WO2010000713A1 - Linear-dendritic polyglycerol compounds, method for the production thereof and use thereof - Google Patents

Abstract

The invention relates to novel linear-dendritic polyglycerol compounds, to a method for the production thereof and the use thereof for solubilizing hydrophobic substances, in particular as carrier or transport system for active substances and/or signal substances.

Description

 Linear dendritic polyglycerol compounds, process for their preparation and their use

The invention relates to linear dendritic polyglycerol compounds of the general formulas (1), (2) or (3), processes for their preparation and their use for the solubilization of hydrophobic substances, in particular as a carrier or transport system for active and / or signaling substances.

Many newly developed, pharmaceutically interesting active ingredients have the problem of very low water solubility and thus poor bioavailability. One of the biggest problems with the medical treatment of diseases is the targeted transport of active substances into the diseased target site, ie into a tissue, an organ, or into the corresponding cell. Membranes are the most important barrier that shields the target from the active substances to be transported. Another problem is the degradation or derivatization of free drugs in the organism. The synthesis of water-soluble derivatives or prodrugs can not be carried out in many cases with the desired success. As a further problem especially cytostatics in the fight against tumors often have a high non-specific toxicity to healthy tissue in vivo. For some time now, the search for new methods for solubilizing active ingredients has been at the center of scientific / industrial interest. Another goal is to minimize any side effects on healthy tissue by passive or active accumulation of the drug at the target site. For the desired effect in this case, a smaller amount of therapeutic agent would be necessary.

The introduction of a signal substance, optionally coupled to an active substance, e.g. for imaging methods such as e.g. MR or IR imaging typically poses similar problems. Consequently, chemically functionalized carriers and signaling substances permit only limited carriers, signaling substance combinations and active substance combinations. In addition, the active substance, if covalently or coordinatively bound to the signaling substance or carrier, must be chemically released at the target site.

Conventional formulations for drug solubilization usually contain larger amounts of solvent mixtures of, for example, ethanol or polyethylene glycol. In addition, one also finds the use of phospholipids / liposomes. Nanoparticulation and application eg in emulsions is used in some cases, especially for topical and non-systemic use. Cyclodextrins or surfactants such as Cremophor EL ("Polyoxyl-35-Castor OiI), a nonionic emulsifier consisting of a mixture of fatty acid glycerol polyglycol esters, are also used for the active ingredient solubilization. Fatty acid polyglycol esters and polyethylene glycols.

A new and promising way to solubilize hydrophobic substances is the use of polymeric micelles. Polymeric micelles are among the most advantageous carriers for transporting water-insoluble drugs. Polymeric micelles are characterized by a core-shell structure. Pharmaceutical research on polymeric micelles has focused primarily on (linear) copolymers having a multi-block structure. For this purpose, a plurality of tri-block copolymers such as Pluronics ^® and Synperonics ^® ( "Poloxamer" PEO-PPO-PEO, poly (ethylene oxide) -block (propylene oxide) -block-poly (ethylene oxide) of different

Block length has been developed and already commercially available. The amphiphilic block copolymers spontaneously form spherical, worm or lamellar aggregates depending on the structure, composition and concentration. In the hydrophobic interior of polymeric micelles water-insoluble substances can be stored and thus made bioavailable.

The shell is responsible for the stabilization of the micelles and for interactions with plasma proteins and cell membranes. It usually consists of chains of hydrophilic, biocompatible polymers such as polyethylene oxide (PEO). Through the core-shell structure, ie by the hydrophilic shell consisting for example of the biocompatible polyethylene oxide (PEO block copolymers) and a lipophilic core, drugs are solubilized and stabilized, which eventually leads to prolonged circulation times in the blood ("stealth properties of PEO ). Numerous publications in this field describe the successful encapsulation of hydrophobic substances with amphiphilic block copolymers. ^{1 "4}

So far, in the literature in addition to mostly ionic "low-weight surfactants almost exclusively polymeric micellar nanocarriers of linear polymers described.

