of aerotricino 128 (a). To a stirred solution of F-moc-D-Orn (Boc) -OH (389 mg, 0.86 mmol) in DMF (10 ml) was added BOP reagent (378 mg, 0.85 mmol), HOBT hydrate ( 131 mg, 0.86 mmol) and N, N-diisopropylethylamine (171 μL, 0.98 mmol). After stirring the mixture for 40 minutes at room temperature, a solution of aerothricin 3 (1.08 mg, 0.66 mmol) and N, N-diisopropylethylamine (171 μL, 0.98 mmol) in DMF was added to the mixture. (10 ml). After stirring for 2.5 hours at room temperature, piperidine (4 ml) was added, and the mixture was stirred for a further 1 hour at room temperature. The mixture was concentrated in vacuo. The residue was dissolved with n-BuOH (50 ml) and washed with H20 (25 ml x 2, pH adjusted to 3 with 1 N HCl). The n-BuOH layer was concentrated in vacuo. (b) To a stirred solution of Boc-D-Orn (Boc) -OH (9.6 mg, 0.029 mmol) in DMF (1 ml) was added BOP reagent (13.3 mg, 0.030 mmol), HOBT hydrate (4, 6 mg, 0.030 mmol) and N, N-diisopropylethylamine (4.8 μl, 0.028 mmol). After stirring the mixture at room temperature for 30 minutes, a solution of the crude residue (31.9 mg) obtained above, and N, N-diisopropylethylamine (4.8 μL, 0.028 mmol) in dMF were added to the mixture. (1 ml). After stirring for 4 hours at room temperature, the reaction mixture was concentrated in vacuo. (c). The crude residue obtained above was dissolved in TFA (1.5 ml) and stirred at 0 ° C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse phase preparative HPLC. The appropriate fractions were pooled, frozen and lyophilized to obtain 16.6 mg aerotricino 128 in the form of a white amorphous solid.

HPLC (Rt): 27.23 min. (column F. flow rate: 9 ml / min., eluent: trifluoroacetic acid 0.05% - water: 0.05% trifluoroacetic acid - acetonitrile = 55:35); MS-BAR (m / z): 1762 [MH +]. Example 30 Preparation of aerotricin 106 from compound (IX) (a) A mixture of Fmoc-Tyr (But) (21 mg, 0.0457 mmol), HOBT monohydrate (6, 6 mg, 0.0431 mmol) , BOP reagent (18.8 mg, 0.0424 mmol) and diisopropylethylamine (DIEA, 20 μl) in DMF (0.5 ml), was stirred at room temperature for 1 hour and then added to a mixture of N (or n) ) -Boc-IX (19.3 mg, 0.0131 mmol) obtained in Example 6 and DIEA (10 μl) in DMF (1 mL). After stirring for 3 hours at room temperature, the resulting mixture was treated with piperidine (0.375 ml) for 1 hour and then concentrated in vacuo. The residue was washed with dichloromethane and diethyl ether to remove the reagents. Purification of the residue by HPLC gave the desired linear peptide A, as a white solid (16.6 mg). HPLC (Rt): 19 min. (Soken-ODS column / 20 x 250 mm, flow rate: 9 ml / min., eluent: H20: CH 3 CN = gradient, AcOH 1%). (b) A mixture of Fmoc-D-Ala monohydrate (1.2 mg, 0.034 mmol), HOBt monohydrate (4.7 mg, 0.031 mmol), BOP reagent (13.6 mg, 0.031 mmol) and DIEA (8 μl) in DMF (0.5 ml), stirred at room temperature for 1 hour and then added to a mixture of linear peptide A obtained above (16.6 mg, 0.0098 mmol) and DIEA (6 μl) in DMF (1 ml). The reaction mixture was stirred at room temperature and the activated ester was added until almost all of the starting material had reacted. The resulting mixture was concentrated in vacuo. The residue was washed with dichloromethane and diethyl ether to remove the reagents. The crude product was treated with trifluoroacetic acid at 0 ° C for 1 hour. The mixture was concentrated under reduced pressure. Purification of the residue by HPLC provided the