CYCLIC PEPTIDE NUCLEI AND DERIVATIVES THEREOF

Abstract: New peptide compounds of formula (I), wherein R<1> is alkyl or aralkyl, R<2> is amino(lower)alkyl or protected amino(lower)alkyl, R<3> is hydroxy, protected hydroxy, amino or protected amino, R<4> is hydroxy, or R<3> and R<4> are linked together to form -Z- (in which -Z- is -O- or -NH-), and R<5> is hydrogen or an amino protective group, R<6> is hydroxy, or R<5> and R<6> are linked together to form bond, with proviso that when R<3> is hydroxy, protected hydroxy, amino or protected amino and R<4> is hydroxy, then R<5> and R<6> are linked together to form bond, and a pharmaceutically acceptable salt thereof, which is useful as a medicament.

Description: DESCRIPTION Cyclic peptide nuclei and derivatives thereof TECHNICAL FIELD This invention relates to new peptide compounds and pharmaceutically acceptable salts thereof which are useful as a medicament. BACKGROUND ART Some peptide compounds have been known as described, for example, in WO 92/19648. DISCLOSURE OF INVENTION This invention relates to new peptide compounds. One object of this invention is to provide the new and useful peptide compounds and pharmaceutically acceptable salts thereof which possess a high antimicrobial activity (especially, antifungal activity) and a strong inhibitory activity on β-l,3-glucan synthase. Another object of this invention is to provide process for preparation of the peptide compounds and salts thereof. A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said peptide compounds or a pharmaceutically acceptable salt thereof. Still further object cf this invention is to provide a use cf saio peptide compounds cr a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of infectious diseases incluαmg ?neumocys is carinii infection (e.g., Pneu ocvstis caπr. pneumonia, etc.; caused by a variety of pathogenic microorganisms in human being and animals. The object peptide compounds of the present invention BAD ORIGINAL ώ - 9 - are novei and can be represented by the following general formula (I) : wherein R- is alkyl or aralkyl, P- is amino (lower) alkyl or protected amino (lower) alkyl, F. J is hydroxy, protected hydroxy, amino or protectec amino, D R^ is hydroxy, or R J and R- are linked together to form -Z- !in which -Z- is -C- cr -NH- , and ?."" is hydrogen or a amine protective group, R c is hydroxy, cr C P." and R c are linked together to form bond, with proviso that w en R is nyαroxy, protectec nyαroxy, ammo or protecteα amine and __ R' is hydroxy, 5 then ?~ and R c are iinkeα toσether to form bond. BAD ORIGINAL The object compound (I) of the present invention can be prepared by the processes as illustrated in the following. Process LLL 20 (II) or its reactive derivative at the amino group, cr a salt thereof val i ve _. - BAD ORIGINAL - ά - (la) or a salt thereof ■ocess _? • (lb) cr a salt therec: _ c, _ elimination reaction of the amino protective group 1 0 15 or a salt thereof - c - Process (3; (Ic) or a salt thereof cvc_-izatιon (Id) or a salt thereo. (IV) or its reactive derivative at the amir.o group, or a salt thereof or its reactive derivative at tne carDoxy group, or a salt tnerecf (If) or a salt thereof elimination reaction of the amino protective group sa t .ere. (Ig) or a salt thereof cyclization ( Ih) or a salt thereof Process .7) di) or its reactive derivative at the amino group, or a salt thereof acylation dj ) or a salt thereof - 11 - (Ik) or a salt thereof Hydrolysis (I/) or a salt thereof wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and -Z- are each as defined above, R 2 is amino(lower)alkyl, R^ is acylamino (lower) alkyl, R 3 is amino or protected amino, Rj 3 is protected amino, R g is hydrogen or an amino protective group, and Rj~ is an amino protective group. The starting compounds (II) and (IV) of the present invention can be prepared by the processes as illustrated in the following. Process (A) (VI) or a salt thereof cleavage of two amido bond by the enzyme - 13 - (ID or a salt thereof Process (B) (I/) or a salt thereof deacylation (IV) or a salt thereof wherein R 1 and R are each as defined above Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.) , an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic cr sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.) . In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends tc include within the scope thereof are explained in detail as follows . The term "lower" is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s) , unless otherwise provided. The term "higher" is used to intend a group having ~ tc 2C carbon atoms, unless otherwise proviάeα. Suitable "lower alky, terms "a ine ;lower; alkyl" "protected amino (lower) alkyl" may include straight cr branched one having I to 6 carbon atom(s) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, tert-pentyl, hexyl, and the like. Suitable "alkyl" and "alkyl moiety" in the term "aralkyl" may include straight cr oranched one having 1 tc _ ' BADORIGINAL carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and the like. Suitable "aryl moiety" in the term "aralkyl" may include phenyl, naphthyl and the like. Suitable "hydroxy protective group" in the term "protected hydroxy" may include acyl, mono (or di or tri)phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like. Suitable "amino protective group" may include acyl, and the like. Suitable "protected amino" and "protected amino moiety" in the term "protected amino (lower) alkyl" may include acylamino or an amino group substituted by a conventional protecting group such as mono (or di or tri) aryl (lower) alkyl, for example, mono (or di or tri)phenyl (lower) alkyl (e.g., benzyl, trityl, etc.) or the like. Suitable "acyl" and "acyl moiety" in the terms "acylamino", "acylamino (lower) alkyl" and "acyloxy" may include carbamoyl, aliphatic acyl group and acyl group aromatic ring, whicn -~ pe.rferreα :o as arorr a; Suitable example of said acyl may be illustrated as follows : Carca oyl; Thiocarbamcyl; Aliphatic acyl such as lower cr higher alkanoyi (e.g., for yl, acetyl, propanoyl, butanoyl, 2-methyIpropanoyl, pentanoyl, 2, 2-dimethylpropanoyI, hexanoyl, heptanoyl, cctanoyl, nonanoyi, decanoyi, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., ethylsulfonyl, ethylsuifonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); cyclo(lower) alkvlcarbonvl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); or the like; Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) lkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar (lower) alkenoyl [e.g., phenyl (lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyi, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyi, etc.), naphthyl (lower) alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; ar(lower) lkoxycarbonyl [e.g., phenyl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbcnyl, naphthyloxycarbonyl, etc.); aryloxy(lower) alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); aryiglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyi (e.g., pher.yisulfcr.vl, p-tclylsulfonyl, etc., ; _r the like; and the like. ^rererrec e ooαiments cr tne oc ecz compcunc ,_. are . : follows. wherein R- is ) alkyl, R- is amino (lower) alkyl cr acylamino (lower) lkyl (more oreferablv lower alkoxvcarbonviamino- - 16 - (lower) alkyl, R is hydroxy, acyloxy, amino or acylamino (more preferably ar (lower) alkoxycarbonylamino; most preferably phenyl (lower) alkoxycarbonylamino) , R 4 is hydroxy, or R 3 and R4- are linked together tc form -Z- (in which -Z- is -0- or -NH-), and R- 1 is hydrogen or acyl (more preferably ar (lower) lkoxycarbonyl; most preferably phenyl (lower) alkoxycarbonyl, R is hydroxy, or c _r R J and R° are linked together to form bond, with proviso that when R J is hydroxy, acyloxy, amino or acylamino (more preferably ar(lower) alkoxycarbonyl; most preferably phenyl (lower) alkoxycarbonyl . and __ R- is hydroxy, then R^ and R are linked together to form bond. The processes for preparing the object and the starting compounds are explained in detail in the following. Process LU The compound (la! or a sal reacting the compound (II) cr its reactive derivative at the ami e group, or a salt thereof with the compound (III' cr it reactive derivative at the carboxy group, cr a salt thereof. Suitable reactive derivative at the amine group cf tr.e compound ;ili may include Schiff's base type imino or its ta to eric e amine type iso er formed by the reaction of tr.e cempounα 'II) with a carbonyl compound such as aldehyde, ketone or the like; a siiyl derivative formed by the react o: of the compound (II) with a siiyl compound such as N,0- ethylsiiyl) acetamide, N-trimethyl≤ilylacetamide cr BAD ORIGINAL 0 the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene, and the like. Suitable reactive derivative of the compound (III) may- include an acid halide, an acid anhydride, an activated ester, and the like. The suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenyiphosphoric acid, diphenylphosphoric acid, dibenzylphcsphoric acid, haloger.atea phosphoric acid, etc.,, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., ethanesulfonic acid, ethanesuifonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyIbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with i idazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl ester, ethoxymethyl ester, dimethyliminomethyi [ (CH 3 ) - τ N=CH-lester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyiphenyl ester, phenyiazophenyl ester, phenyithio ester, p-nitrophenyi thioester, p-cresyl th oester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 6-quinoiyl thioester, etc.); ar. ester with a N-hydroxy compound (e.g., N,X-dimethylhydrcxylamine, l-hydrcxy-2- , ~Y. - pyridone, X-hydrox succinimi e, X-nycroxybenzotriazole, X-hydroxyphthalimide, 1-hydroxy-?-chicro-lH-ben o riazcie, etc., ; and the like. These reactive αeπvatives car. optionally be selected from them accordingly to the kind of the compound (III) tc be used. The reaction is usually carried out i a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methvlene chloride, ethvlene chicride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof. When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence cf a conventional condensing agent such as N,N' -dicyclohexyicarbodiimide; N-cyclohexyi-N'-morpholinoethyicarbodiimide; N-cyclohexyl-N'- (4-dιethylaminocyclohexyl) carbodiimide; N,N' -diisopropyicarbociimide; N-ethyl-N 1 - (3-dimethylaminopropyl) carbodiimide; N,N-carbonyl-bis (2-methyIιmiaazoie) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cycIohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride) ; phosphorous trichloride; thionyl chloride; oxalyl chloride; triphenyiphosphite; 2-echyl- ~ -hydroxybenzisoxazolium salt; 2-ethyl-5- ( -sulfcphenyi) isoxa∑oiium hydroxide intra¬ molecular salt; 1- (p-chiorobenzenesulfonyloxy) -β-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like. The reaction may also be carried cut the presence c f ar. organic cr inorganic base such as ar. alkali metal bio rbcr.ate, tri (lower,> alkylamir.e .e.g., triethylamine, etc. : , pyridine, N- lower. aikyimcrphorine, N, -di ;lower - al ylbenzylam e, cr the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. Process (2' Zr ' .e compound (Ic) or a salt thereof can be prepared by BADORIGINAL 0 subjecting the compound (lb) or a salt thereof to elimination reaction of the amino protective group. Suitable method of this elimination reaction may include conventional one such as hydrolysis, reduction and the like. (i) For hydrolysis : The hydrolysis is preferably carried out in the presence of a base or an acid including lewis acid. Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethyiamine, triethylamine, etc.], picoline, 1, 5-diazabicyclo [4.3.0] -non-5-ene, cr the like. Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc. . The elimination using Lewis acid such as trihaloacet c acid [e.g., trichloroacetic aciα, trifluoroacetic acid, etc.], or the like is preferably carried out m the presence of cation trapping agents [e.g., a isole, phenol, etc.] . The reaction is usually carried out m a conventional solvent sucn as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.; , tetranyαrcfuran, dioxane, toluene, methylene chloride, ethylene αichlcride, cnlorcfcrm, N,N- dimetnylformamide, N,N-dimethylacεtamice cr any other organic solvents which do not adversely affect tne reaction, cr the mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming. r, ~ ~ ~ r reαuction BAD ORIGINAL J> Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction. Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen suifide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) , or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobro ic acid, etc.) . Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.) , palladium, catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.) , nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.) , cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, Uiiman iron, etc.), and the like. The reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.) , tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichioride, chloroform, X, X-cimetnylformamiαe, X, X-cιmethylacetamιde cr any other organic solvents which G: net ..aversely affect the reaction, o^ t * 3 ""' "u e t er of. Additionally, in case that the above-mentioned acids tc be used in chemical reduction are in liquid, they can aisc oe used as a solvent. The reaction temperature cf this reduction is net critical and the reaction is usually carried out under cooling tc warming. ' B AD OR IGINAL 0 Process < 3 ) The compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to cyclization reaction. The reaction is usually carried out in a conventional solvent such as acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, cr the mixture thereof. The