TETRAPEPTIDES DERIVING FROM DALBAHEPTIDE ANTIBIOTICS

Abstract: Tetrapeptides of general formula (I) deriving from dalbaheptide antibiotics wherein: W and Z represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group (aglucodalbaheptides); Y represents a carboxyacid group or a functional derivative of said carboxyacid group; R and R0 each independently represent amino or a protected amino group; R1 represents hydrogen or a protecting group of the carboxyacid function; and its salts with acids and bases as well as its inner salts. A process for producing the tetrapeptides of formula (I) from the corresponding dalbaheptides and aglucodalbaheptides.

Description: TETRAPEPTIDES DERIVING FROM DALBAHEPTIDE ANTIBIOTICS This invention concerns tetrapeptides of general formula (I) deriving from dalbaheptide antibiotics (I) wherein: and Z represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group (aglucodalbaheptides); Y represents a carboxyacid group or a functional derivative of said carboxyacid group; R and RQ each independently represent amino or a protected amino group; and Ri is hydrogen or a protecting group of the carboxyacid function. The invention includes the salts of the above represented tetrapeptides with acids or bases as well as their inner salts. A further object of this invention is a process for producing the tetrapeptides of formula (I) above from the corresponding dalbaheptides and aglucodalbaheptidesf that is, the dalbaheptides wherein any sugar unit is removed. With the term dalbaheptide are defined all antibiotic substances having in common a highly modified linear heptapeptidic structure made up of seven amino acids, five of which are constantly aryl- and arylmethylaminoacids, said structure being determinant of a common mechanism of action, i.e. the specific complexation with the D-alanyl-D-alanine terminus of one or more intermediates of the cell wall synthesis which leads to cell disruption (see also: F. Parenti and B. Cavalieri, "Novel glycopeptide antibiotics of the dalbaheptide group". Drugs of the future. Vol. 15 (i) : 57-72 (1990)). The dalbaheptide antibiotics can be conventionally represented by the following general structure formula II wherein: W, Z, Xi, X2 and T represent the relative portions of 20 an antibiotic of the dalbaheptide group; and Y represents a carboxyacid group or a functional derivative thereof. The formula (II) includes the salts of dalbaheptide antibiotics with acids and bases as well as their 25 inner salts. In the general structure represented by the formula (II), the above mentioned five fundamental aryl- and arylmethylaminoacids are those connected with the 3 Q rests Z and W. Apart from slight differences in the substitutions on the respective aryl portion, the five aryl- and arylmethyl aminoacids are substantially common to all members of the dalbaheptide antibiotics group, while the different type and structure of the 35 two remaining aminoacid portions which bear the substituents Xi and X 2 allow a further classification of the dalbaheptides so far known into four different sub-groups, each of which is referred, for practical reasons, to a well known antibiotic of the group that, in the previous scientific literature , has been generally identified as glycopeptide antibiotics. Said four sub-groups can be defined respectively as ris ocetin-type, vancomycin-type, avoparcin-type and synmonicin-type antibiotics. This classification is not limiting the scope of this invention but it is useful for the purpose of a more precise description of this invention. According to the terms and definitions of this specification, the dalbaheptide antibiotics as well as the four sub-groups into which they are presently classified, include both products produced as metabolites of microbial strains, as well as semisynthetic derivatives thereof. The fermentation products generally bear sugar moieties conjugated with the hydroxy groups positioned on the aryl or arylmethyl portions of the five fundamental aminoacids, or on the i and / or X2 moieties when they contain hydroxylated aromatic ring moieties. In a few cases, one phenolic hydroxy function may be esterified with a sulfuric acid rest. In the fermentation products the function represented by the symbol Y generally is a carboxyacid or a lower alkyl carboxyester, while the symbol T, in general, represents an amino or a lower alkyl amino (e.g. methylamino) rest. In the dalbaheptides literature are reported also compounds wherein T represents a di-(lower alkyl)amino group (e.g. orienticin D, chloroorienticin C, D, E), or a trimethylam onio group whose positive charge is neutralized by a carboxylate anion formed by the carboxylic group represented by the symbol Y (e.g. antibiotic M43A, B and C). However, these dalbaheptides (and the respective aglycons) cannot be useful as direct precursors of the tetrapepetide of formula (I) according to the process of this invention. The semisynthetic derivatives described in the patents and scientific literature are, for instance, products deriving from complete or partial hydrolysis of the sugar portions, thus having free hydroxy groups on the aryl or the arylmethyl portions, products deriving from the elimination of the benzylic hydroxy group on the arylmethyl portions, products deriving from the introduction of specific sugar moieties or aliphatic or alicyclic rests on a phenolic hydroxy function, products deriving from the modifications of the carboxylic moiety Y to form functional derivatives thereof, e.g. esters, amide or hydrazide derivatives or products deriving from the modification of the portion T yielding variously substituted amino groups (e.g. by alkylation or acylation) or resulting from the introduction of protecting groups of said aminic function or products deriving from the acylation of the aminic rests of the amino sugar moieties, or products resulting from the dehalogenation of the aryl moieties originally containing halo substituents or products deriving from the introduction of halo (preferably chloro, bromo and jodo) substituents on the aryl moieties. Said semisynthetic derivatives may contain more than one of the above mentioned modifications of the basic structure of the natural products. A more complete detailed description of the dalbaheptide antibiotics is given in the European Patent Application Publication No. 409045 which indicates the appropriate references to identify a large number of members of this class of compounds and their method of obtainment. For the purpose of a more detailed description of this invention the tetrapeptides of formula (I) can be formally identified as compounds deriving from the aglycons of the dalbaheptide antibiotics. In fact, although for the manufacture of the tetrapeptides of formula (I) both the glycosylated dalbahpetides and the corresponding pseudoaglycons and aglycons may be utilized as starting materials, for the purpose of clarity and semplicity in this description and claims, it will be made reference to aglucodalbaheptides as the formal precursors of the tetrapeptides of formula (I) since the final compounds and most of the intermediates of their manufacture process do not contain the typical sugar unit(s) of the original dalbaheptides. By following the same method utilized above for the description of the dalbaheptide antibiotics, the aglycons of the dalbaheptide antibiotics (aglucodalbaheptides) which are the formal precursors of the tetrapepetides of this invention can be represented conventionally with the following general structure (Ha) wherein: W, Z, Xi, and X 2 represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group; 20 T represents amino, alkylamino or a protected amino group from which the original amino group can be readily restored; and Y represents a carboxyacid group or a functional derivative thereof. 25 The formula (Ha) includes the salts of aglucodalbaheptide antibiotics with acids and bases as well as their inner salts. According to this invention, the tetrapeptides of 30 general formula (I) can be obtained from the above mentioned aglucodalbaheptide precursors of general formula (Ha) through a series of reaction steps (see Reaction Schemes 1 and 2). 35 d Reaction Scheme 1 Reaction Scheme 2 1) protection of amino group(s)and phenolic step(c 2 ) hydroxy groups 2) oxidation 3) deprotection (optional) CH — " co NH CH CH-R„ CO NH CH CQ R COOR, 'NH Y-CH (I) JO the first of which (step (a)), involves the reductive cleavage of the peptidic bond between the second and third aminoacid (starting from the right) of the seven aminoacids chain of the aglucodalbaheptide antibiotics of formula (Ha) to obtain a pentapeptide of formula (HI) wherein W, Z, Xi and K- 2 represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group, T represents amino, alkylamino or a protected amino group from which the original amino group can be readily restored, Y represents a carboxyacid group or a functional derivative of said carboxyacid group or the salts of the above represented pentapeptide antibiotics with acids or bases as well as their inner salts. As explained above, this step (a) can also be carried out by using as the starting material the corresponding original glycosylated dalbaheptide or a pseudoaglycon thereof yielding a pentapeptide intermediate which still contains all or part of the typical sugar units. In said case, this intermediate is successively converted to the pentapeptide of formula (HI) by removing the sugar moieties, for instance, by acid hydrolysis. The method of preparation of these pentapeptides of formula (HI) is already described in European Patent Application Publication No.409045 and, therefore, the novel process for the manufacture of the tetrapeptides of formula (I) as claimed in this application, actually starts with the successive steps (bi), and (b2) represented in Scheme 1 and Scheme 2, respectively. These further reaction steps are following two different alternative pathways. One of these two alternative pathways involves first (step (bi) of )l Rection Scheme 1) selectively protecting the free amino groups and all phenolic hydroxy groups of the above pentapeptide of formula (HI )and then oxidizing the hydroxymethyl moiety to carboxy to obtain the 5 corresponding carboxy derivative, which is subsequently deprotected at the amino group and, optionally, at the phenolic hydroxy groups, to yield a novel pentapeptide intermediate of the following general formula (IV) wherein W, Z, Xi and X2 represent Q the relative portions of the aglycon of an antibiotic of the dalbaheptide group, T is amino, alkylamino or a protected amino group from which the original amino group can be readily restored, Y represents a carboxyacid group or a functional derivative of said 5 carboxyacid group, including the salts of the above represented pentapeptide with acids or bases as well as their inner salts. The above pentapeptide intermediate (IV) is then submitted to a double Edman degradation (step (ci)) 0 that affords the product of formula (I) by elimination of the two aminoacid moieties bearing the symbols Xi and X2 in the pentapeptide of formula (IV). According to a variation of this reaction pathway which is comprised by Reaction Scheme 1, the above 5 pentapeptide of formula (III) can be protected at the amino groups with a protecting group different from that utilized to protect the phenolic hydroxy groups and removable under conditions which do not alter the protection at said phenolic hydroxy group, so that, Q after oxidation of the hydromethyl group, the amino groups can be selectively deprotected. The resulting oxidized pentapeptide, protected at the phenolic hydroxy groups, but possessing the unprotected amino groups, is then submitted to the double Edman degradation to yield final compound (I) still possessing the phenolic hydroxy group protected with the original protecting group which can be optionally removed at the end of the sequence of this reaction step. The other reaction pathway leading to the tetrapeptide of formula (I) from the pentapeptide of formula (III) involves (step (b 2 ) of Rection Scheme 2) submitting first the pentapeptide of formula (HI) to a double Edman degradation to eliminate the two aminoacids bearing the symbol Xi and X 2 to yield an intermediate of formula (V) wherein W, Z and Y have the same meaning as in formula (HI) and including its salts with acids or bases as well as its inner salts. Then (step (c 2 )), the primary amino groups and the phenolic hydroxy groups of said intermediate of formula (V) are selectively protected and the resulting compound is submitted to oxidizing conditions to convert the hydroxymethyl moiety to carboxy, yielding a compound of formula (I) wherein the amino groups and the phenolic hydroxy groups are protected. If desired, these groups can be deprotected by common procedures known in the art. As it will be further explained in more detail, the symbol Y in the final tetrapeptides (I) may represent a carboxy group or a functional derivative thereof which includes those derivatives containing a protecting group of the carboxylic function which can be introduced during one of the steps described above and which can be optionally removed either