DE3790635B4 - New sugar derivs. of biologically active peptide(s) - have prolonged duration of action, and are coupled by other than direct N-glycoside bond or direct amide bond - Google Patents

Abstract

New sugar deriv. (I) of a biologically active peptide, with prolonged duration of action when compared with the non-modified peptide, contains at least on one of the amino aicd units a sugar residue attached to an amino gp. by coupling other than a direct N-glycosidic bond, and additionally, when it is a condensation prod. of a carboxyl gp.-contg. sugar and a peptide with less than 8 amino acid units, by a coupling other than a direct amide bond. Also claimed are certain intermediates and the solid phase synthesis of octerotide or a peptide having 2 alcohol gps. or one alcohol gp. and one thiol gp.. A claimed deriv. is (N-desoxyfructosyl-Cys1)-oxytocin.

Description

The The present invention relates to a process for producing a Peptide alcohol and starting compounds therefor.

The present invention is useful in the preparation of a sugar derivative of a biologically active Peptides, which compared to the not one. Sugar. modified Peptide a longer one Has duration of action and that at least one of the amino acid units contains a sugar residue, which to an amino group thereof by a coupling which none corresponds to direct N-glycosidic bond, and in addition by a coupling is attached that does not correspond to a direct amide bond, if it is a Rondensationsprodukt of one, a carboxyl group containing sugar and a peptide having less than 8 amino acid units is.

in the These compounds are referred to below as sugar derivatives.

Under a non-sugar modified peptide becomes structurally corresponding peptide understood that no sugar residue or no Has sugar residues. Such a peptide will not be hereafter termed modified peptide.

It It was found that the sugar derivatives are particularly interesting and surprising show pharmacological properties, in particular a longer duration of action, what later is still received.

in this connection In particular, it was recognized that the mentioned Properties by incorporation of a sugar residue or sugar residues even when the bond is different than in a normal glycosylation of, for example, Asn or Ser.

Preferably these sugar residues are incorporated at amino groups of amino acids, which are removed from the active site of the peptide.

Of the term used herein Peptides include peptides (e.g. Dipeptides and tripeptides), oligopeptides, polypeptides and proteins. Preferably, the peptide consists of more than 7 amino acid units, conveniently the peptide is composed of 8 to 32 amino acid units. The term amino acid unit as used herein also includes a Aminoalcohol unit, for example a reduced amino acid.

Of the As used herein, biologically active peptides include, in particular Compounds having a pharmacological or therapeutic efficacy have, for example, compounds with hormonal, enzymatic or immunomodulatory activity, or such efficacy stimulate or inhibit. To these biologically active peptides belong natural Peptides made from natural or cells obtained by fermentation, for example produced by genetic engineering, or synthetic peptides, and also derivatives or analogues of such peptides.

Under Derivatives and analogs are understood in particular to be natural peptides, in which one or more amino acid units are missing and / or are replaced by one or more other amino acid residues and / or one or more functional groups through one or more others functional groups are replaced and / or one or more groups are replaced by one or more other isosteric groups. In general, all modified derivatives thereof become biologically includes active peptides that have a qualitatively similar Efficacy as the unmodified peptides have.

at The sugars used may be, for example, any known monosaccharide or oligosaccharide, in particular a Monoose, diox or triose or a derivative thereof, for example an amino acid derivative and / or carboxylic acid derivative and / or a reduced and / or esterified derivative thereof.

These Sugar can for example, to an N-terminal amino group and / or at least an amino group of the peptide bound in its side chain is available.

Of the Sugar can either directly with one of its functional groups or indirectly via a bridge, for example an alkylene carbonyl group.

These Binding can be prepared in a known manner, and on this particularly preferred methods will be discussed later.

at a preferred group of sugar derivatives is the sugar residue attached to an amino group of the peptide through a coupling, the corresponds to no direct N-glycosidic bond or direct amide bond.

A Group of sugar derivatives leaves by Amadori rearrangement or Heyns rearrangement produce.

Are useful also oral pharmaceutical preparations, containing a sugar derivative, in particular a compound with at least 8 amino acid units.

• a) der Formel I
  
  für den über die CH₂-Gruppe an die NH-Gruppe eines biologisch aktiven Peptids gebundenen Desoxyrest einer Ketose steht, P der Rest eines biologisch aktiven Peptids der Formel NH₂-P ist, worin sich die NH-Gruppe am N-terminalen Ende oder in einer Seitenkette des Peptids P befindet,
• b) der Formel II
  
  
  für den über die freie Bindung an der NH-Gruppe eines biologisch aktiven Peptids gebundenen Desoxyrest einer Aldose steht und P der Rest eines biologisch aktiven Peptids der Formel NH₂-P ist, worin sich die NH-Gruppe am N-terminalen Ende oder in einer Seitenkette des Peptids P befindet,
• c) der Formel III G₃-CO-NR_y-P IIIworin G₃CO der Rest einer Uronsäure, einer Polyhydroxymonocarbonsäure oder einer Polyhydroxydicarbonsäure ist, Ry für Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkanoyl mit 1 bis 4 Kohlenstoffatomen steht und P der Rest eines biologisch aktiven Peptids der Formel NH₂-P mit wenigstens 8 Aminosäureeinheiten ist und sich die Gruppe NR_y am N-terminalen Ende oder in einer Seitenkette des Peptids P befindet,
• d) der Formeln IVa, IVb, IVc oder IVd
  
  worin P für den Rest eines biologisch aktiven Peptides der Formel H₂N-P steht, die Reste der Formeln
  
  Zuckerreste sind, Ry Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkanoyl mit 1 bis 4 Kohlenstoffatomen ist und Q, Q', Q'' und Q''' für Gruppen stehen, die den Peetidrest mit dem Zuckerrest verbinden und sich die an P gebundene NH-Gruppe am N-terminalen Ende oder in einer Seitenkette des Peptids befindet, oder
• e) der Formeln Va oder Vb NON₂C-(CHOH)_c-CY-CH₂-NH-P Va
  
  worin Y für H₂ oder H, OH steht, c für 2 oder 3 oder 4 steht, und P ein Rest eines biologisch aktiven Peptids der Formel H₂N-P ist, wobei sich die an P gebundene NH-Gruppe am N-terminalen Ende oder in einer Seitenkette des Peptids P befindet und irgendeine der freien Hydroxylgruppen im Polyolrest der Verbindungen der Formel V gegebenenfalls glykosylisch an ein reduzierendes Monasaccharid, Disaccharid oder Oligosaccharid oder einen Aminozucker gebunden sind, und die Säureadditionssalze sowie Komplexe dieser Polypetidderivate, mit den Maßgaben dass
• a) bei den Verbindungen der obigen Formel I der Substituent P etwas anderes als ein Rest eines Gastrinpeptids mit einer C-terminalen Gruppe, die mit -Asp-phe-NH₂ endet, ist,
• b) der Rest P-NH₂ kein natürliches Insulin ist, falls bei den Verbindungen der Formel IVb die Gruppe Q' ein einen Phenylring enthaltender zweiwertiger Rest ist oder bei den Verbindungen der Formel IVd die Gruppe Q''' der Rest einer aliphatischen Dicarbonsäure ist, oder
• c) der zweite Aminosäurerest am N-terminalen Ende des Peptids P-NHR_y kein Rest einer Aminodicarbonsäure ist, falls bei den Verbindungen der Formel III die Gruppe G₃-CO der Rest einer gegebenenfalls N-acylierten Muraminsäure ist.

Particularly useful are the following sugar derivatives of biologically active peptides

• a) of the formula I.
  
  for the deoxy group of a ketose bound via the CH ₂ group to the NH group of a biologically active peptide, P is the residue of a biologically active peptide of the formula NH ₂ -P, in which the NH group at the N-terminal end or is located in a side chain of the peptide P,
• b) of formula II
  
  
  is the deoxyrate of an aldose bound via the free bond to the NH group of a biologically active peptide and P is the residue of a biologically active peptide of the formula NH ₂ -P, in which the NH group at the N-terminal end or in a Side chain of the peptide P is located,
• c) of formula III G ₃ -CO-NR _y -P III wherein G ₃ CO is the radical of a uronic acid, a polyhydroxymonocarboxylic acid or a polyhydroxydicarboxylic acid, Ry is hydrogen, alkyl having 1 to 3 carbon atoms or alkanoyl having 1 to 4 carbon atoms, and P is the residue of a biologically active peptide of the formula NH ₂ -P having at least 8 amino acid units and the group NR _{y is located} at the N-terminal end or in a side chain of the peptide P,
• d) of the formulas IVa, IVb, IVc or IVd
  
  where P is the radical of a biologically active peptide of the formula H ₂ NP, the radicals of the formulas
  
  Sugar residues are, Ry is hydrogen, alkyl of 1 to 3 carbon atoms or alkanoyl of 1 to 4 carbon atoms, and Q, Q ', Q''andQ''' are groups connecting the peptidyl moiety to the sugar moiety and those attached to P bonded NH group is located at the N-terminal end or in a side chain of the peptide, or
• e) of formulas Va or Vb NON ₂ C- (CHOH) _c -CY-CH ₂ -NH-P Va
  
  wherein Y is H ₂ or H, OH, c is 2 or 3 or 4, and P is a residue of a biologically active peptide of the formula H ₂ NP, wherein the P-linked NH group at the N-terminal end or is in a side chain of the peptide P and any of the free hydroxyl groups in the polyol residue of the compounds of formula V are optionally glycosylically linked to a reducing monosaccharide, disaccharide or oligosaccharide or an amino sugar, and the acid addition salts and complexes of these polypetide derivatives, with the provisos that
• a) in the case of the compounds of the above formula I, the substituent P is slightly different from a residue of a gastrin peptide having a C-terminal group ending with -Asp-phe-NH ₂ ,
• b) the radical P-NH _{2 is} not a natural insulin, if in the compounds of the formula IVb the group Q 'is a divalent radical containing a phenyl ring or in the case of the compounds of the formula IVd the group Q''' is the radical of an aliphatic dicarboxylic acid , or
• c) the second amino acid residue at the N-terminal end of the peptide P-NHR _{y is} not a residue of an aminodicarboxylic acid, if in the compounds of formula III the group G ₃ -CO is the residue of an optionally N-acylated muramic acid.

at Gastrin is a peptide that causes an increase in gastric acid secretion results.

All the sugar residues mentioned above may be monosaccharides, disaccharides or oligosaccharides. These sugars can contain heptoses, hexoses and / or pentoses, which can occur as pyranoses or furanoses.

at all mentioned above Formulas I to V only one sugar residue per peptide residue is shown. Are useful also sugar derivatives of peptides containing more than one free amino group have on the peptide residue, and these derivatives therefore contain, for example 2 or 3 sugar residues per peptide residue.

Are useful therefore, all biologically active peptides that have more than one Contain sugar residue which bound in the manner defined above is.

daß sich die Bindung in α-Stellung oder in β-Stellung befinden kann.The sugar polypetides preferably contain 1 to 3 monosaccharide residues, which may be linked together as disaccharide or trisaccharide. In all the connections mentioned above, the wavy line means

that the bond can be in the α-position or in the β-position.

vorzugsweise

• a) ein Rest der Formel VIa
  
  worin einer der Reste G_a und G_b Wasserstoff und der andere OH ist, einer der Reste G_c und G_d Wasserstoff und der andere OH oder O-Glykosyl ist, wobei der Glykosylrest von einem reduzierenden Monosaccharid, Disaccharid oder Oligosaccharid abgeleitet sein kann, einer der Reste G_e und G_f Wasserstoff und der andere OH ist, einer der Reste G_g und G_h Wasserstoff und der andere Wasserstoff oder CH₂OH ist, wobei die Reste G_a bis G_h beispielsweise so ausgewählt sind, dass der Rest der Formel VIa einem Rest entspricht, der durch eine Amadori-Umlagerung aus einem natürlich oder synthetisch zugänglichen Monosaccharid, Disaccharid, oder Oligosaccharid erhalten werden kann.

In the formula I is the rest

preferably

• a) a radical of the formula VIa
  
  in which one of the radicals G _a and G _{b is} hydrogen and the other OH, one of the radicals G _c and G _{d is} hydrogen and the other is OH or O-glycosyl, where the glycosyl radical can be derived from a reducing monosaccharide, disaccharide or oligosaccharide, one of the radicals G _e and G _{f is} hydrogen and the other is OH, one of the radicals G _g and G _{h is} hydrogen and the other is hydrogen or CH ₂ OH, where the radicals G _a to G _h are selected, for example, such that the radical of the formula VIa corresponds to a residue which can be obtained by an Amadori rearrangement from a naturally or synthetically accessible monosaccharide, disaccharide, or oligosaccharide.

As examples of sugar residues of the formula VIa, the following radicals may be mentioned:
Deoxyfructosyl, deoxytagatosyl, deoxysorbosyl, α-glucosyl (1-4) -deoxyfructosyl, α-glucosyl (1-4) -α-glucosyl (1-4) -deoxyfructosyl.

• b) einen Rest der Formel VIb
  
  worin einer der Reste G_a und G_b Wasserstoff und der andere OH ist, einer der Reste G_c und G_d Wasserstoff und der andere OH oder O-Glykosyl ist, wobei der Glykosylrest von einem reduzierenden Monosaccharid, Disaccharid oder Oligosaccharid erhältlich sein kann, einer der Reste G_e und G_f Wasserstoff und der andere Wasserstoff, COOH, CH₂OH, CH₂-O-P(O)-(OH)₂ oder CH₂O-Glykosyl ist, wobei der Glykosylrest von einem reduzierenden Monosaccharid, Disaccharid oder Oligosaccharid erhältlich ist, wobei die Reste G_a bis G_f beispielsweise so ausgewählt sind, dass der Rest der Formel VIb einem Rest entspricht, der durch eine Amadori-Umlagerung aus einem natürlichen oder einem synthetisch zugänglichen Monosaccharid, Disaccharid oder Oligosaccharid erhalten werden kann.

In formula I is the rest
preferably also for

• b) a radical of formula VIb
  
  in which one of the radicals G _a and G _{b is} hydrogen and the other OH, one of the radicals G _c and G _{d is} hydrogen and the other is OH or O-glycosyl, where the glycosyl radical can be obtainable from a reducing monosaccharide, disaccharide or oligosaccharide, one of the radicals G _e and G _{f is} hydrogen and the other is hydrogen, COOH, CH ₂ OH, CH ₂ -OP (O) - (OH) ₂ or CH ₂ O-glycosyl, wherein the glycosyl radical of a reducing monosaccharide, disaccharide or Oligosaccharide is obtainable, wherein the radicals G _a to G _f, for example, are selected so that the radical of formula VIb corresponds to a radical which can be obtained by an Amadori rearrangement of a natural or a synthetically accessible monosaccharide, disaccharide or oligosaccharide.

leftovers of formula VIb can be, for example, by an Amadori rearrangement from saccharides, such as gentobiose, melibiose, ribose or xylose, or from uronic acids, like glucuronic acid or galacturonic acid, receive.

vorzugsweise

• a) ein Rest der Formel VIIa
  
  worin einer der Reste G_a oder G_b Wasserstoff und der andere eine freie Bindung ist, einer der Reste G_c oder G_d Wasserstoff und der andere OH ist, einer der Reste G_e oder G_f Wasserstoff und der andere OH oder O-Glykosyl ist, wobei der Glykosylrest von einem reduzierenden Monosaccharid, Disaccharid oder Oligosaccharid abgeleitet sein kann, einer der Reste G_g und G_h Wasserstoff und der andere CH₂OH oder CH₂-O-Glykosyl ist, wobei der Glykosylrest von einem reduzierenden Monosaccharid, Disaccharid oder Oligosaccharid abgeleitet sein kann.

In the formula II is the rest

preferably

• a) a radical of the formula VIIa
  
  wherein one of the radicals G _a or G _{b is} hydrogen and the other is a free bond, one of the radicals G _c or G _{d is} hydrogen and the other OH, one of the radicals G _e or G _{f is} hydrogen and the other is OH or O-glycosyl wherein the glycosyl radical may be derived from a reducing monosaccharide, disaccharide or oligosaccharide, one of G _g and G _{h is} hydrogen and the other is CH ₂ OH or CH ₂ -O-glycosyl, wherein the glycosyl radical is a reducing monosaccharide, disaccharide or oligosaccharide can be derived.

The radicals G _a to G _h can therefore be selected, for example, such that the radical of the formula VIIa corresponds to a radical which can be obtained by a Heyns rearrangement from a natural or a synthetically accessible monoketose, diketose or oligoketose.

vorzugsweise auch

• b) ein Rest der Formel VIIb
  
  sein, worin einer der Reste G_a und G_b Wasserstoff und der andere eine freie Bindung ist, einer der Reste G_c und G_d Wasserstoff und der andere OH ist, einer der Reste G_e und G_f Wasserstoff und der andere CH₂OH oder CH₂-O-Glykosyl ist, wobei der Glykosylrest von einem reduzierenden Monosaccharid, Disaccharid oder Oligosaccharid abgeleitet sein kann.

In Formula II, the rest

preferably also

• b) a radical of the formula VIIb
  
  in which one of the radicals G _a and G _{b is} hydrogen and the other is a free bond, one of G _c and G _{d is} hydrogen and the other OH, one of G _e and G _{f is} hydrogen and the other CH ₂ OH or CH ₂ -O-glycosyl, wherein the glycosyl radical may be derived from a reducing monosaccharide, disaccharide or oligosaccharide.

The radicals G _a to G _f can therefore be selected, for example, such that the radical VIIb corresponds to a radical which can be obtained by a Heyns rearrangement from a natural or a synthetically accessible monoketose, diketose or oligoketose.

The Residues of the formulas VIIa or VIIb can be, for example, by a Heyns rearrangement from a sugar such as D-fructose, lactulose, L-sorbose, D-tagatose or D-ribulose.

at of formula III the polyhydroxymonocarboxylic acid or polyhydroxydicarboxylic acid for example, at least 3 hydroxyl groups, with others also Substituents may be present such as amino groups or acetylamino groups.

Examples for such polyhydroxycarboxylic are the sugar-derived onic acids, such as gluconic acid, or Arsäuren, like glucaric acid, and furthermore also quinic acid, acetylmuramyl acetylneuraminic or D-glucosaminic acid.

Examples for uronic acids are glucuronic and galacturic acid.