desired linear peptide B in the form of a white solid (6.1 mg). HPLC (Rt): 19 min. (Soken-ODS column / 20 x 250 mm, flow rate: 9 ml / min., eluent: H20: CH 3 CN = gradient, AcOH 1%). (c) A mixture of Boc-D-Orn (Bu, 5.7 mg, 0.017 mmol), HOBt monohydrate (2.3 mg, 0.015 mmol), BOP reagent (5.4 mg, 0.012 mmol) and DIEA (6 μl) in DMF (0.5 ml), was stirred at room temperature for 1 hr. hour was then added to a mixture of linear peptide B (6.1 mg, 0.0033 mmol) and DIEA (3 μl) in DMF (1 ml). After stirring at room temperature for 2 hours, the resulting mixture was treated with piperidine (0.375 ml) for 1 hour, and concentrated in vacuo. Purification of the residue by HPLC provided the linear peptide C as a white solid (4.1 mg). HPLC (Rt): 16.7 min. (Soken-ODS column / 20 x 250 mm, flow rate: 9 ml / min., eluent: H20: CH 3 CN = gradient, AcOH 1%). (d). Linear peptide C was acidified with 0.01 N hydrochloric acid and extracted with n-butanol. The butanol extract was concentrated in vacuo. The extract was dissolved in DMF (2 ml). Next, HOBt monohydrate (0.1 M in DMF, 60 μL), BOP reagent (0.1 M in DMF, 60 μL) and DIEA (2 μL) were added to the mixture. After stirring at room temperature for 1 hour, the resulting mixture was concentrated in vacuo. The residue was treated with trifluoroacetic acid at 0 ° C for 1 hour. The mixture was concentrated under reduced pressure. Purification of the residue by HPLC provided aerotricin 106 as a white solid (2.2 mg, 9% N (orn) -Boc-IX). The analytical data are described in the table of example 16.

Example A Injectable solutions containing each of the following ingredients were prepared in the conventional manner: Aerotricino 45 20 mg di-phosphate sodium acid, anhydrous 7.6 mg Sodium diphosphate, dihydrate 2.0 mg Ethyl alcohol 150 mg Distilled water, deionized, sterile 850 mg Total 1029.6 mg It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (32)

2. Having described the invention as above, property is claimed as contained in the following claims: 1. Aerotricinos represented by the formula (I). characterized in that RJ is guanidino, tri-lower alkyl-ammonium, N (R) -R ill
3. -N (R, 1150) -CO-R14, N (R, 1150) -CO-CH [N (Rl1? U) v tR.111X] - -R, 13 NHCOCH (R13) -NHCOCH (NH2) - R13, 10 11 13 C CHH -N (R15) -CO-CH [N (R) R] -R 2. ' n N, CH -N (R15) -CO-CH [N (R10) R11] -R13 2 'n 10 R and R * x are each, independently of each other, selected from hydrogen; heteroaryl substituted with one or two amines; lower alkyl optionally substituted with one or more amines, lower aminoalkyl, cyano, guanidino, nitrogen containing heterocycle (s) or phenyl group (s) containing an amino, amidino or guanidino group; R 13 is a residue derived from natural or non-natural amino acids; R 14 is lower alkyl substituted with one or more amines, guanidino, nitrogen containing heterocycle (s) or phenyl group (s) containing an amino, amidino or guanidino group; R 15 is hydrogen, lower alkyl optionally substituted with one or more amines, guanidino, nitrogen-containing heterocycle (s), or phenyl group (s), containing an amino, amidino or guanidino group; R- is hydrogen, hydroxysulfonyl, lower alkyl or lower alkenyl, wherein lower alkyl and lower alkenyl may be optionally substituted with acyl, carbamoyl, amino, lower monoalkylamino or di-lower alkylamino; R "is hydrogen, hydroxyl, nitro, amino, acylamino, (lower alkylcarbamoyl) amino, carboxyl, lower alkoxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl or lower alkynyl, wherein lower alkyl, lower alkenyl and lower alkynyl may be optionally substituted with hydroxyl, amino, lower monoalkylamino, lower alkylamino, lower alkoxycarbonyl or carbamoyl; R4 is alkyl, alkenyl, alkoxy or alkenyloxy which may be optionally substituted with lower alkyl, aryl, cycloalkyl or fluorine atom (s); -CONH2, -CN or -CH2NH2; X is a single bond, or an aryl, biphenyl or terphenyl group optionally containing one or more heteroatom (s), and / or being substituted with halogen atom or lower alkyl; is a single bond, -CH; -, -CH (lower alkyl) -, -CONH- or -CON (lower alkyl) -; Z is -0-, -NH- or -N (lower alkyl) -; m is an integer from 0 to 4, and n is a number in from 2 to 5; with the proviso that when -Y- (CH2) m -X- R4 is unsubstituted alkyl or aralkyl, then R1 is not amino, R2 and R3 are not hydrogen, R5 is not -CONH; and Z is not -O- or -NH- at the same time; and the pharmaceutically acceptable salts thereof. 2. Aerotricins according to claim 1, characterized in that R1 is -N (R10) -R11 with R10 and R11 as defined in claim 1. 3. Aerotricins according to claim 1, characterized - because R1 is - N (R15) -CO-CHfNIR10 ^ 11] - ^ 13, with R10, R11, R13 and R15 as defined in claim 1. 4. Aerotricins according to claim 1, characterized in that R1 NHCOCH (R13) - NHCOCH (NH2) -R13, with R13 as defined in claim 1. 5. Aerotricins according to claim 1, characterized in that R1 is,
4. -COCH [N (R10) R11] -R 13
5. -CO-CH [N (R10) R11] -R13 with R10, R11, R13, R15 and n as defined in claim 1.
6. 6. Aerotricines according to claim 1 characterized in that R1 is with R10, R11, R13, R15 and n as defined in claim 1.
7. 7. Aerotricins according to claim 1, characterized in that it is -N (R15) -CO-R14 with R14 and R15 as defined in claim 1.
8. 8. Aerotricines according to claim 1, characterized in that R1 is with R10 and R11, as defined in claim 1.
9. 9. Aerotricins according to claim 1, characterized in that R1 is amino or guanidino.
10. 10. Aerothricins according to any of claims 1 to 9, characterized in that R2 is hydrogen, hydroxysulfonyl or lower alkyl.
11. 11. Aerotricins according to any of claims 1 to 10, characterized in that R3 is hydrogen, hydroxyl, nitro, amino or acylamino. _-
12. 12. __Aero ± _ri ___ inos_.de_ confc_rmidad_ con. any of claims 1 to 10, characterized in that R3 is (lower alkylcarbamoyl) amino, carboxyl, lower alkoxy or lower alkoxycarbonyl.
13. 13. Aerotricins according to any of claims 1 to 12, characterized in that R5 is -C0NH2 or -CH2NH2.
14. 14. Aerotricins according to any of claims 1 to 13, characterized in that X is a single bond or one of the following radicals: which may also be substituted with halogen atom or lower alkyl.
15. 15. Aerotricins according to any of claims 1 to 13, characterized in that X is a single bond, phenyl, biphenyl or naphthyl, which may be further substituted with halogen atom or lower alkyl.
16. 16. Aerotricins according to any of claims 1 to 15, characterized in that R4 is alkyl or alkoxy, which may be optionally substituted with lower alkyl, aryl, cycloalkyl or fluorine atom (s).
17. 17. Aerotricins according to any of claims 1 to 16, characterized in that m is an integer from 0 to 2.
18. 18. Aerotricinos according to any of claims 1 to 17, characterized in that Y is -CH (CH3) -, - CON (CH3) -, -CONH-, -CH2- or a single bond
19. 19. Aerotricins according to any of claims 1 to 18, characterized in that Z is -NH-.