reaction is usually carried out in the presence of a conventional condensing agent such as N,N 1 -dicyclohexylcarbodiimide; N-cyclohexyl-N' -morpholinoethy1carbodiimide; N-cyclohexyl-N' - (4-diethylaminocyclohexyI) carbodiimide; N,N'-diiscpropylcarbodiimide; N-ethyi-N' - (3-dimethylaminopropyl) carbodiimide; N,N-carbonyl-bis (2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyciohexyiimine; ethoxyacetylene; 1-alkoxy-I-chloroethyiene; trialkyl phosphite; isopropyl pclyphosphate; phosphorous oxychloride (phosphcryl chloride) ; phosphorous trichloride; thionyl chloride; oxalyl chloride; triphenylphosphite; 2-ethyl-7-hydroxybenzisoxazolιum salt; 2-ethyI-5- (m- sulfophenyl ) isoxazoiium hydroxide tra-molecular salt; 1- (p-chicroben e sul cnyioxy. -ό-chlorc-lH-benzo riazcie; so-called Viismeier reagent prepared by the reaction of X,X-dimethylformamide with thienyl chloride, phosgene, phosphorous oxychicriαe, etc.; cr the like. The reaction may also be carried out in the presence cf an organic cr inorganic base such as an alkali metal bicarbonate, tri (lower) alkylamine, pyridine, X- (lower) alkylmorphorine, N,N-di (lower) aikylbenzylamine, cr the like. The reaction temperature is not critical, and the ORIGINA reaction is usually carried out under cooling to heating. The reaction is preferably carried out in the presence of a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, l-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, l-hydroxy-6- chlcro-lH-benzotriazole, etc.) . Process (4. The compound (Ie) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative at the amino group, or a salt thereof with the compound (V) or its reactive derivative at the carboxy group, or a salt thereof. This reaction can be carried out in a similar manner to that of the aforementioned Process < 1 ) . and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process f1) . Process (5) The compound (Ig) or a salt thereof can be prepared by subjecting the compound (If. or a salt thereof to elimination reaction of the amino protective group. This reaction can be carried out in a similar manner to that of the aforementioned Process (2 ) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc. ' can be referred to those cess ( __ The compound (I ) cr a salt thereof can be prepared ieecinσ the compound vcliz. i _s reaction can be carried cut in a similar manner tc that of the aforementioned Process '3.. and therefore the reagents to be used and the reaction conditions (e.g., BAD ORIGINAL solvent, reaction temperature, etc.) can be referred to those of the Process (3) . Process (7) The compound (Ij) or a salt thereof can be prepared by- subjecting the compound (Ii) or its reactive derivative at the amino group, or a salt thereof to acylation reaction. Suitable acylating agent tc be used in the present acylation reaction may include the compound of the formula : R 7 - OH (VII) (wherein R is acyl) or its reactive derivative, or a salt thereof. Suitable reactive derivative at the amino group of the compound (Ii) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Ii) with a carbonyl compound such as aldehyde, ketone or the like; a siiyl derivative formed by the reaction of the compound (Ii) with a siiyl compound such as N,0-bis (trimethylsilyi) acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (Ii) with phosphorus trichloride or phosgene, and the like. Suitable reactive derivative of the compound (VII) may include an acid halide, an ac d anhydride, an activated ester, anc the like. The suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid '.e.g., diaikyiphosphcric acid, pher.ylphosphcnc acid, diphenylphosphoric acid, diben∑ylphosphoric acid, halogenated phosphoric acid, etc., , dialkylphosphorous aciα, sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkyicarbonic acid, aliphatic carboxylic acid (e.g., pivaiic acid, BAD ORIGINAL pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [ (CH 3 ) 2 + N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyi ester, 2, -dinitrophenyi ester, trichlorophenyi ester, pentachicrophenyi ester, mesylphenyi ester, phenylazophenyl ester, phenylthio ester, p-nitrophenyi thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) ; an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, l-hydroxy-2- (IK, - pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-lH-benzotriazole, etc.) ; and the like. These reactive derivatives can optionally be selected from them accordingly to the kind cf the compound (VII) to be used. The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, X,N-dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof. When the compound (VII; s used in free acid form cr t; salt form m the reaction, the reaction is preferably carrie: out m the presence cf a conventional condensing agent sucn as N, N' -dicycichexylcarbodiimide; N-cyclohexyl-N' - morpholmoethylcarbodiimide; X-cyclohexyl-X' - (4- diethylaminocyclohexyi) carbodiimide; X, N' -diisopropylcarbodiimide; X-ethyl-N' - (3- cimethyiaminopropyl) carbodiimide; X, X-carbonyi-bis (2- me hy1imidazole) ; pentamethyieneketene-N-cycIohexyiimine; diphenylketene-N-cyclohexyiimine; ethoxyacetylene; BADORIGINAL 1-alkoxy-l-chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride) ; phosphorous trichloride; thionyl chloride; oxalyl chloride; triphenylphosphite; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyI-5- ( - sulfophenyl) isoxazolium hydroxide intra-molecular salt; I- (p-chlorobenzenesulfonyloxy) -6-chloro-lH-benzetriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like. The reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylm.orphorine, N,N-di (lower) alkylbenzvlamme, or the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. Process (8) The compound (IC) or a salt thereof can be prepared by subjecting the compound (Ik) or a salt thereof tc hydrolysis reaction. This reaction can be carried cut in a similar manner to that of the aforementioned Process 12 i , and therefore the reagents tc be used and the reaction conditions (e.g., solvent, reaction temperature, etc. can ce referred to tnose cf the Process (2) . Process (A' Zhe compound (II) or a salt thereof can be prepared oy subjecting the compound (VI; cr a salt thereof tc cleavage reaction cf two amido bond by the enzyme. Suitable example cf said enzyme may include the one produced by certain microorganisms cf the Acetmoplanaceae, for example, Actinccianes utahensis IFO-13244, Actinoplar.es BAD ORIGI - 26 - utahensis ATCC 12301, Actinopiar.es missourienses NRRL 12053, cr the like; and the like. This reaction is usually carried out in a solvent such as phosphate buffer, Tris-HCl buffer or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction can be carried out at room temperature or under warming. Process (B) The compound (IV) or a salt thereof can be prepared by subjecting the compound (I.) or a salt thereof tc deacylation. This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction, reaction