In the compounds of the formula IV, the substituents G ₄ , G 4 ' . G 4 '' 4 and G 4 '' ' the meanings given above for the substituents G ₁ or G ₂ .

oder insbesondere einen Rest -C_bH_2b-CO-, worin der Index b beispielsweise für 1 bis 6 steht. Die Gruppe Q ist beispielsweise ein Rest -CH₂-CO-. Insbesondere steht Q für -CO- oder -CS-. Die Gruppen -NH-Q''- und -NH-Q''' bedeuten Reste, die eine Gruppe NH₂ des Peptids mit dem Zuckerrest verbindet, und hierbei handelt es sich insbesondere um Reste von ω-Aminocarbonsäuren. Ein Beispiel für eine solche Gruppe ist der Rest -NH-C_b-H_2b-CO-. Von den Verbindungen der Formel V sind die Verbindungen der Formel Va bevorzugt, und zwar insbesondere die Verbindungen, bei denen n für 3 steht.The group Q or Q 'connects an NH ₂ group of the peptide with a group NH ₂ or HO of the sugar residue and is for example the radical of a dicarboxylic acid or preferably a -C _b H ₂ -CO radical, wherein b is 0 to 6 stands. The rest can be branched. The rest Q 'means, for example, the rest

or in particular a radical -C _b H _2b -CO-, wherein the index b is, for example, 1 to 6. For example, the group Q is a radical -CH ₂ -CO-. In particular, Q is -CO- or -CS-. The groups -NH-Q "- and -NH-Q"'represent radicals which connect an NH _{2 group of} the peptide to the sugar radical, and these are, in particular, radicals of ω-aminocarboxylic acids. An example of such a group is the radical -NH-C _b -H _2b -CO-. Of the compounds of the formula V, the compounds of the formula Va are preferred, in particular the compounds in which n is 3.

All the above mentioned Residues P are residues of biologically active peptides. To such peptides belong all natural and synthetic peptides (also derivatives and analogs thereof - see Introduction) with hormonal, enzymatic or immunomodulatory Effectiveness. This effectiveness can be both stimulating as well be inhibitory. examples for such peptides are somatostatin, calcitonin, oxytocin, vasopressin, Insulin, LH, LHRH, GRF, Gastrin, Sustanz P, Cathepsin, Encephaline as well as all derivatives and analogues of these peptides with similar Efficacy as the peptides or with an antagonizing activity.

The Sugar derivatives preferably contain at least 8 amino acid units, for example, 8 to 32, especially 8 to 20, and especially 8 to 10, amino acid units.

Prefers are the peptides of formulas I and II.

at In the above and following formulas, the sugar residue is simplicity merely by the structure of the pyranose. Naturally belong to the invention, the Furanosestrukturen and the open-chain Structures, as far as they can occur in the relevant sugars.

The Compounds of the above formulas can be used for the synthesis of compounds This type of well-known methods are produced.

• a) wenigstens eine Schutzgruppe, die an einem mit Zucker derivatisierten Peptid vorhanden ist, entfernt wird oder
• b) zwei Peptideinheiten, wovon jede mindestens eine Aminosäure oder einen Aminoalkohol in geschützter oder ungeschützter Form und eine Peptideinheit den Zuckerrest enthält, durch eine Amidbindung verbunden werden, wobei die Peptidbindung in einer Weise erfolgt, dass sich die gewünschte Aminosäuresequenz ergibt, und dann gegebenenfalls die Stufe a) des Verfahrens durchgeführt wird, oder
• c) wenigstens ein gegebenenfalls geschützter Zuckerrest in ein geschütztes oder ungeschütztes Peptid eingeführt wird und dann gegegebenenfalls die Stufe a) des Verfahrens durchgeführt wird, oder
• d) eine funktionelle Gruppe eines ungeschützten oder geschützten mit Zucker derivatisierten Peptids in eine andere funktionelle Gruppe umgewandelt oder entfernt wird, so dass sich ein ungeschütztes oder ein geschütztes glykosyliertes Peptid ergibt, und im letztgenannten Fall die Stufe a) des Verfahrens durchgeführt wird, oder
• e) ein mit Zucker derivatisiertes Peptid, worin die Mercaptogruppen von Cys-Resten in freier Form vorliegen, oxidiert und so ein Peptid gebildet wird, worin 2 Cys-Reste durch eine S-S-Brücke verbunden sind.

The sugar derivatives can be prepared, for example, by

• a) at least one protecting group present on a sugar derivatized peptide is removed or
• b) two peptide units, each containing at least one amino acid or an aminoalcohol in protected or unprotected form and a peptide unit the sugar residue, are linked by an amide bond, wherein the peptide bond is carried out in such a way that the desired amino acid sequence results, and then optionally Stage a) of the method is carried out, or
• c) introducing at least one optionally protected sugar residue into a protected or unprotected peptide and then optionally carrying out stage a) of the process, or
• d) a functional group of an unprotected or protected sugar-derivatized peptide is converted or removed to another functional group to give an unprotected or a protected glycosylated peptide, and in the latter case, the step a) of the method is carried out, or
• e) oxidizing a sugar-derivatized peptide in which the mercapto groups of Cys residues are in free form to form a peptide in which 2 Cys residues are linked by an SS bridge.

Under Sugars are also referred to herein as mentioned at the beginning of the description Sugar derivatives understood as amino sugar, oxidized and reduced Sugar or esterified sugar.

The The above reactions are known per se and can be analogous to the following examples, the procedures a) and b) in particular according to the synthesis method described below carried out can be. If desired, can in these reactions, protecting groups that are involved in peptides or Sugars are suitable for functional groups are used that are not involved in the implementation take part. Among such protecting groups are also polymer resins understood with functional groups.

The Compounds of the formula I can be prepared by a protected peptide, which is a free Contains amino group, in a slightly acidic medium with a reducing monosaccharide, Disaccharide or oligosaccharide or a corresponding uronic acid or an ester of this (Amadori rearrangement) is implemented and then the protective groups are removed.

These Implementation can be in one for the Amadori rearrangement usual Manner performed become. The added acid can be, for example, glacial acetic acid. When reacting with a uronic acid can on an additional Acid dispensed become. Preferably, an excess of carbohydrate is used, the for example, 10 equivalents to 1 equivalent the peptide compound. The implementation will be in a polar Solvent, such as methanol, preferably at temperatures of about 60 to 70 ° C.

The Compounds of formula II can be prepared by using a protected peptide which is a free peptide Has amino group, in a weakly acidic medium with a ketose (Heyns rearrangement) is implemented. This implementation may be among the same conditions as the Amadori rearrangement (see above).

The compounds of formula III may be prepared by reacting a protected peptide having a free amino group with an acid of the formula G ₃ -COOH or a reactive derivative of such an acid, and then removing the protecting group or groups. This is a customary amidation reaction which can be carried out in a manner known per se. In particular, the acid halides can be used as reactive derivatives of carboxylic acids. The amides can also be prepared, for example, with the free acids in the presence of hydroxybenzotriazole and dicyclohexylcarbodiimide.

• a) das Peptid zuerst mit dem Brückenglied umgesetzt und das Produkt dann mit dem Zucker zur Reaktion gebracht wird oder
• b) der Zucker zuerst mit dem Brückenglied umgesetzt und das glykosylierte Brückenglied dann mit dem Peptid zur Reaktion gebracht wird.

The compounds of the formulas IVa, IVb, IVc and IVd can be prepared by

• a) the peptide is first reacted with the bridge member and the product is then reacted with the sugar or
• b) the sugar is first reacted with the bridge member and then the glycosylated bridge member is reacted with the peptide.

These Implementations can performed in a known manner become. In general, the amides, esters or acetals are the major ones Products. The sugar derivatives can be cleaned in a known manner.

worin L für O oder S steht und
G₄ wie oben definiert ist
und worin die in der Gruppe G₄ vorhandenen freien Hydroxylgruppen geschützt sind, nämlich beispielsweise acyliert sind,
an ein Peptid P-NH₂ in geschützter Form kuppelt und dann. die Schutzgruppen abspaltet.The compounds of the formula IVa, in which Q is -CO- or -CS- can be prepared, for example, by reacting the corresponding glycosyl isocyanate or glycosyl isothio cyanate of the formula

wherein L is O or S and
G _{4 is} as defined above
and in which the free hydroxyl groups present in the group G ₄ are protected, namely are acylated, for example,
coupled to a peptide P-NH ₂ in protected form and then. splits off the protecting groups.

These Reaction can be used to prepare urea derivatives in conventional Manner performed become.

The Compounds of the formulas IVc and IVd can be used, for example, with application made an Amadori rearrangement or a Heyns rearrangement as for example for the production of compounds of formulas I and II has been described.

• a') eine Aldose, Desoxyaldose oder Ketose mit dem Peptid P-NH₂ einer reduktiven Aminierung unterzogen wird oder
• b') die Hemiacetalgruppe einer Verbindung der Formel I oder II reduziert wird,

wobei jeder Reaktant gewünschtenfalls temporär geschützt sein kann.For example, a compound of formula Va or Vb can be prepared by:

• a ') an aldose, deoxy-canose or ketose with the peptide P-NH _{2 is} subjected to a reductive amination or
• b ') the hemiacetal group of a compound of the formula I or II is reduced,

wherein each reactant may be temporarily protected if desired.

The reductive amination and the reduction can be carried out in the usual way. The reductive amination can be accomplished, for example, with NaBH ₃ CN. Here, a pH of 7 is preferred. The reduction of the hemiacetal group can be accomplished with borohydrides, for example with NaBH ₄ . Here, a pH of about 6 is preferred.

Provided the preparation of the starting materials is not specifically described herein is, the respective starting materials are known or under Application of methods known per se produced, for example using literature analogues for analogous compounds or methods described herein or using the following described inventive method.

worin A Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkanoyl mit 1 bis 4 Kohlenstoffatomen ist,
die Gruppe =N-CH(Z₁)-CO für

• 1) einen (L)- oder (D)-Phenylalaninrest, der gegebenenfalls durch Halogen, NO₂, NH₂, OH, Alkyl mit 1 bis 3 Kohlenstoffatomen und/oder Alkoxy mit 1 bis 3 Kohlenstoffatomen substituiert ist, oder
• 2) den Rest einer natürlichen lipophilen α-Aminosäure oder einer entsprechenden (D)-Aminosäure, bei der es sich um eine andere Aminosäure als oben unter 1) angegeben handelt,

steht, wobei
Z₁ in der Gruppe =N=CH(Z₁)-CO- den Rest eines Aminosäurerests der oben unter 1) und 2) definierten Art bedeutet,
A' Wasserstoff oder Alkyl mit 1 bis 3 Kohlenstoffatomen ist,
Y₁ und Y₂ unabhängig voneinander irgendeine der folgenden Bedeutungen haben:

• 1) Wasserstoff,
• 
  worin m eine ganze Zahl von 1 bis 4 ist R_a für CH₃ oder C₂H₅ steht und R_b für H, CH₃ oder C₂H₅ steht,
• 
  worin n eine ganze Zahl von 1 bis 5 ist,
• 4) -CO-NHR_c worin R_c eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 6 Kohlenstoffatomen ist
• 
  worin R_d der Rest einer natürlichen α-Aminosäure (unter Einschluß von Wasserstoff) ist, der sich am α-Kohlenstoffatom befindet, und R_e eine Alkylgruppe mit 1 bis 5 Kohlenstoffatomen bedeutet,
• 
  worin R'a und R ' / b unabhängig voneinander Wasserstoff, CH₃ oder C₂H₅ sind, R₈ und R₉ unabhängig voneinander Wasserstoff, F, Cl, Br, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkoxy mit 1 bis 3 Kohlenstoffatomen bedeuten, p für 0 oder 1 steht, q für 0 oder 1 steht und r für 0, 1 oder 2 steht oder worin Y₁ und Y₂ zusammen eine Bindung bilden, B für Phe oder im Phenylrest durch F, Cl, Br, NO₂, NH₂, OH, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkoxy mit 1 bis 3 Kohlenstoffatomen substituiertes Phe steht, C für L- oder D-Trp steht, das gegebenenfalls im Benzolring durch F, Cl, Br, NO₂, NH₂, OH, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkoxy mit 1 bis 3 Kohlenstoffatomen substituiert ist, D für Lys steht, dessen α-Aminogruppe durch Methyl substituiert sein kann, E für Thr, Ser oder Val steht, F für COOR₁, CH₂OR₂, CO-NR₃R₄ oder die Gruppe
  
  steht, R₁ Wasserstoff oder Alkyl mit 1 bis 3 Kohlenstoffatomen ist, R₂ Wasserstoff oder der Rest eines physiologisch annehmbaren und physiologisch hydrolysierbaren Esters ist, R₃ Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen, Phenyl oder Phenylalkyl mit 7 bis 10 Kohlenstoffatomen ist, wobei dieser Rest jedoch nur Wasserstoff oder Methyl sein kann, falls R₄ für -CH(R₅)-X₁ steht, R₄ Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen oder ein Rest der Formel
  
  ist, R₅ der Rest einer natürlichen Aminosäure (unter Einschluß von Wasserstoff), welcher sich am α-Kohlenstoffatom befindet, oder ein Rest HO-CH₂-CH₂ oder HO(-CH₂)₃ ist, worin die Gruppe IX die L- oder D-Konfiguration haben kann, X₁ für COOR₁, CH₂OR₂ oder die Gruppe
  
  steht, R₆ Wasserstoff oder Alkyl mit 1 bis 3 Kohlenstoffatomen ist, R₇ Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen, Phenyl oder Phenylalkyl mit 7 bis 10 Kohlenstoffatomen ist, wobei die Reste B, D und E in L-Form vorliegen und die Reste in den Stellungen 2 sowie 7 und auch die Reste Y₁4) und Y₂4) unabhängig in der D- oder L-Form vorliegen und die Salze sowie Komplexe dieser Verbindungen.

A preferred class includes the sugar derivatives of somatostatin peptides containing, for example, 4 to 9 amino acids. The term somatostatin peptides also includes analogs and derivatives thereof. Particularly useful are the sugar derivatives of compounds of formula VIII

where A is hydrogen, alkyl having 1 to 3 carbon atoms or alkanoyl having 1 to 4 carbon atoms,
the group = N-CH (Z ₁ ) -CO for

• 1) an (L) - or (D) -phenylalanine radical, which is optionally substituted by halogen, NO ₂ , NH ₂ , OH, alkyl having 1 to 3 carbon atoms and / or alkoxy having 1 to 3 carbon atoms, or
• 2) the remainder of a natural lipophilic α-amino acid or a corresponding (D) amino acid, in which it is a different amino acid than indicated above under 1),

stands, where
Z ₁ in the group = N = CH (Z ₁ ) -CO- represents the residue of an amino acid residue of the type defined above under 1) and 2),
A 'is hydrogen or alkyl of 1 to 3 carbon atoms,
Y ₁ and Y ₂ independently of one another have any of the following meanings:

• 1) hydrogen,
• 
  wherein m is an integer from 1 to 4 R _{a is} CH ₃ or C ₂ H ₅ and R _{b is} H, CH ₃ or C ₂ H ₅ ,
• 
  wherein n is an integer from 1 to 5,
• 4) -CO-NHR _c wherein R _{c is} a straight-chain or branched alkyl group having 1 to 6 carbon atoms
• 
  wherein R _{d is} the residue of a natural α-amino acid (including hydrogen) located on the α-carbon atom and R _{e is} an alkyl group of 1 to 5 carbon atoms,
• 
  wherein R ' a and R '/ b are independently hydrogen, CH ₃ or C ₂ H ₅ , R ₈ and R _{9 are} independently hydrogen, F, Cl, Br, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms, p is 0 or 1, q is 0 or 1 and r is 0, 1 or 2, or wherein Y ₁ and Y ₂ together form a bond, B is Phe or in the phenyl radical by F, Cl, Br, NO ₂ , NH ₂ , OH, alkyl having 1 to 3 carbon atoms or alkoxy having 1 to 3 carbon atoms is substituted Phe, C is L- or D-Trp, which is optionally in the benzene ring by F, Cl, Br, NO ₂ , NH ₂ , OH, alkyl substituted with 1 to 3 carbon atoms or alkoxy having 1 to 3 carbon atoms, D is Lys whose α-amino group may be substituted by methyl, E is Thr, Ser or Val, F is COOR ₁ , CH ₂ OR ₂ , CO -NR ₃ R ₄ or the group
  
  R _{1 is} hydrogen or alkyl of 1 to 3 carbon atoms, R _{2 is} hydrogen or the residue of a physiologically acceptable and physiologically hydrolyzable ester, R _{3 is} hydrogen, alkyl of 1 to 3 carbon atoms, phenyl or phenylalkyl of 7 to 10 carbon atoms, but this radical can only be hydrogen or methyl if R ₄ for -CH (R ₅ ) -X ₁ , R _{4 is} hydrogen, alkyl having 1 to 3 carbon atoms or a radical of the formula
  
  R _{5 is} the residue of a natural amino acid (including hydrogen) located on the α-carbon atom, or an HO-CH ₂ -CH ₂ or HO (-CH ₂ ) ₃ radical, wherein the group IX is the L - or D configuration, X ₁ for COOR ₁ , CH ₂ OR ₂ or the group
  
  R _{6 is} hydrogen or alkyl of 1 to 3 carbon atoms, R _{7 is} hydrogen, alkyl of 1 to 3 carbon atoms, phenyl or phenylalkyl of 7 to 10 carbon atoms, wherein the radicals B, D and E are in L-form and the Residues in the positions 2 and 7 and also the radicals Y ₁ 4) and Y ₂ 4) are independently present in the D or L form and the salts and complexes of these compounds.

Such Compounds are described in US-A-4,395,403, the contents of which are incorporated herein by reference including this their examples introduced becomes.

In the peptide derivatives of formula VIII above, the following definitions or combinations thereof are preferred:
If the group = N-CH (Z ₁ ) -CO- has the above definition 1), then this radical is preferably an (L) - or (D) -phenylalanine residue or an (L) - or (D) -tyrosine residue, in which Z is benzyl or p-OH, especially the (D) -phenylalanine residue.

If the group = N-CH (Z ₁ ) -CO- has the above definition 2), then preference is given to radicals in which Z _{1 is} alkyl having 3 carbon atoms, preferably having 4 or more carbon atoms, for example up to 7 carbon atoms.

The group = N-CH (Z ₁ ) -CO- means in particular a radical of the type defined above under 1).

The radicals Y ₁ and Y ₂ preferably have the meaning given above under 1), 2) or 4). In particular, they form a bond together.

B is preferably for Phe or for Tyr.