20. 20. Aerotricines according to any of claims 1 to 18, characterized in that Z is -0-.
21. 21. Aerotricines according to any of claims 1 to 20, characterized in that they are selected from the group formed by aerotricinos 2, 4 to 32, 63, 96-99, 101 to 131.
22. 22. Aerotricinos according to any of the claims 1 to 20, characterized in that they are selected from the group consisting of aerotricinos 14, 15, 21, 26 to 29, 63, 98, 99 and 101 to 131.
23. 23. Aerotricinos according to any of claims 1 to 22, to be used in medical therapy.
24. 24. Compounds represented by the formula
25. (III) characterized in that R2, R3 and R5 are as defined in claim 1, and R6 is an amino protecting group; with the proviso that when R5 is -CONH2, then Rz or R3 are other than hydrogen; and the salts the. 25. A compound represented by the formula (IX). and the salts the. 26. Compounds represented by the formula
26. (X), characterized in that R7 is an amino protecting group, and the salts the.
27. 27. Compounds represented by the formula (XII). characterized in that RD is an amino protecting group, and the salts the.
28. 28. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 22 and a pharmaceutically acceptable carrier.
29. 29. The use of a compound as defined in any of claims 1 to 22, for the preparation of medicaments for the treatment or prophylaxis of mycoses.
30. 30. A biologically pure culture of Deuteromycotina NR7379 (FERM-BP-6391).
31. 31. A method for the preparation of aerotricins described in any of claims 1 to 2, characterized in that the process comprises: (a) culture of a microorganism belonging to the genus Deuteromycotina and isolation of aerotricino 1, 2 and / or a linear peptide of formula (IX) as defined in claim 25 from the culture broth; or (b) condensation of a compound of formula (III), wherein R ", R" and R 'are as defined in claim 1, and R "" is an amino protecting group; with a compound of formula (IV), wherein R "is an amino protecting group, Re is hydrogen or lower alkyl, and R4 X, Y and m are as defined in claim 1, followed by removal of the protective group of the amino R, the successive cyclisation and removal of the amino protecting group R6, or (c) nitration of the aerotricins of the formula (I), wherein R3 is a hydrogen atom; and R1, R2, R, R, X, Y, Z and m are as defined in claim 1; or (d) r.duction of the nitrogen group of the aerotricins of formula (I) above, wherein R 3 is a nitro group; and Ru RU? R5- X, Y, Z and are as defined in claim 1; or (e) acylation of the amino group of the aerothricins of the formula (I) above, wherein RJ is an amino group; and R1, R, R4, R5, X, Y, Z and m are as defined in claim 1; followed if necessary, by the removal of the amino protecting group, or (f) cyanoethylation or 2, 2-dicynaethylenation of the amino group of the aerothricins of the formula (I), wherein R 1 is an amino group or -N (R 15 ) -COCH (NH2) -R13; and R13, R15, R2, R3, R4, R5, X, Y, Z and m are as defined in claim 1; followed by the reduction of the cyano group (s), and if necessary, by the elimination of the protecting group (s), or (g) reductive alkylation of the amino group of the aerotricins of formula (I) above, wherein R1 _ is amino, (2-cyanoethyl) amino, or -N (R15) tCO-CHfNIR10 ^ 11] -R13; with R10 and Rn independently of one another are selected from hydrogen or (2-cyanoethyl) amino; and R13, R15, R:, R3, R4, R5, X, Y, Z and m, are as defined above; with an aldehyde of formula (V), R -CHO (V) wherein R9 is hydrogen, lower alkyl which may be further substituted with one or more protected amino, nitrogen-containing heterocycle (s), or phenyl group (s) containing a protected amino group; followed, if necessary, by the elimination of the amino protecting group (s), or by the reduction of the group, cyano ,. or (h) arylation of the amino group of the aerotricins of the formula (I) above, wherein R1 is an