A major disadvantage of linear polymeric drug carriers is that they are almost always heterogeneous and are polydispersed mixtures. The polymer molecules are contained with a variety of different molecular weights, which often also have only a limited number of functional groups and / or reactive sites. The polymerization reactions obtained from classical linear block copolymers such as poloxamer (Pluronics ^®) have a broad molecular weight distribution, and thus are polydisperse. Hyperbranched polyglycerol as a hydrophilic molecular building block is also not structurally defined, however, in order to obtain a controlled transport that is important in pharmacological applications, however, defined compounds are desirable. There are studies on perfectly branched polyamidoamine dendrimers (PAMAM) as unimolecular transporters. However, these are very sensitive and also unstable at elevated temperatures, meaning that these macromolecules are significantly degraded. Furthermore, Noiret et al. ⁶ symmetrical polyglycerinamines showing micellar properties. But these do not form micelles defined on the one hand and also have a relatively high critical micelle concentration (cmc) of> 10 ^"4 M, so that they can be used as nanocarriers only partially in question applies.

From Wyszogrodzka et al. ⁷ , dendritic triblock amphiphiles have been described which have a biphenyl-functionalized central unit. However, they have the disadvantage that they do not ensure an encapsulation of insoluble substances.

A remaining unresolved problem is the generation of nonionic and structurally defined micelles which are useful as active nanocarriers for hydrophobic drugs and dyes. There is therefore still a need for new biocompatible and biodegradable polymeric micelle systems that do not contain PEG (polyethylene glycol) but still show good solubilization properties.

The invention was therefore based on the object of finding novel systems which are readily accessible synthetically and which are suitable for solubilization and for the transport, in particular, of poorly soluble active substances and diagnostic agents, e.g. suitable for IR and MRI imaging.

The object is achieved by the provision of nonionic, linear dendritic polyglycerol compounds having the general formulas (1), (2) or (3). All compounds have at least one glycerol dendon of the 0th to 10th generation in combination with a linear hydrophobic residue.

The invention further relates to the synthesis of these compounds and their use, preferably as nanocarriers in aqueous systems for the solubilization of hydrophobic dyes, drugs and / or diagnostic agents or for the encapsulation of substances and stabilization.

The compounds of the invention are characterized by the general formulas (1), (2) or (3).

in which mean

PG a polyglycerol dendron generation 0 to 10 [G0-G10] of repeating glycerol units, wherein R ³ = H, -C (CHs) _2, -CH _3, -SO ₃ Na, PO ₃ Na, or - (CH), CO-ONa with I = 1 -36,

Y - (bond) or a different from PG polyglycerol dendron [G0-G10] from repeating glycerol units, wherein the number n in the rest (- Z - R ¹ - Z - R ² ) _n of the generation of the dendron depends is selected from - (bond), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-, -SS-,

in the case of several radicals Z, these may be the same or different,

X is a linker which in the case of several radicals X may be identical or different and is selected from -O-, -CH ₂ -O-, -S-, -CH ₂ -S-, -COO-, -OOC-, - CH ₂ OOC, -NH-CO-, -NH-COO-, -OOC-NH-, -NH-CO-, -CH ₂ NH-CO-, -CO-NH-, -SS-, -CH ₂ -SS-,

or a cleavable linker means

R ¹ - (bond), a linear (saturated and unsaturated) alkyl chain having 1 to 36 carbon atoms, an aryl and / or heteroaryl radical and / or a perfluoroalkyl or partially fluorinated alkyl radical (C 1 -C 16) and

R ² corresponds to the meaning of R ¹ , wherein R ¹ and R ^{2 may be the} same or different from each other, but not both - (bond) or only an aryl radical,

with the proviso that compounds of formula (1) in which PG is a polyglycerol dendron of generation O or 1 [G0-G1], where R ³ = H,

X = -OOC,

Z = - and

R ¹ , R ^{2 represent} an alkyl chain (C1 to C72) are excluded.