with an enzyme or the like. The said hydrolysis and reduction can be carried out in a similar manner to that of the aforementioned Process (2) , and therefore the reagents tc be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those cf the Process (2) . Further, the said reaction with the enzyme can be carried out in a similar manner tc that of the aforementioned Process (A) , and therefore the reagents to be used and the reaction conditions 'e.g., solvent, reaction temperature, etc. ) can be referred to those of the Process fA> . Zhe object and starting compounds, and pharmaceutically acceptable salts thereof may mcluαe a scivate [e.g., enclosure compound (e.g. hydrate, etc.) ] . Suitable salts cf the object, starting compounds ana their reactive derivatives in Processes (I. -(8) , (A; and (3 can be referred to the ones as exemplified for the compound . — / - The compounds obtained by the above processes can be isolated and purified by a conventional method such as BAD ORIGINAL pulverization, recrystallization, column chromatography, reprecipitation, or the like. It is to be noted that the compound (I) and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixture thereof are included within the scope of this invention. The object compounds (I) and pharmaceutically acceptable salts thereof possess a high antimicrobial activity (especially, antifungal activity) inhibiting the growth of a variety of pathogenic microorganisms, and a strong inhibitory activity on β-l,3-glucan synthase. Accordingly, they are useful for prevention and/or treatment of infectious diseases including Pneumocystis carinli infection (e.g. Pneumocystis carinii pneumonia) caused by a variety of pathogenic microorganisms. The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the peptide compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier, cr excipient suitable for rectal, pulmonary (nasal or buccai inhalation) , nasal, ocular, external (topical), oral, cr parenteral (including subcutaneous, intravenous ana intramuscular; administration or insufflation. The active ingredient may be compound, for example, with the usual non-toxic, pharmaceutically acceptable carrier for tablets, petters, torches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any- other form suitable for use. And, if necessary, addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The peptide compound (I) or a Pharmaceutically acceptable salt thereof is/are included m BAD ORIGINAL Sfti the pharmaceutical composition in an amount sufficient to produce the desired antimicrobial effect upon the process or condition of diseases. For applying the composition to human, it is preferable to apply it by intravenous, intramuscular, pulmonary, or oral administration, or insufflation. While the dosage of therapeutically effective amount cf the peptide compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-20 mg of the peptide compound (I) per kg weight of human being in the case of intramuscular administration, a daily dose of C.l-20 mg of the peptide compound (I) per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the peptide compound (I) per kg weight of human being is generally given for treating or preventing infectious diseases. Especially in case of the treatment or prevention of Pneumocystis carinii infection, the followings are to be noted. For administration of inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized as powders which may be formulated and the powder compositions may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system fcr inhalation is a metered dose inhalation aerosol, wnich may be formulated as a suspension cr solution cf compound in suitable prcpeliar.ts such as fiuorocarbons or hydrocarbons . Because of desirability to αirectly treat lung and bronchi, aerosol administration is a preferred method cf administration. Insufflation is also a desirable method, especially where infection may have spread to ears and other body cavities. Alternatively, parenteral administration may be employed using drip intravenous administration. BAD ORIGINAL The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail. Preparation 1 To a solution cf methyl (3R) -3-hydroxy hexadecanoate (2.0 g) in methanol (30 ml) was added a IN aqueous sodium, hydroxide (10 ml) . Reaction mixture was refluxed at 80°C for 30 minutes. After the solvent was evaporated, the residue was dissolved in ethyl acetate and washed with IN hydrochloric acid. The organic layer was dried over with sodium, sulfate and evaporated in vacuo to give (3R) -3-hydroxy hexadecanoic acid (1.95 g) . To a solution of (3R) -3-hydroxy hexadecanoic acid (1.95 g) in dichloromethane (20 ml) was added 2,2,2- trichloroethanoi (688 ul), I-ethyi-3- (3-dimethylamino- propyl) carbodiimide hydrochloride (1.37 g) and 4-dimethyl- amino pyridine (87.6 mg) and the reaction mixture was stirred for 1 hour at room temperature. After the solvent was evaporated, the residue was dissolved in ethyl acetate and washed with IN hydrochloric acid, a saturated aqueous sodium bicarbonate and water successively. .After drying over with magnesium sulfate, solvent was evaporated to give 2,2,2- trichloroefhvi (3R) -3-hvdroxv hexadecanoate (2.95 g) . outoxycaroonyi-L-crnithine ( " 3.3 mg; and 2, 2, 2-trichlorcetr.y. (3R -3-hydroxy hexadecanoate (8C.7 rr.g, in dichloromethane '1 ml was added (benzctriazcl-1-yl) oxy-fripyrroiidinc- phosphoniu hexafluorophosphate (PyBcp) (104.1 mg) and 4- dimethylamino pyridine (48.8 mg) at room temperature. After the solution was stirred for 6.5 hours, solvent was evaporated in vacuo. The residue was purified by preparative thin layer chromatography ( erck 5744 (Merck Co . , Ltd.) ~ r BAD ORIGINAL give 2 , 2, 2-trichloroethyl (3R) -3- [N 2 -benzyloxycarbonyl-N^- tert-butoxycarbonyl-L-ornithyl]oxy-hexadecanoate (50 mg) . 2 H NMR (300MHz, CDC1 3 , δ) : 7.36 (5K, m) , 5.35 (1H, m) , 5.30 (1H, m) , 5.10 (2H, s), 4.75 (2H, s), 4.58 (1H, 5 m), 4.34 (1H, m) , 3.12 (2K, m) , 2.74 (2H, ) , 1.95- 1.20 (28H, m) , 1.43 (9H, s), 0.88 (3H, t, J=7Hz) FABMS (m/z) : 751 (M+H)~ Preparation 2 0 To a solution of N -benzyIoxycarbonyl-N D -tert- butoxycarbonyl-L-lysine (76.1 mg) and 2, 2, 2-trichloroethyl (3R) -3-hydroxy hexadecanoate (80.7 mg) in dichloromethane (0.5 ml) was added (benzotriazol-1-yl) oxy-tripyrrolidino- phosphcnium hexafluorophosphate (PyBop) (104.1 mg) and 4- 5 dimethylamino pyridine (48.8 mg/ at room temperature. After the solution was stirred for 6.5 hours, the solvent was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (merck 5744) to give 2,2,2- trichloroethyl (3R) -3- [N 2 -benzyloxycarbonyl-N 6 -tert- 0 butoxycarbonyl-L-Iysyl] oxy-hexadecanoate (79.4 mg) . 