C is preferably for (D) -Trp.

D preferably means Lys.

e is preferably Thr.

insbesondere für die Gruppe

worin der Rest -CH(R₅)-X₁ vorzugsweise die L-Konfiguration hat.F is preferably the group

especially for the group

wherein the radical -CH (R ₅ ) -X ₁ preferably has the L-configuration.

R ₃ is preferably hydrogen.

Isobutyl, CH₂CH₂OH oder (CH₂)₃-OH, vor allem CH₂OH oder

und insbesondere

X₁ bedeutet vorzugsweise die Gruppe

oder CH₂OR₂, und insbesondere CH₂OR₂.R ₅ is CH ₂ OH,

Isobutyl, CH ₂ CH ₂ OH or (CH ₂ ) ₃ -OH, especially CH ₂ OH or

and particularly

X ₁ is preferably the group

or CH ₂ OR ₂ , and especially CH ₂ OR ₂ .

R ₂ is preferably hydrogen.

R ₂ in the meaning of the remainder of an ester is preferably HCO, alkylcarbonyl having 2 to 12 carbon atoms, phenylalkylcarbonyl having 8 to 12 carbon atoms or benzoyl.

The Remains in positions 2 and 7 preferably have the L configuration.

Hiervon sind die Verbindungen der Formeln VIIIa, VIIIb, VIIIe und VIIIf ganz besonders bevorzugt.Particularly preferred glycosylated somatostatin derivatives are those which have a sugar residue on the N-terminal amino group, such as compounds of the following formulas:

Of these, the compounds of the formulas VIIIa, VIIIb, VIIIe and VIIIf are very particularly preferred.

worin A^p der Desoxyrest einer Ketose oder einer entsprechenden Uronsäure ist, der über eine CH₂-Gruppe an die NH-Gruppe gebunden ist,
wobei diese Desoxygruppe durch eine Amadori-Umsetzung aus einer Aldose oder einer entsprechenden Uronsäure mit der freien Aminogruppe des Somatostatins erhältlich ist, und
Z₁, A', Y₁, B, C, D, E und Y₂ die oben im Zusammenhang mit der Formel VIII angegebenen Bedeutungen haben.A compound group includes the compounds of formula VIIIpa

where A ^{p is} the deoxy radical of a ketose or a corresponding uronic acid which is bonded to the NH group via a CH ₂ group,
wherein this deoxy group is obtainable by an Amadori reaction from an aldose or a corresponding uronic acid with the free amino group of somatostatin, and
Z ₁ , A ', Y ₁ , B, C, D, E and Y _{2 have} the meanings given above in connection with the formula VIII.

worin G ein Acylrest einer Uronsäure, einer Polyhydroxycyclohexancarbonsäure, von N-Acetylmuraminsäure oder N-Acetylneuraminsäure ist,
A Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkanoyl mit 1 bis 4 Kohlenstoffatomen bedeutet und
Z, A', Y₁, B, C, D, E, Y₂ und F die oben angegebenen Bedeutungen haben.Another compound group includes the compounds of formula VIIIpb

wherein G is an acyl radical of a uronic acid, a polyhydroxycyclohexanecarboxylic acid, N-acetylmuramic acid or N-acetylneuraminic acid,
A is hydrogen, alkyl of 1 to 3 carbon atoms or alkanoyl of 1 to 4 carbon atoms and
Z, A ', Y ₁ , B, C, D, E, Y ₂ and F have the meanings given above.

Conveniently, G is glucuronic acid, galacturonic or quinic acid.

worin Q Wasserstoff oder die Glykosylgruppe eines Monosaccharids, Disaccharids oder Oligosaccharids ist,
n eine ganze Zahl von 1 bis 6 bedeutet,
A Wasserstoff, Alkyl mit 1 bis 3 Kohlenstoffatomen oder Alkanoyl mit 1 bis 4 Kohlenstoffatomen ist und
Z, A', Y₁, B, C, D, E, Y₂ und F die oben angegebenen Bedeutungen haben.Another compound group includes the compounds of formula VIIIpc

wherein Q is hydrogen or the glycosyl group of a monosaccharide, disaccharide or oligosaccharide,
n is an integer from 1 to 6,
A is hydrogen, alkyl of 1 to 3 carbon atoms or alkanoyl of 1 to 4 carbon atoms and
Z, A ', Y ₁ , B, C, D, E, Y ₂ and F have the meanings given above.

To Another preferred class includes the sugar derivatives of Calcitonins.

The term calcitonins is understood to mean both the naturally occurring calcitonins, as can be extracted or synthetically produced from natural sources, cell cultures and the like, and the derivatives and analogs thereof. Useful natural calcitonins include human, salmon, eel, chicken, bovine, sheep, rat or porcine calcitonin, and especially human _; Salmon, chicken and eel calcitonins.

To Derivatives and analogues of these calcitonins include above all natural calcitonin structures, in which one or more amino acid residues are replaced by one or more other amino acid residues are replaced and / or the bridge S-S through an alkylene bridge is replaced and / or one or more amino acid residues have been omitted.

worin R für H oder R''CO steht, wobei R''CO der Acylrest einer Carbonsäure ist,
Y'1 der am α-Kohlenstoffatom einer α-Aminosäure befindliche Rest ist,
Y'2 für den am α-Kohlenstoffatom einer α-Αminosäure befindlichen Rest oder für die Reste

-CH₂-S-S-CH₂-CH₂-COOH, -(CH₂)_s-COOHoder -CH₂-S-Y₃ steht,
Y₃ Alkyl mit 1 bis 4 Kohlenstoffatomen, gegebenenfalls durch Methyl oder Methoxy substituiertes Benzyl oder CH₃CONH-CH₂- ist,
o eine ganze Zahl von 1 bis 4 bedeutet,
A₆ für Thr oder D-Thr steht,
s eine ganze Zahl von 3 bis 5 ist,
A₈ den Aminoacylrest einer neutralen, lipophilen L-α-Aminosäure bedeutet,
A₉ der Aminoacylrest einer neutralen lipophilen L- oder D-α-aminosäure ist und
Z₁ ein Polypetidrest ist, der sich in den Stellungen 10 bis 31 eines natürlichen Calcitonins oder eines Derivats oder Analogen hiervon mit hypocalcemischer Wirkung befindet,
wobei die 1 bis 4 Reste Y'1 in der Formel X unabhängig voneinander gleiche oder unterschiedliche Bedeutungen haben können und mit Ausnahme des Aminoacylrestes A₈ alle Aminosäurereste in der Formel X die L-Konfiduration oder D-Konfiguration haben können,
sowie die Salze und Komplexe dieser Verbindungen.The sugar derivatives of calcitonins of the formula X are particularly preferred

wherein R is H or R''CO, where R''CO is the acyl radical of a carboxylic acid,
Y ' 1 is the radical on the α-carbon of an α-amino acid,
Y ' 2 for the residue located on the α-carbon atom of an α-amino acid or for the radicals

-CH ₂ -SS-CH ₂ -CH ₂ -COOH, - (CH ₂ ) _s -COOH or -CH ₂ -SY ₃ stands,
Y _{3 is} alkyl having 1 to 4 carbon atoms, benzyl optionally substituted by methyl or methoxy, or CH ₃ CONH-CH ₂ -,
o is an integer from 1 to 4,
A _{6 is} Thr or D-Thr,
s is an integer from 3 to 5,
A _{8 represents} the aminoacyl radical of a neutral, lipophilic L-α-amino acid,
A _{9 is} the aminoacyl radical of a neutral lipophilic L- or D-α-amino acid and
Z _{1 is} a polypeptide residue located in positions 10 to 31 of a natural calcitonin or a derivative or analogue thereof having a hypocalcemic effect,
where the 1 to 4 radicals Y ' 1 in the formula X independently of one another may have identical or different meanings and, with the exception of the aminoacyl residue A _8, all amino acid residues in the formula X may have the L-configuration or D-configuration,
and the salts and complexes of these compounds.

Such Compounds are described, for example, in GB-A-2 184 729, their contents together with the examples contained therein introduced becomes.

In formula X, Z _{1 is} a peptide residue which is in positions 10 to 31 in various known calcitonins, such as human, salmon, eel, chicken, bovine, ovine, rat or porcine calcitonin and also derivatives and Analogous to these calcitonins may be present with similar efficacy. Derivatives and analogues of these calcitonins are understood to mean, in particular, natural calcitonins in which one or more amino acid residues have been replaced by one or more other amino acid residues or the bridge SS has been replaced by an alkylene bridge or one or more amino acid residues have been omitted. These peptide residues Z ₁ normally contain 22 amino acids, but can also have a correspondingly smaller amount of amino acid residues by omission of one or more amino acid residues (desaminoacyl derivatives).

• a) Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala
• b) Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr
• c) Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr

The group Z ₁ preferably has the following meanings:

• a) Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala
• b) Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr
• c) Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr

Compounds of the formula X in which Z _{1 has} the meanings indicated under b) or c), in particular those compounds in which Z ₁ corresponds to the definition given under c), are particularly preferred.

The Group R''CO is preferred the acyl radical of an aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acid.

• a') Gesättigtes oder ungesättigtes, geradkettiges oder verzweigtes Alkyl mit 1 bis 17 Kohlenstoffatomen, insbesondere gesättigtes Alkyl mit 3 bis 9 Kohlenstoffatomen,
• b') Cycloalkyl mit 5 bis 7 Kohlenstoffatomen oder Cycloalkylalkyl, worin die Cycloalkylgruppe 5 bis 7 Kohlenstoffatome und die Alkylgruppe 1 oder 2 Kohlenstoffatome enthält,
• c') Adamantyl, Adamantylmethyl oder Adamanthylethyl,
• d') Phenyl, Benzyl oder Phenethyl.

The substituent R "preferably has the following meanings:

• a ') saturated or unsaturated, straight-chain or branched alkyl having 1 to 17 carbon atoms, in particular saturated alkyl having 3 to 9 carbon atoms,
• b ') cycloalkyl having 5 to 7 carbon atoms or cycloalkylalkyl, wherein the cycloalkyl group contains 5 to 7 carbon atoms and the alkyl group contains 1 or 2 carbon atoms,
• c ') adamantyl, adamantylmethyl or adamantylethyl,
• d ') phenyl, benzyl or phenethyl.

In the above-mentioned definitions for the radical R ", the alkyl, cycloalkyl or phenyl radicals may be substituted by the usual substituents, such as by halogen, NO ₂ , OH, alkoxy and the like.

Of the For example, rest R''CO can the α-deaminamine residue a natural α-amino acid, being for the radical R "means the meanings given above under a '), b') and c ') are preferred.

The rest X ' 1 and Y ' 2 which are present on the α-carbon atom of an α-amino acid are, in particular, radicals which are bonded to the α-carbon atom of a natural α-amino acid, but radicals of other α-amino acids may also be used, and examples of these are Cyclohexylalanine or α-aminoisobutyric acid.

• a) der N-terminale Aminoacylrest (welcher dem zweiten Aminosäurerest in der Sequenz der natürlichen Calcitonine ent spricht) vorzugsweise Ser, Gly oder Ala,
• b) der zweite Aminoacylrest (welcher dem dritten Aminosäurerest in der Sequenz der natürlichen Calcitonine entspricht) vorzugsweise Asn oder Ser,
• c) der dritte Aminoacylrest (welcher dem vierten Aminosäurerest in der Sequenz der natürlichen Calcitonine entspricht) vorzugsweise Leu, Asn, Ser, Phe, D-Leu oder der Rest von Cyclohexylalanin,
• d) der vierte Aminoacylrest (welcher dem fünften Aminosäurerest in der Sequenz der natürlichen Calcitonine entspricht) vorzugsweise Ser oder Ala.

If the index o in the formula X stands for 4, then

• a) the N-terminal aminoacyl radical (which corresponds to the second amino acid radical in the sequence of the natural calcitonins), preferably Ser, Gly or Ala,
• b) the second aminoacyl residue (which corresponds to the third amino acid residue in the sequence of the natural calcitonins), preferably Asn or Ser,
• c) the third aminoacyl residue (which corresponds to the fourth amino acid residue in the sequence of the natural calcitonins) preferably Leu, Asn, Ser, Phe, D-Leu or the residue of cyclohexylalanine,
• d) the fourth aminoacyl residue (which corresponds to the fifth amino acid residue in the sequence of natural calcitonins), preferably Ser or Ala.

Stands the index o in the formula X for 3, then have the N-terminal, second and third amino acid residues the same preferred meanings as above under the definition b) if the index o stands for 4.

Stands the index o in the formula X for 2, then the N-terminal and the second amino acid residues have the same preferred meanings as above under the definitions c) and d) if the index o stands for 4.

If the index o in the formula X for 1, then the N-terminal and second amino acid residues are preferred Ser or Ala.

The radical A ₆ is preferably Thr.

steht vorzugsweise für Cys, ein Derivat von Cystein der oben für Y'2 an gegebenen Art oder einen neutralen lipophilen α-Aminoacylrest, insbesondere Ala, oder einen anderen neutralen liphophilen α-Aminoacylrest, insbesondere Ala.The group

preferably represents Cys, a derivative of cysteine of above Y ' 2 in a given way or a neutral lipophilic α-aminoacyl, especially Ala, or another neutral lipophilic α-aminoacyl, especially Ala.

The radical A ₈ is preferably the aminoacyl radical of a neutral lipophilic α-amino acid, in particular Val or Gly.

The radical A ₉ is preferably the aminoacyl radical of a neutral lipophilic α-amino acid, especially Leu or Phe.

at the compounds of the formula X, the index o is preferably 2, where R then H or R''CO, or the Above all, index o means 1, where R is then R''CO stands.

All amino acid residues preferably have the L configuration.

The glycosylated calcitonins (including derivatives and analogues of calcitonins) are in particular compounds which are glycosylated on the N-terminal amino group or in one or more amino groups on one or more side chains, and examples of these are the following compounds:

The abbreviation Calc is in it the rest of a natural one Calcitonins or a derivative or analogue of such a calcitonin, this remainder being over an amino group at the N-terminal end or in a side chain is bound to the sugar residue.

• a) Es wird wenigstens eine Schutzgruppe, die in einem geschützten Polypeptid mit der in der Formel X angegebenen Sequenz vorhanden ist, entfernt.
• b) Zwei Peptideinheiten, von denen jede wenigstens eine Aminosäure oder ein Derivat hiervon, wie dies für die Formel X beschrieben ist, in geschützter oder ungeschützter Form enthält, werden durch eine Amidbindung miteinander ver knüpft, wobei die Peptidbindung in einer Weise gebildet werden soll, daß sich die in der Formel X vorhandene Aminosäuresequenz ergibt, worauf sich gegebenenfalls die oben erwähnte Verfahrensstufe a) anschließt.
• c) Eine Verbindung der Formel X, worin R Wasserstoff ist, wird in geschützter oder ungeschützter Form mit einer Säure der Formel R''COOH oder mit einem reaktionsfähigen Derivat einer solchen Säure umgesetzt, worauf sich gegebenenfalls wiederum die obige Verfahrensstufe a) anschließt.
• d) Zur Herstellung einer Verbindung der Formel X, worin Y'2 für
  
  oder CH₂-S-S-CH₂-CH₂-COOH steht, wird entweder eine Verbindung der Formel XII
  
  in geschützter oder ungeschützter Form mit einer Verbindung der Formel XIII
  
  umgesetzt, worin R₁₀ eine Gruppe ist, die die Bildung einer Brücke S-S mit dem S-Atom der anderen Gruppe CH₂SH im Polypetid der Formel XII erleichtert R₁₁ Wasserstoff oder eine Aminoschutzgruppe ist, R₁₂ für OH oder eine Carboxylschutzgruppe steht und V Wasserstoff oder eine Gruppe NH bedeutet, oder es wird eine Verbindung der Formel XIV
  
  in geschützter oder ungeschützter Form, worin R₁₀ wie oben definiert ist, mit einer Verbindung der Formel XV
  
  umgesetzt, worauf dann gegebenenfalls wiederum die Verfahrensstufe a) durchgeführt wird.

The calcitonin derivatives of formula X can be prepared by methods well known in the synthesis of polypeptides of this type. The polypeptides of the above formula can be prepared, for example, in the following manner:

• a) at least one protecting group present in a protected polypeptide of the formula given in formula X is removed.
• b) Two peptide units, each of which contains at least one amino acid or a derivative thereof, as described for the formula X, in protected or unprotected form, are linked together by an amide bond, the peptide bond being formed in a manner in that the amino acid sequence present in the formula X results, followed where appropriate by the abovementioned process step a).
• c) A compound of the formula X in which R is hydrogen is reacted in protected or unprotected form with an acid of the formula R "COOH or with a reactive derivative of such an acid, which is followed, in turn, by the above process step a).
• d) For the preparation of a compound of formula X, wherein Y ' 2 For
  
  or CH ₂ -SS-CH ₂ -CH ₂ -COOH is either a compound of formula XII
  
  in protected or unprotected form with a compound of formula XIII
  
  where R _{10 is} a group which facilitates the formation of a bridge SS with the S atom of the other CH ₂ SH group in the polypeptide of formula XII R _{11 is} hydrogen or an amino protecting group, R _{12 is} OH or a carboxyl protecting group and V Hydrogen or a group NH means, or it will a compound of formula XIV
  
  in protected or unprotected form, wherein R _{10 is} as defined above, with a compound of formula XV
  
  then, where appropriate, in turn, the process step a) is performed.

If the preparation of the starting materials not particularly described is, then these compounds are known or can by using conventional Process can be prepared and cleaned. The end products of Formula X can also in usual Be cleaned so that they contain less than 5% polypeptide by-products contain. The peptides used as starting materials for the methods a) and b) can also be in a conventional manner either in solution or by the solid phase method.

The production of peptide units, the remainder X ' 2 a group -CH ₂ -SS-CH ₂ -CH ₂ -COOH or CH ₂ -SS-CH ₂ CH (NH ₂ ) -COOH can be carried out analogously to the above-mentioned method d).

oder S-SO₃-. In this method d) compounds of the formulas XIII or XIV are used in which R ₁₀ represents such a known residues, which react with mercaptans to form a bond SS. The substituent R ₁₀ has in particular the following meanings: S-alkyl, -S-COO-alkyl

or S-SO ₃ -.

In these radicals are in particular alkyl for lower alkyl having 1 to 4 carbon atoms. The introduction these radicals in compounds with free groups SH are analogous to methods known in sulfur chemistry.

To Another preferred class of compounds is the group of LHRH antagonists.