simultaneously with the removal of the other protecting groups or separately, under specific conditions. As it is obvious to any person skilled in the art, if the starting material or the intermediate derivatives (II), (IV) and (V) contain further groups which can adversely affect the successive reaction step(s), they may be protected by introduction of suitable protective groups which can optionally be removed after the completion of the successive step(s) . If desired, a tetrapeptide of formula (I) wherein Ri represents hydrogen may be transformed into the corresponding derivative wherein Ri is a protecting group of the carboxyacid function. Analogously, when a compound of formula (I) is obtained wherein R and Ro each independently represents a free amino group, said compound can be optionally transformed into the corresponding derivative of formula (I) wherein R and Ro each independently represents a protected amino group. As described above, the dalbaheptide starting materials for the obtainment of the tetrapeptides of this invention are known compounds or may be prepared (aglucodalbaheptides) from the corresponding dalbaheptides by hydrolysis methods per se known in the art. References 1-29 here below give some examples of aglucodalbaheptides and their obtainment. (See also the above mentioned paper by F. Parenti and B. Cavalleri at page 64). According to a more specific description of most of the aglucodalbaheptide precursors so far known (or which can be prepared from the dalbaheptides so far known), the structure of which has been determined (which is not limiting the scope of this invention), the symbols W and Z in the aglucopeptide precursors of formula (Ha), in the intermediates of formulas (HI), (IV) and (V) and tetrapeptide end compounds of formula (I) deriving therefrom, can respectively represent the following partial structures: l-t W = Z = wherein: -r i): A is.hydrogen or a protecting group of the phenolic hydroxy rest; R 2 , R3 and R4, are each independently, hydrogen or halogen wherein the halogen preferably is chloro or bromo and are most preferably in the ortho position with respect to the ether bond; R5 and Rg are each independently hydrogen, or a group OR 7 wherein R 7 is hydrogen or a protecting group of the benzylic hydroxy rest. As shown in formula (Ha) above, the group W is simultaneously linked to the second, fourth and sixth aminoacid (starting from the right) rest of the heptapeptidic chain of dalbaheptides; ii): the groups ORβ and OR9, preferably, are respectively in the para and ortho position with respect to the bond connecting the two phenyl rings and the radical Re and Rg each independently represents hydrogen or a protecting group of the phenolic hydroxy rest; the group OR 1 0 is, preferably, in the position ortho with respect to the bond connecting the two phenyl rings and the radical Rio represents hydrogen or a protecting group of the phenolic hydroxy rest; the group R11 is, preferably, in the position meta with respect to the bond connecting the two phenyl rings and represent hydrogen or halogen, most preferably, hydrogen or chloro. As shown in formulas I, (Ha), HI, IV and V above, the group Z is linked to the aminoacids corresponding to the fifth and seventh aminoacid (starting from the right) rests of the heptapeptidic chain of dalbaheptides. The encircled numbers in the aromatic rings indicate the respective aminoacids of the original dalbaheptide chain to which the specific aryl or aralkyl moiety is bound. The meanings of the symbols Xi and X 2 in formula (Ha) which permit the differentiation of the aglucodalbaheptides so far known (or that can be obtained from the dalbaheptides so far known) into four sub-groups are respectively the following: Xi represents a phenyl or a benzyl group wherein the phenyl ring may optionally bear one or two substituents selected from halogen, preferably chloro, lower alkyl, preferably methyl, and hydroxy, or it may also represent a (Ci - C 2 ) aliphatic rest substituted with a carboxylic or carboxamide function, a thiomethyl or a methylsulfinyl group. X 2 represents a phenyl group which may optionally bear one or two substituents selected from halogen, preferably chloro, lower alkyl, preferably methyl, and hydroxy or it may represent a (C 1 -C 4 ) aliphatic rest, preferably methyl or isobutyl. Xi and X 2 taken together may also represent a oxybis(phenylene) rest where one or both phenyl rings may optionally be substituted as indicated above. The above meanings of the symbols Xi and X 2 apply also to the intermediate derivatives of formula (III) and (IV) resulting from the respective precursor (Ha) according to the process of this invention. For the purpose of a more specific representation of most of the aglucodalbaheptide precursors of formula (Ha) above so far known or which can be prepared from the corresponding dalbaheptides (including their semisynthetic derivatives) and of the intermediate derivatives of formulas (HI) and (IV), the symbol T identifies an amino group wherein one U hydrogen atom may optionally be substituted by an alkyl radical of 1 to 12 carbon atoms which, in turn, can optionally bear one or more substituents, by a (C 4 -C 7 ) cycloalkyl or T may represent a protected amino group whereby the original aminic group can be readily restored during one of the steps of the process preceding the Edman degradation (See Reaction Scheme 1 and 2) The symbol Y in formulas (I), (Ha), (HI), (IV) and (V) represents a carboxy group, a functional derivative thereof such as a carboxyester, a carboxamide or a carbohydrazide group and includes the protected carboxy groups from which the free carboxy group can be easily restored under specific conditions which do not affect the aminoacid chain. This definition includes the naturally occurring lower alkyl esters as well as the esters formed by reaction of the carboxylic function with alcohols, e.g. aliphatic alcohols optionally bearing substituents (e.g. hydroxy, halo, lower alkoxy, amino, lower alkylamino, di-(lower alkyl)amino, cyano and phenyl, optionally substituted by lower alkyl, lower alkoxy, halo or nitro) in the aliphatic chain, and includes also a wide series of substituted amides which are formed by reaction of the carboxy group with aliphatic, cycloaliphatic and heterocyclic amines. In particular, among the aliphatic amines, the lower alkylamines and the di-lower alkylamines are preferred and may optionally contain a substituent on the aliphatic chain such as amino, lower alkylamino, di- (lower alkyl)amino, pyrrolidino, piperazino, N-(lower alkylJpiperazino, morpholino, hydroxy, lower alkoxy, carboxy, carbo(lower alkoxy), carbamyl, mono- and di- (lower alkyl)carbamyl and the like; among the cycloaliphatic amines, the C 4 -C7 cycloaliphatic primary amines are preferred; among the heterocyclic amines saturated nitrogen containing 5 to 7 membered heterocyclic ring are preferred, e.g. pyrrolidine, morpholine, piperazine, and N-(lower alkyl)piperazine The above descriptions and definitions of the symbols W, Z and Y, when referred to the tetrapeptides derived from the above said aglucodalbaheptides, point to a preferred embodiment of this invention which is represented by the tetrapeptide derivatives of formula (la) I S wherein A, R, Ro, Ri, R 2 / R3/ -~A > RS# Rβ# R 7F Re, Rιo# R 11 and Y have the same meanings as above The salts of the end compounds of formula (I) , of t - starting compounds of formula (Ha) (or the corresponding glycosylated dalbaheptides of general formula (II)) and of the intermediates of formulas (III), (IV) and (V) can be those deriving from the salification with an acid of the basic functions of 0 the molecule, e.g., the aminic functions resulting from the cleavage of the peptidic bond of the original dalbaheptide peptidic chain in the end compounds of formula (I) and in the intermediates of formulas (HI), (IV) and (V), or the aminic function identified 5 by the symbol T in both the starting materials of formula (Ha) and in the intermediates of formulas (HI) and (IV), or an aminic function contained as substituent in the carboxyester, carboxamide or carbohydrazide moiety represented by the symbol Y in Q any of the compounds of formula (I), (Ha), (HI), (IV) and (V). Representative acid addition salts are those formed by reaction with both inorganic and organic acids, for example, hydrochloric, sulfuric, phosphoric, succinic, citric, lactic, maleic, fumaric, 5 cholic, d-glutamic, d-camphoric, glutaric, phthalic, tartaric, methanesulfonic, benzenesulfonic, benzoic, salicylic, trifluoroacetic acid and the like. Alternatively, the salts may be formed through salification of the carboxylic acid function Q represented by the symbol Y of the end compounds, intermediates or starting materials, or an acidic function contained as substituent in the carboxyester, carboxamide or carbohydrazide portion identified by the symbol Y or any acidic function which may be 5 present in any other portion of the molecule, such as the carboxy group deriving from the cleavage of the original peptidic chain in the end compounds of formula (I) (COORi, Ri = hydrogen) and the intermediates of formula (IV), with an appropriate base, such as, for instance, an alkali metal hydroxide or carbonate or an organic amine, such as a mono-, di- 5 or tri-(lower alkyl)amine and the like. The inner salts are those formed through internal salification in the cases of simultaneous presence of basic (e.g. amino) and acid (e.g. carboxy) functions of sufficient strength in the starting materials, intermediates and 10 tetrapeptide end compounds. The characteristics which allow a further classification of the so far known dalbaheptides into four-sub-groups are in no way limiting the scope of -1 5 this invention in that new natural products and derivatives thereof falling into the general classification of dalbaheptide antibiotics can be obtained and can be converted to tetrapeptides of formula (I) according to the process of this ø invention. However, for a more precise identification of representative starting compounds that can be used according to this invention for obtaining the corresponding tetrapeptides of formula (I), in the following is given a further detailed description of 5 the four dalbaheptide sub-groups mentioned above and of the tetrapeptides deriving from their corresponding aglycons according to a preferred embodiment of this invention. 0 Referring to the formula II above, the sub-group identified as ristocetin-type dalbaheptides is characterized by the fact that the symbols Xi and X 2 taken together represent an oxybis(phenylene) rest wherein one or both phenyl rings may optionally bear 5 one or two substituent selected from halogen. preferably chloro, lower alkyl, preferably methyl, and hydroxy wherein the hydroxy group can be optionally conjugated with a sugar moiety through an acetalic bond or esterified with a sulfuric acid residue. Other dalbaheptide antibiotics which can be assigned to this sub-group include the following: actaplanin, teicoplanin, antibiotic A 35512, antibiotic A 41030, antibiotic A 47934, ardacin A, B, C, antibiotic A 40926, kibdelin (ref. 24), parvodicin, and antibiotic OK 68597. (See pertinent references in European Patent Application Publicatio No. 409045). The semisynthetic derivatives of the above mentioned natural products are also included in this sub-group. See, for instance, the aglycone and pseudoaglycones of ardacins and the derivatives thereof wherein Y is a carboxamide or a carbohydrazide rest; the aglycone and pseudoaglycone of parvodicin; the hydrolysis products of actaplanins; the acylation derivatives of ristocetin, actaplanin and their pseudoaglycons, the bromine analogs of actaplanin; the aromatic aldehyde derivatives of ristocetin; the derivatives of teicoplanin and antibiotic A 40926 which are more specifically considered below. (See pertinent references in European Patent Application Publication No. 409045). Accordingly, one of the objects of this invention consists in the tetrapeptides deriving from the ristocetin-type aglucodalbaheptides which can be formally represented through formula (Ha) above where , z, T and Y are defined as above, Xi and X 2 are as specifically defined for the identification of the ristocetin-type dalbaheptides sub-group with the proviso that any sugar unit is removed. For example, from aglucoristocetin (Y = COOCH 3 ) and its corresponding acid (Y = COOH) which have the following formula (Hb): (Hb) the corresponding specific tetrapeptide of formula (lb) can be derived according to this invention (lb) wherein: R, Ro# and Ri have the same meaning as above; Y represents a carboxyacid group, carbomethoxy or another protected carboxyacid group; and the phenolic hydroxy groups may optionally be protected. The starting aglucoristocetin and its correspoding acid may be obtained according to the literature from ristocetin A or B and their pseudoaglycones (See references 1, 2, 3 and 4). Aglucoteicoplanin and its semisynthetic derivatives of formula (He) 2-1 ( HC) represents a particular group of precursors which can be assigned to the ristocetin-type aglucodalbaheptides and which can be transformed into the corresponding tetrapeptides of formula (Ic) according to this invention 2..