Aryl radicals are preferably C5-C20-aryl groups, preferably aryl is phenyl, biphenylyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, which is also represented by one or more substituents C ₁ to C ₃ -alkyl, C ₁ to C ₂ - Alkoxy or halogen (or F, Cl) may be substituted, are preferably used as aryl phenyl, biphenylyl and Naphthylreste. A heteroaryl group is one? monυcyoiäbche to tπcychsche group having 1 to 4 Hoteroatomoπ which are selected from the Gruppo consisting of einom Stsckstoffatom, oxygen atom or Schwefeiatom D \ e heteioeychsche group is, for example Pyπoiyl pyrazolyl, Jmidazoiy !, Thiazoiyl, oxazolyl _s isothiazolyl isooxazoiyi, 1, 3, 5-Tπazoiyl, 1, 2,4- Tπa7θ! Yl 1, 3,5-ThIaUIaZoIyI, 1 3,5-Oxadia7θ! Yl, pyryl, Pyπdazinyl, Pyπmidyi. PyrazyL Bonzofuranyi isobenzofuranyl, bastothienyl, indoiyl, chromonyi, quinolyl, isozoyl, phthalazinyl, or quinoxaiinyi, and the like, are preferably a thiazolyl group.

In the context of the present invention, the term Aikyi comprises saturated or monoblock polyunsaturated linear alkyl groups. Suitable alkyl groups are 7B straight-chain C 1 -C 4 -alkyl and preferably C ₆ -C ₂ -alkyl-group, in particular butyl, butenyl, butynyl, Pentyl, pentenyl, pentynyl, hexyl, hexenyl, hexynyl, heptyl, heptenyl, heptynyl, octyl, octenyl, octynyl, nonyl, nonenyl, nonynyl, decyl, decenyl, decynyl, undecyl, undecenyl, undecynyl, dodecyl, dodecenyl, dodecynyl, tridecyl, Tridecenyl, tridecinyl, tetradecyl, tetradecenyl, tetradecinyl, pentadecyl, pentadecenyl, pentadecinyl, hexadecyl, hexadecenyl, hexadecinyl, heptadecyl, heptadecenyl, heptadecinyl, octadecyl, octadecenyl, octadecinyl, eicosyl, heneicosyl, docosyl or tetracosyl.

Perfluoroalkyl or partially fluorinated alkyl (C1-C16) represents a perfluorinated or partially fluorinated alkyl group having up to 33 fluorine atoms, preferably CF _3, C ₂ F ₅ C ₃ F ₇ C ₄ F _9, C ₅ F11 COFI _3, C ₇ F 1 ₅ , Cs Fi ₇ C ₉ F1 ₉ and C1 ₀ F21.

Preferred compounds of the formulas (1), (2) or (3) are characterized by at least one polyglycerol dendron as head group PG from the 1st generation. For the purposes of the invention, compounds which have a PG-dendron head group of a generation of 2 to 10 (between 2 and 10) are particularly preferred.

Preferred linkers X in (1), (2) or (3) are selected from

-S. -OOC-, -COO-, -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO-,

Cleavable linkers are known to the person skilled in the art and are understood to mean compounds which are enzymatically or reductively spaitbas, sauroiahi! photoiabs! odor thermolabile preferably, they are ester, amide, acetal, [min, disulfide or hydrazone groups. For example, a review of cleavable linkers is provided by B. Rhomberg et al. before ¹⁰ .

Z in (1), (2) or (3) is preferably selected from -, -S-S-, -O-, -S-, -COO, -OOC-.

R ¹ is preferably -, aryl, preferably phenylyl, biphenylyl or naphthyl and / or a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, R ² may be a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms , Aryl, preferably phenylyl, biphenylyl or naphthyl, and / or perfluoryl and / or partially fluorinated alkyl (C1-C16).

Particularly preferred compounds (1), (2) or (3) according to the invention are furthermore those which have at least one aryl and / or heteroalkyl radical.