These compounds are preferably sugar derivatives of compounds of the formula XVI, R ₁ -A ₁ -B ₁ -C ₁ -D ₁ -E ₁ -F ₁ -G ₁ -H ₁ -I ₁ -K ₁ -NH ₂ XVI in which the individual symbols have the following meanings:
R ₁ is H or an acyl group having 1 to 7 carbon atoms,
A _{1 represents} D-Phe, which is optionally substituted in the phenyl ring by F, Cl, Br, NH ₂ , CH ₃ or OCH ₃ , in particular in position 4, β-D-naphthylalanine, D-Trp, optionally in the Positions 5 or 6 is substituted by F, Cl, Br, NH ₂ or OCH ₃ and / or in position 1 is substituted by formyl or acetyl, proline, 3,4-dehydroproline or D-pyroglutamine,
B ₁ is D-Phe, which is optionally substituted in the phenyl ring by F, Cl, Br, NH ₂ , CH ₃ or CH ₃ O, D-α-methylphenylalanine, which is optionally substituted in position 4 by Cl, or -D naphthylalanine,
C _{l represents} D-Trp which is optionally substituted in positions 5 or 6 by F, Cl, Br, NH ₂ and / or OCH ₃ and / or in position 1 by HCO or CH ₃ CO, β-D-naphthylalanine , 3-D-pyridylalanine, D-Tyr or Phe, which is optionally substituted by F, Cl, Br, NH ₂ , CH ₃ or CH ₃ O,
D ₁ stands for Ser,
E ₁ is Tyr or phenylalanine which is optionally substituted in the phenyl ring by Cl, Br, NH ₂ , CH ₃ or CH ₃ O,
F ₁ is D-Phe which is optionally substituted in the phenyl ring by F, Cl, Br, NH ₂ , CH ₃ or CH ₃ O, D-Trp which is optionally substituted in positions 5 or 6 by F, Cl, Br, NH ₂ or CH ₃ O and / or in position 1 by formyl or acetyl, D-Tyr, β-D-naphthylalanine, D Leeu, D-Ile, D-Nle, D-Val, D-Ser (OtBu), D-Arg optionally dialkylated by (C ₁ -C ₆ ) alkyl or (C ₅ -C ₆ ) cycloalkyl , D-homoarginine, optionally dialkylated by (C ₁ -C ₆ ) alkyl or (C ₅ -C ₆ ) cycloalkyl, D-His, D-His (Bzl), D-Lys or D-Orn, wherein these two last radicals are optionally disubstituted by (C ₁ -C ₆ ) -alkyl or (C ₅ -C ₆ ) -cycloalkyl, D-Phe (p-NH ₂ ) or α-p-aminocyclohexylalanine,
G ₁ is Leu, Nle, Nva, N-α-methylleucine, Trp, Phe, Met or Tyr,
H ₁ is Arg, Lys or Orn, which is optionally substituted by (C ₁ -C ₆ ) -alkyl or (C ₅ -C ₆ ) -cycloalkyl,
I ₁ is Pro, hydroxyproline or 3,4-dehydroproline and
K ₁ stands for D-Ala.

The groups E ₁ and F ₁ may, if desired, be replaced with one another. If desired, the groups D ₁ and K ₁ can be radicals Cys which are linked via a bridge SS.

If desired, one of the groups D ₁ and K _{1 may be} Asp or Glu and the other of these groups may be orn, diaminopropionic acid or diaminobutyric acid, the radicals D ₁ and K ₁ being linked via an amide bridge.

• (i) E₁ = Tyr oder Phe, das gegebenenfalls in der oben angegebenen Weise substituiert ist, und zwar im Falle von F₁ = D-Phe oder Lys, oder
• (ii) E₁ = D-Phe oder Lys, und zwar im Falle von F₁ = Tyr oder Phe, das gegebenenfalls in der oben angegebenen Weise substituiert ist, G₁ = Leu, H₁ = Arg, I₁ = Pro und K₁ = D-Ala.

The following meanings for the mentioned symbols are preferred:
R ₁ = acetyl or formyl,
A ₁ = D-Phe, D-Phe (p-Cl), α-D-naphthylalanine or 3,4-dehydroproline,
B ₁ = D-Phe, which is optionally substituted in the manner indicated above, this substitution preferably being a monosubstitution,
C ₁ = D-Trp, which is optionally substituted in the manner indicated above, this substitution preferably being a monosubstitution,
D ₁ = Ser,

• (i) E ₁ = Tyr or Phe, optionally substituted as above, in the case of F ₁ = D-Phe or Lys, or
• (ii) E ₁ = D-Phe or Lys, in the case of F ₁ = Tyr or Phe, which is optionally substituted in the manner indicated above, G ₁ = Leu, H ₁ = Arg, I ₁ = Pro and K ₁ = D-Ala.

at the above mentioned LHRH antagonists is the sugar residue preferentially to the N-terminates Amino group or to a free amino group in a side chain bound.

The sugar derivatives preferably have the following structures in which the antagonist H ₂ N-LHRH is a LHRH antagonist of the formula XVI:

at The above-mentioned formulas XVIa to XVIf are for the sake of simplicity always shown only the binding of a sugar residue to an amino group. If desired, can However, several sugar residues may be present. Preferably two such sugar residues present.

The Starting materials and the syntheses for the preparation of not modified LHRH antagonists are described, for example, in EP-A-0 081 887 and EP-A-0 201 260.

• a) Oxytocin und Vasopressin und deren Derivate, wie Lys⁸-Vasopressin und Orn⁸-Vasopressin,
• b) Insulin und
• c) Wachstumshormonfreigabefaktor.

Other preferred polypeptides include:

• a) oxytocin and vasopressin and their derivatives, such as Lys ⁸ -vasopressin and Orn ⁸ -vasopressin,
• b) insulin and
• c) growth hormone release factor.

The Starting materials and sugar derivatives can be obtained by liquid phase synthesis or solid phase synthesis.

The Sugar derivatives are most easily obtained by solid-phase synthesis produce.

It became a particularly convenient process for the preparation of peptide alcohols found that at the C-terminal end of the peptide chain two alcohol groups or an alcohol group and a thiol group. This method is particularly suitable for the preparation of peptide alcohols, the contain a C-terminal threoninol, serinol or cysteinol residue.

To Examples of include suitable compounds some of the somatostatin compounds described herein.

The Solid phase peptide synthesis has proven to be particularly rapid and inexpensive Process for the preparation of peptides proved and therefore provides a common today for this Method is.

in this connection As is known, first an amino acid via their carboxyl group under Formation of an ester group or amide group to a hydroxyl group or amino group of an insoluble one Synthes resin bound, whereupon in the desired sequence, the other amino acids be bound and finally the finished polypeptide from the carrier resin is split off.

These There is no synthesis in normal polypeptides with C-terminal amino acids Problems. Polypeptide alcohols having a C-terminal end Amino alcohol instead of an amino acid contained, however, go does not readily bond with carrier resins which are hydroxyl groups or amino groups, and / or can be ended after Synthesis not so easy on the carrier resin secede.

• a) Eine herkömmliche Herstellung des entsprechenden Polypeptids, das am C-terminalen Ende eine Aminosäure enthält (wie der Ester eines hydroxylgruppenhaltigen Harzes), und eine anschließende reduktive Aufspaltung unter Verwendung von Borhydriden, wodurch die Carboxylgruppe zugleich in eine Alkoholfunktion überführt wird (US-A-4 254 023 und US-A-4 254 024).
• b) Eine Bindung des terminalen Aminoalkohols als Ether an ein Hydroxymethylharz unter Verwendung von Carbonyldiimidazol und eine nach der Synthese des Peptids erfolgende Abspaltung unter Verwendung von HCl/TFA

oder HBr/TFA (Kun-hwa Hsieh und G. R. Marshall, ACS National Meeting, New Orleans, 21.-25. März 1977).The following methods have already been proposed as possible solid-phase processes for the preparation of peptide alcohols:

• a) A conventional preparation of the corresponding polypeptide containing an amino acid at the C-terminal end (such as the ester of a hydroxyl group-containing resin), followed by a reductive cleavage using boron hydrides, whereby the carboxyl group is converted simultaneously into an alcohol function (US-A 4,254,023 and US-A-4,254,024).
• b) Binding of the terminal aminoalcohol as ether to a hydroxymethyl resin using carbonyldiimidazole and cleavage after synthesis of the peptide using HCl / TFA

or HBr / TFA (Kun-hwa Hsieh and GR Marshall, ACS National Meeting, New Orleans, March 21-25, 1977).

These However, both methods require drastic conditions in the Splitting.

It it has now been found that the cleavage of the peptide from the resin with simultaneous formation of the C-terminal peptide alcohol then under mild conditions leaves, when the C-terminal aminoalcohol via an acetal bond to the Resin is bound.

According to the invention Peptide alcohol containing 2 alcohol groups at the C-terminal end of the peptide chain Contains 1 alcohol group and 1 thiol group, by acid hydrolysis of a Acetals from the peptide alcohol and a polymeric resin containing formylphenyl groups contains educated. This process is called the synthesis of the invention designated.

The resulting reaction can be represented by the formula as follows:

ist der Rest eines unlöslichen Syntheseharzes.
Z ist eine direkte Bindung oder ein Rest, der das Harz mit der acetalisierten Formylphenylgruppe verbindet.
X steht für O oder S.
R₁ ist Wasserstoff oder Methyl.
Y ist der Rest eines Peptidalkohols, der beispielsweise Schutzgruppen tragen kann. Die gegebenenfalls acetalisierte Gruppe CHO befindet sich dabei in m- oder p-Stellung zum Rest Z.In it, the mentioned symbols have the following meanings:

is the remainder of an insoluble synthetic resin.
Z is a direct bond or moiety linking the resin to the acetalated formylphenyl group.
X stands for O or S.
R ₁ is hydrogen or methyl.
Y is the residue of a peptide alcohol which may carry, for example, protecting groups. The optionally acetalated group CHO is in m- or p-position to the radical Z.

Out establish the simplicity is in the formulas given in the above reaction scheme I and II each indicated only one substitution group on the resin. To a molecule Of course, the polymeric resin is a series of such groups bound. The cleavage of Peptidalkahols from the resin by hydrolysis The acetal group is, as already indicated above, under acidic Conditions, for example by means of dilute trifluoroacetic acid. These Hydrolysis can be carried out at room temperature.

in der Formel Ir dann eine Polyäthylenkette).If Z in the formula Ir is a direct bond, then the phenyl radicals carrying the acetal groups are bonded directly to the polymer radical and belong to the polymer. Examples of such compounds of formula Ir are the acetals of a formylated Palystyrolharzes (here

in the formula Ir then a polyethylene chain).

is Z contains a remainder, then this remainder a group, which consists of a conversion between a reactive Group which is directly or indirectly bound to the polymer, and another reactive Group that binds directly or indirectly to the acetalated formylphenyl group is bound results.

The radical Z may have, for example, the following formula IIIr: - (D) _p -O ₁ -Q ₂ - (E) _q - (formula IIIr), in which the individual symbols have the following meanings:
Q ₁ = residue of a reactive group attached to the polymer,
Q ₂ = residue of a reactive group attached to the acetalated formylphenyl group,
D = radical linking the group Q ₁ to the polymer,
E = radical connecting the group Q ₂ with the acetalated formylphenyl group.

The Indices p and q are independent each other for 0 or Z.

The group Q ₁ -Q ₂ is preferably an ester group or amide group, and especially a carboxamide group. Q ₁ is preferably NH, and Q ₂ is preferably CO.

The Groups D and E are independent each other, for example, alkylene radicals or Alkylenoxyreste with 1 to 5 carbon atoms.

-D-Q₁ für den Rest eines aminomethylierten Polystyrolharzes steht und der Rest der Formel

ein Rest der Formel IVr ist

worin R Wasserstoff oder Methyl bedeutet und
m für 0 oder 1 steht,
wobei sich die Acetalgruppe wiederum in Stellung m oder p befindet.Examples of compounds of the formula Ir, wherein Z is a radical of the formula IIIr, are the compounds in which

-DQ _{1 represents} the remainder of an aminomethylated polystyrene resin and the remainder of the formula

is a radical of formula IVr

wherein R is hydrogen or methyl and
m is 0 or 1,
where the acetal group is again in position m or p.

während P Polystyrol ist.In such a case, Z means the group

while P is polystyrene.

The radical IVr preferably has the formula

Instead of of the aminomethylated polystyrene, other polymers can also be used be, especially those with free amino groups, such as Polyacrylamides bearing aminoethyl groups.

The acetalated formyl-phenyl group is, as already mentioned above, to the polymer is preferably bound by an amide bond. hereby ensures that the bond of the acetalated formylphenyl to the resin during the synthesis of the polypeptide and during its elimination from the Polypeptide is stable and that the cleavage in the desired On the acetal, so that on the one hand the peptide alcohol is formed and on the other hand, the Formylphenylrest remains on the resin.

If desired, the peptide alcohol can also be bound at a distance from the resin by incorporating so-called spacers between the reactive groups of the polymer, in particular amino groups, and the reactive groups of the acetalized formylphenyl derivative, in particular carboxyl groups. For certain reactions on polypeptide alcohol, this is conveniently done prior to cleavage, such as by oxidation of cysteine residues. In this case, the radical D or E in the formula IIr additionally contains the spacer, wherein Q ₁ or Q _{2 is} the reactive radical of the spacer.

Of the used spacers may for example be an ω-aminocarboxylic acid, such as ε-aminocaproic acid.

When using an aminomethylated polystyrene, a radical of the formula IVr and of ε-aminocaproic acid as a spacer, the group Z then corresponds, for example, to the following formula:

worin A eine Schutzgruppe für die Aminofunktion ist und sich die Acetalgruppe in Stellung m oder p zum Rest Z befindet. Zu diesem Zweck wird zuerst die Schutzgruppe A abgespalten und die freie Aminogruppe dann mit der nächsten N-geschützten Aminosäure usw. so lange umgesetzt, bis alle Aminosäuren an das Harz in einer Sequenz gebunden sind, die dem gewünschten Peptidalkohol entspricht.The compounds of the formula Ir can be prepared using methods customary in solid-phase technology, starting from a compound of the formula Vr

wherein A is a protective group for the amino function and the acetal group is in position m or p to the radical Z. For this purpose, the protecting group A is first cleaved off and the free amino group then reacted with the next N-protected amino acid, etc., until all amino acids are attached to the resin in a sequence corresponding to the desired peptide alcohol.

The amino protecting groups selected for the amino acids or aminoalcohol used must be such that they can be cleaved under non-acidic conditions, since under acidic conditions hydrolysis of the acetal groups occurs. As such protecting groups, for example, the groups CF ₃ CO- or FMOC- (9-Fluorenylmethyloxycarbonyl) can be used. These protecting groups can be cleaved in a basic medium using methods customary in peptide chemistry.

It can also only the protective groups in the side chains and the amino protecting group the last amino acid used to be acid labile and then simultaneously are cleaved from the resin with the formation of the peptide alcohol.

When Protecting group, the BOC group is preferred.

The bases used are preferably KOH or piperidine or NaBH ₄ .

Of the Construction of the peptide chain can be carried out in a conventional manner starting from a peptide residue with free amino groups and an amino acid with free or activated carboxyl groups are carried out.

The Reaction can be carried out with the addition of, for example, hydroxybenzotriazole and dicyclohexylcarbodiimide.

• a) ein eine Aldehydgruppe tragendes Harz der Formel IIr
  
  worin sich die Gruppe CHO in Stellung m oder p zum Substituenten Z befindet, mit einem N-geschützten Aminoalkohol der Formel HX-CHR₁-CH(NHA)-CH₂OH, der gegebenenfalls in aktivierter Form vorliegt, umgesetzt wird oder
• b) ein Harz der Formel
  
  mit einer Verbindung der Formel VIr
  
  worin sich die Acetalgruppe in Stellung m oder p zur Gruppe Q'1 -(E)_q befindet und die Reste Q'1 und Q'2 zwei reaktionsfähige Gruppen sind, die unter Bildung einer Brücke Q₁-Q₂ miteinander reagieren, umgesetzt wird.

The compounds of the formula Vr can be prepared, for example, by

• a) an aldehyde group-bearing resin of the formula IIr
  
  wherein the group CHO is in the position m or p to the substituent Z, with an N-protected aminoalcohol of the formula HX-CHR ₁ -CH (NHA) -CH ₂ OH, which is optionally present in activated form, is implemented or
• b) a resin of the formula
  
  with a compound of the formula VIr
  
  wherein the acetal group in position m or p to the group Q ' 1 - (E) _q is located and the radicals Q ' 1 and Q ' 2 two reactive groups are reacted, which react to form a bridge Q ₁ -Q ₂ .

The Acetalization according to method a) can in the presence of an acid be carried out as a catalyst. To do this suitable acids belong p-toluenesulfonic acid and p-trifluoromethylsulfonic acid.

If desired, may be a trimethylsilyl group as a protective group for a free alcohol are used.

The esterification according to process b) can be carried out under very mild conditions, such as by reacting a carboxylic acid derivative with a polymer that carries a group OH or NH _2.

mit einer Verbindung der Formel HX-CHR₁-CH(NHA)-CH₂OH hergestellt werden.The compounds of formula VIr may be prepared by acetylation of a compound of formula

with a compound of the formula HX-CHR ₁ -CH (NHA) -CH ₂ OH getting produced.

These Acetylation can be carried out as described above in process a).

During the Construction and cleavage of the peptide alcohol from the resin can be further Implementations be accomplished, for example, a distance of protecting groups, such as S-protecting groups, or oxidation of Cysteine residues.

Such Implementations can be carried out after the cleavage of the peptide alcohol in the liquid phase.

Using the synthesis of the invention can be produced in a simple manner pharmacologically active and other peptides that at the C-terminal end of two alcohol groups or an alcohol holgruppe and a thiol group included.