-T (ic) In the above formula (He), when representing aglucoteicoplanin, R 2 , R5, R 1 2 and R 1 3 are hydrogen, R3 and R 4 are chloro, Re is hydroxy and Y is a carboxyacid group (Ref. 5, 6). The corresponding tetrapeptide derived from aglucoteicoplanin according to this invention is represented by formula (Ic) wherein R, Ri and Ro have the same meaning as above, R 2 and R5 are hydrogen, R3 and R 4 are chloro. Re is hydroxy, and Y is a carboxyacid group or a protected carboxyacid group and the phenolic hydroxy groups may optionally be protected. A series of derivatives of teicoplanin and aglucoteicoplanin is known or may be prepared (aglucoteicoplanin derivatives) from the corresponding teicoplanin semisynthetic derivatives wherein (formula (He)) at least one of the symbols Y, R3, R 4 , Re, Rι 2 and R 1 3 assumes a meaning different from those listed above for the identification of aglucoteicoplanin. For instance: the symbol Y of the formula (He) above may represent a functional derivative of the carboxyacid group such as a carboxyester, e.g. a lower alkyl ester wherein the alkyl moiety may optionally contain a further substituent such as, for example, hydroxy, lower alkoxy, amino, lower alkylamino, di-(lower alkyl)amino, cyano, halo and phenyl, optionally substituted by lower alkyl, lower alkoxy, halo or nitro (Int. Appln. Publ. No. WO./8600075) , a carboxamide, or, preferably, a substituted carboxamide, for example, an amide with a lower alkyl amine wherein the lower alkyl moiety may optionally contain a substituent selected from amino, lower alkylamino, di-(lower alkyl)amino, pyrrolidino, piperazino, N-(lower alkylJpiperazino, morpholino, hydroxy, lower alkoxy, carboxy, carbo(lower alkoxy), carbamyl, mono- and di-(lower alkyl)carbamyl or an amide with a di-(lower alkyl)amine, or an amide with a saturated 5 to 7 me bered heterocylic ring, e.g., pyrrolidine, morpholine, piperazine and N-(lower alkyl)piperazine, (E.P.A. Publ. No. 218099, Int. Pat. Appln. Publ. No. WO/06600, Int. Pat. Appln. Publ. No. WO 90/11300 and E.P.A. Publ. No. 370283); the rest NRι 2 Ri3 can represent an amino group modified by reaction with a readily removable protecting group or by conversion into alkylamino e.g. lower alkylamino wherein the alkyl portion may bear further substituents such as those disclosed above (see E.P.A. Publ. Nos. 276740, 351597 and 351685); each of the groups R 3 , R 4 and Re, independently, may represent hydrogen (ref. 7, 8, 9). 2 Each of the above mentioned modifications in the different portions of the aglucoteicoplanin molecule may occur independently (i.e. only one variation does occur while all other meanings of the symbols defining aglucoteicoplanin remain unchanged) or simultaneously (see e.g. E.P.A. Publ. Nos. 352538 and 370283), yielding suitable precursors for the obtainment of tetrapeptide derivatives of this invention of formula (Ic) wherein the symbols R 2 , R3, R4, R5, Re and Y have the same meanings as those of the corresponding starting materials, R, Ro and Ri have the same meanings as above and the phenolic hydroxy groups may optionally be protected. Of course, if the modified portion(s) of the starting teicoplanin derivatives contain substituent(s) which may be affected by the reaction conditions of one or more step of the process of this invention, they may be conveniently protected before undergoing the specific reaction(s) course and then, optionally, deprotected at the end of the process. 0 A further particular group of compounds falling within the ristocetin-type aglucodalbaheptides sub-group comprises the aglycon of antibiotic A 40926 complex (ref. 12). Also this compound or its corresponding glycosylated dalbaheptides are suitable starting materials for conversion into the corresponding tetrapeptides embraced by the general formula (I) through the process of this invention. The dalbaheptide antibiotic sub-group identified as vancomycin-type dalbaheptides is characterized by the fact that (reference is made to formula II above) the symbol Xi represents a (Cι~C 2 )aliphatic rest substituted with a carboxyacid group or carboxamide function and the symbol X 2 represents a (C 1 -C 4 )aliphatic rest. In particular, in the most common examples of antibiotic substances falling within this sub-group, Xi is a residue deriving from aspartic acid, aspargine or glutamine, while X 2 is a residue deriving from alanine or leucine. Other dalbaheptide antibiotics which can be assigned to this sub-group include the following: A 51568 A and B, orienticins, eremomycin , A 42867, A 82846, chloroorienticins, MM 47761 and MM 49721, decaplanin, MM 45289 and MM 47756. All these dalbaheptide antibiotics are well known to those skilled in the field. (See also pertinent references in European Patent Application Publication No. 409045). The semisynthetic derivatives of the above mentioned natural products are included in this -sub¬ group. See for instance: the various glycosylated derivatives of the hydrolysis products of vancomycin. 2.3 A 51568A and B; the desvancosaminyl and des(vancosaminyl-O-glucosyl)-derivatives of vancomycin, A 51568A; A 51568B, and the derivatives of A 82846; the reaction products of the aminic rests of some vancomycin-type dalbaheptides with aldehydes and ketones and the corresponding hydrogenation products, the N-acyl derivatives of vancomycin-type antibiotics, mono- and didechlorovancomycin and the hydrolysis products of eremomycin. All these dalbaheptide antibiotics are well known to those skilled in the field. (See also pertinent references in European Patent Application Publication No. 409045). Accordingly, one of the objects of this invention consists in the tetrapeptide deriving from the vancomycin-type aglucodalbaheptides which can be formally represented through the formula (Ha) above where W, Z, T and Y are defined as above, Xi and X 2 are as specifically defined for the identification of the vancomycin-type dalbaheptide sub-group, with the proviso that any sugar unit is removed. For example, aglucovancomycin (ref. 10, 11) has the following structure formula (lid): (lid) wherein Y is a carboxyacid group. According to this invention, the corresponding tetrapeptide of formula (Id) can be derived from aglucovancomycin: (Id) wherein: R, Ro and Ri have the same meaning as above; Y is a carboxyacid or a protected carboxyacid group; and the phenolic hydroxy groups may optionally be protected. The avoparcin-type dalbaheptide sub-group is characterized by the fact that: the symbol Xi in the general formula (II) represents a phenyl or benzyl group wherein the phenyl ring may optionally bear one or two substituents selected from hydroxy and halogen, preferably chloro; the symbol X 2 represents a phenyl group which may optionally bear one or two substituents selected from halogen. preferably chloro, and hydroxy which may optionally be conjugated with a sugar moiety (e.g. rhamnose). Other dalbaheptide antibiotics which can be 5 assigned to this group include the following: actinoidin A, B, chloropolysporin A, B, C , actinoidin A 2 and helvecardin A, B , MM 47767, MM 55256. Semisynthetic derivatives of avoparcin-type sub-group of dalbaheptide antibiotics are for instance the 0 demannosyl chloropolyspo in B derivatives, the chloropolysporin pseudoaglycone, the derhamnosyl α- and β-avoparcin, the mannosyl aglycones of avoparcin (LL- AV290) and other derivatives wherein one or more sugar moieties are hydrolyzed. All these dalbaheptide 5 antibiotics are well known to those skilled in the field. (See also pertinent references in European Patent Application Publication No. 409045). Accordingly, one of the objects of this invention o consists in the tetrapeptides deriving from the avoparcin-type aglucodalbaheptides which can be generally represented through formula (Ha) above where W, Z, T and Y are defined as above, Xi and X 2 are as specifically defined for the identification of the avoparcin-type dalbaheptide sub-group with the proviso that any sugar unit is removed. For example, α- and β-aglucoavoparcin (ref. 13, 14) have the following structure formula (He): (He) wherein: Y is a carboxyacid group; and Ri 6 is hydrogen or chloro. According to this invention, from α- and β-aglucoavoparcin a tetrapeptide of formula (Ie) can be derived (Ie) wherein: R, Ro and Ri have the same meaning as above; Y is a carboxyacid or a protected carboxyacid group; and the phenolic hydroxy groups may optionally be protected. The dalbaheptide antibiotics sub-group identified as synmonicin-type antibiotics is characterized by the fact that (reference is made to formula II above): the symbol. Xi represents a C 2 alkyl rest substituted on the terminal carbon with a thiomethyl or methylsulfinyl group; and the symbol X 2 represent a phenyl group bearing a hydroxy substituent which may be conjugated with a sugar moiety. Synmonicin (CWI-785) complex, its components and some of its hydrolysis products seem to be, for the moment, the only members of this sub-group. (See pertinent references in European Patent Application Publication No. 409045). 0 Accordingly, one of the objects of this invention consists in the tetrapeptides deriving from the synmonicin-type aglucodalbaheptides which can be formally represented through formula (He) above where: W, Z, T and Y are defined as above; Xi and X 2 5 are as specifically defined for the identification of the synmonicin-type dalbaheptide sub-group with the proviso that any sugar unit is removed. o For instance, aglucosynmonicin A and B (ref. 15, 16) have the following structure formula (Hf): 5 0 3 (Hf) wherein: Y is a carboxyacid group; and R 1 7 is methylsulfinyl or thiomethyl, According to this invention a tetrapeptide derivative of the same formula (Ie) above can be derived from both aglucosynmonicin A and B. The tetrapepetides of formula (I) are useful as intermediates for the preparation of synthetic aglucodalbaheptides wherein the first and third aminoacids constituents, that is, those which in formula (Ha) bear the substituents X 2 and Xi, can be introduced by the skilled chemist through the insertion of the appropriate aminoacid units into the tetrapeptide moiety by means of peptide chemistry reactions. In the following description are given more specific details on the way the specific steps of the process may be carried out. Step (a): The procedure of the first step of the process for preparing the tetrapeptides of this invention from aglucodalbaheptides is extensively described in European Patent Application Publication No. 409045 and comprises submitting a aglucodalbaheptide antibiotic as defined above in a hydroalcoholic medium to a reductive cleavage with an alkali metal borohydride, preferably selected from sodium borohydride, potassium borohydride and sodium cyanoborohydride at a temperature comprised between 0°C and 40°C. The hydroalcoholic medium is a mixture of H 2 0 and a lower alkanol wherein the ratio H 2 0/alcohol ranges between 40/60 and 90/10 (v/v), preferably between 60/40 (v/v) and 70/30 v/v, most preferably is 65/35 (v/v). Although the reaction occurs, in some cases, also in the presence of lower amounts of water, e.g. in mixtures H 2 0/alcohol 30/70 or 20/80, in general, the reaction rate is very low when the ratio H 2 0/alcohol is lower than 40/60. Preferred lower alkyl alcohols are linear and branched (C 1 -C 4 ) alkyl alcohols, among which the most preferred is ethanol. In a particular preferred embodiment of this step of the process a hydroalcoholic mixture H 2 0/ethanol 65/35 (v/v) is used. 28 Sometimes, in particular cases, a small amount of a polar co-solvent can be added to completely dissolve the dalbaheptide starting material during the course of the reaction, e.g. N,N-dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU), dimethylsulfoxide. In some cases, a small amount of n-butanol can be added to minimize foaming. As alkali metal borohydride the sodium borohydride is the most preferred one. The suitable amount of alkali metal borohydride employed may vary depending on the particular compound used as starting material, the solvent used and the temperature of the reaction, but it is advisable to use an amount of alkali metal borohydride in a large excess over the stoichio etric requirement in such a way that the pH of the reaction mixture is alkaline, preferably between pH 8 and 12. Anyway, in general, the molar ratio between the alkali metal borohydride and the antibiotic starting material is comprised between 50 and 300. The reaction temperature may vary considerably depending on the specific starting materials and reaction conditions. In general, it is preferred to conduct the reaction at a temperature between O and 4O°C, more preferably at room temperature. Also the reaction time may vary considerably depending on the other reaction parameters. In general, the reaction is completed in about 10-48 hours. In any case, the reaction course is monitored by TLC or, preferably, by HPLC according to methods known in the art. On the basis of the results of these assays a man skilled in the art will be able to evaluate the reaction course and decide when to stop the reaction and start working up the reaction mass according to known per se