The compounds according to the invention are macromolecular nonionic amphiphiles and are distinguished by a strictly modular structure. Hydrophilic structural component is the at least one defined polyglycerol-dendron (PG) of different generation as a head group. The polyglycerol-dendron head groups are characterized by a perfectly uniform structure, or at the core of the oxygen radical in the 2-position is replaced by another linker. Preferably, the compounds of the invention have at least one generation Dendron head G1 to G10, more preferably from the 2nd generation.

In one embodiment variant of the invention, preferred compounds have at least one aryl and / or heteroaryl radical which is / are arranged centrally in the immediate vicinity of the at least one polyglycerol-dendron head group and / or is located at the end of the hydrophobic radical.

Surprisingly, the compounds according to the invention in aqueous solutions form uncharged defined aggregates, i.d.R. Micelles, where the glycerol unit is perfectly branched. Polyglycerol, like polyethylene glycol, is well biocompatible and has good permeability through lipid membranes.

Preference is given to compounds having a dendritic PG head group from the 2nd generation. The invention is based on the finding that the aggregation numbers of the dendritic amphiphiles according to the invention are dependent on the dendritic head group. The forming aggregates are relatively small and their aggregation number decreases with increasing generation of the dendritic head group. The aggregates formed are present as spherical or non-spherical micelles, as vesicles or lamellae. A number of compounds form spherical micelles with a hydrodynamic micelle diameter ranging between 5 and 12 nm. Preferably, spherical micelles are formed with a diameter of 6 to 9 nm on average. Aggregation number and micelle formation concentration (cmc) are characteristic quantities for each amphiphile.

Of great advantage is that the compounds of the invention are non-ionic amphiphiles, i. the hydrophilic group carries no charge and thus does not dissociate into ions. Nonionic amphiphiles have a significantly better compatibility in vivo than ionic surfactants.

Particular preference is given to compounds (1) in which

PG = PG dendron from the 2nd generation means, wherein R ³ is H,

X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO-,

R ¹ = -, aryl, preferably phenylyl, biphenylyl or naphthyl, a linear (saturated and unsaturated) alkyl chain having 1 to 36 carbon atoms, Z = -, -S-, -COO-, -OOC- and

R ² = a linear (saturated and unsaturated) alkyl chain having 1 to 36 carbon atoms, aryl, preferably phenylyl, biphenylyl or naphthyl, and / or a C 1 -C 16 partially fluorinated

Represent alkyl.

Preferred compounds (1) according to the invention having a dendritic PG head group can be classified into the following groups:

Compounds with alkyl side chain,

Compounds having alkyl side chains and with (central) aromatic moiety adjacent to the dendritic polyglycerol head group,

Compounds with alkyl side chain and aromatic moiety at the end of the hydrophobic moiety

For the purposes of the invention, the compounds are in addition to the hydrophilic PG head group an alkyl radical and at least one aryl and / or heteroaryl radical, particularly preferred compounds.

Particularly preferred compounds (1) according to the invention are:

1- [G1] -PG-1 H- [1,2,3] triazole-4-carboxylic acid undecyl ester (22) - Example 1.1

1 - [GI] -PG-I H- [1,2,3] triazole-4-carboxylic acid hexadecyl ester (21) - Example 1.2

4- (1- [G1] -PG-1 H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (23) - Example 1.3

1- [G2] -PG-1 H- [1,2,3] triazole-4-carboxylic acid hexadecyl ester (24) - Example 1.4

1- [G2] -PG-1 H- [1,2,3] triazole-4-carboxylic acid undecyl ester (25) - Example 1.5

4- (1- [G2] -PG-1 H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (26) - Example 1.6

4- (1- [G3] -PG-1 H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (27) - Example 1.7

Hexadecanoic acid [GI] -PG amide (7) - Example 1.8

Hexadecanoic acid [G2] -PG amide (33) - Example 1.9

Bz-C1 1 -PG [GI .O] -OH - Example 2.1

Bz-CI 1-PG [G2.0] -OH - Example 2.2

Bz-C18-PG [G2.0] -OH - Example 2.3

Bz-C18-PG [G3.0] -OH - Example 2.4

NaCl 1-PG [G2.0] -OH - Example 2.5

NaCl 8-PG [G2.0] -OH - Example 2.6

NaCl 8-PG [G3.0] -OH - Example 2.7

Bi-CI 1-PG [G2.0] -OH - Example 2.8

Bi-CI 8-PG [G2.0] -OH - Example 2.9

Bi-CI 8-PG [G3.0] -OH, - Example 2.10.