AcOH

= Essigsäure

BOC

= tert.-Butyloxycarbonyl

But

= tert.-Butyl

DCCI

= Dicyclohexylcarbodiimid

DMF

= Dimethylformamid

Fmoc

= 9-Fluorenylmethoxycarbonyl

MeOH

= Methanol

NEt₃

= Triethylamin

Thr-ol

= Threoninolrest = CH₃-CHOR-CH(CH₂OH)-NH-

TFA

= Trifluoressigsäure

HOBT

= N-Hydroxybenzotriazol

hpGRF

= Wachstumshormonfreigabefaktor der menschlichen Bauchspeicheldrüse

HOSu

= N-Hydroxysuccinimid,

In the following examples, all temperatures are in degrees Celsius and the [Α] 20 D -Values not corrected. It uses the following abbreviations:

AcOH

= Acetic acid

BOC

= tert-butyloxycarbonyl

but

= tert-butyl

DCCI

= Dicyclohexylcarbodiimide

DMF

= Dimethylformamide

Fmoc

= 9-fluorenylmethoxycarbonyl

MeOH

= Methanol

NEt ₃

= Triethylamine

Thr-ol

= Threoninol residue = CH ₃ -CHOR-CH (CH ₂ OH) -NH-

TFA

= Trifluoroacetic acid

HOBT

= N-hydroxybenzotriazole

hpGRF

= Growth hormone release factor of the human pancreas

HOSu

= N-hydroxysuccinimide,

at all the peptides obtained are polyacetate Polyhyärate with a peptide content of 70 to 90%.

By HPLC analysis shows that the peptides contain less than 5% of others Containing peptides.

Of the Factor F given in the following examples shows the peptide content in the products obtained, where F = 1 has a peptide content of 100% corresponds. The difference is up to 100% [(1 - F) × 100] from acetic acid and water.

All Sugars have the α configuration, unless otherwise stated.

-Thr-ol werden mit 3 ml Trifluoressigsäure (100%) versetzt und solange bei Raumtemperatur gehalten, bis sich das gesamte Ausgangsmaterial gelöst hat (5 Minuten). Durch Zugabe von 20 ml Diisopropylether wird die Titelverbindung gefällt und anschließend abfiltriert und mit Diisopropylether gewaschen. Durch Kieselgelchromatographie (Laufmittel: CHCl₃/MeOH/BOAC/H₂O 7/3/0,5/0,5) wird die Titelverbindung gereinigt und als weißes Lyophilisat isoliert.
[α20D ]: –31,3° (c = 0,52 in 95% AcOH) F: 0,88400 mg

3 ml of trifluoroacetic acid (100%) are added to -Thr-ol and kept at room temperature until all the starting material has dissolved (5 minutes). By addition of 20 ml of diisopropyl ether, the title compound is precipitated and then filtered off and washed with diisopropyl ether. By silica gel chromatography (eluent: CHCl ₃ / MeOH / BOAC / H ₂ O 7/3 / 0.5 / 0.5), the title compound is purified and isolated as a white lyophilisate.
[α 20 D ] : -31.3 ° (c = 0.52 in 95% AcOH) F: 0.88

• 
  Zu einer Lösung von 10 g
  
  Acetat in 100 ml DMF werden bei Raumtemperatur 2,25 g Di-tert. butyl-percarbonat, gelöst in 30 ml DMF, langsam zugetropft. Nach zwei Stunden bei Raumtemperatur wird das Lösungsmittel im Vakuum abgezogen und der Rückstand mit 200 ml Diisopropylether versetzt. Der sich bildende Niederschlag wird abfiltriert, mit Diisopropylether gewaschen und getrocknet. Zur Reinigung des Rohproduktes wird dieses über Kieselgel chromatogphiert (Laufmittel: CH₂Cl₂/MeOH 9/1) und anschließend als weißes amorphes Pulver isoliert. [α20D ] 29,8° (c = 1,28 in DMF)
• 
  2 g D-(+)-Glucose und 0,5 g des Endproduktes der Stufe a) werden in 20 ml MeOH/HOAc 9/1 (v/v) gelöst und drei Stunden bei 60-70°C gehalten. Nach dem Eindampfen wird in wenig Methanol aufgenommen und die Titelverbindung mit Diisopropylether gefällt. Zur Reinigung wird über Kieselgel chromatographiert (Laufmittel: CH₂Cl₂/MeOH 9/1). Man erhält ein amorphes Pulver. [α]20D = 12,0° (c = 1,04 in DMF)

The starting product can be prepared as follows:

• 
  To a solution of 10 g
  
  Acetate in 100 ml of DMF at room temperature 2.25 g of di-tert. Butyl percarbonate, dissolved in 30 ml of DMF, slowly added dropwise. After two hours at room temperature, the solvent is removed in vacuo and the residue is mixed with 200 ml of diisopropyl ether. The precipitate which forms is filtered off, washed with diisopropyl ether and dried. To purify the crude product, this is chromatographed on silica gel (eluent: CH ₂ Cl ₂ / MeOH 9/1) and then isolated as a white amorphous powder. [α 20 D ] 29.8 ° (c = 1.28 in DMF)
• 
  2 g of D - (+) - glucose and 0.5 g of the end product of step a) are dissolved in 20 ml of MeOH / HOAc 9/1 (v / v) and kept at 60-70 ° C for three hours. After evaporation, the mixture is taken up in a little methanol and the title compound is precipitated with diisopropyl ether. For purification, it is chromatographed on silica gel (eluent: CH ₂ Cl ₂ / MeOH 9/1). An amorphous powder is obtained. [Α] 20 D = 12.0 ° (c = 1.04 in DMF)

Beispiel 2: N^α-(α-Glucosyl(1-4)-desoxyfructosyl]-SMS

ausgehend von D(+)-Maltose statt D-Glucose
F: 0,91
[α]20D = –7,9° (c = 0,71 in 95% AcOH) Beispiel 3: N^α-[α-Glucosyl(1-4)-α-glucosyl(1-4)-β-desoxyfructosyl]-SMS

ausgehend von Maltotriose statt D-Glucose
[α]20D = +11,3° (c = 0,71 in 95% AcOH) Beispiel 4: N^α-Fructofuranuronsäure-SMS

ausgehend von D-Glucuronsäure statt D-Glucose
[α]20D = –29,4° (c = 0,34 in 95% AcOH) Beispiel 5: N^α-Desoxysorbosyl-SMS

ausgehend von D(+)-Galaktose statt D-Glucose
[α]20D = –30,4° (c = 0,50 in 95% AcOH) Beispiel 6: N^α-(O-β-D-Glucosyl-(1-4)-desoxyfructosyl]-SMS

ausgehend von D(+)-Cellobiose
[α]20D = –28,1° (c = 0,47 in 95% AcOH) Beispiel 7: N^α-L(–)-Desoxyfructosyl-SMS

ausgehend von L(–)-Glucose statt D(+)-Glucose
[α]20D = –20° (c = 0,46 in 95% AcOH) Beispiel 8: N^α-(O-β-D-Glucosyl-(1-6)-desoxyfructosyl]-SMS

ausgehend von Gentiobiose statt D-Glucose
[α]20D = 23,5° (c = 0,46 in 95% AcOH) F: 0,76 Beispiel 9: N^α-(O-β-D-Galaktosyl-(1-4)-desoxyfructosyl]-SMS

ausgehend von D(+)-Lactose statt D-Glucose
[α]20D = –29,3° (c = 0,55 in 95% AcOH) Beispiel 10: N^α-[O-α-Galaktosyl-(1-6)-desoxyfructosyl]-SMS

ausgehend von Melibiose statt D-Glucose
[α]20D = +8,4° (c = 0,5 in 95% AcOH) F: 0,76 Beispiel 11: [N-(1-Desoxy-D-fructosyl)-Tyr³]-SMS

ausgehend von Tyr³-SMS statt SMS
[α]20D = –32,2° (c = 0,9 in 95% AcOH) F: 0,87 Beispiel 12: [N-(α-D-Glucopyranosyl-(1-4)-1-desoxy-fructosyl)-Tyr³]-SMS

ausgehend von D(+)-Maltose anstelle von D-Glucose und von Tyr³-SMS anstelle von SMS
[α]20D = –4,7° (c = 1,0 in 95% AcOH) F = 0,81 Beispiel 13:

ausgehend von D-Glucoheptose anstelle von D-Glucose. [α]20D = –12,9° (c = 1,0 in 95% AcOH) F = 0,91 Beispiel 14:

ausgehend von D(+)-Glucose und SMS ohne eine Schutzgruppe an der ε-NH₂ Gruppe von Lysin.
[α]20D = –42,4° (c = 0,37 in 95% AcOH) F = 0,83 Beispiel 15:

ausgehend von Glucoheptose und SMS ohne eine Schutzgruppe an der ε-NH₂ Gruppe des Lysins.
[α]20D = –9,3° (c = 0,41 in 95% AcOH) F = 0,84 Beispiel 16: Fructosyl-6-phosphat-SMS

ausgehend von D-Glucose-6-phosphat anstelle von D-Glucose.
[α]20D = –19,5° (c = 1,0 in 95% AcOH) F = 0,89 Beispiel 17:

ausgehend von D-Ribose anstelle von D-Glucose.
[α]20D = –31,8° (c = 1,0 in 95% AcOH) Beispiel 18: N^α-Desoxyfructosyl-(D)Phe-Cys[COC(COC(CH₃)₃]-Phe-(D)Trp-Lys-Thr-Cys[000(CH₃)₃]-Thr-ol

Analogously to Example 1, the following compounds (all as acetates) were prepared (in these compounds SMS is the polypeptide radical

Example 2: N ^α - (α-Glucosyl (1-4) -deoxyfructosyl] -SMS

starting from D (+) - maltose instead of D-glucose
F: 0.91
[Α] 20 D = -7.9 ° (c = 0.71 in 95% AcOH) Example 3: N ^α - [α-Glucosyl (1-4) -α-glucosyl (1-4) -β-desoxyfructosyl] -SMS

starting from maltotriose instead of D-glucose
[Α] 20 D = + 11.3 ° (c = 0.71 in 95% AcOH) Example 4: N ^α -Fructofuranuronic acid SMS

starting from D-glucuronic acid instead of D-glucose
[Α] 20 D = -29.4 ° (c = 0.34 in 95% AcOH) Example 5: N ^α -Desoxysorbosyl SMS

starting from D (+) - galactose instead of D-glucose
[Α] 20 D = -30.4 ° (c = 0.50 in 95% AcOH) Example 6: N ^α - (O-β-D-Glucosyl- (1-4) -deoxyfructosyl] -SMS

starting from D (+) - cellobiose
[Α] 20 D = -28.1 ° (c = 0.47 in 95% AcOH) Example 7: N ^α -L (-) - deoxyfructosyl-SMS

starting from L (-) - glucose instead of D (+) - glucose
[Α] 20 D = -20 ° (c = 0.46 in 95% AcOH) Example 8: N ^α - (O-β-D-Glucosyl- (1-6) -deoxyfructosyl] -SMS

starting from gentiobiose instead of D-glucose
[Α] 20 D = 23.5 ° (c = 0.46 in 95% AcOH) F: 0.76 Example 9: N ^α - (O-β-D-galactosyl- (1-4) -deoxyfructosyl] -SMS

starting from D (+) - lactose instead of D-glucose
[Α] 20 D = -29.3 ° (c = 0.55 in 95% AcOH) Example 10: N ^α - [O-α-Galactosyl- (1-6) -deoxyfructosyl] -SMS

starting from melibiose instead of D-glucose
[Α] 20 D = + 8.4 ° (c = 0.5 in 95% AcOH) F: 0.76 Example 11: [N- (1-Deoxy-D-fructosyl) -Tyr ³ ] -SMS

starting from Tyr ³ -SMS instead of SMS
[Α] 20 D = -32.2 ° (c = 0.9 in 95% AcOH) F: 0.87 Example 12: [N- (α-D-glucopyranosyl- (1-4) -1-deoxy-fructosyl) -tyr ³ ] -SMS

starting from D (+) - maltose instead of D-glucose and from Tyr ³ -SMS instead of SMS
[Α] 20 D = -4.7 ° (c = 1.0 in 95% AcOH) F = 0.81 Example 13:

starting from D-glucoheptose instead of D-glucose. [Α] 20 D = -12.9 ° (c = 1.0 in 95% AcOH) F = 0.91 Example 14:

starting from D (+) - glucose and SMS without a protective group on the ε-NH ₂ group of lysine.
[Α] 20 D = -42.4 ° (c = 0.37 in 95% AcOH) F = 0.83 Example 15:

starting from glucoheptose and SMS without a protective group on the ε-NH ₂ group of lysine.
[Α] 20 D = -9.3 ° (c = 0.41 in 95% AcOH) F = 0.84 Example 16: Fructosyl 6-phosphate SMS

starting from D-glucose-6-phosphate instead of D-glucose.
[Α] 20 D = -19.5 ° (c = 1.0 in 95% AcOH) F = 0.89 Example 17:

starting from D-ribose instead of D-glucose.
[Α] 20 D = -31.8 ° (c = 1.0 in 95% AcOH) Example 18: N ^α -deoxyfructosyl- (D) Phe-Cys [COC (COC (CH ₃ ) ₃ ] -Phe- (D) Trp-Lys -Thr-Cys [000 (CH ₃ ) ₃ ] -Thr-ol

• b) N^α-Desoxyfructosyl-(D)-Phe-Cys-Phe-(D)Trp-LystBOC)-Thr-Cys-Thr-ol 0,51 g der Endverbindung der Stufe a) in einem Gemisch von 10 ml Dioxan und 2 ml NEt₃/AcOH Puffer pH 8,6 unter Argon wird versetzt mit total 0,4 g Dithioerythritol. Man rührt ca. 15 Stunden bei Raumtemperatur und engt im Vakuum ein. Ausgefallenes Produkt wird abzentrifugiert. Der Rückstand wird mit wenig H₂O gewaschen, dann im Vakuum getrocknet. Man erhält die Titelverbindung. [α]20D = +3,8° (c = 0,8 in DMF)
• c) N^α-Desoxyfructosyl-(D)Phe'-Cys[COC(CH₃)₃)-Phe-(D)Trp-Lys(BOC)-Thr-Cys[COC(CH₃(₃]-Thr-ol 0,38 g der Endverbindung der Stufe b) werden unter Argon in 25 ml N-Methylpyrrolidon gelöst, bei 0° mit 0,3 ml N-Methylmorpholin und 0,31 ml Pivaloylchlorid versetzt und ca. 16 Stunden bei 0° gerührt. Man verrührt mit Ether/Diisopropylether. Ausgefallenees Produkt wird abzentrifugiert. Der Rückstand wird mit wenig DMF gelöst und das Produkt durch Zugabe von MeOH und H₂O ausgefällt. Man zentrifugiert. Der Rückstand wird im Vakuum getrocknet und ohne weitere Reinigung weiter verwendet.
• d) N^α-Desoxyfructosyl-(D)Phe-Cys[COC(CH₃)₃]-Phe-(D)Trp-Lys-Thr-Cys[COC(CH₃)₃]Thr-ol Der Rückstand aus Stufe c) wird bei 0° in 5 ml TFA/H₂O (9:1) gelöst und 15 Minuten gerührt. Das Produkt wird durch Zugabe von einem Gemisch von Ether/10% 5n HCl/Ether ausgefällt. Man filtriert, wäscht mit Ether und trocknet. Der Rückstand wird durch Chromatographie an Kieselgel in einem Gemisch von CHCl₃/MeOH/AcOH/H₂O gereinigt. Fraktionen die das gewünschte Produkt enthalten, werden vereinigt, im Vakuum unter Zugabe von H₂O eingeengt, dann lyophilisiert. Man erhält die Titelverbindung. [α]20D = –15,3° (c = 1,0 in 95% AcOH) F: 0,88

0.58 g of the compound of Example 1 in 10 ml of DMF are mixed with 0.08 ml of NEt ₃ , then with 0.12 ml of (BOC) ₂ O. The mixture is stirred for about 15 hours at room temperature, concentrated in vacuo and stirred with ether. Precipitated product is filtered off. The residue is dissolved with a little MeOH, then the product is precipitated by the addition of H ₂ O. It is filtered, washed with a little H ₂ O, dried and the title compound is obtained.
[Α] 20 D = + 14.5 ° (c = 0.7 in DMF)

• b) N ^α -deoxyfructosyl- (D) -Phe-Cys-Phe- (D) Trp-LystBOC) -Thr-Cys-Thr-ol 0.51 g of the end compound of step a) in a mixture of 10 ml of dioxane and 2 ml of NEt ₃ / AcOH buffer pH 8.6 under argon is added with a total of 0.4 g of dithioerythritol. The mixture is stirred for about 15 hours at room temperature and concentrated in vacuo. Precipitated product is centrifuged off. The residue is washed with a little H ₂ O, then dried in vacuo. The title compound is obtained. [Α] 20 D = + 3.8 ° (c = 0.8 in DMF)
• c) N ^α -deoxyfructosyl- (D) Phe'-Cys [COC (CH ₃ ) ₃ ) -Phe- (D) Trp-Lys (BOC) -Thr-Cys [COC (CH ₃ ( ₃ ) -Thr-ol 0.38 g of the end compound of step b) are dissolved under argon in 25 ml of N-methylpyrrolidone, mixed at 0 ° with 0.3 ml of N-methylmorpholine and 0.31 ml of pivaloyl chloride and stirred at 0 ° for about 16 hours Stirring with ether / diisopropyl ether Precipitated product is centrifuged off The residue is dissolved with a little DMF and the product is precipitated by addition of MeOH and H ₂ O. The mixture is centrifuged and the residue is dried in vacuo and used further without further purification.
• d) N ^α -deoxyfructosyl- (D) Phe-Cys [COC (CH ₃ ) ₃ ] -Phe- (D) Trp-Lys-Thr-Cys [COC (CH ₃ ) ₃ ] Thr-ol The residue from step c ) is dissolved at 0 ° in 5 ml of TFA / H ₂ O (9: 1) and stirred for 15 minutes. The product is precipitated by adding a mixture of ether / 10% 5N HCl / ether. It is filtered, washed with ether and dried. The residue is purified by chromatography on silica gel in a mixture of CHCl ₃ / MeOH / AcOH / H ₂ O. Fractions containing the desired product are combined, concentrated in vacuo with the addition of H ₂ O, then lyophilized. The title compound is obtained. [Α] 20 D = -15.3 ° (c = 1.0 in 95% AcOH) F: 0.88

(hergestellt wie im Beispiel 1a) beschrieben) werden in 100 ml MeOH/HOAc 9/1 gelöst und 16 Stunden bei 65°C gehalten. Nach dem Eindampfen wird in wenig Methanol gelöst und das Rohprodukt mit Diisopropylether gefällt. Ohne Reinigung wird das so erhaltene Rohprodukt in die Schutzgruppenspaltung (BOC-Spaltung) eingesetzt.2 g of D (-) - fructose and 1 g

(prepared as described in Example 1a) are dissolved in 100 ml MeOH / HOAc 9/1 and kept at 65 ° C for 16 hours. After evaporation, the mixture is dissolved in a little methanol and the crude product precipitated with diisopropyl ether. Without purification, the resulting crude product is used in the protective group cleavage (BOC cleavage).