S3 techniques which include, for instance, extraction with solvents, precipitation by addition of non- solvents, etc., in conjunction with further separations and purification by column chromatography, when needed. After the reaction is completed, in most cases, but not necessarily in all cases, mostly depending on the starting dalbaheptide, a clear solution is formed; then the excess of the alkali metal borohydride is eliminated by adding a suitable amount of an acid, for example, a (C 1 -C 4 )alkyl organic acid, a (Ci-Cβ)alkyl sulfonic acid, an aryl sulfonic acid and the like, dissolved in a polar protic solvent such as, for example, a (C 1 -C 4 )alkyl alcohol. According to Europan Patent Application Publication No. 409045, the pentapeptides of formula (HI) may be alternatively prepared by hydrolysis of the corresponding glycosylated pentapeptides which, in turn, are obtained by applying the reductive cleavage process to the glycosylated dalbaheptides of general formula (II). By following this route the glycosylated pentapeptide obtained from the reductive cleavage is transformed in the corresponding aglucopentapeptide of formula (III) by submitting it to selective hydrolysis conditions such as those described in E.P.A. Publ. No. 146053 or E.P.A. Publ. No. 376042. In some cases, this is a preferred procedure for the lower amount of reducing agent required, shorter reaction time and higher reaction yield. In addition, in particular in the case of teicoplanin, side-epimerization is minimized. The pentapeptide compounds resulting from the reductive cleavage step described above can be 4 o directly isolated in the form of free bases or salts with acid or bases as described above or can be utilized as such for the further steps (bi) or (b 2 ). Step (bi) A crucial point of this step consists in the appropriate selection of the protecting groups. In fact, the selective protection of the primary amino group resulting from the reductive cleavage step, of the amino group of the terminal aminoacid and of the phenolic hydroxy groups of the pentapeptide (HI) is essential to avoid undesidered modifications of the substrate during the oxidation reaction to convert the hydroxymethyl group resulting from the reductive cleavage to carboxyacid group. Therefore, the protecting groups selected must be resistant to the oxidation conditions and must be readily removable after the oxidation process without altering the basic structure of the molecule. If necessary, protective groups can also be introduced on other oxidation sensitive rests of the substrate (HI), e.g. the benzylic hydroxy rests which can be identified by the symbols R5 and Re or in other portions of the molecule which are sensitive to the oxidation conditions applied. However, in some cases, for instance with a substrate (HI) deriving from aglucoteicoplanin and its derivatives, it has been observed that the benzylic hydroxy group represented by the symbol Re is inert to both the oxidation reaction and the protecting agents. Also in the case of a substrate (HI) deriving from aglucovancomycin, both benzylic hydroxy groups represented by the symbols Rs and Re are inert to both the oxidation reagents and the reagents used to introduce the protecting groups. The protective groups of the amino moiety and of the phenolic hydroxy groups (and of any other oxidation sensitive groups, when needed) can be either of the same or differen type, depending on the reagents and conditions applied in the oxidation reaction. The type of substrate (HI) is also to be considered for selecting the appropriate way and type of protection. Protecting groups and the relative procedures for their introduction and removal are described, for instance, in: T.W. Greene, "Protective Groups in Organic Synthesis", J. Wiley, N.Y., 1981. In general, acyl radicals may be usefully employed for the protection of both amino and phenolic hydroxy groups. Said acyl radicals may be removed by hydrolysis, solvolysis or reduction depending on their nature. Typical examples of these acyl radicals are lower alkanoyl radicals optionally substituted by halogen or lower alkoxy such as, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, methoxyacetyl, benzoyl radicals optionally substituted by nitro groups such as benzoyl, 2-nitrobenzoyl and 2,4-dinitrobenzoyl, lower alkoxycarbonyl radicals optionally substituted by halogen such as methoxycarbony1, ethoxycarbonyl, tert-butoxycarbonyl, 2-bromoethoxycarbonyl, 2,2,2-trichloroethoxycarbony1, 2,2,2-trifluoro-ethoxycarbonyl or 2,2-dimethyl-2,l,l- trichloro-ethoxycarbonyl, phenyl-lower alkoxycarbonyl radicals optionally substituted on the phenyl group such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and 4-methoxybenzyloxycarbonyl and 3,4-methoxy- benzyloxycarbonyl. Typical protective groups of the phenolic hydroxy rests are those forming an ether which is resistant to the oxidation process and can be removed under conditions which do not affect the remaining portions of the molecule. Examples of said ethers are ethers with lower alkyl radicals optionally substituted by halogen or lower alkoxy, such as methyl, ethyl, t- butyl, trichloroethyl, methoxymethyl and methoxyethyl , ~i 2 ethers with phenylmethyl radicals wherein the phenyl group may optionally be substituted by nitro or lower alkoxy such as benzyl, 2-nitrobenzyl and 4-methoxybenzyl, ethers with lower alkanoylmethyl or benzoylmethyl radicals optionally substituted on the lower alkanoyl and benzoyl portion such as acetylmethyl, dichloroacetylmethyl, trifluoroacetylmethyl, benzoylmethyl, 4-chloro- or 4-bromo-benzoylmethyl, 4-nitrobenzoylmeth l, ethers with fully hydrogenated heterocyclic radicals of 5 to 7 members containing one oxygen atom such as 2- tetrahydrofuranyl- and 2-tetrahydropyranylether. For example, when it is desired to protect in a different way the amino groups and the phenolic hydroxy groups according to the process variation mentioned before, the amino groups can be protected with tert-butoxycarbonyl radicals, while the phenolic hydroxy group may be protected with benzyloxycarbonyl radicals. For carrying out step (bi), as well as other steps of the process of this invention, it is not necessary to protect the carboxyacid group which may be identified by the symbol Y, but it may be desirable to obtain a tetrapeptide (I) wherein the carboxyacid group represented by Y is protected by a group which can be useful or necessary in the successive use of tetrapeptide (I) as intermediate for the preparation of synthetic aglucodalbaheptides. Therefore, in said case, it may by suitable to have introduced the protecting group of said carboxyacid function (when it is not already present in the original dalbaheptide or aglucodalbaheptide) in the earlier reaction steps of the process of this invention. For instance, the carboxyacid function is suitably protected when transformed in esterified form, the ester group being readily cleavable under reductive or solvolytic -} 3 conditions. Accordingly, most of the groups mentioned above for the protection of the phenolic hydroxy group can be utilized also for the protection of the carboxyacid function. For instance, esterification with lower alkyl, phenylmethyl and benzoylmethyl radicals wherein the lower alkyl and the phenyl portion may optionally be substituted as described above, results in a suitable protection of the carboxyacid function. According to a preferred embodiment of the invention, the amino groups are protected in a first stage by introduction of a lower alkoxycarbonyl or a phenyl-lower alkoxycarbonyl radical, for instance, a tert-butoxycarbonyl or benzyloxycarbonyl radical . For this purpose, the pentapeptide of formula HI is reacted with a reagent capable of inserting said radical onto the amino group such as di-tert- butylcarbonate, di-tert-butyl-dicarbonate, 2,4,5- trichlorophenyl-tert-butylcarbonate or benzyl chloroformate in the presence of an excess of a mild base. The reaction is usually carried out in the presence of a solvent at a temperature between 0 and 50°C, preferably between 15 and 25°C. Usually, the reagent providing the protecting group is employed in about equimolecular amount or in a slight excess with respect to number of the amino groups of the pentapeptide (HI) which require protection during the oxidation step. In the usual cases, where the amino groups of the pentapeptide requiring protection are two (the one of the first aminoacid and the one resulting from the reductive cleavage of the previous step (a)), about two equimolecular amounts of protecting agent for each equimolecular amount of pentapeptide are employed. The solvent is preferably selected from the mixtures of water and a water miscible organic solvent, when di-(lower alkyl)carbonates or di-(lower alkyl)dicarbonates are used as reagents providing the protecting groups. The water miscible organic solvent is usually selected from lower alkanols, acetone, tetrahydrofuran and dioxane. The proportion between water and water miscible solvent is varying between 1:9 and 9:1,. preferably between 4:6 and 6:4. With reagents like the 2,4,5-trichlorophenyl- tert-butylcarbonate and benzyl chloroformate, polar organic solvents like dimethylformamide or dimethylsulfoxide and their mixture with a lower alkanol, acetone, tetrahydrofuran and dioxane are preferred. The mild bases which are preferably utilized are selected from alkali metal carbonates, alkali metal bicarbonates (e.g. potassium carbonate and sodium bicarbonate), tri-(lower alkyl)amines (e.g. triethylamine), and mixtures thereof. According to the above mentioned preferred procedure, the protection of the phenolic hydroxy groups is effected in a second stage through the formation of ethers, esters, or carbonate esters as described above such as, for instance, lower alkyl ethers, benzyl ethers and benzoylmethyl ethers wherein the alkyl and phenyl moiety may optionally be substituted as indicated above, or lower alkanoyl esters, benzoyl esters, lower alkoxycarbonyl esters and benzyloxycarbonyl esters wherein the alkyl and phenyl moiety may optionally be substituted as indicated above. The formation of the above mentioned ethers may be carried out, for instance, by reaction of the pentapeptide (HI) protected on the amino groups with a reagent consisting of the appropriate ether forming a radical bound to a suitable living group, such as a lower alkyl, benzyl or benzoylmethyl chloride, bromide, sulfate, or p-toluenesulfonate in the presence of an excess of a base and a polar organic solvent, for instance, dimethylformamide or dimethylsulfoxide, preferably under anhydrous conditions. Suitable bases are selected from alkali metal carbonates, e.g. sodium carbonate, potassium carbonate, and cesium carbonate and tri-(lower alkyl)amines, e.g. triethylamine, tributylamine and methyl-dibutylamine. The temperature of the reaction ranges from -10 to 40°C, preferably from 10 to 25°C. The formation of the esters may be carried out, for instance, by reaction of the same pentapeptide (HI) protected on the amino groups with a suitable acylating agent consisting of the appropriate protective acyl group bound to a leaving group such as a lower alkanoyl, benzoyl, lower alkoxycarbonyl, benzyloxycarbonyl chloride or bromide or a corresponding reactive ester or anhydride. The reaction is usually carried out in the presence of an organic solvent, and an excess of a base, preferably under anydrous conditions. The solvent is preferably selected from the polar organic solvents, e.g. dimethylformamide or dimethylsulfoxide, and their mixtures with acetone, tetrahydrofuran, and dioxane. In some cases, for instance, when a benzyloxycarbonyl protecting group is used for the phenolic hydroxy groups, a mixture of the above organic solvents with water, preferably in a 1:1 proportion is a suitable solvent mixture. In fact, under these conditions, the reactivity of the primary hydroxymethyl group toward the protecting agents is minimized. The base is usually selected from alkali metal carbonates, e.g. sodium carbonate, potassium carbonate and cesium carbonate (as all preferred ones), and the 41 organic tertiary bases, e.g. the tri-(lower alkyl) amines such as triethylamine, tributylamine and the like. The temperature of the acylation reaction usually ranges between 5 and 35°C, preferably 15 and 20°C. In both ethers and esters formation, the reagent is usually added portionwise during a certain interval of time to reach a final amount which is in a 2 to 6 molar excess over the stoichio etric amount necessary to protect all the hydroxy groups (apart from the hydroxy group of the hydroxymethyl rest) of the pentapeptide substrate which are not inert to the successive oxidation. In most cases described above the introduction of ether protecting groups affords also the formation of the corresponding ester of the original carboxyacid moiety identified by the symbols Y in the pentapeptide (III), when it is not already transformed into a functional derivative thereof. Although the main target of these protective steps is to selectively protect all amino and the hydroxy groups which are sensitive to the successive oxidation, with the exception of the hydroxymethyl rest produced by the previous reductive cleavage, the resulting protected pentapeptide derivative may not be a unitary product, but, rather, it may contain a certain amount of product(s) which present(s) a lower degree of protection or, even, may contain a certain amount(s) of product(s) protected at undesired position(s) such as the hydroxymethyl moiety. However, it may not be practical to eliminate these products from the mixture resulting from this second step (bi) of the process of the invention, but, it may be more practical to use this crude product, without submitting it to any special purification procedure, in the successive oxidation reaction. 