Preferred compounds of formula (2) are compounds in which

PG = PG dendron from the 1st generation, wherein R ³ = H or -C (CH _{3) 2,}

Y = a polyglycerol-dendron starting from the 0th generation, which differs from PG, from repeating glycerol units, where n in the radical (-Z-R ¹ -Z-R ² ) _{n is} the number of

Surface groups of the generated dendron, where n = 2 -2048,

X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 C

atoms,

Z = -, -S-, and

R ² = a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms and / or a partially fluorinated alkyl radical C1-C16.

Particularly preferred compounds (2) are compounds with

X =

The most preferred compounds are

Compounds in which Y n has alkene side chains and

Compounds in which Y n has partially fluorinated alkyl side chains which may be interrupted by S-.

Particularly preferred compounds (2) according to the invention are: C ₆ -GO-Ck-GLO - Example 3.1 C ₆ -G 0 -Ck-G 2 O - Example 3.2 C ₆ -G 0 -Ck-G3.0 - Example 3.3 Cn-GO- ck-GI .0 - example 3.4 Cn-G0-ck-G2.0 - example 3.5 Cn-G0-ck-G3.0 - example 3.6 Rf-C ₆ -GO-ck-GLO - example 3.7 Rf-C ₆ - G0-Ck-G2.0 - example 3.8 Rf-C ₆ -G0-Ck-G3.0 - example 3.9 Rf Cn-GO-Ck-GLO - example 10/3 Rf Cn-G0-Ck-G2.0 - example 3.1 1 Rf-Cn-G0-Ck-G3.0 - Example 3.12 [G1.0] -propagyl-click- [G1.5] -azidethiol (5) - Example 4.1 [G2.0] -propagyl-click - [G1.5] azide-thiol (6) - Example 4.2 [G3.0] -propagyl-click [G1.5] -azide-thiol (7) - Example 4.3 [G1.0] -propagyl-click - [G1.5] -azide-OH (8) - Example 4.4 [G2.0] -propagyl-click- [G1.5] -azide-OH (9) - Example 4.5 [G3.0] -propagyl-click - [G1.5] azide-OH (10) - Example 4.6 Rf is the straight-chain fluoroalkyl radical.

Preferred compounds of formula (3) are characterized by PG = PG-1-generation dendron wherein R ³ = H, Y = - (bond) or glycerol-unit GO, where n = 1 or 2 X = -OOC -NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 C

Atoms, Z = is selected from - (bond), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-,

R ² = represent a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms and / or a C 1 -C 16 partially fluorinated alkyl.

The invention also relates to the preparation of the novel compounds. The underlying modular design and the use of simple, carried out under non-inert experimental conditions coupling reactions allow in good yield a fast and straightforward synthesis of the structurally perfect-branched new compounds.

The production takes place professionally as coupling reaction between hydrophobic and hydrophilic building blocks. The central coupling step of the two components of different polarity can be carried out, for example, as a Cu-catalyzed cycloaddition of the compounds which are provided with alkyne and azide functionality and then joined by the per se known click reaction ⁸ ' ⁹ . In a preferred embodiment, the bond between hydrophilic and hydrophobic structural part takes place via a 1, 3-dipolar cycloaddition of alkyne and azide functionality ("Click reaction, for example, to form a triazole ring). ⁸ ' ⁹ The compounds of this invention can be prepared by either providing the hydrophilic components with azide functionality and the hydrophobic components with alkyne functionality and then the coupling of the two building blocks or vice versa the hydrophobic groups are provided with azide and the hydrophilic groups with alkyne, then the coupling reaction be subjected, where appropriate protective groups are used, which are then possibly split off again.