1 K NMR (300MHz, CDC1 3 , δ) : 7.34 (5K, m) , 5.38 (1H, m) , 5.30 (1H, m) , 5.09 (2H, s), 4.74 (2H, s), 4.59 (1H, m) , 4.31 (IK, m) , 3.09 (2H, m) , 2.74 (2H, ) , 1.83 (2H, m) , 1.65 (4H, m) , 1.42 (9H, s) , 1.55-1.20 5 (24H, m) , 0.86 (3H, t, J=6Hz) FABMS (m/z) : 76 " (M ^ Na)- Reparation 3 Tc a solution of 2, 2, 2-trichloroethyl (3R)-3-[N ~ - C benzylcxycarbcnyl-X°-tεrt-butoxycaroonyl-L-ornithylj oxy- hexadecanoate (100 mg) in 9 aqueous acetic acid (3 ml; was added zinc powder (400 mg) at 0°C and stirred for 1 hour. After the reaction mixture was filtered, the filtrate was evaporated in vacuo. The residue was dissolved in ethyl 5 acetate and washed with diluted hydrochloric acid. Z e \ » NAL organic layer was dried over with sodium sulfate and evapo¬ rated in vacuo to give (3R) -3- [N 2 -benzyloxycarbonyl-N 5 -tert- butoxycarbonyl-L-ornithyl]oxy-hexadecanoic acid (86.5 mg) . 1 H NMR (300MHz, CDC1 3 , δ) : 7.34 (5H, m) , 5.45 (IK, d, J=8Hz), 5.30 (1H, m; , 5.10 (2K, s), 4.80 (IK, m) , 4.30 (IK, m) , 3.08 (2K, ) , 2.59 (2K, m) , 1.8C-1.2C (28H, ) , 1.43 (9H, s), C.87 (3H, t, J=7Hz) FABMS (m/z) : 643 (M+Na) + Preparation 4 The following compound was obtained according to a similar manner to that of Preparation 3. (3R) -3-[N -Benzyloxycarbonyl-N c -tert-butoxycarbonyl-L- lysyl]oxy-hexadecanoic acid. : H NMR (300MHz, CDC1 3 , δ) : 7.35 (5H, m) , 6.32 (IK, π) , 5.35 (2H, ) , 5.11 (2H, s), 4.76 (1H, m) , 4.38 (1H, m) , 3.10 (2H, m) , 2.58 (2H, m) , 1.85-1.20 (39H, m) , 0.88 (3K, t, J=6Hz) FABMS (m/z) : 657 (M+Na) ÷ IR (KBr. : 3355, 2925, 1730, 1725, 1685, 1650, 1525 cm "1 The Starting Compounds used and the Object Compounds obtained in the following Preparations and Examples are given in the Table as below, in which the formulae of the Starting Compounds are in the upper and the formulae cf the Object Compounds are the lower, respectively, unless otherwise prcvideα. In the following Examples and Preparations, there are employed the other abbreviations in addition tc the abbreviations adopted by the IϋPAC-1 ' JB (Commission on Biological Nomenclature) . The abbreviations used are as follows. Bcc : t-butoxycarbonyl. Z : benzyloxycarbonyl BAD ORIGINAL Jj a ~ ' Prepara¬ tion No. Startmc Compound lompound A Object Compound tc be continued on the next page - 3S - . ._ - Δ? - , ^ - - 43 - - 44 - ι ι - 50 - - D-, - Preparation 5 A stock culture of Actinoplanes utahensis IFO-13244 is prepared and maintained on agar slant. A loopful of the slant culture was inoculated into a seed medium consisted of starch l ? , sucrose 1 % , glucose 1 ~ _, cotton seed flour 1 ' peptone 0.51, soy bean meal 0.5 ' and calcium carbonate 0.1 -. The inoculated vegetative medium, was incubated in a 225 mi wide mouth Ξrlenmeyer flask at 3C°C for about 72 hours on a rotary shaker. This incubated vegetative medium was used directly to inoculate into a production medium, consisted of sucrose 2 " ., peanut powder 1%, dipotassium hydrogenphosphate (K 7 HPO^) 0.121 potassium dihydrogenphosphate (KK 2 P0 4 ) 0.05 -_ and magnesium sulfate hep -tahv-drate (MσSO •.- 7H_<_ > Oi 0.025-1. The inoculated production medium was allowed to ferment in a 30 . jar fermentor at a temperature of 30°C for about 80 hours. The fermentation medium was stirred with conventional agitators at 250 rpm and aerated at 20 r per minute. The vegetative mycelium was collected from the fermented broth by filtration and once washed with water. The washed mycelium was directly used to obtain Object compound. Starting compound was prepared by the fermentation disclosed in EP 0 584 36C Al. Starting compound was dissolved in .2K phosphate buffer (pK 7.6) at a concentration of 2.5 mg/ l. To a 2 f cf the solution was added a 400 g wet weight cf washed mycelium cf Actinoplanes utahensis IFO-13244 obtained above. Zhe reaction was carrieα out at 6C Q C under for 20 hours. Reduction of Starting compound and increase cf Object compound were measured using a HPLC equipped with a reverse phase column. From a 5 g of Starting compound, a 1.3 g cf Object compound was formed in the reaction mixture. D ORIGINAL The reaction mixture described above was filtered with a filter aid. The mycelial cake was discarded. The filtrate thus obtained was passed through a column (350 ml) of YMC GEL ODS-AM 120-S50 (YMC Co., Ltd.) packed with water. The column was washed with 1 t of water and 2 . of 5 ~ aqueous methanol and then eluted with 1 . of 3 _ aqueous methanol. The eluate was evaporated in vacuo to give a dry powder. The powder was dissolved in water (20 ml) and then applied on a column (350 mi, cf YMC GEL ODS-AM 120-S50 packed with 10. aqueous acetonitrile containing 0.5-.. ammonium dihydrogenphosphate (NH H2PO4) . The column was eluted with the same solvent system and elution was monitored by analytical HPLC, using a column of YMC-Pack ODS-AM AM303 (250 x . <ό mm. I.D., S-5 120A; YMC Co., Ltd.) and a solvent system of 12.5 ; . aqueous acetonitrile containing 0.5c NK^H^PO^ at a flow rate of 1 ml/minute, detecting with a UV monitor at 210 nm. The fractions containing Object compound were combined and evaporated in vacuo to remove acetonitrile and then passed through a column (180 ml) of YMC GEL ODS-AM I20-S50 packed with water. The column, was washed with 1.8 f of water and 0.6 ." of 5. aqueous methanol and then eluted with 0.6 C of 30 r aqueous methanol. The eluate was concentrated in vacuo to remove methanol and lyophilized tc give 1.15 g cf Object compound as a white powder. -K NMR (400MHz, CD 3 OD, δι : ~ .04 (2H, d, J=8Kz) , 6. ~ C (2H, d, J=8Hz. , 4." ~ (IK, d, J=5Hz. , 4.63-3.83 :21K, i, 3.80 (IK, αα, J=4, 11Hz) , 3.19 (IK, dd, =5, 14Hz) , 2 . ~ - :1K, αα, =I1. 14Kz; , 2.46 (2K, , , 2.25 (2K, , 2.11 (IK, ) , 2.04 (2K, m, , 1.23 (jr., α, J-C..2, , _.._._ .J ., α, _■—c__z ' , _._. ' (-.-_, α, J=6Hz) , 1.16 (3K, d, J=6Kz , 0.9 " (3K, d, J=6Hz, , 0.95 (3K, d, J=6Hz) F-A3-MS (m/z) : 1183 (JM-H. ~ IR (K3r) : 3300, 2980, 1655, 1540, 1455, 1235 cm "1 BAD ORIGINAL ft Prepara ion ' To a solution of Starting compound (Object compound obtained in Example 8 shown below) (20 g) in water (500 mi) was added 2N sodium, hydroxide solution (500 ml) and stirred under ice cooling for 1 hour. And then 2N hydrochloric acid solution (500 ml) was added tc neutralize the reaction- mixture containing the Compound A. To the neutralized solution was added 4 C of IM phosphate buffer (pH 7.5) and 13 C of water and a 3 kg wet weight of washed mycelium of Actinoplanes utahensis IFO-13244 prepared according to a similar manner to that of Preparation 5. The reaction was carried out at 37°C with stirring fcr 24 hours. Increase of Object compound was measured using a HPLC equipped with a reverse phase column. From a 20 g of Starting compound, a 10 g of Object compound was formed in the reaction mixture. The reaction mixture described above was filtrated with a filter aid. The mycelial cake was discarded. The filtrate thus obtained was passed through a column (500 ml. of DIAIOX HP-20 (Mitsubishi Chemical Industrials Ltα.) packed with water. The column was washed with water (1.5 C) and 20 aqueous methanol (1.5 t) and then eluted with 80- aqueous methanol (1.5 0. The eluate was evaporated m vacuo to give a αry powder. ha powder was dissolved m water (1 mi i and then applied en a column ,2 . cf YMC GEZ ODS-AM 12--Ξ5C 'YMC Co., Ltd.) packed with 1 " 5 aqueous acetonitrile containing 3.5 λ ' K/K-PO . Tr.e column was eluted with the same solvent system and eiuticn was monitored by analytical HPLC, using a column cf YMC-?ack ODS-AM AM3C3 (250 mm. x 4.6 mm. I.D., S-5 12CA; YMC Co., Ltd.) and solvent system of 17.5-- aqueous acetonitrile containing 0.5 : XK.K 7 ?C^ at a flow rate of 1 ml/minute detecting with a L monitor at 210 nm. The fractions containing Object compound were combined and OR IGINAL evaporated in vacuo to remove acetonitrile and then passed through a column (500 ml) of DIAION HP-20 packed with water. The column was washed with water (3 C) and 20 aqueous methanol (2 (!) and then eluted with 80°. aqueous methanol (2 f) . The eluate was concentrated in vacuo to remove methanol and lyophilized to give 7.6 g of Object compound as a white powder. 