4 The selection of the oxidizing agent and the relative reaction pH essentially depend on the protecting groups utilized in the previous stages. Although several oxidation reagents and pH conditions have been tested, satisfactory results have been achieved only by using potassium permanganate at a neutral or basic pH or, preferably, the so called Jones reagent, i.e. chromium trioxide in diluted sulfuric acid. With potassium permanganate as the oxidizing agent the reaction is conducted at pH between 7 and 12, preferably, between 8.5 and 12, in aqueous conditions, preferably in the presence of a water miscible organic solvent such as acetone, tetrahydrofuran or dioxane. With Jones reagent, the reaction is carried out by adding portionwise an excess of a standard solution of Jones reagent to a solution of protected pentapeptide in an organic solvent miscible with water such as acetone, tetrahydrofuran or dioxane at a temperature between 15 and 35°C, preferably between 20 and 30°C. The reaction product from the oxidation reaction is isolated according to the usual procedures known in the art which imply elimination of the reduced inorganic materials and the reagent excess which, in general, is decomposed before elimination, and may be submitted to the successive deprotection stage without any particular purification. The procedures followed for the removal of the protecting groups from the oxidation product depend on the type of the protecting groups utilized. As mentioned above, acid or base catalyzed solvolysis, hydrogenolysis or reductive cleavage are the usual methods applied for the removal of the protective groups. The more appropriate methods may be selected by the skilled technician also by relying on -I Θ the indications given in the text book indicated above. For instance, when the amino or hydroxy groups are protected by way of esters with the benzyloxycarbonyl groups or ethers with the benzyl radical, catalytic hydrogenation may represent the most preferred deprotection procedure. The hydrogenation is usually carried out at room temperature at a pressure which corresponds to the atmospheric pressure or of 1-2 atmospheres over the atmospheric pressure, in the presence of an hydrogenation catalyst, e.g. 5% to 10% Pd/BaSθ 4 or 5% Pd/C, an inert organic solvent such as lower alkanols, dimethylformamide, dioxane, tetrahydrofuran and their mixtures, and an acid, for example, glacial acetic acid or a diluted aqueous mineral acid, e.g. 0.1N hydrochloric acid. The removal of the acyl groups such as lower alkanoyl or (lower alkoxy)carbony1 from the amino or hydroxy groups may be carried out by acidolysis, or acid or basic hydrolysis, for example with diluted alkyl hydroxides or diluted mineral acids, or with strong organic acids. For instance, the tert-butoxycarbonyl groups protective of the aminic functions can be suitably removed from the oxidized product by dissolving the oxidized product in trifluoroacetic acid at room temperature and stirring the solution for 1-3 hours and then evaporating the obtained solution under reduced pressure. The deprotected product (IV) may be isolated according to procedures per se known in the art and, if needed, purified by means of reverse-phase column chromatography, for instance, by loading a solution of the above mentioned deprotected product (IV) in aqueous acetonitrile at a pH between 3 and 4 on a silanized silica-gel column and then developing the column with a linear gradient of acetonitrile in water (e.g. 15% v/v to 50% v/v) and collecting the eluted fractions under HPLC control. Step (ci) : The Edman degradation and its successive evolutions are methods currently applied in the peptide chemistry to remove the N-terminal aminoacids from the peptidic chain (See ref. 30) According to the more recent developments of the original procedure, the Edman degradation essentially consists in reacting a peptide containing terminal α-amino group(s) with a lower alkyl or aryl isothiocyanate (e.g. methylisothiocyanate, phenyl isothiocyanate, p-nitrophenylisothiocyanate and naphthylisothiocyanate) to form a thiocarbamyl-peptide derivative intermediate which is then submitted to cleavage of the terminal thiocarbamyl aminoacid portion by cyclization to thiohydantoin derivative. This last step results in the selective elimination of the N-terminal aminoacid(s) of the peptidic chain. The Edman degradation procedure has been applied to aglucovancomycin and related antibiotics for the selective cleavage of the N-terminal amino acid, i.e. N-methyl-leucine (the first aminoacid from the right- hand side), yielding a vancomycin hexapeptide derivative which is devoid of antibacterial activity (Ref. 31) According to a preferred embodiment of this step (ci), the double Edman degradation is carried out on the pentapeptide (IV) which has two N-terminal aminoacid moieties, by contacting the above mentioned pentapeptide (IV) with a 0.2-0.5 molar excess of methylisothiocyanate or phenylisothiocyanate, over the stoichiometric amount at a pH value between 8 and 9 in an aqueous solvent mixture (e.g. pyridine:water 1:1) at a temperature between 0 and 35°C, preferably at room temperature. The obtained bis- LXo (methylthiocarbamyl) intermediate may be isolated from the reaction mixture according to common procedures and then submitted to double cleavage/cyclization without any further purification. The cleavage/cyclization procedure involves heating the above intermediate in an acidic medium which does not affect the other essential portion of the molecule. For instance, this step may be suitably performed by dissolving the intermediate into trifluoroacetic acid and maintaining this solution at 40-60°C for a period of time which is sufficient to complete the reaction (HPLC control may be applied) . In most cases, heating may not be necessary and the cleavage/cyclization reactions occur even at temperature comprised between 10 and 40°C. The resulting reaction mixture is evaporated to dryness and then washed with a solvent which is capable of removing the thiohydantoin side product, or it is purified by method per se known in the art, e.g. by reverse-phase column chromatography. Usually, satisfactory results are obtained by applying the same conditions utilized for the purification of the pentapeptide (IV) . By following this method the tetrapeptide (I) wherein Ri is hydrogen, R and Ro are amino is obtained as an acid addition salt with trifluoroacetic acid. This salt may be converted into the corresponding free base by neutralizing a water solution thereof. Salts of the tetrapeptide with bases or transformation into other acid addition salts, may be achieved by means of the common procedures which are well known in the art. If desired, the primary amino functions of the obtained tetrapeptide free base may be converted into protected amino groups by using the same protective reagents and methods described above. Analogously, a tetrapeptide of formula (I) wherein Ri is hydrogen can be optionally transformed into the corresponding compound wherein Ri represents a protecting group of the carboxyacid function by means of known procedures such as those mentioned above. Step (b 2 ): The alternative process for the preparation of the tetrapepetides of general formula (I) starts with submitting the pentapeptide (HI) to Edman degradation for the simultaneous elimination of the two aminoacids bearing the substituents Xi and X 2 . The reaction conditions applied here are essentially the same as those described under step (ci). In this case, being the resulting product (V) an intermediate compound to be used in the successive step of the process, it may not be necessary to apply extensive purification procedures to the crude reaction product besides washing it with solvents, e.g. diethyl ether, to remove the thiohydantoin side products. Step (C2): Also in this case, as well as in step (bi) of the other reaction pathway, one of the essential points of the procedure consists in the appropriate selection of the protecting groups. The same protecting groups, reagents and reaction conditions listed under the above description of step (bi) can be applied here to the substrate (V) . The selective protection of the amino and phenolic hydroxy groups (and, optionally, any other oxidation sensitive group) can be carried out simultaneously or in two separate stages. A two stage procedure is particularly preferred here since it allows to take advantage of the vicinity of the primary amino group and the hydroxymethyl rest by providing to this latter a temporary protection while performing the second protection stage (i.e. the protection of the phenolic hydroxy groups) under more drastic conditions. This approach permits to obtain a product to be submitted (after the removal of the intermediate protection of the hydroxymethyl group) to the successive oxidation, which shows a higher and more selective protection degree at the phenolic hydroxy groups than the one resulting from step (bi). A practical procedure to provide a temporary protection of the hydroxy group of the hydroxymethyl moiety consists, for instance, in the formation of an oxazolidine intermediate involving both the hydroxy group of the hydroxymethyl moiety and 10 the vicinal primary amino group (which has been previously protected, e.g. by means of a (lower alkoxy)carbony1 or phenyl-(lower alkoxy)carbony1 group). According to this preferred procedure, the primary 15 amino groups of the substrate (V) are protected, for instance, by a (lower alkoxy)carbonyl or a phenyl- (lower alkoxy)carbonyl radical, most preferably, a tert-butoxycarbonyl or benzyloxycarbonyl radical. The 20 reaction conditions and the procedures for recovery and purification of the resulting products are essentially the same as those described for carrying out the protection of the amino groups in step (bi). If necessary, a further purification can be performed by m.- applying reverse-phase chromatography as described for the purification of the compounds of formula (IV) under the description of step (bi) above. The formation of the oxazolidine protecting group is usually carried out by contacting the above _. mentioned substrate of formula (V) , protected on the amino groups, with an acetal or ketal, preferably a ketal from a C3-C6 aliphatic or C 5 -C 7 alicyclic ketone and a lower alkanol, e.g. 2,2-dimethoxypropane or 1,1-dimethoxycyclohexane. The reaction is carried out 5 in anhydrous conditions in the presence of an inert solvent, e.g. acetone, tetrahydrofuran, dioxane and LX3 the like and a catalytic amount of a strong acid, e.g. hydrogen chloride, concentrated sulfuric acid, p.toluenesulfonic acid, trifluoromethanesulfonic acid. The resulting reaction mixture, after neutralization, e.g. with sodium bicarbonate, is elaborated to yield the oxazolidine derivative wherein the oxazolidine ring incorporates both the primary hydroxy function and the protected (tert-butoxycarbonyl or benzyloxycarbonyl) amino group. This intermediate oxazolidine product is then submitted to the further reactions for selectively protecting the phenolic hydroxy groups (and any other oxidation sensitive moiety, if necessary). The protecting groups and the suitable reagents for their introduction into the above mentioned substrate are essentially the same as those described for the protection of the phenolic hydroxy groups in step (bi) above. Accordingly, the formation of lower alkyl, benzyl or benzoylmethyl ethers, optionally substituted as indicated above in the lower alkyl or phenyl portion and the formation of lower alkanol, benzoyl, lower alkoxycarbonyl and benzyloxycarbonyl esters are the preferred methods for providing the desired protection. The appropriate reactants and reaction conditions are essentially the same as those described for the protection of the phenolic hydroxy rests under step (bi) above. Moreover, in this case a larger excess of the reagent(s) providing the protective groups may be employed and/or a wider temperature interval which may extend from 0 to 50°C and/or a larger reaction time can be applied for obtaining a higher protection degree. After completion of this stage, the temporary protection of the primary hydroxy group of the hydroxymethyl moiety is selectively removed to allow its conversion to carboxyacid group by oxidation. S-4 The removal of the oxazolidine protecting moiety may be carried out by acid hydrolysis at a temperature between 0 and 35°C in an organic water miscible solvent such as, for instance, a lower alkanol, acetonitrile, tetrahydrofuran, dioxane and the like. The