For this purpose, 1 g of the crude product obtained is mixed with 20 ml of trifluoroacetic acid (100%) and kept at room temperature until all the starting material has dissolved (5 minutes). By addition of 200 ml of diisopropyl ether, the title compound is precipitated and then filtered off and washed with diisopropyl ether (eluting with silica gel chromatography (eluent: CHCl ₃ / MeOH / HOAc / H ₂ O 7/3 / 0.5 / 0.5)), the title compound is purified and isolated as a white lyophilisate.
[Α] 20 D = -6.7 ° (c = 0.3 in 95% AcOH) F: 0.73

Beispiel 20: 2-[Tyr³-SMS]-2-desoxy-D-glucose

The second product which can be obtained is the following 1: 1 mixture of isomes which has the reverse configuration at the carbon atom C _{2 of} the carbohydrate radical:

Example 20: 2- [Tyr ³ -SMS] -2-deoxy-D-glucose

The title compound is prepared analogously to Example 19 starting from Tyr ³ -SMS instead of SMS.
[Α] 20 D = -2.9 ° (c = 1.0 in 95% AcOH) F = 0.95

Thr-ol werden mit 3 ml Trifluoressigsäure (100%) bis zur vollständigen Lösung behandelt (5 Minuten). Anschließend wird die Titelverbindung durch Zugabe von 20 ml Diisopropylether als Trifluoracetat gefallt und nach Filtration, Trocknung und anschließender Kieselgelchromatographie (Laufmittel: CHCl₃/MeOH/HOAc/H₂O 7/3/0,5/0,5) wird die Titelverbindung als weißes Lyophilisat rein isoliert (Acetat).
[α]20D = -29,2 (c = 0,48 in 95% AcOH) F: 0,85170 mg mg glucuronic acid amide from

Thr-ol are treated with 3 ml trifluoroacetic acid (100%) until complete (5 minutes). The title compound is then precipitated by addition of 20 ml of diisopropyl ether as trifluoroacetate and after filtration, drying and subsequent silica gel chromatography (eluent: CHCl ₃ / MeOH / HOAc / H ₂ O 7/3 / 0.5 / 0.5) is the title Ver Binding as white lyophilisate purely isolated (acetate).
[Α] 20 D = -29.2 (c = 0.48 in 95% AcOH) F: 0.85

117 mg Glucuronsäure und 135 mg HOBT wird eine Lösung von 135 mg DCCI in 2 ml DMF zugegeben. Mach 48 Stunden und gleichzeitigem Auftauen auf Raumtemperatur wird der entstandene Dicyclohexylharnstoff abfiltriert und die Titelverbindung durch Zugabe von 20 ml Diisopropylether gefällt. Nach Filtration, Trocknung und Chromatographie über Kieselgel (Laufmittel: CH₂Cl₂MeOH 9/1) wird die Titelverbindung rein isoliert.
[α]20D = +16,7° (c = 0,50 in DMF)

The starting product can be prepared as follows:
To a cooled to -30 ° C solution in DMF of 450 mg B-DPhe-

117 mg glucuronic acid and 135 mg HOBT are added to a solution of 135 mg DCCI in 2 ml DMF. After 48 hours and simultaneous thawing to room temperature, the resulting dicyclohexylurea is filtered off and the title compound is precipitated by adding 20 ml of diisopropyl ether. After filtration, drying and chromatography on silica gel (eluent: CH ₂ Cl ₂ MeOH 9/1), the title compound is isolated in pure form.
[Α] 20 D = + 16.7 ° (c = 0.50 in DMF)

Analogously to Example 21, the title compound was obtained starting from L (-) - quinic acid.
[Α] 20 D = -50 ° (c = 0.44 in 95% AcOH) F: 0.97

Analogously to Example 21, starting from the sialic acid, the title compound was obtained.
[Α] 20 D = -60.8 ° (c = 0.6 in 95% AcOH) F: 0.95

werden in 10 ml Methanol gelöst und mit einigen Tropfen 1 N NaOCH₃-Lösung in Methanol auf pH 10 gestellt. Nach 15 Minuten Reaktionszeit wird mit Ionentauscher (z.B.: AMHERLYST^R 15, H⁺) neutralisiert und der Ionentauscher abfiltriert. Das Filtrat wird eingeengt und der Rückstand mit 3 ml Trifluoressigsäure 5 Minuten behandelt. Die Titelverbindung wird als Trifluoracetat durch Zugabe von 20 ml Diisopropylether gefällt und wird nach Filtration, Trocknung und Kieselgelchromatographie (Laufmittel: CHCl₃/MeOH/HOAc/H₂O 7/3/0,5/0,5) als weißes Lyoghilisat rein isoliert.
[α]20D = –39,2° (c = 0,60 in 95% AcOH) F: 0,91250 mg

are dissolved in 10 ml of methanol and adjusted to pH 10 with a few drops of 1 N NaOCH ₃ solution in methanol. After 15 minutes reaction time is neutralized with ion exchanger (eg: AMHERLYST ^R 15, H ⁺ ) and the ion exchanger is filtered off. The filtrate is concentrated and the residue is treated with 3 ml of trifluoroacetic acid for 5 minutes. The title compound is precipitated as trifluoroacetate by addition of 20 ml of diisopropyl ether and, after filtration, Drying and silica gel chromatography (eluent: CHCl ₃ / MeOH / HOAc / H ₂ O 7/3 / 0.5 / 0.5) as a white Lyoghilisat purely isolated.
[Α] 20 D = -39.2 ° (c = 0.60 in 95% AcOH) F: 0.91

The Starting product can be prepared as follows:

a) Tetra-O-acetyl-O-β-D-glucosyl-glycolic acid benzyl ester

To a solution of 830 mg of bicyclic acid benzyl ester in 50 ml of CH ₂ Cl ₂ is introduced 2.5 g molecular sieve 4 Å, powder and, after addition of 2.8 g silver trifluoromethanesulfonate, a solution of 4.1 g acetobromo glucose in 50 ml CH ₂ Cl ₂ dropwise.

After 15 minutes, the reaction is quenched with 4 ml of pyridine, filtered off from solid components, and the filtrate is shaken out with 10% NaHSO ₄ solution. The title compound is isolated by silica gel chromatography (eluent: CH ₂ Cl ₂ / MeOH 99/1).
[Α] 20 D = -22.4 ° (c = 1.7 in CHCl ₃ )

b) Tetra-O-acetyl-O-β-D-glucosyl-glycolic acid

800 mg of tetra-O-acetyl-O-β-D-glucosyl-glycolic acid benzyl ester are dissolved in 40 ml of ethanol / water 1/1 (v / v) and admixed with 400 mg of palladium / activated carbon 10%. Hydrogenation on the "PARR - APPARATUS" at 50 PSI leads to the title compound, which is isolated in crystalline form after filtration and concentration in vacuo.
[Α] 20 D = -35.5 ° (c = 1.03 in MeOH)

und 45 mg HOBT in 2 ml DMF, gekühlt auf –30°C, werden 45 mg DCCI, gelöst in 1 ml DMF zugegeben. Nach 48 Stunden und Auftauen auf Zimmertemperatur wird der entstandene Dicyclohexylharnstoff abfiltriert und die Titelverbindung aus dem Filtrat durch Zugabe von 20 ml Diisopropylether ausgefällt.To a solution of 81 mg of tetra-O-acetyl-O-β-D-glucosyl-glycolic acid, 225 mg

and 45 mg HOBT in 2 ml DMF, cooled to -30 ° C, 45 mg DCCI dissolved in 1 ml DMF are added. After 48 hours and thawing to room temperature, the resulting dicyclohexylurea is filtered off and the title compound is precipitated from the filtrate by addition of 20 ml of diisopropyl ether.

Thr-ol). Beispiel 25: N-(O-β-D-Galaktosyl-oxyacetyl)-SMS

[α]20D = –37,5° (c = 1 in 95% AcOH) F: 0,95 Beispiel 26: N^α-(O-β-Cellobiosyl-oxyacetyl)-SMS

[α]20D = –32,5° (c = 1 in 95% AcOH) F: 0,91 Beispiel 27: N^α-(O-β-(D)-Glucosyl-oxyisobutyryl)-SMS

[α]20D = –32,9° (c = 1 in 95% AcOH) F: 0,93 Beispiel 2: N^α-(O-α-(D)-Glucosyl-α-(L)-oxyisovaleryl)-SMS

[α]20D = –44,3° (c = 1 in 95% AcOH) F: 1,00 Beispiel 29: [N-Acetylmuramyl-(D)Phe¹]-SMS

[α]20D = –15,4° (c = 0,13 in 95% AcOH) F: 0,9 Beispiel 30: β-D-Glucosyl-thiocarbamoyl-SMS

Analogously to Example 24, the following compounds were also prepared (where SMS is the radical

Thr ol). Example 25: N- (O-β-D-galactosyl-oxyacetyl) -SMS

[Α] 20 D = -37.5 ° (c = 1 in 95% AcOH) F: 0.95 Example 26: N ^α - (O-β-Cellobiosyl-oxyacetyl) -SMS

[Α] 20 D = -32.5 ° (c = 1 in 95% AcOH) F: 0.91 Example 27: N ^α - (O-β- (D) -glucosyl-oxyisobutyryl) -SMS

[Α] 20 D = -32.9 ° (c = 1 in 95% AcOH) F: 0.93 Example 2: N ^α - (O-α- (D) -glucosyl-α- (L) -oxyisovaleryl) -SMS

[Α] 20 D = -44.3 ° (c = 1 in 95% AcOH) F: 1.00 Example 29: [N-Acetylmuramyl- (D) Phe ¹ ] -SMS

[Α] 20 D = -15.4 ° (c = 0.13 in 95% AcOH) F: 0.9 Example 30: β-D-Glucosyl-thiocarbamoyl-SMS

Treat 620 mg of E-Fmoc-SMS in 50 ml of a 3: 1 mixture of CH ₃ CN / H ₂ O with 0.45 ml of triethylamine, add 272 ml of 2,3,4,6-tetra-O-acetyl- β-D-glucosyl isothiocyanate and the mixture is kept for 1 hour at room temperature. The mixture is evaporated under vacuum. The residue is taken up in a little methanol and treated with diisopropyl ether, whereby the product precipitates in practically pure form.

To cleave the Fmoc group and the acyl group, the product is dissolved in 50 ml of absolute methanol and the solution is treated with a catalytic amount of NaOCH ₃ in methanol. After 30 minutes, the reaction is terminated on the basis of a thin-layer chromatographic analysis, whereupon the mixture is neutralized with 1% acetic acid and evaporated under vacuum. The residue is taken up in water and extracted with ethyl acetate. The aqueous layer is lyophilized. The residue is purified over silica gel and desalted, for example, over Duolit.

The title compound is obtained as a lyophilisate.
[Α] 20 D = -48.5 ° (c = 1 in 95% AcOH) F = 1

The starting material E-Fmoc-SMS can be prepared as follows:
5 g of SMS acetate and 5 g of NaHCO _{3 are} treated in 100 ml of a 3: 1 mixture of DMF / H ₂ O with 1.6 g of Fmoc-HOSu. After one hour of treatment at room temperature, the mixture is diluted with 400 ml H ₂ O and extracted with 250 ml of a 95: 5 mixture of ethyl acetate and methanol. The organic layer is dried with Na ₂ SO ₄ and concentrated. After column chromatography on silica gel, the starting material is obtained as an amorphous substance.
[Α] 20 D = 24.3 ° (c = 1.13 in DMF)

Example 31: cellobiosylthiocarbamyl-SMS

[α]20D = –4,3° (c = 1 in AcOH) F = 0,87 Starting from octa-acetyl-cellobiosyl-isothiocyanate, the title compound is prepared with the formula:

[Α] 20 D = -4.3 ° (c = 1 in AcOH) F = 0.87

Example 32: B-D-Glucosylcarbamoyl-SMS

[α]20D = –39,9° (c = 1 in 95% AcOH) F = 0,81Starting from 2,3,4,6-tetra-O-acetyl-β-D-glucosyl isocyanate, the title compound is prepared with the formula:

[Α] 20 D = -39.9 ° (c = 1 in 95% AcOH) F = 0.81

Example 33: cellobiosylcarbamoyl-SMS

[α]20D = –37,9° (c = 1 in 95% AcOH) F = 0,85 Beispiel 34: 1-Desoxy-D-sorbityl-SMS

Starting from octa-acetyl-cellobiosyl-isocyanate, the title compound is prepared with the formula:

[Α] 20 D = -37.9 ° (c = 1 in 95% AcOH) F = 0.85 Example 34: 1-deoxy-D-sorbityl-SMS

Treat 0.5 mg of the title compound of Example 1 in 50 ml of methanol first with NaBH ₄ and then with 5% acetic acid under conditions such that the pH does not rise above 7. The total amount of NaBH _{4 used} is about 10 equivalents.

After completion of the reaction (4 to 5 hours), the mixture is treated with acetic acid to destroy excess NaBH ₄ . The mixture is then concentrated under vacuum. The residue is desalted, for example with Duolit and purified over silica gel. In addition to 1-deoxy-D-mannityl SMS is obtained as the main compound, the title compound, which is formed as a lyophilisate.
[Α] 20 D = -17.6 ° (c = 1 in 95% AcOH) F = 0.82

Example 35: α-D-Glucosyl (1-4) -deoxysorbityl-SMS

[α]20D = +1,6° (c = 1 in AcOH) F = 0,9 Beispiel 36: 1,2-Didesoxy-sorbityl-SMS

In an analogous manner to Example 34, starting from the title compound of Example 2, the following compound is prepared:

[Α] 20 D = + 1.6 ° (c = 1 in AcOH) F = 0.9 Example 36: 1,2-dideoxy-sorbityl-SMS

Treat 0.55 g of HOC-SMS in 30 ml of dioxane with 50 mg of NaBH ₃ CN and then add 250 mg of 2-deoxy-D-glucose. The pH of the mixture is adjusted to 7 with 0.1 ml of HCl and heated to 100 ° C. for 6 hours. The mixture is cooled, frozen and lyophilized. The residue is taken up in ethyl acetate (50 ml) and shaken with water. The organic layer is dried and evaporated under vacuum. The BOC group is cleaved in the usual way with TFA. The product is purified on silica gel and desalted, for example, over Duolit to give the title compound.
[Α] 20 D = 25.5 ° (c = 1 in 95% HOAc) F = 0.83

In an analogous manner, the compounds of the above Examples 34 (starting from glucose) and 35 (starting from maltose) can also be prepared. Example 37: N ^α -isocaproyl des (1-4) - [Ala ⁷ , N ^ε - (1-deoxy-fructosyl) -Lys ^11,18 ] Salmcalcitonin

Dissolve 10.3 g of N ^α -isocaproyl-des (1-4) - [Ala ⁷ ] salmcalcitonin polyacetate and 1.8 g of D (+) - glucose in a mixture of 94 ml of DMF and 6 ml of acetic acid. After 2 hours, at 50 ° C, the product is completely precipitated by addition of ether, filtered off with suction, washed with ether and dried in vacuo. For purification, about 5-10 g of the product are dissolved in water, the solution is applied to a reverse phase column 4 × 25 cm, C-18 on silica gel and chromatographed with a gradient of water and 0-80%. a solvent mixture consisting of 38 parts of water, 60 parts of acetonitrile and 2 parts of 85% phosphoric acid. The fractions containing the pure product are combined, filtered through a column of about 100 ml of a weakly basic zone exchanger in the acetate form and washed with water. The filtrate is lyophilized to give the title compound as a polyacetate, polyhydrate.
[Α] 20 D = -34.8 ° (c = 0.73 in CH ₃ COOH 95%) F: 0.93 FAB mass spectroscopy 3407 (MN ⁺ )

The N used as the starting ^α -Isocaproyl-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr -Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH ₂ can be prepared as follows:

a) N ^α -isocaproyl-Ser (Bu ^t ) -Thr (Bu ^t ) -Ala-Val-Leu-OCH ₂ -phenyl- (p) OCH ₂ -co (polystyrene-1% -dinvylbenzene)

1 g of p-hydroxymethyl-phenoxymethyl-co (polystyrene-1% -dinylbenzene) is gelled in dimethylformamide / methylene chloride 1: 4 (v / v), filtered off with suction and washed with a solution of 0.74 g of Fmoc-leucine and 0.19 g 1-hydroxybenzotriazole in 5 ml of the above-mentioned solvent mixture. While stirring, 0.43 g of dicyclohexylcarbodiimide and 85 mg of 4-dimethylaminopyridine are added, each in 5 ml of the same solvent mixture. The mixture is stirred for 16 hours at 20 °, filtered off with suction and washed with the solvent mixture, then with dimethylformamide. Fmoc-Leu-OCH ₂ -phenyl- (p) -OCH ₂ -co (polystyrene-1% -dinylbenzene) is obtained.