1 K NMR (400MHz, CD 3 0D, δ) : 7.03 (2K, d, J=8Hz) , 6.70 (2H, d, J=8Hz), 4.78 (IK, d, J=5Hz. , 4.62-3.85 (22H, m) , 3.80 (IK, dd, J=4, 11Hz), 3.20 (1H, dd, J=5, 12Hz), 3.05 (2H, m) , 2.77 (1H, dd, J=10, 12Hz), 2.47 (2H, m) , 2.25 (2H, m) , 2.05 (3K, m) , 1.87 (1H, m) , 1.71 (IK, m) , 1.52 (2K, m) , 1.42 (9K, m) , 1.23 (3H, d, J=6Hz), 1.21 (3H, d, J=6Hz) , 1.20 (3K, d, J=6Hz), 1.18 (3H, d, J=6Hz), 1.16 (3H, d, J=6Hz), 0.97 (3H, d, J=6Hz), 0.95 (3K, d, J=6Hz) FABMS (m/z) : 1398 (M-r-H) ' IR (KBr) : 3305, 2975, 1655, 1520, 1455, 1250 cm "1 [ ]^, 5 = -20.8° (C=1.0, MeOH' Example 1 To a solution of (3R) -3- [N--benzyloxycarbonyl-N ; - ) -tert- butoxycaroonyi-L-ornithyl] oxy-hexadecanoic acid (31 mg) m dichloromethane (0.5 ml) was added pivaloyl chloride (6.15 ul and triethylamine (6.9 7 ul) at C°C ana the mixture was stirred for 1 hour at same temperature. The reaction mixture was droped into a solution of Starting compound (Object compound obtained in Preparation 5 ,59 mg m X,N- αi ethylformamide (1.5 ml ι and trietnylam e '6.97 ul , at _°C and the reaction mixture was stirred for 4 hours at room temperature. After the solvent was evaporated m vacuo the residue was purified by ODS open column to give Object compound '39 mg) . 1 K NMR (300MHz, CD 3 OD, S. : ~ .32 (5K, m 1 , " .00 (2K, d, J=8.5Hz), 6.68 (2K, d, J=8.5Kz), 5.22 (1H, . , 5.07 L (2H, s), 4.66 (1H, d, J=5Hz), 4.63-3.8 (22H, m) , 3.73 (1H, dd, J=4, IIHzj, 3.02 (3H, m) , 2.78 (IK, dd, J=9, I4Hz), 2.53 (2K, m) , 2.45 (2H, d, J=7Hz) , 2.26 (2H, m) , 2.00 (3K, m) , 1.79 (1H, m) , 1.73-1.45 (5H, m) , 1.43 (9H, ≤), 1.4-1.2 (37H, m) , 0.92 (9K, m) FABMS (m/z) : 1808 (M-rNa) "r IR (KBr) : 3305, 2925, 1735, 1655, 1515, 1455, 1245 cm "1 [α]ξ 2 = -6.2° (C=2.0, MeOH) Example 2 The Object compound was obtained according to a similar manner to that of Example 1. X K NMR (400MHz, CD 3 OD, δ) : 7.33 (5H, m) , 7.02 (2K, d, J=8.5Hz), 6.71 (2H, d, J=8.5Hz), 5.23 (1H, m) , 5.09 (2H, s), 4.68 (1H, d, J=5Hz), 4.65-3.70 (23H, m) , 3.02 (3H, m) , 2.81 (1H, dd, J=9, 14Hz), 2.54 (2K, m) , 2.48 (2K, br d, J=7Kz), 2.26 (2H, ) , 2.02 (3K, m) , 1.73 (1H, m) , 1.62 (3K, m) , 1.42 (9K, s), 1.5- 1.2 (38H, m) , 1.20 (3K, d, J=7Hz), 0.95 (3K, d, J=7Hz), C.93 (3H, d, J=7Hz), 0.90 (3K, t, J=7KZ' FABMS (m/z) : 1822 (M+Na) " IR (K3r) : 3305, 2925, 1730, 1655, 1540, 1455, 1250 cm "1 Example 3 To a solution cf Starting compounα (Object compound cctained in Example 1; (39 mg! in methanol (3 ml) was addeα 10 palladium-carbon (40 mg) and the mixture was hydrogenated (1 atm) at room temperature for 6 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo tc give Object compound (32.4 g) . : K NMR (400MHz, CD-,0D, δ. : " .02 (2K, d, J=6.5Kz) , BAD ORIGINAL - 53 - 6.72 (2H, d, J=8.5Hz), 5.31 (1H, m) , 4.72 (1H, d, J=5Hz), 4.6-3.8 (22H, m) , 3.75 (IH, m) , 3.09 (2K, m) , 3.00 (IK, dd, J=6, 14Hz) , 2.80 (IK, dd, J=9, 14Hz), 2.6 (2H, ) , 2.4 " (2K, d, J=7Hz), 2.27 (2K, m), 2.03 (3H, m) , 1.95-1.5 (6K, ) , 1.44 (9H, s) , 1.4-1.18 (34H, m) , 1.15 (3H, d, J=7Hz), 0.95 (3K, d, J=7Hz), 0.92 (3H, d, J=7Hz) , 0.89 (3H, t, J=7Kz) FABMS (m/z) : 1652 (M*H1 + IR (KBr) : 3315, 2925, 1745, 1655, 1520, 1455, 1250 cm "1 [αjg 2 = +0.7° (C=1.62, MeOH) Example 4 The Object compound was obtained according to a similar manner to that of Example 3. ~ Η NMR (400MHz, CD 3 OD, δ) : 7.02 (2K, d, J=8.5Hz), 6.72 (2H, d, J=8.5Hz), 5.31 (IH, m) , 4.75-3.7 (24H, m) , 3.04 (3K, m) , 2.80 (IK, m) , 2.54 (2H, ) , 2.4^ (2H, br d, J=7Hz), 2.27 (2K, m) , 2.03 (3K, m) , 1.43 (9H, s), 1.9-1.2 (42H, m) , 1.15 (3K, d, J=7Hz), 0.95 (3H, d, J=7Kz) , 0.93 (3H, α, J=7Hz) , 0.90 (3K, t, J=7Hz) FA3MS im/z) : 1666 (M ^ -H) " IR (KBr) : 3310, 2925, 1740, 1655, 1515, 1455, 1250 cm "1 [α]= 2 = -0.3° (C=i.C, MeOH, Example 5 To a solution of Starting compound (Object compound obtained in Example 3) (32.4 mg 1 in X,N-dimethyl cr amide 21 ml was added l-ethyI-3- (3-dimethyIaminoρropyl) carbodiimide- hydrochlcride (WSCD.KCl) (7.7 g) and 1-hydroxy benzctriazcle (HOBT) (5.4 mg) at room temperature. After the reaction mixture was stirred for 2 hours, WSCD.KCl (3.83 mg, and HOBT [ 2 . ~ mg > were added tc the solution and stirred for 2 hours at room temperature. After tne solvent was evaporated in BADORIGJNAL _ : Q _ vacuo the residue was purified by ODS open column to give Object compound (22 mg) . 1 H NMR (400MHz, CD 3 OD, δ) : 7.08 (2K, d, J=8Hz) , 6.84 (2H, d, J=8Hz), 5.12 (IH, m) , 4.97 (IK, d, J=4Hz), 4.69 (lH,s), 4.65-3.84 (20H, m) , 3.74 (2H, br s), 3.05 (2K, ) , 2.90 (2H, d, J=8Hz), 2.60-1.80 (UK, m) , 1.70-1.43 (4H, ) , 1.43 (9H, s), 1.40-1.16 (34K, m) , 1.15 (3H, d, J=6Hz) , 0.9 (9H, m) FA3MS (m/z) : 1656 (M+Na) ~ IR (K3r) : 3305, 2930, 1735, 1655, 1515, 1455, 1250 cm "1 [ ]g 2 = +4.5° (C=1.0, MeOH) Example 6 The Object compound was obtained according to a similar manner to that of Example 5. : H NMR (400MHz, CD 3 OD, δ) : 7.11 (2K, d, J=8Hz), 6.86 (2H, d, J=8Hz), 5.09 (IK, ) , 4.98 (IK, d, J=3Hz), 4.73-3.85 (21H, m) , 3.72 (2K, br s), 3.05 (2H, m) , 2.90 (2K, d, J=8Hz), 2.63-2.17 (6H, m) , 2.13-1.75 (5H, m) , 1.72-1.15 (40H, m) , 1.14 (3K, d, J=7Hz. , 0.90 (3K, d, J=7Hz), 0.87 (3K, d, J=7Hz) , 0.86 (3K, t, J=7Hz) FABMS (m/z) : 1670 (M+N )~ IR (KBr) : 3335, 2925, 1735, 1655, 1515, 1455, 1250 cm -1 Example A solution cf Starting compounα (Object compound obtained in Example 6) (42 mg) in trifluoroacetic acid (1.5 ml) was stirred at 0°C for 30 minutes. After the solvent was evaporated in vacuo, the residue was purified by preparative HPLC tc give Object compound (20.1 mg) . 