acid employed is preferably a diluted strong mineral acid, e.g. hydrochloric acid, hydrobromic acid and sulfuric acid. The above acidolytic conditions must be sufficiently mild to avoid the removal of the ln other protective groups previously introduced. The product obtained is recovered by common procedures and then utilized in the next oxidation reaction without any further purification. The oxidation of the substrate (V) selectively protected at the primary amino groups and the phenolic hydroxy groups (and, 15 when needed, at other oxidation sensitive groups, apart from the primary hydroxy group of the hydroxymethyl rest), is carried out according to the same method described under step (bi) above with 20 potassium permanganate at basic or neutral pH or, preferably, with the Jones reagent. It has been observed that with potassium permanganate, when the protection of the phenolic hydroxy rests is effected by formation of benzoyl- __ methyl ethers, these protecting groups are, at least partially, oxidized and removed during the oxidation reaction. This problem may be kept under control by monitoring, e.g. by HPLC, the reaction mixture. By using potassium permanganate at a pH value higher than 9, in the case of the presence of a lower alkyl ester group on the carboxyacid function, a possible hydrolysis of said ester function may take place, thus re-generating the original fee carboxyacid group. In this case, it is more suitable to use the __ Jones reagent. When using the Jones reagent the oxidized product obtained corresponds to compound of formula (I) wherein both the primary amino groups and the phenolic hydroxy groups (and any other oxidation sensitive group which may have required protection) are still bearing their respective protecting groups. This product may be recovered and purified according to procedures per se known in the art, for instance, by reverse-phase column chromatography as described for the substrate (IV) under step (bi) above or may be submitted to the deprotection stage without any further purification. The optional deprotection of the amino and phenolic hydroxy groups may be carried out in different stages, or simultaneously, depending on the type of protecting groups utilized and the degree of protection which is desired to be maintained in the final product (I). For instance, for the use of the compound (I) as precursor for the synthesis of new aglucodalbaheptides, it may be convenient to have the carboxylic function represented by the symbol Y in a protected form, e.g. as a carboxy ester. In such cases, when this group has been previously protected as an ester, it is necessary to carry out the deprotection of both the amino and the phenolic hydroxy groups under conditions which do not modify such ester function. In general, when the protection of the primary amino groups and of the phenolic hydroxy groups of the substrate (V) has been carried out in two stages, also the deprotection of these groups from the oxidized substrate (I) is carried out in two stages. For instance, the removal of the benzyloxycarbonyl groups from the phenolic hydroxy groups (and from any other group which has been protected in the same way) may be carried out by hydrogenolysis, e.g. by catalytic hydrogenation under the same conditions s-i described under step (ci) above, while the removal of the lower alkoxycarbonyl groups from the primary amino groups (and from any other group which has been protected in the same way) can be carried out by acid hydrolysis or solvolysis (e.g. in trifluoroacetic acid as described under step (ci) above). When this stage is performed as the last stage of the process, it may be useful to recover the obtained product of formula (I) , wherein both the amino and the phenolic hydroxy groups are deprotected, as an acid addition salt with the same acid utilized for the hydrolysis or solvolysis (e.g. with trifluoroacetic acid). This product may be purified or converted into the corresponding free base or into another acid addition salt by the same procedures mentioned under step (ci) above. Also in this case, the tetrapeptide of formula (I) wherein Ri represents hydrogen may be optionally transformed into the corresponding functional derivative wherein Ri represents a protecting group by procedures per se known in the art. In the same way, when a product of formula (I) is obtained wherein R and Ro each independently represent a free amino group, it may be transformed into the corresponding product of formula (I) wherein R and Ro each independently represents a protected amino group by common procedures. Ct EXAMPLES The analytical methods and procedures utilized for the characterization of the compounds prepared according to the following examples are described in a separate paragraph following the examples section. Example 1: Preparation of the pentapeptide derivative from reductive cleavage of deglucoteicoplanin (step (a)) Method A: A suspension of 19 g (about 10 mmol) of teicoplanin A 2 complex in 600 ml of a mixture H 2 0/ethanol 65/35 is stirred at 10-15°C for 90 min, while adding portionwise 40 g of NaBH 4 pellets. A clear solution forms which is stirred at room temperature for 5 hours then it is diluted with 1 liter of MeOH and 0.5 1 of EtOH and slowly poured into a solution of 100 ml of acetic acid in 0.5 1 of MeOH. The solvents are evaporated at 35°C under reduced pressure and the jelly residue is redissolved in 1 liter of H 2 0. The resulting solution is loaded at the top of a column of 200 g of silanized silica-gel in H 2 0. After eluting with 2 1 of H 2 0, the column is developed with a linear step gradient from 10% to 80% of CH3CN in 0.01N acetic acid, in 15 hours at the flow rate of 400 ml/h while collecting 25 ml fractions. The fractions containing pure product are pooled and the solvents are evaporated, at 40°C under reduced pressure, in the presence of butanol to avoid foaming. The solid residue is collected, washed with 200 ml of diethyl ether and dried at room temperature in vacuo for 3 days to give 16 g (about 80% yield) of the pentapeptide of the reductive cleavage of teicoplanin A 2 complex. r This product is suspended in 850 ml of 2,2,2-trifluoroethanol and dry HC1 is bubbled at 70°C into the suspension while stirring for 16 hours. The insoluble product is then collected and dissolved in a sufficient amount of H 2 0/ethanol 65/35 which is loaded at the top of a column of 200 g of silanized silica-gel in H 2 0. The column is eluted with 2 1 of H 2 0 and then developed with a linear step gradient from 10% to 80% of CH 3 CN in H 2 0 in 15 hours at the flow rate of 400 ml/h while collecting 25 ml fractions. The fractions containing pure products are pooled and the solvents are evaporated at 40°C under reduced pressure. The solid residue is collected and dried in vacuo to give 3.5 g of the compound of the title in a total yield of 25% from teicoplanin A 2 complex (HPLC, method a : tn 11.6 minutes) Method B: A suspension of 13 g (about 10 mmol) of deglucoteicoplanin in a mixture H 2 0:ethanol 65:35 (600 ml) is stirred at 10-15°C for 90 min, while addding portionwise 100 g of NaBH 4 pellets. The solution which forms is stirred for 16 hours and then handled as in the first part of Method A above. In this case, 200 ml of acetic acid is employed to destroy the NaBH excess. After chromatography on silanized silica gel the eluted fractions containing pure product are pooled and evaporated to give 3.7 g of the compound of the title in a 27% yield from deglucoteicoplanin. Example 2: Protection of the amino functions of the compound of Example 1 with the tert-butoxycarbonyl group (step (bj.)) To a stirred solution of 24 g (about 20 mmol) of the pentapeptide derivative of Example 1 in 400 ml of s-3 a mixture dioxane-water 1:1 (v/v), 20 ml of a 1M aqueous solution of sodium bicarbonate is added followed by a solution of 9 g (about 40 mmol) of di-tert-butyl-dicarbonate in 100 ml of a mixture dioxane-water 1:1 (v/v). The reaction mixture is stirred at room temperature for 5 hours, then, it is diluted with 250 ml of water. The resulting solution is adjusted at pH 4 with IN HC1 and extracted with ethyl acetate (2 x 200 ml). The organic layer is separated, washed with water (2 x 100 ml), dried over sodium sulfate, then it is concentrated at room temperature under reduced pressure to a small volume (about 50 ml). On adding 450 ml of diethyl ether, a solid separates which is collected by filtration to yield 27 g (about 95%) of the title compound. (HPLC, method b: t R = 11.3 minutes) Example 2(a): Protection of the carboxyacid group of the compound of Example 2 (step (bi)) To a stirred solution of 30 g (about 22 mmol) of the compound of Example 2 in 220 ml of dimethylformamide, 2.5 g (about 23 mmol) of potassium bicarbonate is added, followed by a solution of 22 ml (about 23 mmol) of methyl iodide in 30 ml of dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture is poured into 1 1 of water. The resulting cloudy solution is adjusted at pH 3 with IN HC1 and extracted with 1 1 of a ethyl acetate:1-butanol 1:1 (v/v) mixture. The organic layer is separated, washed several times with water until the aqueous washings possess neutral pH, then it is concentrated at 40°C under reduced pressure to a small volume. On adding a large excess of diethyl ether a solid precipitate is obtained which is collected and dried m vacuo at room temperature overnight yielding bo 30 g of pure title compound (HPLC, method b: t R = 16.1 minutes). Example 3: Protection of the phenolic hydroxy groups of the compound of Example 2 with benzyloxycarbonyl groups (step (bi)) To a stirred solution of 5.6 g (about 4 mmol) of the compound of Example 2 in 200 ml of an anhydrous mixture dimethylsulfoxide:tetrahydrofuran 4:1 (v/v), 11 g (about 80 mmol) of potassium carbonate and 11 ml (about 80 mmol) of triethylamine are added at room temperature. The resulting suspension is stirred at room temperature for 1 hour, then it is cooled to 15°C and a solution of 7.5 ml (about 53 mmol) of benzyl chloroformate in 20 ml of dry tetrahydrofuran is added dropwise in 30 minutes. After stirring at room temperature overnight, the reaction mixture is poured into 1.8 1 of a stirred mixture water:ethyl acetate:acetic acid (glacial) 49:49:2 (v/v/v). The organic layer is separated, dried over sodium sulfate, then the solvent is evaporated at room temperature under reduced pressure to give an oily residue which solidifies by slurring with diethyl ether. The solid thus obtained is collected to give 6.6 g of a mixture of at least five products (HPLC), corresponding to the title compound with different degrees of protection at the phenolic hydroxy groups. This product is suitable for the next oxidation step. (HPLC, method c: t R = 15.9, 19.0, 26.2, 29.8, 32.3 minutes) Example 3(a): Protection of the phenolic hydroxy groups of the compound of Example 2(a) with benzyloxycarbonyl groups (step (bi)) To a stirred solution of 30 g (about 21 mmol) of the compound of Example 2(a) in 900 ml of a dioxane:water 1:1 (v/v) mixture, 21 g (about 65 mmol) of cesium carbonate is added. After stirring at room temperature for 30 minutes, a solution of 18 ml (about 130 mmol) of benzyl chloroformate in 50 ml of dioxane is added dropwise, then the reaction mixture is stirred at room temperature for additional 18 hours. Afterwards, the reaction mixture is poured into 1.5 1 of a stirred mixture ethyl acetate:water 1:1 (v/v) acidified at pH 3 with IN HC1 and the organic layer is separated and worked up as described above in Example 3, yielding 36 g of the title compound as a mixture of products with different degrees of protection at the phenolic hydroxy groups, as above described in Example 3. (HPLC, method c: t R = 25.5, 28.8, 29.2, 30.3, 32.5 minutes) Example 4: Oxidation of the compound of Example 3 to the corresponding acid (step (bi)) The Jones reagent, "standard solution", is prepared according to the procedure described in Fieser & Fieser "Reagents for Organic Synthesis", Vol. 1: pag.142, John Wiley & Sons, Inc., New York (1967). To a stirred solution of 6 g of the product of Example 3 in 90 ml of tetrahydrofuran, 21 ml of a "standard solution" of Jones reagent is added dropwise, in 1.5 hours, while maintaining the temperature between 20°C and 25°C. After 30 minutes, the reaction mixture is poured into 800 ml of a mixture water:ethyl acetate 1:1 (v/v), under vigorous stirring. The organic layer is separated, washed several times with a IN aqueous solution of sodium metabisulfite until peroxides are completely decomposed, afterwards it is dried over sodium sulfate 5 and concentrated to a final volume of about 50 ml. On adding 450 ml of diethyl ether, a solid separates which is collected by filtration to yield 5.7 g of the title compound as a mixture of at least three main reaction products (HPLC). The crude reaction mixture 10 (containing also about 30% of unreacted material, probably protected at the primary hydroxymethyl group as well) is submitted to the catalytical hydrogenation step without any further purification. (HPLC, method c: t R = 18.0, 21.5, 24.7 minutes) 15 Example 4(a): Oxidation of the compound of Example 3(a) to the corresponding acid (step (bj.)). By following the same procedure as that described 20 in Example 4, starting from 36 g of the compound of Example 3(a), 34.3 g of the title compound are obtained. (HPLC, method c: t R = 19.7, 22.3, 25.8 minutes). 