Preferably, the preparation of a compound of general formula (1), (2) or (3) is characterized by using the click chemistry, the target compound as 1, 3-dipolar cycloaddition of an alkyne and azide functionality, which optionally hydrophobic and hydrophilic building block is obtained, wherein the central coupling step of the two blocks of different polarity preferably as Cu-catalyzed cycloaddition of alkyne and azide functionality in THF and / or a water / THF two-phase system with the addition of CuSCy5H ₂ O and ascorbic acid or its salts as catalysts and a base such as NaOH or DIEPA (diisopropylethylamine) or Et ₃ N (triethylamine) takes place.

As hydrophilic units, the polyglycerol dendrons of the desired generation are synthesized. Synthetic methods for building perfectly branched structures of dendrimers with different generations are known in the art.

Bydiophiien PoSygiycerol dendrons are molecularly uniform macromolecules with a highly symmetric structure They arise from small molecules by a repetitive reaction sequence with increasing branches at the ends of which are the functional groups that are in turn starting point for wide o branchings Thus, the number of monomer end groups increases exponentially with each reaction time, resulting in a hemispherical tree structure at the end. The number of reaction stages, or wiper hydration units, respectively. is also referred to as a generation Due to their uniform construction, the invention used according to the invention, the polyglycerol-topical group dendrons have a defined molar mass and are therefore monodisperse

The preparation of compounds (1) can be carried out by providing the hydrophilic PG head groups with azide functionality and the hydrophobic radical with alkyne functionality:

As a rule, the corresponding R ³ -functionalized dendrons are first of all generations represented, which then converted by a simple reaction sequence preferably consisting of mesylation and azide formation in the respective azides can be. The synthesis of OH-functionalized dendrons requires the incorporation of protecting groups for the vicinal OH free groups, preferably acetal protecting groups are selected.

The alkyne functionalization of the hydrophobic building block is e.g. by esterification of corresponding alkyl alcohols with corresponding alkynecarboxylic acids in a suitable solvent, if appropriate in the presence of a suitable catalyst and under excess alcohol.

The "click" reaction is realized, for example as follows:. Azide and alkyne are dissolved / water mixture in a THF CuSO ₄ -SH O _2, ascorbic acid and NaOH are added, wherein the concentration of NaOH in deviation from the Sharpless 2 4-fold is increased, and the reaction mixture is preferably stirred for two to five days at room temperature.The solvent is removed, if necessary, inorganic additives are removed and any protecting groups present are eliminated, the crude product is optionally purified.

For the synthesis of amide compounds (1), the compounds having azide functionality are preferably hydrogenated by means of Pd / C and the hydrophobic moieties are prepared by reacting a corresponding carboxylic acid to the corresponding acylaminoester in the presence of a coupling reagent, e.g. Dicylcohexyl-carbodiimide / N-hydroxysuccinimide (DCC / NHS) prepared and then assembled to the desired target compound.

The preparation of compounds (1) can furthermore be carried out by providing the hydrophobic radicals with azide functionality and the hydrophilic radicals having alkyne functionality. If the hydrophobic residues are provided with azide functionality, this functionalization is e.g. via a corresponding diol with methanesulfonyl chloride and sodium azide or direct reaction of an alkyl bromide with sodium azide. With the addition of corresponding carboxylic acids or carboxylic acid derivatives, a desired hydrophobic Azidrest can be prepared. The alkyne functionalization of the hydrophilic dendritic polyglycerol moiety is e.g. on the reaction of the protected hydroxy-polyglycerol dendron with an alkynyl halide.

The "click" reaction is carried out, for example, as follows: Azide and alkyne are dissolved in THF and DIPEA is added in a concentration of 10-15 mol% Aqueous solution of CuSO ₄ -5H ₂ O (10-15 mol%) and Sodium ascorbate (20-30 mol%) is added and the reaction mixture is stirred for a few hours to days at room temperature Solvent is removed, if necessary, inorganic additives are removed and cleaved off protecting groups, the crude product is optionally purified.