1 H NMR (400MHz, CD OD, δ> : 7.09 (2K, d, J=8Hz, , 6.68 I BAD ORIGINAL (2H, d, J=8Hz), 5.12 (IH, m) , 5.00 (IH, br s), 4.67-3.85 (21H, m) , 3.73 (IH, br s), 3.64 (IH, br d, J=llHz) , 2.96 (3H, m) , 2.85 (IH, m) , 2.65-2.18 (6H, m) , 2.13-1.85 (5H, m) , 1.72-1.25 (40K, m) , 1.14 (3H, d, J=7Hz), 0.88 (9H, ) FABMS (m/z) : 1548 (M+K) " IR (KBr) : 3310, 2930, 1740, 1660, 1520, 1455, 1085 cm "1 [α] 2 , 2 = +11.6= (C=I.O, MeOH) Example 8 To a solution of Starting compound (20 g) prepared by the fermentation disclosed in E? 0 584 360 Al in dioxane (250 ml) and water (250 ml) was added di-tert-butyl-dicarbonate (6 g) and triethylamine (2 ml) at a room temperature and stirred for 2 hours. After solvent was evaporated in vacuc, 500 ml of water was added. The solution was passed through a column (1 C) of YMC GEL ODS-AM 120-S50 (YMC Co., Ltd.) packed with water. The column was washed with 3 . of water and 3 . of 50. aqueous methanol and then eluted with 3 i? of 95- aqueous methanol. The eluate was concentrated in vacuc to remove methanol and lyophilized to give 20 g of Object compound as a white powder. 1 K NMR (400MHz, CD 3 OD, δ) : 7.08 (2K, d, (2K, d, J=8Kz) , 5.12 (IK, m) , 4.97 (IK, d, J=4Kz • , 4.69 (IH, s) , 4.65-3.84 (2OK, m) , 3.74 (2K, br s, , 3.05 (2K, m) , 2.90 (2K, d, J=8Hz,, 2.60-1.80 (UK, m! , 1.70-1.43 (4K, , , 1.43 (9K, sj, 1.40-1.16 34K, m) , 1.15 (3K, α, J=6Hz. , 0.9C (9H, m FA3MΞ (m/z; : 1634 (M-H) " IR (KBr) : 3305, 2930, 1 " 35, 1655, 1515, 1455, 1250 cm "1 [α] 4 = τ5.9° (C=1.0, MeOH) βAD ORIGINAL - D i - Example 9 To a solution of (3R) -3-benzyloxycarbonylamino- hexadecanoic acid (29 mg) in dichloromethane (1.0 ml) was added pivaloyl chloride (8.82 ul)and triethylamine (9.98 ul) at 0°C and the mixture was stirred for 1 hour at same temperature. The reaction mixture was droped into a solution of Starting compound (Object compound obtained in Preparation 6) (100 mg) in N, -dimethylformamide (1.0 ml) and triethylamine (9.98 ul) at 0°C and the reaction mixture was stirred for 4 hours at room temperature. After the solvent was evaporated in vacuo the residue was purified by ODS open column to give Object compound (70 mg) . 1 K NMR (400MHz, CD 3 OD, δ) : 7.33 (5K, m) , 7.02 (2K, d, J=8Hz), 6.71 (2H, d, J=8Hz), 5.06 (2H, m) , 4.69 (IH, d, J=5Hz), 4.63-3.83 (23H, m) , 3.75 (IH, m) , 3.05 (2H, t, J=7Hz), 3.00 (IH, dd, J=7, 14Hz) , 2.82 (IH, dd, .7=9, 14Hz), 2.45 (4H, m) , 2.27 (2H, m) , 2.02 (3H, m) , 1.89 (IH, m) , 1.74 (IH, m) , 1.42 (9H, s) , 1.64-1.15 (41H, m) , 0.95 (3H, d, J=7Hz) , 0.92 (3H, d, J=7Hz), 0.90 (3K, t, J=7Hz) FABMS (m/z) : 1807 (M-rNa) + IR (KBr) : 3320, 2925, 1660, 1540, 1455, 1255 cm "1 [α]g 4 = τ3.1° (C=1.0, MeOK) Example 10 The Object compound was obtained according to a similar manner to that of Example 9. 1 K NMR (400MHz, CD 3 OD_ δ : " 7.35-7.2 (7K, m) , " .15 (3K, - , -. 2 (2K, α, =3Hz), 6.72 (2K, d, J=6Kz , 5.05 (2K, r.) , 4.69 ι, IK, α, =5Hz, , 4.65-3.8 (23K, ) , 3.74 (IK, m) , 3.05 (2K, t, J=7Hz) , 3.00 (IK, dd, J=7, I4Hz), 2.81 (IK, dd, J=9, 14Hz) , 2.58 !2K, m) , 2.45 (4K, ) , 2.26 (2K, m) , 2.02 (3K, m) , 1.89 (IH, m) , 1.74 (IK, m) , 1.42 (9H, s), 1.65-1.16 (27K, m) , 0.95 (3H, d, J=7Hz), 0.92 (3K, d, J=7Hz BAD ORIGINAL > FABMS (m/z) : 1785 (M+Na) ~ IR (KBr) : 3325, 2930. 1690, 1535, 1455, 1250 cm "1 Example 11 7o a solution of Starting compound (Object compound obtained in Example 9) (70 mg) in methanol (6 ml) was added 10 " _ palladium-carbon (100 mgt and the mixture was hydrogenated (I atm) at room temperature for 6 hours. The reaction mixture was filtered and the filtrate was evaporateα in vacuc to give Object compound (46.1 mg) . 1 K NMR (400MHz, CD 3 0D, δ> : 7.03 (2H, d, J=8Hz), 6.72 (2H, d, J=8Hz), 4.73 (IK, d, J=5Hz), 4.62-3.83 (22H, m) , 3.75 (IH, m) , 3.52 (IK, m) , 3.05 (3H, m) , 2.80 (IH, dd, J=9, 14Hz), 2.75-2.4 (4H, m) , 2.28 (2H, m) , 2.05 (3H, m) , 1.88 (IK, m) , 1.42 (9H, s), 1.8-1.15 (42H, m) , 0.9 " (3H, d, J=7Hz), 0.94 (3H, d, J=7Hz), C.90 (3K, t, J=7Hz) FABMS (m/z) : 1651 (M-"-H) " " " IR (KBr) : 3325, 2930, 1665, 1515, 1455, 1250 cm "1 [α]§ 2 = -1.15° (C=1.83, MeOH) Example 12 The Object compound was obtained according to a similar manner tc that of Example 11. : K NMR (400MHz, CD3OD, δ) : " .22 (2K, m. , 7.15 (3K, ... , f ' . U _J t _ __, ^__, _. _____ , , - . -_ , , -_ , u o_ι_ , , — . __ (IK, d, J=5Kz), 4. 5-3.. 22K, , 3.74 (IK, , 3.48 (IK, ; , 3.05 ;3H, m, , 2.80 (IK, dd, J=9, 14Kz) , 2. ^ -2.4 (6H, ; , 2.25 (2K, ) , 2.04 (3H, m , 1.39 (IH, mi, 1.42 (9K, s) , 1.8-1.3 (13H, my , 1.22- 1.16 (15K, ) , 0.97 (3K, d, J=7Hz) , 0.94 (3H, d, J=7Hz) •TABMS (m/z) : 1629 (M~H)~ \ BΛD ORIGINA IR (KBr) : 3305, 2935, 1670, 1520, 1455, 1250 cm "1 [α.lg 2 = -1.5° (C=1.0, MeOH) Example 13 To a solution of Starting compound (Object compound obtained in Example 11) (46 mg) m dimethylformamide (28 ml) was added WSCD.KCl (10.7 mg) and HOBT (7.5 mg) at room temperature. After the reaction mixture was stirred for 2 hours, WSCD.KCl (5.2 g) and HOBT (3.8 mg) were added tc the solution and stirred for 2 hours at room temperature. After the solvent was evaporated in vacuo, the residue was purified by ODS open column to give Object compound (19.4 mg) . X H NMR (400MHz, CD 3 OD, δ) : 7.06 (2H, d, J=8Hz) , 6.76 (2H, d, J=8Hz), 4.86-3.6 (25H, m) , 3.04 (3H, m) , 2.90 (IH, dd, J=9, 14Hz), 2.48 (2H, m) , 2.33 (IH, dd, J=9, 14Kz), 2.25 (2H, m) , 2.02 (3H, m) , 1.43 (9H, s), 1.6-1.2 (44H, m) , 1.19 (3H, d, J=7Hz), 0.92 (3H, d, J=7Hz), 0.91 (3H, d, J=7Hz), 0.9C ,3H, t, J=7Hz) FABMS (m/z) : 1633 (M+H)~ IR (KBr) : 3310, 2925, 1655, 1520, 1450, 1250 cm "1 [α]ξ 2 = -^3.3° (C=0.95, MeOH) Example 14 The Object compound was obtained according tc a similar manner to that cf Example 13. : K NMR (400MHz, CD 3 OD, 5) : 7.22 (2H, m. , 7.15 ;3K, m, , 7.05 '2K, d, J=SHz, , 6. "* 5 (2K, c, =8Hz) , 4.63-3.6 (25H, mi, 3.04 (3H, m, , 2.9C (IH, dd, 0=9 14Hz), 2.56 (2H, m) , 2.47 (4K, m) , 2.33 (IK, dd, I4Hz) , 2.25 (2H, m) , 2.02 (3H, m) , 1.42 OH, s) , 1.65-1.15 (30H, ) , 0.92 (3H, d, J=7Hz , 0.89 (3K, d, J=7Hz; FABMS (m/z) : 1611 (M-H) " , IR (K3r; : 3310, 2935, 1655, 1515, 1450, 1250 cm "1 BAD ORIGINAL Example 15 A solution of Starting compound (Object compound obtained in Example 13) (19.4 mg) in trifluoroacetic acid (0.5 ml) was stirred at 0°C for 30 minutes. After the solvent was evaporated in vacuo, the residue was purified by preparative HPLC tc give Object compound (19.4 mg) . i K NMR (400MHz, CD 3 OD, δ. : 7.05 (2H, d, J=8Hz), 6.84 (2H, d, J=8Hz) , 4.95 (IH, d, J=4Hz) , 4.74 (IH, br s) , 4.64 (3H, ) , 4.5-3.8 (18H, m) , 3.69 (2K, ir.) , 2.94 (4H, m) , 2.52-2.15 (5H, m) , 2.04 (3H, m) , 1.75 (IH, s), 1.65-1.2 (43H, m) , 1.17 (3K, d, J=7Hz), 0.89 (3H, t, J=7Hz), 0.89 (3H, d, J=7Hz), 0.8 ^ '3H, d, J=7Hz) FABMS (m/z) : 1533 (M+H) + IR(KBr) : 3310, 2930, 1660, 1520, 1455, 1085 cm "1 [α]22 = +16 _6° (C=0.5, MeOH) Example 16 The Object compound was obtained according to a similar manner tc that of Example 15. 1 H NMR (400MHz, CD 3 OD, δ) : 7.22 (2K, m) , 7.14 (3K, m) , 7.04 (2H, d, =8Hz), 6.84 (2H, d, J=8Hz), 4.95 (IK, d, J=4Hz) , 4.73 (IH, br s; , 4.65 (2H, m) , 4.5- 3.8 (19K, m) , 3.70 (2K, m) , 2.94 (4K, m> , 2.5 ~ - 2Z , m; , 2.46 (IK, dd, J=8, 14Hz • , 2.43-2.16 (5K, 1 , 2.02 (4K, , 1.75 (IK, , 1.63-1.2 (24K, m) , 1.1 " (3H, c, J=7Hz), 0.69 (3K, d, C=7Kz), 0.8 " (3K, d J=7Hz, FA3MS (m/z) : 1511 (M-rH) ' IR (KBr) : 3295, 2935, 1665, 1515, 1455, 1235, 1070 cm "1 [α] 2 . 2 = -17.1° (C=1.C, MeOH) l BAO OW^ L