Of Fmoc-Leu-OCH ₂ -phenyl- (p) OCH ₂ -co (polystyrene-1% -divinylbenzene) (1.56 mcg = 0.7 mmol), the N ^α -Fmoc group is cleaved off by treatment with piperidine ( 20% v / v) in DMF for 10 minutes. It is washed well with DMF and added, dissolved in 5 ml of DMF, 0.71 g Fmoc-Val-OH, 0.28 g of 1-hydroxy benzotriazole and 0.32 ml of diisopropylcarbodiimide. After 45 minutes, it is filtered off with suction and the peptide resin washed well with DMF. Repeating the removal of the N ^α -Fmoc group and coupling with the following amino acid in the sequence in the order:
Fmoc-Ala-OH (0.65g), Fmoc-Thr (Bu ^t ) -OH (0.83g) and Fmoc-Ser (Bu ^t ) -OH (0.80g). In the last reaction cycle (cleavage of the Fmoc protecting group, acylation with protected amino acid), the amino acid derivative is replaced by isocaproic acid (0.41 g), the amounts of 1-hydroxybenzotriazole are increased to 0.53 g and diisopropylcarbodiimide to 0.54 g and coupled during 15 hours. The protected peptide-resin is washed well with DMF and methylene chloride, dried in vacuo at 40 ° C. for 15 hours and the protected peptide-resin is obtained as a colorless powder.

b) N ^α -isocaproyl-Ser-Thr-Ala-Val-Leu-OH

N ^α -Isocaproyl-Ser (Bu ^t) -Thr (Bu ^t) -Ala-Val-Leu-OCH ₂ -phenyl (p) OCH ₂ -CO (polystyrene-1% divinylbenzene) (1.0 g) is stirred in a mixture of trifluoroacetic acid (5 ml) and methylene chloride (5 ml). It is filtered, washed with the same mixture (5 ml), then with methylene chloride, concentrated in vacuo and precipitated completely by addition of ether. The precipitate is washed well with ether and dried in vacuo over solid potassium hydroxide to give the title compound as a colorless, amorphous powder.

c) Na-isocaproyl-Ser-Thr-Ala-Val-Leu-Gly-Lys (BOC) -Leu-Ser-Gln-Glu (OBu ^t ) -Leu-His-Lys (BOC) -Leu-Gln-Thr Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH ₂

To a solution of N ^α -Isocaproyl-Ser-Thr-Ala-Val-Leu-OH (0.165 g) in DMF (7 ml) was added H-Gly-Lys (BOC) -Leu-Ser-Gln-Glu (OBu ^t ) -Leu-His-Lys (BOC) -Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH ₂ hydrochloride (0.59 g), 3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (0.017 g), dicyclohexylcarbodiimide (0.065 g) and as much N-ethyl-N, N-diisopropylamine until a sample of the reaction mixture on humidified pH paper indicates a pH response of about 6. After 16 hours, precipitate by addition of ether, dried and the title compound.

d) N ^α -isocaproyl-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-ASn -Thr-Gly-Ser-Gly-Thr-Pro-NH ₂

Dissolve 050 g of the partially protected peptide of step c) in a mixture of trifluoroacetic acid (508 v / v) and methylene chloride. After 1 hour, add thereto 50 ml of ether containing 0.6 mmol of HCl. It is filtered, washed with ether and dried in vacuo. The product is purified by reverse phase chromatography in a gradient of acetonitrile in H ₃ PO ₄ (2%). The pure substance-containing, combined fractions are filtered through a basic ion exchanger in the acetate form. It is lyophilized and the title compound is obtained as polyacetate, polyhydrate.
[Α] 20 D = -32.2 ° (c = 0.3 in 95% AcOH) F = 0.87 Example 38: N ^α -isocaproyl-des- (1-4) - [Ala ⁷ , N ^ε - (α-D-glucosyl- (1-4) -deoxyfructosyl) -Lys ^11,18 ] salmon calcitonin

[α]20D = –40,0° (c = 0,27 in 95% AcOH) F = 0,84 Beispiel 40: N^α,Lys¹¹-N^ε,Lys¹⁸N^ε-Tris-(1-desoxyfructosyl)-salmcalcitonin

[α]20D = –5,3° (c = 0,38 in 95% AcOH) F = 0,75 Beispiel 41: N^α-Isocaproyl-des-(1-4)-[N^ε-(1-desoxyfructosyl)-Lys^7,11,18]-salmcalcitonin-(5-32)-amid

[α]20D = –37,4° (c = 0,155 in 95% AcOH) F = 0,84 Beispiel 42: N^α-Chinoyl-(Ala⁷]salmcalcitonin-(5-32)-amid

Analogously to Example 37, with D (+) - maltose monohydrate instead of D (+) - glucose, the corresponding di-N ^ε -Maltolosyl derivative is prepared. The reaction time at 50 ° C is extended to 15 hours. Isolation and purification are identical, giving the title compound as a polyacetate, polyhydrate.
FAB mass spectroscopy: 3730.9 (MH ⁺ )
[Α] 20 D = -15.2 ° (c = 0.16 in 95% AcOH) F: 0.97 Example 39: N ^α -Isocaproyl- [N ^ε - (1-desoxyfructosyl) -Lys ⁷ ] -salmcalcitonin (5-32 ) amide

[Α] 20 D = -40.0 ° (c = 0.27 in 95% AcOH) F = 0.84 Example 40: N ^α, Lys ^{11 ε} -N, Lys ¹⁸ N ^ε -tris (1-desoxyfructosyl) -salmcalcitonin

[Α] 20 D = -5.3 ° (c = 0.38 in 95% AcOH) F = 0.75 Example 41: N ^α -isocaproyl-des- (1-4) - [N ^ε - (1-desoxyfructosyl) -Ly ^7,11,18 ] -salmcalcitonin (5-32) -amide

[Α] 20 D = -37.4 ° (c = 0.155 in 95% AcOH) F = 0.84 Example 42: N ^α- Chinoyl- (Ala ⁷ ] salmcalcitonin (5-32) -amide

In analogy to Example 21, the title compound was prepared. [Α] 20 D -35.7 ° (c = 0.37 in 95% AcOH) F: 0.88 Example 43: N ^α- Chinoyl- [Ala ⁷ ] salmcalcitonin (4-32) -amide

In analogy to Example 21, the title compound was prepared.
[Α] 20 D = -39.3 ° (c = 0.29 in 95% AcOH) F: 0.89

The required for Examples 42 and 43 starting peptides [Ala ^7] -Salmcalcitonin- [5-32) amide and [Ala ^7] -Salmcalcitonin- [4-32] -amide can be prepared analogously to the starting product of Example 37th Example 44: [N-deoxy-fructosyl-Cys ¹ ] oxytocin

0.5 g of 0 (+) - glucose and 0.5 g of oxytocin are dissolved in 50 ml of MeOH / HOAc 9/1 and stirred for 3 hours 65 ° C held. It is then evaporated, chromatographed on silica gel and desalted over oolite (H ₂ O / ethanol / HOAc gradient).

A white lyophilisate is obtained
[Α] 20 D = -23 ° (c = 0.32 in 95% AcOH) F: 0.95 Example 45: Ac- (D) Phe (4-Cl) - (D) Phe (4-Cl) - (D) Trp- Ser-Tyr (D) Lys-

60mg Ac- (D) Phe (4-Cl) - (D) Phe (4-Cl) - (D) Trp-Ser-Tyr- (D) Lys-Leu-Arg-Pro (D) Ala-NH ₂ and 72 mg of D (+) glucose are dissolved in a mixture of 10 ml of MeOH and 1 ml of AcOH and stirred at 60 ° C for about 20 hours. The product is precipitated with ether and centrifuged off. The residue is dissolved in about 100 ml H ₂ O, the pH is adjusted to 8 with dilute NaOH. The product is adsorbed on a column of Duolit ES 861 and eluted with a gradient H ₂ O → dioxane → H ₂ O-AcOH (60: 40: 3). Fractions containing the desired product are concentrated in vacuo, then lyophilized. The title compound is obtained.
[Α] 20 D = -25 ° (c = 0.5 in 95% AcOH) F: 0.83

Example 46: N ^αA1 , N ^αB1 , N ^εB29 -tris (1-desoxyfructosyl) porcine insulin

A suspension of 1 g (0.17 mmol) and 0.47 g (2.6 mmol) of glucose in 10 ml of a 9: 1 mixture of dimethylformamide and acetic acid is stirred for 1 hour at 60 ° C. Then the solvent is removed at 30 ° C under high vacuum. The residue is dissolved in 300 ml of H ₂ O, adjusted to pH 7, and the mixture is desalted through a small column (Duolit ES 861, 2.5 x 15 cm). The glucose is eluted with water and the peptide eluted with a 59: 39: 2 mixture of isopropanol, water and ethyl acetate.

The solvent is removed and the mixture is lyophilized. The residue is taken up in 300 ml of water and purified by reverse phase chromatography.
(2 x 25 cm column, RP 18, 10 nm, buffer 57 mmol NaClO ₄ , 20 mmol triethylamine, 8.4 mmol phosphoric acid, pH 3 with 4N NaOH, gradient 0-65% AB.
Buffer A: 9: 1 mixture of pH 3 buffer and acetonitrile
Buffer B: 4: 6 mixture of pH 3 buffer and acetonitrile

The fractions containing the title compound are collected, combined, concentrated, diluted with 300 ml of water and passed through a column of the type described above for desalting. The salts are eluted with water. The peptide is eluted with a 59: 39: 2 mixture of isopropanol, water and ethyl acetate. The appropriate fractions are combined and concentrated to give the title compound.
[Α] 20 D = 56.3 ° (c = 0.5 in 95% AcOH) F = 0.88 Example 47: N ^α , Lys ¹² -N ^α , Lys ²¹ -N ^ε- Tris (1-desoxyfructosyl) - (D) [Ala ² ] -hpGRF- (1-29) -NH ₂

The title compound is prepared analogously to Example 37 starting from (D) [Ala ² ] hpGRF.
[Α] 20 D = -5.6 ° (c = 0.2 in 95% AcOH) F = 0.82 Example 48: N ^α , N ^ε -Bis (1-desoxyfructosyl) lys-vasopressin

A suspension of 118 mg (0.1 mmol) of Lys ⁸ -vasopressin and 360 mg (2 mmol) of glucose in 5 ml of a 9: 1 mixture of methanol and ethyl acetate is stirred for 2 to 4 hours at 65 ° C. Then the solvent is removed under vacuum. The residue is taken up in 30 ml of water and the solution is lyophilized. To remove the excess glucose, the peptide (solution in 40 ml of water of pH 7.3) is adsorbed on a Duolit-filled column (1.5 × 10 cm). The glucose is eluted with water and the peptide is eluted with a 59: 39: 2 mixture of isopropyl alcohol, water and ethyl acetate. The mixture is purified on a silica column using as eluent a 7: 4: 1: 1 mixture of chloroform, methanol, ethyl acetate and water.

The fractions containing the above compound are concentrated and lyophilized to give the title compound.
[Α] 20 D = -52 ° (c = 0.5 in 95% AcOH) F = 0.84 Example 49:

The title compound is prepared analogously to Example 45 starting from Ac- (D) Phe (pCl) - (D) Phe (pCl) - (D) -Trp-Ser-Lys- (D) Phe-Leu-Arg-Pro (D. ) Ala-NH ₂ - acetate and D (+) - glucose produced.
[Α] 20 D = -36 ° (c = 0.5 in 95% AcOH) F = 0.86 Example 50:

The title compound is prepared analogously to Example 45 starting from H- (D) Phe (pCl) - (D) Phe (pCl) - (D) -Trp-Ser-Tyr- (D) Phe-Leu-Arg-Pro (D. ) Ala-NH ₂ - acetate and D (+) - glucose produced.
[Α] 20 D = -32 ° (c = 0.5 in 95% AcOH) F = 0.94 Example 51:

• 1) Adsorption an Duolit ES 861 und Elution mit einem Gemisch aus Dioxan, H₂O und AcOH.
• 2) Säulenchromatographie über Kieselgel unter Verwendung eines Gemisches aus CHCl₃, AcOH und H₂O als Eluierungsmittel.
• 3) Präparative Hochleistungsflüssigkeitschromatographie (HPLC) (Umkehrphase) mittels einer Octadecyl-Kieselgel-Säule. Elution mit einem Acetonitrilgradienten in 2% H₃PO₄.

A mixture of 200 mg H- (D) Phe (pCl) - (D) Phe (pCl) - (D) Trp-Ser-Tyr- (D) Lys-Leu-Arg-Pro (D) Ala-NH ₂ and 520 mg of D (+) - glucose in a 15: 1 mixture of DMF and AcOH is stirred for 3 hours at 60 ° C. The mixture is concentrated under vacuum, precipitated with ether, filtered and dried, whereupon the residue is purified as follows:

• 1) Adsorption on Duolit ES 861 and elution with a mixture of dioxane, H ₂ O and AcOH.
• 2) Column chromatography on silica gel using a mixture of CHCl ₃ , AcOH and H ₂ O as eluant.
• 3) Preparative high performance liquid chromatography (HPLC) (reverse phase) using an octadecyl silica gel column. Elution with an acetonitrile gradient in 2% H ₃ PO ₄ .

Combine the fractions containing the above compound, filter through a column containing a weakly basic ion exchange resin in acetate form, concentrate and lyophilize to give the title compound.
[Α] 20 D = -22.6 ° (c = 0.5 in 95% AcOH) F = 0.63

The Syntheses according to the invention can carried out as follows become.

Example S 1

Preparation of octreotide (= SMS)

1) Preparation of the anchor acetal (N-CF ₃ CO-threoninol acetal of p-formylphenoxy-acetic acid)

105 g (1.0 mol) of L-threoninol are introduced into 200 ml of methanol under nitrogen purge. To the obtained clear solution becomes at 0 ° C a solution from 200 ml of trifluoroacetic acid methyl ester added dropwise in 250 ml of methanol. The internal temperature is using Ice bath to about 10 ° C held. After 1.5 hours, threoninol is no longer detectable in the reaction solution. Evaporate at 40 ° C makes a white one crystalline residue. This is dissolved in 200 ml of ethyl acetate at 70 ° C solved and precipitated with 100 ml of hexane. Then it is at 0 ° C cooled, washed with hexane and dried at room temperature. The N-trifluoroacetyl-threoninol is obtained.

50.3 g (0.25 mol) of the resulting product are dissolved in 1.25 liters of tetrahydrofuran solved and added dropwise with 75 ml of trimethylchlorosilane. Immediately subsequently is a mixture of 70 ml of triethylamine and 250 ml of tetrahydrofuran added. It creates a white Suspension, which is stirred for 4 hours at room temperature. Then it is filtered and the filtrate at 40 ° C forming an oil evaporated.

The oil is in Dissolved 1.5 liters of methylene chloride and 90.4 g of p-formyl-phenoxyacetic acid are added in portions at room temperature. Then a total of 9 ml Trifluormethansulfonsäuretrimethylsilylester in portions added. It is stirred for 24 hours at room temperature, then filtered and the residue washed well with methylene chloride.

The Filtrate is at 40 ° C evaporated and gives as a residue an orange-red resinous product. This product is about silica gel Chromatograph. The elution is carried out with ethyl acetate. By Evaporate the desired Fractions will be the ones mentioned above 97% purity compound (high performance liquid chromatography) receive.

2) Construction of the protected octapeptide

you suspended 17.2 g of aminomethylated polystyrene (Brand Dow 0.7 weight percent N, which corresponds to 0.50 mmol of aminomethyl groups per g of resin) in 80 ml of methylene chloride / dimethylformamide 4: 1 suspended. To are gradually added 4.17 g of the final product of step 1), 1.6 g of hydroxybenzotriazole (HOBT) and 4.0 g of dicyclohexylcarbodiimide (DCCI). After 2 Stirring for hours at room temperature the Kaiser test is negative. The mixture is filtered and washed. The washed resin is dissolved in 100 ml of tetrahydrofuran / methanol Suspended 3: 1 and treated portionwise with 10.4 g of sodium borohydride. It is stirred for 6 hours at room temperature, filtered and washed. The resin is resuspended in methylene chloride / dimethylformamide (4: 1) and with 5.57 g of FMOC-Cys (S-t-Bu) OH, 1.74 g of hydroxybenzotriazole (HOBT) and 3.6 g of dicyclohexylcarbodiimide (DCCI). This will be cleaved the FMOC protecting group with piperidine (2 x 20 minutes contact time).

In analogously, the N-FMOC-protected amino acids Thr-OH, Lys (BOC) -OH, D-Trp-OH, Phe-OH, Cys (S-t-Bu) OH and D-Phe-OH by means of BOBT / DCCI coupled to give the FMOC-protected octapeptide resin receives. The final loading is 0.26 mmol / g.

3) oxidation and cleavage

The Resin obtained is in 100 mF trifluoroethanol / methylene chloride 1: 1 suspended and mixed with 50 ml of tributylphosphine. Stirring 70 Hours at room temperature. Then it is filtered, washed and washed with 100 ml of a 1: 1 mixture of tetrahydrofuran and an unomial Amminacetatlösung added. To this is added 1.1 ml of 30% aqueous hydrogen peroxide given. The mixture is stirred at room temperature for 24 hours. Then the resin is washed and washed with a mixture of 20 ml trifluoroacetic acid, 80 ml of methylene chloride, 10 ml of water and 2 ml of thioanisole. The Mixture is stirred for 2 hours and filtered and then washed with trifluoroacetic acid and methylene chloride. 200 ml of diethyl ether are added to the filtrate. The rainfall is filtered off.

Of the Residue is in an aqueous Buffer solved and then desalted using, for example, Duolit. By then Freeze-drying of the acetate the title compound as the acetic acid salt.

Example S 2: Preparation of N ^α - [α-glucosyl (1-4) -deoxyfructosyl] -SMS (see Example 2)

To In the above Example S 2, 333 g of the resin bound Octapeptids made. The cysteine protecting groups become reductive away. The peptide bond to the resin is by means of hydrogen peroxide in one. Mixture of tetrahydrofuran and water to cyclic Oxidized octapeptide.

To Washing in tetrahydrofuran and then in DMF, the peptide resin in 3600 ml of a mixture of DMF and AcOH (8: 1) shaken. The Suspension is treated with 526 g of D (+) maltose monohydrate. The mixture gets to 60 ° C heated and = stirred for 18 hours at this temperature.

you that cools Mixture, the peptide resin is filtered off and washed in turn with it DMF and methanol. Then it is washed with methylene chloride. thereupon the peptide is split off from the resin by adding the whole Mixture of 2900 ml of methylene chloride and 716 ml of trifluoroacetic acid and treated a trace of water.

The Filtrate is stirred Partly admixed with 597 g of sodium carbonate, whereupon 30 Stirred for another minute and then filtered. The residue is washed with methylene chloride and methanol.

The Filtrate is concentrated to dryness, followed by desalting using a column that with a polystyrene containing no functional groups, such as Duolit filled or using one for high performance liquid chromatography suitable reverse phase material, such as silicone treated Silica gel containing long-chain fatty alcohol groups (for example Labomatic, Switzerland, Brand HB-SIL-18-20-100). hereby one reaches the pure title connection.

The Sugar derivatives are pharmacologically active and are therefore suitable as therapeutic agents.

The effectiveness of the sugar derivatives can be determined by standard pharmaceutical and biopharmaceutical tests. The connections. are generally after administration by injection or oral Administration at least as effective as the unmodified peptide, namely the corresponding sugar-free peptide. They are generally better absorbed, more soluble in water, and have a longer duration of action.

The Sugar derivatives can therefore be used for the same indications how to use the unmodified peptides.

The Sugar derivatives can in usual bioavailability tests compared with the unmodified peptides.