25 Example 5: Removal of the benzyloxycarbonyl protecting groups from the compound of Example 4 (step (bi)) A solution of 5 g of the above crude product in 200 ml of a mixture methanol:dimethylformamide:acetic 30 acid (glacial) 5:2:2 (v/v/v) is hydrogenated (1 atm, 25°C) in the presence of 2.5 g of 5% Pd/C. About 300 ml of hydrogen is absorbed within 2 hours, afterwards the catalyst is filtered off. Methanol is evaporated -._ at room temperature under reduced pressure and the remaining solution is poured into 500 ml of water. The resulting cloudy solution is extracted with 500 ml of n-butanol. The organic layer is separated, washed with 500 ml of water, then it is concentrated at 45°C under reduced pressure to a final volume of about 30 ml. On adding 200 ml of diethyl ether a solid separates which is collected by filtration, washed with 100 ml of diethyl ether, and then dried at room temperature in vacuo overnight to give 3.2 g of a crude product containing (HPLC) about 60% of the title compound which is still protected by tert.butoxycarbonyl groups on the amino functions. (HPLC, method b: t R = 6.0 minutes) Example 5(a): Removal of the benzyloxycarbonyl protecting groups from the compound of Example 4(a) (step bi)) By exactly following the same hydrogenolysis procedure as that described in Example 5, from 34.3 g of the compound of Example 4(a), 24.5 g of crude title compound (HPLC, about 55%) are obtained. Example 6: Removal of the tert-butoxycarbonyl protecting groups from the compound of Example 5 (step (bi)) The crude product of Example 5 (3.2 g) is dissolved in 50 ml of trifluoroacetic acid. The resulting solution is stirred at room temperature for 1.5 hours, then the solvent is evaporated at room temperature under reduced pressure. The oily residue is slurried with diethyl ether yielding a solid which is collected and washed with diethyl ether (50 ml). This procedure yields 2.7 g of crude product containing about 40% (HPLC) of the title compound which is purified by reverse-phase column chromatography as described hereinafter. The above crude product is dissolved in 50 ml of a mixture acetonitrile:water 1:1 (v/v) and the resulting solution is adjusted at pH 3.5 with IN sodium hydroxyde, then it is diluted with 250 ml of water and loaded on a column of 250 g of silanized silica-gel (0.06-0.2 mm, Merck) in water. The column is developed with a linear gradient from 15% to 50% (v/v) of acetonitrile in water in 20 hours at a flow- rate of about 100 ml/hour, while collecting 10 ml fractions. Those fractions containing (HPLC) pure title compound are pooled, and the solvent is evaporated (in the presence of enough n-butanol to avoid foaming) at 40°C under reduced pressure, yielding 400 mg (about 25%) of pure title compound. (HPLC, method a: t = 9.0 minutes). Example 6(a): Removal of the tert-butoxycarbonyl protecting groups from the compound of Example 5(a) (step (bi)) The crude product of example 5(a) (24.5 g) is dissolved in 300 ml of trifluoroacetic acid. The resulting solution is stirred at room temperature for 30 minutes, then the solvent is evaporated at room temperature under reduced pressure. The oily residue is slurried with diethyl ether, yielding a solid which is collected and washed with diethyl ether (200 ml). This procedure yields 21 g of crude (HPLC, about 55%) title compound which is then purified by reversed- phase column chromatography on silanized silica-gel according to the same procedure as that described in Example 6, thus giving 9.7 g (about 60%) of pure title compound. (HPLC, method a: t = 11.3 minutes) Example 7: Edman degradation of the product of Example 6 (step (ci); formula (Ic): R=Ro=amino, To a stirred solution of 1 g (0.82 mmol) of the product of Example 6 in 20 ml of a mixture pyridine:water 1:1 (v/v), a solution of 145 mg (1.98 mmol) of methylisothiocyanate in 2.5 ml of the same solvent mixture is added dropwise at room temperature. T e reaction mixture is stirred at room temperature for 16 hours, then it is poured into 50 ml of water. The cloudy aqueous solution is extracted with 100 ml of diethyl ether (the organic layer is discarded), then it is adjusted at pH 3 with IN hydrochloric acid and extracted with 100 ml of n-butanol. The organic layer is washed with water (4 x 100 ml) and then it is concentrated at 40°C under reduced pressure to a small volume. On adding 200 ml of diethyl ether, a solid separates which is collected by filtration (1.1 g) and re-dissolved in 25 ml of trifluoroacetic acid. The resulting solution is stirred at 50°C for 10 minutes, afterwards the solvent is evaporated. The oily residue is slurried with 50 ml of diethyl ether giving a solid which is collected by filtration, washed with 50 ml of diethyl ether and dried at room temperature in vacuo overnight. Yield 0.96 g of crude (about 60%, HPLC titre) title compound. This product is purified by reverse-phase column chromatography as above described for the final purification of the compound of example 6, yielding 240 mg of pure title compound, as the di-trifluoroacetate. The internal salt (140 mg) can be obtained by dissolving 200 mg of the di-trifluoroacetate in 5 ml of water, adjusting the solution at pH 6.5 with IN NaOH and filtering the solid which separates. u (HPLC, method a: t R = 6.8 minutes) Example 7(a): Edman degradation of the product of Example 6(a) (step (ci)); formula (Ic): R=Ro=amino, Rι=R 2 =R 5 =hydrogen, R 3 =R 4 =chloro, R 6 =hydroxy, Y=carbomethoxy) A solution of 6.5 g (about 5 mmol) of the product of Example 6(a) and 1.25 ml (about 10 mmol) of phenylisothiocyanate in 100 ml of a pyridine:water 1:1 (v/v) mixture is stirred at room temperature for 3 hours. Afterwards, the reaction mixture is poured into 200 ml of water and the resulting cloudy solution is adjusted to pH 3 with IN HC1, then is is extracted with ethyl acetate (2 x 200 ml). The organic layer is discarded and the aqueous phase is extracted again with 200 ml of 1-butanol. The organic layer is separated, washed with water (2 x 200 ml), then it is concentrated at 40°C under reduced pressure, to a small volume (about 30 ml). On adding diethyl ether (about 100 ml) a solid precipitate is obtained which is collected, washed with diethyl ether and dried at room temperature in vacuo overnight, yielding 6.7 g of the intermediate diphenylisothiourea which is used without any further purification in the successive step. The above product is dissolved in 150 ml of dry trifluoroacetic acid and the resulting solution is stirred at 50°C for 10 minutes, afterwards the solvent is evaporated. The oily residue is purified by reversed-phase column chromatography as above described for the final purification of the compound of Example 6a, yielding 1.35 g of pure title compound, as the di-trifluoroacetate (HPLC, method a: t R = 10.3 minutes) Example 8: Edman degradation of the compound of Example 1 (step (b 2 ) ) To a stirred solution of 13 g (10.83 mmol) of the compound of Example 1 in 260 ml of a mixture pyridine:water 1:1 (v/v), a solution of 1.9 g of methylisothiocyanate in 40 ml of the same solvent mixture is added dropwise at room temperature. The reaction mixture is stirred at room temperature for 22 hours. Afterwards, it is concentrated at 35°C under reduced pressure to dryness. The oily residue is re- dissolved in 300 ml of toluene and the solvent is evaporated, yielding a solid (18 g) which is slurried with diethyl ether and suspended in 400 ml of water. The resulting suspension is adjusted at pH 3 with IN HC1 and extracted with n-butanol (2 x 200 ml). The organic layer is washed with water (400 ml) and then it is concentrated at 40°C under reduced pressure to a final volume of about 50 ml. On adding 450 ml of diethyl ether, a solid separates which is collected by filtration and washed with 150 ml of water, then with 500 ml of diethyl ether. Yield 13.2 g (about 95%; HPLC titre) of bis-(methylthiocarbamyl) intermediate. (HPLC, method a: t = 15.1 minutes) This product is dissolved in 100 ml of trifluoroacetic acid. The resulting solution is stirred at 50°C for 10 minutes (in the meantime a red solution forms), and then the solvent is evaporated at room temperature under reduced pressure. The oily residue is slurried with diethyl ether (350 ml) and the solid which forms is collected by filtration, washed with 250 ml of diethyl ether and then dried at room temperature in vacuo overnight, obtaining 12 g of crude (74%; HPLC titre) title compound which is used without any further purification for the next step. An analytical pure sample (250 mg) is prepared by reverse-phase column chromatography under the same conditions as those previously described in Example 6. (HPLC, method a: t = 11.3 minutes) Example 9: Protection of the amino functions of the compound of Example 8 with tert-butoxycarbonyl groups (step (c 2 )) To a stirred solution of 11.5 g of the crude product of Example 8 in 250 ml of a mixture water:dioxane 1:1 (v/v), 12 g of sodium bicarbonate is added. Then, the resulting suspension is cooled to 0°C and a solution of 6 g of di-tert-butyl-dicarbonate in 50 ml of dioxane is added dropwise while cooling at 0-5°C. The reaction mixture is stirred at room temperature for 5 hours; afterwards it is adjusted at pH 4 with IN HC1 and extracted with 250 ml of ethyl acetate. The organic layer is separated, washed with water (2 x 200 ml) and then it is dried over sodium sulfate. After concentration at 30°C under reduced pressure to a small volume (about 30 ml), diethyl ether (300 ml) is added and the precipitated solid is collected to give 8.6 g of crude (85%; HPLC titre) title compound which is purified by reverse-phase chromatography under the same conditions as those described in Example 6, but eluting with a linear gradient from 20% to 70% of acetonitrile in water, to yield 6.7 g of pure title compound. (HPLC, method b: t R = 12.2 minutes) Example 10; Protection of the phenolic hydroxy groups of the compound of Example 9 with carbobenzyloxy groups (step (c 2 )) (- 3 To a stirred suspension of 6 g (5.5 mmol) of the compound of Example 9 in 500 ml of anhydrous acetone, 120 ml of 2,2-dimethoxypropane and 0.27 g (1.4 mmol) of p-toluenesulfonic acid are added. After stirring for 90 minutes, a solution of 0.24 g of sodium bicarbonate in 4 ml of water is added. The resulting solution (pH 6.3) is concentrated at 35°C under reduced pressure to dryness and the solid residue is collected, obtaining 6.4 g of the oxazolidino intermediate which is then carbobenzoxylated on the phenolic hydroxy groups according to the alternative methods A and B described herein below. (HPLC, method b: t R = 17.9 minutes) Method A: To a stirred solution of 0.39 g (0.34 mmol) of the above oxazolidine intermediate in 12 ml of dry dimethylsulfoxide, 0.57 g (4.13 mmol) of potassium carbonate is added. After 30 minutes, 0.58 ml (4.13 mmol) of triethylamine and a solution of 0.48 ml (3.4 mmol) of benzylchloroformate in 2 ml of tetrahydrofuran are added while cooling to 15°C. After stirring at room temperature for 24 hours, an additional amount of 0.57 g of potassium carbonate followed by 0.48 ml of benzylchloroformate are added at 15°C. After 30 minutes at room temperature under vigorous stirring, the reaction mixture is poured in a solution of 5 ml of glacial acetic acid in 95 ml of water. The resulting solution is extracted with ethyl acetate (2 x 200 ml). The organic layer is separated, washed with water (2x 150 ml), and then dried over sodium sulfate. The solvent is evaporated at 40°C under reduced pressure and the oily residue is slurried successively with petroleum ether and diethyl ether to give 0.42 g of a mixture of at least three main components (HPLC), corresponding to the title compound with different degrees of protection at the phenolic groups. This product, without any further purification, is suitable for the successive reaction step. (HPLC, method c: t R = 19.1, 30.6, 33.4 minutes) Method B: To a stirred solution of 2.1 g (1.86 mmol) of the above oxazolidine intermediate in 70 ml of dry dimethylsulfoxide, 3.63 g (11.2 mmol) of cesium carbonate is added. After stirring at room temperature for 90 minutes, 2.8 ml (20 mmol) of benzyl chloroformate is added dropwise at 20-25°C. The reaction mixture is stirred at room temperature for 5 minutes and then it is poured into a solution of 5 ml of glacial acetic acid in 250 ml of water. The resulting solution is worked up as described above under Method A, yielding 3 g of a mixture of two main products (HPLC) corresponding to the two more lipophilic components of the mixture obtained by Method A. This product is more suitable for the successive reaction step. (HPLC, method c: t R = 30.6 (15%), 33.4 (85%) minutes) To a stirred suspension of the product (3 g) obtained according to Method B above in 150 ml of acetonitrile, 15 ml of IN hydrochloric acid is added and the resulting solution is stirred at room temperature for 90 minutes. Afterwards, a stirred mixture of 350 ml of water and 500 ml of ethyl acetate is added. The organic layer is separated