amino group, and R ", R3, R4, R5, X, Y, Z and m, are as defined in claim 1, with a compound of formula (VI), R12-Q (VI) wherein R12 is a heteroaryl containing nitrogen, which may be further substituted with a protected amino or a nitro group, and Q is an atom of halogen such as chlorine or bromine, followed, if necessary, by the removal of the amino protecting group, or by the reduction of a nitro group, or (i-1) acylation of the amino group of the aerothricins of the formula ( I) above, wherein R1 is an amino, and R2, R3, R4, R5, X, Y, Z and m, are as defined in claim 1, followed, if necessary, by the elimination of the protecting group of the amino, or (i-2) acylation of the amino group of the aerothricins of the formula (I) above, wherein R1 is -N (R10) -R ?: [wherein R10 and R11 are both lower alkyl s substituted with an amino group] or -N (R15) -COCH [N (R1C) R11] -R13 [wherein R15 is lower alkyl substituted with an amino group; R10, R11 and R13 are as defined in claim 1, with the proviso that the amino group (s) present in R10, R11 and R13 are protected], followed by removal of the protecting group of the amino, or (j) mono N-alkylation of the aerothricins of the formula (I) above, wherein R1 is amino; and R2, PT, R4, R £, X, Y, Z and m, - are as defined in claim 1; and the subsequent N-acylation, followed, if necessary, by the removal of the amino protecting group, or (k) conversion of the amino group of the aerothricins of the formula (I) above, wherein RJ is an amino group; -N (R 10) -R 1: L [wherein R 10 11 and R are independently selected from the group consisting of optionally substituted lower alkyl with one or more amino group (s) or phenyl containing an amino group]; -N (R15) -CO-CH [N (R10) R11] -R13 [wherein R10, R11 and R13 are as defined in claim 1, and R15 is lower alkyl optionally substituted with one or more group (s) amino), heterocycle (s) containing nitrogen - or - group (s) phenyl containing an - amino group j; or -NHCO-R14 [wherein R14 is lower alkyl substituted with one or more amines, nitrogen containing heterocycle (s) or phenyl group (s) containing an amino group] and R% R3, R4, R5, X, Y, Z and m are as defined in claim 1; in a guanidino group, by treatment with an activated amidine derivative, or (1) O-alkylation of phenolic hydroxyl group of the aerothricins of the above formula (I), wherein R2 is hydrogen and RU R3, R4, R5, X , Y, Z and m are as defined in claim 1; or (m) iodination of the aerotricins of the above formula (I), wherein R2 and R3 are hydrogen and R1, R4, R5, X, Y, Z and m are as defined in claim 1; followed by the palladium (0) catalyzed coupling of the resulting iodinated derivative of the formula (I), wherein R3 is an iodine and R !, R2, R3, R ", R5, X, Y, Z and m are as" "has - defined -" in "claim 1; - and - if" it is necessary, elimination of the amino protecting group, or (n) dehydrogenation of the carbamoyl group of lss-a-erstrrci-pss' of the formula ( I) - above, in "where RB is -CONH2 and R1, R2, R2, R3, X, Y, Z and m are as defined in claim 1, followed if necessary, by removal of the amino protecting group , or (o) reduction of the carbamoyl or cyano group of the aerotricins of the formula (I) above, wherein R5 is -CONH2 or -CN, and R :, R2, R3, R4, X, Y, Z and m are as is defined in claim 1, followed if necessary by the removal of the amino protecting group, or (p) hydroxy sulfonation of the tyrosine radical of the aerothricins of the formula (I) above, where R2 is hydrogen, and RU R3, R4, R5, X, Y, Z and m are as defined in claim 1; followed by removal of the protective group (s), or (q) conversion of the linear peptide of the formula (IX) above in the aerotricins of the formula (I) above, by the synthesis of the peptides, followed by a modification, according to a method selected from the previous procedures (c) a (or!
32. 32. The invention as described so far.