The Sugar derivatives can be, for example, longer time after their administration still in the blood plasma than the unmodified peptides, as usual Experiments to determine bioavailability can be shown.

The For example, sugar derivatives and the unmodified peptide may be Dogs by oral or intravenous Administration in one for producing a therapeutic effect sufficient single dose.

The Compounds are applied in doses that involve detection of the peptide or a metabolite thereof in the blood. The detection can in conventional Be made way, for example by a radioimmunoassay.

At the mentioned above For example, experiment has shown that the compound of Example 2 after oral administration compared to octreotide Ten times higher Blood concentration results.

The absolute bioavailability the compound of Example 2 when administered orally and intravenously, measured on the basis of the AUC value (area under the curve) is around five times higher than at octreotide. The half-life for excretion after intravenous administration is about 2.3 hours compared to about 0.5 hours for octreotide.

Additionally have The sugar derivatives have the advantage that they are to a greater extent by the kidneys are eliminated. This can be done by the usual Watch tests.

you administered starving male Rats (225 to 375 g) oral water (50 ml per kg). After 30 minutes For example, the animals are treated with inactin (100 mg per kg i.p.). anesthetized. Bile duct and bladder are cannulated. Both jugular veins become exposed. To stimulate a diuresis, a vein enters a Infusion of 5% glucose and 1% ethanol (5 ml per hour), The other vein is for taking blood samples (0.5 ml) to each Hour during 4 hours.

The Sugar derivative compound and the unmodified peptide subcutaneously at a dose of about 10 to about 1000 μg per kg administered. The concentration of each compound is in common Way, for example by radioimmunoassay determined.

Examination of the compound of Example 2 and octreotide at a dose of 10 μg per kg, according to the above test, gives the following results:

octreotide will be over both the bile as well as the urine excreted while elimination of the compound of Example 2 predominantly about the urine takes place.

The improved absorption of the sugar derivatives after oral administration can be determined as follows:
The sugar derivative compound and the unmodified analog are administered orally to OFA rats (for example, at a dose of 10 mg per kg). After a certain period of time, for example after 15, 30 and 60 minutes, blood samples are collected. These are then analyzed for their drug content, which can be done for example by radioimmunoassay.

For example, in this experiment, the compound of Example 44 at a dose of 10 ng / kg has a 50 to 100 higher absorption than the unmodified peptide oxytocin. The results obtained are shown in the following table: Table: Rat plasma levels after oral administration in ng / ml

The pharmacological effects of the sugar derivatives can be determined by conventional pharmacological tests, for example after injection, and if desired with the effects the unmodified Peptides, for example with respect their effectiveness and duration of action.

By corresponding pharmacological tests can be, for example examine the effects of sugar derivatives on hormones in animals. Compounds that inhibit the excretion of hormones can be tested by measuring the lowering of the blood levels of the hormone.

The sugar derivatives which inhibit excretion of growth hormone (GH), in particular the compounds of formula VIII and especially the compounds of formula VIII a to f, and lower the levels of growth hormone in the blood, can be tested in the following manner:
Inactivated rhesus monkeys (at least 5 monkeys) in primate chairs receive the sugar derivatives in a banana piece as carrier. The compounds are administered at a dose of about 0.1 mg per kg to about 10 mg per kg _po . A catheter is used to withdraw blood from the saphenous vein. The blood GH concentration is measured by RIA (radioimmunoassay).

at For example, this test with rhesus monkeys reveals that the Compound of Example 2 at a dose of 0.1 mg per kg GH excretion longer decreased by at least 50% for 10 hours while the unaltered peptide Octreotide, by comparison, gives only a 5 hour sustained reduction.

Another test is done as follows:
Male rats are bled one hour after administration of the GH excretion inhibiting compound in several logarithmic staggered doses after decapitation. The serum GH level is determined by RIA. In this experiment, the sugar derivatives are subcutaneous effective at doses of about 0.02 to about 30 μg per kg.

In this test, it has been found, for example, that the compounds of Examples 1, 2, 21 and 24 have ID ₅₀ values of 0.045, 0.194, 0.3 and 0.2 μg per kg of sc, whereas in the same test for natural somatostatin gives an ID ₅₀ value of 93 μg per kg sc (the ID ₅₀ value indicates the amount of compound needed to lower the GH content by 50% compared to the untreated control animals.

in the Unlike the natural Somatostatin gives the sugar derivatives in this experiment a long-term (for example, 6 hours sustained) inhibition of GH excretion and are therefore extremely effective in this regard.

The GH-lowering activity of these compounds can also be observed after oral administration to male rats containing estradiol implants. In this experiment, there are relatively small changes in GH levels. The experiment is carried out as follows:
Male rats weighing about 300 g are implanted under ethereal anesthesia tube (length 50 mm, diameter 3 mm) with 50 mg oestradiol under the back lingual. At different times (1 to 6 months later) the animals are repeatedly used for experiments. The test substance is administered either subcutaneously or orally.

Directly before and also at different times after administration of the substance one removes the Animals about 0.8 ml of blood from the retroorbital plexus. The blood is centrifuged and the serum GH level determined by RIA.

This experiment shows that the sugar derivatives after oral administration are even more effective after several hours than the corresponding unmodified peptides. The ID ₅₀ value for the compounds of Examples 1 and 2 after 2 hours is about 17 to 40 times lower than the ID ₅₀ value of the unmodified peptide octreotide. Further results are shown in the following table:

The Sugar derivatives can therefore be used in indications where one Inhibition of GH excretion desired is. Such indications include Diabetes mellitus, the prevention and treatment of angiopathy proliferative retinopathy and acromegaly.

The GH excretion inhibiting sugar derivatives also inhibit pancreatic secretion. This inhibition leaves identify themselves on the basis of animal experiments, and this can be, for example that in Scand. J. Gastroint. 6, 423 (1975) by S.J. Konturek et al described method can be applied.

The The GH excretion inhibiting sugar derivatives also inhibit gastric acid secretion and give an increase the pH of the gastric juice.

This activity of the sugar derivatives can be determined, for example, by the following experiment:
The GH excretion-inhibiting sugar derivatives are administered to starved rats in whose stomach a fistula is implanted at doses of about 0.05 mg per kg to about 5 mg per kg by gavage. After 1 hour, the fistula is opened. The gastric juice is collected at intervals of 30 minutes. The collected volumes are recorded and subjected to a determination of their acid concentration.

At the The above experiment gives the compound of Example 2 an increase in the pH to 6 to 8 during 3.5 hours. Octreotide, on the other hand, raises the pH to 6 to 7 during only 2 hours. The compound of Example 2 is in this experimental system at least 60 times more effective than cimetidine.

The the GH excretion inhibiting sugar derivatives, in particular the compounds of formula VIII are therefore suitable for treatment gastrointestinal disorders, as for the treatment of gastric ulcers, gastrointestinal bleeding, acute pancreatitis and gastroenteropancreatic tumors (e.g. Vipomas, insulinomas, glucagonomas and the like).

The GH excretion inhibiting sugar derivatives also inhibit proliferation and / or keratinization of epidermal cells and are therefore useful also for the treatment of dermatological diseases with a pathological proliferation and / or keratinization of epidermal cells related, in particular for the treatment of psoriasis.

Further can These compounds are also used to treat a degenerative senile Dementia including the senile dementia of the Alzheimer's type (SDAT) or for the treatment of Cluster headache, namely recurrent headache.

at All these indications are said to inhibit GH excretion Sugar derivatives can be used in a daily dose of about 2 micrograms to 20 mg. If desired, can the compounds also in divided doses 2 to 4 times a day in Unit dosage form or be administered in a sustained release form. Such Unit doses can about 0.5 μg contain up to 10 mg of the respective active substance.

The sugar derivatives of calcitonin and of calcitonin analogs or derivatives, especially the derivatives of formula X, lower the plasma level of calcium. They antagonize the parathyroid hormone and cause a positive calcium balance in the bones. Dia hypocalcemic effect of the new verbin Applications may be measured in a known manner by the method of M. Azria et al. reported at the Calcitonin Symposium in Milan on Oct. 24, 1984 and incorporated herein by reference in the Current Clinical Practice Series no. 42, Excerpta Medica 1984, page 104. In this method, a Ca ²⁺ ion-selective electrode is used, with which the content of calcium ions in the blood of young rabbits or dogs can be continuously measured. The compounds are administered intravenously at doses of about 0.1 to about 10 μg per kg, which is about one international unit per kg, for example. The measurements are taken over a period of 5 hours and the AUC value (area under the curve) is calculated.

The Connections can also tested in other tests for example, in J. Endocrinology (1965), 33, p 469, standard hypocalcemic test described by M. Kumar et al., And in this Test results in rats at different doses for the hypocalcemic Compounds a hypocalcemic Efficacy of 300 to 6000 international units per mg.

at In these experiments, it was found that the compounds of Examples 37 and 38 at intravenous Administration to dogs (5 μg per kg) a much longer one Duration of action as the unmodified peptide. To 3 hours was for the compounds C and D a lowering of the calcium level in the Blood observed by 15 to 18%. For however, the unmodified peptide did not decrease after 6 hours the calcium level can be detected more. At the connections Examples 37 and 38 was the lowering of the calcium level after 3 hours still pronounced.

The hypocalcemic Compounds are therefore indicated in all the states where one Reduction of the calcium level in the plasma or an influence the bone metabolism desired is like hypercalcaemia due to a lack of endogenous thyrocalcitonin as a result of Failure of thyroid tissue or a hyperfunction of the parathyroid gland. Next are these connections Also indicated for all bone diseases that are on an increased Bone degradation based or where a calcium fixation in the Bone desired is, as with the different types of osteoporosis, for example in post-cardiac, post-traumatic, by corticosteroid therapy or inactivity conditional or malicious Diseases etc. based osteoporosis, fractures, osteomalacia, rachitic and renal osteodystrophy, pain, such as Bone pain associated with osteoporosis, neurodystrophic Diseases, Paget's disease and a combination therapy with Calcium phosphate.

For the above mentioned calcium-dependent Indications are these compounds in daily doses of about 5 applied to about 1500 international units. These cans can be used as Single dose once a day or if desired once every 2 or 3 days.

The Sugar derivatives which are sugar derivatives of LHRH or Analogous to this, also inhibit the excretion of luteohormone, so that you For example, are suitable for ovulation inhibition in animals.

This activity of the sugar derivatives is determined using the test method described in Experientia 30, 1174-1176 (1974) by M. Marko and E. Flückiger:
For this purpose adult female rats of the Ivanovas Wistar strain (Sprague Dawley, Iva: SDIV, 200 to 250 g) are kept under standard conditions: the light is on for 14 hours (from 4 to 18 o'clock), the temperature is 24 ° C, the relative humidity is 55 to 60%, the animals receive food and water ad libitum.

animals with regular 4-day cycles administered on the day of ovulation at 13 o'clock the respective compound by subcutaneous injection or by oral route. The next day you kill the animals at 9 o'clock in the morning and counts the eggs in both fallopian tubes by means of a dissecting microscope. As ovulation inhibition applies only if no eggs are found. The mean number of eggs per ovulating rat is also determined in every treatment group.

The The above sugar derivatives are generally in a range of about 0.0005 to about 10 mg per kg effective. The connection of the example For example, when administered subcutaneously, it exhibits efficacy of 0.01 mg per kg.

The luteohormone excretion activity of this compound can also be assayed in vitro as follows. Firstly, cultures of pituitary cells are prepared using the method described in Methods in Enzymology 37, 82-93 (1975) by W. Vale and G. Grant or US Pat already before in Life Sciences, 33, 233-240 (1983) by M. Marko and D. Römer. The primary cultures are kept for 4 days at 37 ° C in an incubator. The cells are then washed and incubated for 3 hours in 1 ml of a medium containing LHRH or the test compound. At the end of the incubation, the supernatant fluid is removed and tested for LH content by a special radioimmunoassay.

In this experiment, the test compounds generally prove to be effective in a concentration range of about 10 ^-12 to about 10 ^-7 moles, by dose-dependently inhibiting LHRH-induced excretion of LH.

at All LH-RH indications should be administered in daily doses of about 2 μg to 20 mg. If desired, can the compounds also in divided doses 2 to 4 times daily in unit dosage form or in slow-release form for use. Such unit doses can about 0.5 μg contain up to 10 mg of active ingredient.

The Sugar derivatives can after every conventional Be administered way, for example, enteral, such as oral, for example in the form of drinking solutions, Tablets or capsules, nasal, for example in the form of liquid or powdery Sprays and ointments, or parenteral, for example in injectable form solutions or suspensions.

The for the respective route of administration, such as nasal or oral administration, in each case suitable dose of sugar derivatives can by conventional experiments for determining the bioavailability using the same substance, intravenously, intramuscularly or subcutaneously is injected, determined. For oral administration the daily dose is generally about 10 to about 100 times higher than in an intramuscular or subcutaneous injection.

to Treatment for diabetes, ulcers or acromegaly will be the compound of Example 2 expediently administered orally at a dose of 3 to 10 mg three times a day.

The Sugar derivatives can in any pharmaceutically acceptable form, such as in free form, namely in the form of the free base, or, if the compound is an acid, in free acid form, or in the form of a pharmaceutically acceptable salt. The salt form For example, an acid addition salt or, if the compound is an acid is a pharmaceutically acceptable cationic salt. The Connections can also be administered in complex form. Additionally or alternatively, the Compounds also in the form of a solvate, such as a hydrate, are present.

The Sugar derivatives have the order of magnitude in each of these forms same effectiveness.

Are useful also pharmaceutical compositions of a sugar derivative in a pharmaceutically acceptable form associated with at least a pharmaceutical carrier or diluents. Such compositions can be prepared in a conventional manner.

A A drinking ampoule or an injectable solution may be per ml, for example 0.5 mg of the compound of Example 2 in acetate form, 11.45 mg of citric acid, 6.32 mg NaOH and 4.5 mg NaCl.

Further useful is also the use of the sugar derivatives in any of the above indications given, such as a decrease in GH excretion, in diabetes mellitus, with a decrease in gastric secretion and in acromegaly for the somatostatin-like sugar derivatives.

Finally is also the use of the sugar derivatives to make one for the treatment the above indications of a suitable drug useful, as a drug to reduce GH excretion, treatment of diabetes mellitus, humiliation of gastric secretion and treatment of Acromegaly for the somatostatin-like sugar derivatives.

Claims (10)

Process for the preparation of a peptide alcohol of the formula

wherein Y is the residue of a peptide alcohol having at the C-terminal end of the peptide chain two alcohol groups or an alcohol group and a thiol group, R _{1 is} hydrogen or methyl and X is O or S, characterized in that a resin of the formula Ir

which carries the peptide alcohol, wherein

the residue is an insoluble synthetic resin and Z is a direct bond or residue linking the resin to the acetalated formylphenyl group and having the following formula IIIr: - (D) _p Q ₁ -Q ₂ - (E) _q - (formula IIIr), wherein the individual symbols have the following meanings: Q ₁ -Q ₂ is an ester group or amide group, wherein Q ₁ is bonded to the polymer and Q ₂ is bonded to the acetalated formylphenyl group, D and E are independently alkylene radicals or Alkylenoxyreste having 1 to 5 Carbon atoms, wherein D connects the group Q ₁ with polymer and E connects the group Q ₂ with the acetalated formylphenyl group, p and q are independently 0 or 1, wherein the acetalated group CHO in position m or p to the radical Z is and to a molecule of the resin polymer, a number of acetalized formylphenyl groups are bonded, hydrolyzed under acidic conditions. A method according to claim 1, characterized in that the remainder

is a polystyrene radical. Method according to one of claims 1 or 2, characterized in that the radical Z is a group of the following formula

wherein R is hydrogen or methyl m is 0 or 1 and

is a polystyrene radical. Method according to one of claims 1 to 3, characterized in that X is O and R _{1 is} methyl. A process according to any one of claims 1 to 4, wherein Q _{1 is} NH and Q _{2 is} CO. Method according to one of claims 1 to 5 for the production from octreotide. Compound of formula Ir

wherein the indicated symbols have the following meanings

is the residue of an insoluble synthetic resin. Z is a direct bond or moiety linking the resin to the acetalated formylphenyl group and having the following formula IIIr: - (D) _p -Q ₁ -Q ₂ - (E) _q - (formula IIIr), wherein the individual symbols have the following meanings: Q ₁ -Q ₂ is an ester group or amide group, wherein Q ₁ is bonded to the polymer and Q ₂ is bonded to the acetalated formylphenyl group, D and E are independently alkylene radicals or Alkylenoxyreste having 1 to 5 Carbon atoms, wherein D connects the group Q ₁ with polymer and E connects the group Q ₂ with the acetalated formylphenyl group, p and q are independently 0 or 1, X is 0 or S, R ₁ is hydrogen or methyl and Y is the residue of a peptide alcohol which may optionally bear protecting groups and which has two alcohol groups or an alcohol group and a thiol group at the C-terminal end of the peptide chain, wherein the acetalated group CHO is in the m or p position to Z and to one molecule of the resin polymer a number of acetalated formylphenyl groups are attached. Compound of formula Vr

wherein the indicated symbols have the following meanings:

is the remainder of an insoluble synthetic resin. Z is a direct bond or residue linking the resin to the acetalated formylphenyl group and having the following formula IIIr: - (D) _p -Q ₁ -Q ₂ - (E) _q - (formula IIIr), wherein the individual symbols have the following meanings: Q ₁ -Q ₂ is an ester group or amide group, wherein Q ₁ is bonded to the polymer and Q ₂ is bonded to the acetalated formylphenyl group, D and E are independently alkylene or Alkylenoxyreste having 1 to 5 carbon atoms, wherein D connects the group Q ₁ with polymer and E connects the group Q ₂ with the acetalated formylphenyl group, p and q are independent each other is 0 or 1, X is O or S, R ₁ is hydrogen or methyl, and A is a protective group of the amino function wherein the acetal group is in the m or p position to Z and the resin carries a number of acetalated formylphenyl groups , Compound of the formula VIr

wherein X is O or S, R ₁ is hydrogen or methyl, A is a protecting group of the amino function, E is an alkylene group or alkyleneoxy group having 1 to 5 carbon atoms, Q ₂ 'represents a reactive group, with a different reactive group Q ₁ 'which is bound to a synthetic resin, the groups Q ₁ ' and Q ₂ 'reacting to form a bridge Q ₁ -Q ₂ as defined in claim 1, and q is 0 or 1 where the acetal group is in the position m or position p to the radical Q ₂ '- (E) _p -.