and washed with a 1M solution of sodium bicarbonate in water until the pH of the aqueous washings is neutral. After an additional washing with 300 ml of water, the organic layer is dried over sodium sulfate and concentrated to a small volume (about 30 ml) at room temperature under reduced pressure . On adding diethyl ether (270 ml), a solid separates which is collected by filtration, washed with diethyl ether (100 ml), and then dried at room temperature in vacuo to yield 2.45 g of the title compound as a mixture showing a components ratio (HPLC) corresponding to the one of the respective oxazolidine precursor (but with relative retention times about 6 minutes lower). This product is used without any further purification for the successive oxidation reaction. (HPLC, method c: t R = 23.7, 27.1 minutes) Example 11: Oxidation of the hydroxymethyl group of the product of the Example 10 to carboxy (step (c2); formula (Ic)): R=Ro=tert-butoxycarbonylamino, Rι=R 2 =R 5 =hydrogen, R3=R 4 =chloro, Rβ=hydroxy, Y=carboxy, wherein the phenolic hydroxy groups are protected by carbobenzyloxy rests) The above product (2.45 g) is oxidized with the Jones reagent under the same conditions as those described in Example 4 obtaining 2.3 g of the title compound as a mixture of two main components in a ratio 85:15 (HPLC). (HPLC, method c: t R = 14.5 (15%), 18.7 (85%) minutes) Example 12: Removal of the carbobenzyloxy protecting groups from the compound of Example 11 (step (c 2 )); formula (Ic): R=Ro=tert-butoxycarbonylamino, Rι=R 2 =R5=hydrogen, R3=R 4 =chloro, Y=carboxy) . The product of Example 11 (2.3 g) is hydrogenated under the same conditions as those described in Example 5 obtaining 1.3 g of the title compound. (HPLC, method b: t = 7.9 minutes) Example 13: Removal of the tert-butoxycarbonyl protecting groups from the compound of Example 12 (step (c 2 )); formula (Ic): R=Ro=amino, Rι=R 2 =R5=hydrogen, R3=R 4 =chloro, Y=carboxy) . A solution of the above product (1.3 g) in 30 ml of trifluoroacetic acid is stirred at room temperature for 2 hours, then the solvent is evaporated at 30°C under reduced pressure. The oily residue is slurried with diethyl ether (100 ml) and the solid which forms is collected by filtration. Purification by reverse-phase chromatography under the same conditions of Example 6 yields 1.05 g of pure title compound, as the di-trifluoroacetate. (HPLC, method a: t R - 6.8 minutes) Analytical procedures 1) HPLC Methods Reactions, column eluates and final products are checked by HPLC analyses, which are performed on a column Hibar (250 x 4 mm, Merck) pre-packed with Li-Chrbsorb RP-8 (10 urn), using a Varian Model 5500 Liquid Chromatographic pump equipped with a 20 μl loop injector Rheodyne Model 7125 UV variable detector. Chroma ograms are recorded at 254 nm. Elutions are ?3 carried out at a flow-rate of 2 ml/minute by mixing Eluent A, 0.2% aqueous ammonium formate, with Eluent B, acetonitrile, according to linear step gradients programmed as follows: Method a. Time (minutes): 0 10 20 30 35 45 % of B in A: 5 23 26 35 75 5 Method b. Time (minutes): 0 30 35 40 45 % of B in A: 20 60 75 75 20 Method c. Time (minutes): 0 30 35 40 45 % of B in A: 40 75 85 85 40 2) Acid-base titrations Acid-base titrations are carried out under the following conditions: the sample is dissolved in a mixture methyl cellosolve:H 2 0 4:1, then an excess of 0.01M HC1 in the same solvent mixture is added and the resulting solution is titrated with 0.01N NaOH. Table I shows the equivalent weight of some end compounds and intermediates 3) 1H-NMR The -E NMR spectra are recorded with a 24 mg solution of the proper product in 0.5 ml of DMSO-dβ at 303°K on a Bruker AM 500 NMR-spectrometer equipped with an Aspect 3000 computer, using (CH 3 ) 4 Si (δ O.OOppm) as internal reference. In particular, in Table II are reported only the significative δ values concerning the characterizing portions of some end compounds and intermediates. For 1C spectra the spectrometer frequency was 125.17MHz. The newly introduced carbonyl functions were determined in a iH-detected heteronuclear multiple-bond correlation spectroscopy (M. Bax and D. Marier, J. Magn. Reson. 78, 186, 1988). 4) FAB-MS FAB-MS positive ion spectra are obtained on a Rratos MS-50 double focusing mass spectrometer of 3000 dalton mass range, using 8 kV accelerating voltage. The instrument is operating under computer control. To obtain high quality data, a DS-90 data system in "raw data" acquisition is used. For FAB, a saddle field atom gun is used with Xe gas (2 x 10-5 torr pressure indicated on the source ion gauge) at 6kV voltage and 1 mA current. The samples are dissolved in a mixture methanol:H201:1 containing 0.2N HC1 or, alternatively, in dimethylformamide (DMF). Then, 1 microliter of this solution is mixed with 1 microliter of thioglycerol matrix eventually containing a IN acetic acid on the target. Table I shows the molecular weight of some end compounds and intermediates. 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Claims: 9 i CLAIMS 1. A tetrapeptide of the general formula (I) wherein: W and Z represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group (aglucodalbaheptides) ; Y represents a carboxyacid group or a functional derivative of said carboxyacid group; R and Ro each independently represent amino or a protected amino group; Ri represents hydrogen or a protecting group of the carboxyacid function; and its salts with acid and bases as well as its inner salts. 2. A tetrapeptide of claim 1 which is represented by the following general formula (la) Θ3 wherein: R and Ro each independently represent amino or a protected amino group; Ri is hydrogen or a protecting group of the carboxyacid function; A represents hydrogen or a protecting group of the phenolic hydroxy rest; R 2f R3 and R 4 each independently represent hydrogen or halogen wherein the halogen preferably is chloro or bromo and are most preferably in the ortho position with respect to the ether bond; R5 and Re, each independently, represent hydrogen, or a group OR7 wherein R7 is hydrogen or a protecting group of the benzylic hydroxy rest; the groups ORβ and OR9, preferably, are respectively in the para and ortho position with respect to the bond connecting the two phenyl rings and the radicals Rg and R9 each independently represents hydrogen or a protecting group of the phenolic hydroxy rest; the group OR 10 is, preferably, in the position ortho with respect to the bond connecting the two phenyl rings and the radical Rio represents hydrogen or a protecting group of the phenolic hydroxy rest; the group Rn is, preferably, in the position meta with respect to the bond connecting the two phenyl rings and represents hydrogen or halogen, most preferably, hydrogen or chloro; Y represents a carboxyacid group or a functional derivative thereof; and its salts with acid and bases as well as its inner salts. 3. A tetrapeptide of claim 1 characterized in that it derives from an aglucodalbaheptide of the aglucoristocetin sub-group. ΘH 4. A tetrapeptide of claim 2 which is represented by the following general formula (lb) (lb) wherein: R, Ro, and Ri have the same meaning as in claim 2; Y represents a carboxyacid group, carbomethoxy or another protected carboxyacid group; the phenolic hydroxy groups may optionally be protected; and its salts with acid bases as well as its inner salts. 5. A tetrapeptide of claim 1 characterized in that it derives from aglucoteicoplanin or its semisynthetic derivatives. L?Γ 6. A tetrapepetide of claim 2 which is represented by the following general formula (Ic) (Ic) wherein: R, Ro and Ri have the same meaning as in claim 2; R 2 is hydrogen; R3 is hydrogen or chloro; R 4 is hydrogen or chloro; R5 is hydrogen; Re is hydrogen or hydroxy; Y represents a carboxyacid group or a functional derivative thereof, preferably a carboxyester, a carboxamide or a substituted carboxamide; the phenolic hydroxy groups may optionally be protected; and its salts with acids and bases as well as its inner salts. 7. A tetrapeptide of claim 6 wherein the carboxyester is a lower alkyl ester wherein the lower alkyl moiety may optionally contain a further substituent selected from hydroxy, halo, lower alkoxy, amino, lower 10 alkylamino, di-(lower alkyl)amino, cyano and phenyl optionally substituted by lower alkyl, lower alkoxy, halo, or nitro. 8. A tetrapeptide of claim 6 wherein the substituted , 5 carboxamide is an amide with a lower alkylamine wherein the lower alkyl moiety may be optionally contain a substituent selected from amino, lower alkylamino, di-(lower alkyl)amino, pyrrolidino, piperazino, morpholino, hydroxy, lower alkoxy, 0 carboxy, carbo(lower alkoxy), N-(lower alkyl)- piperazino, carbamyl, mono and di-(lower alkyl)- carbamyl, or an amide with a di-(lower alkyl)amine or an amide with a saturated 5-7 membered heterocyclic ring, preferably, pyrrolidine, morpholine, peperazine 5 , and N-(lower alkyl)piperazine. 9. A tetrapeptide of claim 1 characterized in that it derives from an aglucodalbaheptide of the aglucovancomycin sub-group. 0 10. A tetrapeptide of claim 2 which is represented by the following general formula (Id) 5 S (Id) wherein: R, Ro and Ri have the same meaning as in claim 2; Y represents a carboxyacid group or a protected carboxyacid group; the phenolic hydroxy groups may optionally be protected; and its salts with acids and bases as well as its inner salts. 11. A tetrapeptide of claim 1 characterized in that it derives from an aglucodalbaheptide of the aglucoavoparcin sub-group. 12. A tetrapeptide of claim 2 which is represented by the following general formula (Ie) g (ie) wherein: R, Ro and Ri have the same meaning as in claim 2; Y represents a carboxyacid group or a protected carboxyacid group; the phenolic hydroxy groups may optionally be protected; and its salts with acids and bases as well as its inner salts. 13. A tetrapeptide of claim 1 which is characterized in that it derives from an aglucodalbaheptide of the aglucosynmonicin sub-group. 14. A process for producing a tetrapeptide of the general formula (I): 93 i (I) wherein: W and Z represent the relative portions of the aglycon of an antibiotic of the dalbaheptide group (aglucodalbaheptides); Y represents a carboxyacid group or a functional derivative of said carboxyacid group; R and Ro each independently represent amino or a protected amino group; Ri represents hydrogen or a protecting group of the carboxyacid function; and its salts with acid and bases as well as its inner salts which comprises: i) selectively protecting the free amino groups and the phenolic hydroxy groups of a pentapeptide of the formula (HI) 9o wherein: Z, W, Xi and X 2 represent the relative portions of an aglycon of an antibiotic of the dalbaheptide group; T represent amino, alkylamino or a protected amino group from which the orignal amino group can be readily restored; Y represents a carboxyacid group or a functional derivative thereof; and its salts with acids and bases as well as its inner salts. ii) oxidizing the hydroxymethyl moiety of the selectively protected pentapeptide to carboxy yielding a compound of formula (IV) 9ι wherein Z, W, Xi, X 2 , T and Y have the same meanings as above iii) deprotecting the amino and, optionally, the phenolic hydroxy groups of the compound of formula (IV) iiii) submitting the above deprotected compound to a double Edman degradation and, optionally, protecting the free amino groups and the carboxyacid rests of the resulting compound. 15. A process as in claim 14 wherein the symbol Y of the compound of formula II represents a protected carboxyacid group, preferably, a carbomethoxy group. Sa- 16. A process for producing a tetrapeptide of formula (I) of claim 14 which comprises i) submitting a pentapeptide compound of formula (III) of claim 14 wherein Z, W, Xi, X2, T and Y have the same meanings as in claim 14 to a double Edαan degradation to yield a compound of formula (V) 33 wherein Z, W and Y have the same meanings as above; ii) selectively protecting the free amino groups and the phenolic hydroxy groups of the compounds of formula (V) iii) oxydizing the hydroxymethyl moiety of the selectively protected compound to carboxy and, optionally, deprotecting the amino and phenolic hydroxy groups of the resulting compound and. iiii) optionally, transforming the compound of formula (I) wherein Ri is hydrogen into the corresponding compound of formula (I) wherein Ri is a protecting group of the carboxyacid function. 17. A process as in claim 16 wherein the hydroxymethyl moiety is temporaneously protected prior to the protection of the phenolic hydroxy groups and said temporaneous protection is selectively removed prior to the oxidation of the primary hydroxy group of the hydroxymethyl moiety to carboxyacid group. 18. A process as in claim 17 wherein the temporary protection is affected by means of the formation of an oxazolidine intermediate involving both the hydroxy group of the hydroxymethyl moiety and the vicinal primary amino group.

Inventors: CIABATTI ROMEO, MALABARBA ADRIANO, CIABATTI, ROMEO, MALABARBA, ADRIANO
Applicants: LEPETIT SPA, GRUPPO LEPETIT S.P.A.
Application year: 1991
Main classification: C07K9
IPC codes: A61K38, A61P31, C07K1, C07K5, C07K9