Claims: C L A I M S 1 . A compound of the formula : 20 wherein ' ." is alkyl or aralkyl, R- is amino (lower) alkyl or protected am o (lower) alkyl, is hydroxy, protected hydroxy, amino o: protected amine, R- is hyαroxy, or -_• £ R and R- a: " inked together to form -Z- TO in which -Z- is -0- or -NH-) , and R is hydrogen or an ammo protective group, R" is hydroxy, cr form bond, with proviso tnat J5 when R J is hydroxy, protected hydroxy, ammo or D ORIGINAL protected amino and R is hydroxy, then R 5 and R 6 are linked together to form bond, and a pharmaceutically acceptable salt thereof. 5 2. A compound of claim 1, wherein R 1 is alkyl or phenylalkyl, R- is amino (lower) alkyl or acylamino (lower) alkyl, R J is hydroxy, acyloxy, amine cr acylamino, 10 R 4 is hydroxy, or R 3 and R^ are linked together tc form -Z- (in which -Z- is -0- or -NH-) , and R is hydrogen or acyl, R iε hydroxy, or -5 R 5 and R 6 are linked together to form bond, with proviso that when R is hydroxy, acyloxy, amino or acylamino, and R- is hydroxy, then R and P. are linked together to form bond. 0 A compound of claim 2, wherein R is Cι-C 1 alkyl or phenyl (d -Cg) alkyl, R- is amino (lower) alkyl or lower alkoxycarbonylamino- (lower) alkyl, R 3 is hydroxy, acyloxy, amino cr ar (lower) lkoxycarbonylamino, P. is hydroxy, or R" and R~ are linked together to form -Z- (m which -Z- is -C- cr -XH-. , and R° is hydrogen cr ar (lower) alkoxycarbonyl, R c is hydroxy, or R- and R° are linked together tc form bond, with proviso that when R 3 is hydroxy, acyloxy, amino or ar (lower) alkoxycarbonyl, and ^ BAD ORIGINAL R is hydroxy, then R 5 and R 6 are linked together to form bond. A compound of claim 3, wherein R 1 is C j -C^ alkyl or phenyl (C j -Cg) alkyl, R- is amino (lower) alkyl or lower alkoxycarbonylamino- (lower)alkyl, R 3 is hydroxy, acyloxy, amino or phenyl (lower) alkoxycarbonylamino, R is hydroxy, or R 3 and R 4 are linked together to form -Z- (in which -Z- is -0- or -NH-), and R 5 is hydrogen or phenyl (lower) alkoxycarbonyl, /_: R is hydroxy, or R-" and R 6 are linked together to form bond, with proviso that when R 3 is hydroxy, acyloxy, amino or phenyl (lower) alkoxycarbonyl, and R^ is hydroxy, then R 5 and R are linked together to form bond. A process for preparing a compound cf the formula wherein R^ is alkyl or aralkyl, p R is amino (lower) alkyl or protected amino (lower) alkyl, 3 R is hlyyddrrooxxyy,, pprrootteecctteed hydroxy, amino or protected amino, __, P.- is hydroxy, cr R J and R- are linked together to form -Z- (in which -Z- is -0- or -NK-), and R J is hydrogen or an ammo protective group, R is hydroxy, or R 5 and R 6 are linked together to form bond, with proviso that when R 3 is hydroxy, protected hydroxy, amino or protected amino and R" is hydroxy, then R 5 and R are linked together to form bond, or a salt thereof, which comprises (1) reacting a compound of the formula or its reactive derivative at the amino group, or a salt thereof with a compound of the formula wherein R , R and Z are each as defined above, and R^ is hydrogen or an amino protective group, or its reactive derivative at the carboxy group, or a salt thereof to give a compound of the formula wherein R 1 ' R 2 , R and Z are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula wherein R-, R- and Z are each as defineα above, ana R~ is an ammo prcteot ve group, cr a salt thereof to elimination reaction of the amine protective group to give a compound of the formula : L BAnD ORIGINAL g wherein R ι- , R^ 2 and Z are each as defined above, or a salt thereof , or ' 3, subjecting a compound of the formula : wherein R , R 2 and Z are each as defined above, or a salt thereof to cyclization reaction to give a compound of the formula : .:. J =_ c __.;_ ?.-, R- and Z are each as defined above, or a _c_ or i ~ .acting a compound of the formula wnerem R^ 7 is as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula wherein R- is as defined above, and Rr; is ammo cr protectec am o, or its reactive derivative at the carboxy group, cr a salt thereof to give a compound cf the formula wherein R 1 , R and R 3 are each as defined above, or a salt thereof, cr subjecting a compound of the formula 1 p wherein R- and R^ are each, as defined above, and 3 R is protected amino, or a salt thereof to elimination reaction of the amino protective group to give a compound of the formula : wherein R and P. ~ are each as defined above, inereor , subj ectinα a compound o r the formula BAD UMIGINAL wnerem R- and R^ are each as defined above, or a salt thereof to cyclization reaction to give a compound of the formula : wherein R-1 and R-y- are each as defined above, or a salt thereof, or 7) subjecting a compound of the formula : wherein R 1 , R , R , R and R are each as defined above, and p Rr is ammo (lower) aiκy_, or its reactive derivative at the amino group, or a salt thereof tc acylation reaction tc give a compound cf the formula : BAD O h NAL ^ L - 5 wherein R , R , R , R 5 and R 6 are each as defined above, and p R is acylamino (lower) alkyl, 0 or a salt thereof, or .8) subjecting a compound of the formula JD wherein R 1 and R 2 are each aε defined above, or a salt thereof to hydroiysis reaction to give a compound of the formula : wherein R and R 2 are each as defined above, or a salt thereof. 6. A compound of the formula BAD QtΛ_v* .« ._ - < 10 - or a salt thereof. 7. A process for preparing a compound of the formula or a salt thereof, which comprises subjecting a compound of the formula or a salt thereof to cleavage reaction of two amide bond by the enzyme. A compound of the formula : 12 - p wherein R^ is ammo (lower) alkyl or protected amino (lower; alkyl, cr a salt thereof. 9. A process for preparing a compound cf the formula w0 ^ » p wherein R^ is amino (lower) alkyl cr protected amino (lower) alkyl, or a salt thereof, which comprises subjecting a compound of the formula : ^ BAD O -^^ 15 20 p wherein R^ is as defined above, and R~ is alkyl or aralkyl, ? - or a salt thereof to deacylation reaction, 10. A pharmaceutical composition which comprises, as an active ingredient, a compound cf claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers cr excipients 11. Use of a compound of claim 1 cr a pharmaceutically acceptable salt thereof as a medicament. 33 .ompounc of claim 1 or a pharmaceutically acceptable D ORIGINAL salt thereof for use as a medicament. 13. A method for the prophylactic and/or the therapeutic treatment of infectious diseases caused by pathogenic microorganisms which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.

Inventors: HASHIMOTO MICHIZANE, HASHIMOTO SEIJI, SHIGEMATSU NOBUHARU, HASHIMOTO, MICHIZANE, HASHIMOTO, SEIJI, SHIGEMATSU, NOBUHARU
Applicants: FUJISAWA PHARMACEUTICAL CO, HASHIMOTO MICHIZANE, HASHIMOTO SEIJI, SHIGEMATSU NOBUHARU, FUJISAWA PHARMACEUTICAL CO., LTD., HASHIMOTO, MICHIZANE, HASHIMOTO, SEIJI, SHIGEMATSU, NOBUHARU
Application year: 1996
Main classification: C07K7
IPC codes: A61K38, A61P31, C07K1, C07K7, C07K11