The preparation of compounds (2) is carried out, for example, as follows: In a first step, azide is reacted with a bromo-1-alkene (2 equivalents per OH), optionally quenched, extracted and purified. The resulting product C _n -N ₃ is subjected to a click reaction with a polyglycerol-dentron of the desired generation, which is alkyne-functionalized, wherein catalytic amounts of DIPEA are added in THF. In order to prepare a perfluorinated radical R ² , the compounds are reacted with RfC ₂ H ₄ SH (4 equiv. Per C = C) with heating after the "click" reaction, optionally adding an initiator such as AIBN. The desired target product is cleaned if necessary.

In particular, using DIPEA (diisopropylethylamine) for the click reaction, the target compounds are obtained in very good yield in a few minutes to hours.

The new compounds, which are characterized by at least one polyglycerol dendron head group, form a new family of nonionic amphiphiles that undergo a controlled aggregation process in aqueous solution. In particular, the compounds of the invention with a PG-Dendron head group from the 2nd generation are exceptionally well water-soluble. It is particularly advantageous that each glycerol unit is perfectly branched. Compounds which, in addition to the dendritic PG head group and a linear alkyl chain, have aryl and / or heteroaryl radicals either in the immediate vicinity of the head group and / or at the end of the hydrophobic alkyl radical are particularly preferred.

In aqueous solution, the compounds of the invention are able to form defined aggregates due to their amphiphilic structure. These include spherical and non-spherical micelles, vesicles or lamellae. Preferably, spherical micelles are formed. Micelles form spontaneously above a certain concentration, the so-called critical micelle concentration (cmc). Due to the dendritic head group, the hydrophilic parts (heads) of the molecules align themselves to the adjacent water molecules, whereas the hydrophobic parts (tails) align themselves and thus form their own phase. Micellization is an association process that is based on a true thermodynamic equilibrium.

The critical micelle formation concentration determines when encapsulation of guest molecules can occur. Important for the use of micelles as a transporter of hydrophobic agents is a sufficiently low cmc to ensure that micellar aggregates are present even at high dilution during application. Below the critical micelle concentration, only the monomeric amphiphiles are present, so that already encapsulated guest molecules would be released again.

The shape and size of the micelles are influenced by a number of factors. These include the chemical structure of the amphiphiles, state of charge, polarity of the solvent, amphiphile concentration, foreign electrolyte content and the temperature. By means of light scattering, further information about the aggregates formed can be obtained. While the static light scattering provides information about size and shape, the dynamic light scattering can be used to determine the hydrodynamic radius of the micelles.

Surprisingly, the compounds according to the invention form defined aggregates. The compounds of the invention are particularly suitable for forming defined spherical micelles. Furthermore, the compounds of the invention are monodisperse. All particles have a uniform shape and size. The extremely uniform and well-defined, spherical structure of the aggregates in water of the amphiphiles according to the invention was detected by transmission electron micrographs (TEM). They have a cmc which is significantly smaller than that of compounds of the prior art, e.g. Amphiphiles with polyethylene glycol head groups of comparable molecular weight.

The compounds of the invention are characterized by low micelle concentrations of <10 ^"5 mol / l. The hydrodynamic micelle diameter amounts to 5 to 12 nm, vzw. 6 to 9 nm. Aggregation number and hydrodynamic radius were determined via static and dynamic light scattering measurements. By tensiometry, for example, can be cmc is the concentration at which the surface tension of the solution reaches a plateau and practically does not decrease, for which the surface tension is determined as a function of the concentration of the substance to be measured Intersection of the two curve sections accessible.

For the compounds 4- (1- [G1] -PG-1 H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (Example 1.3), 4- (1- [G2] -PG-1H - [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (Example 1.6) and 4- (1- [G3] -PG-1 H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (Example 1.7) critical micelle formation concentrations of 1, 5x10 ^"5 mol / l, 1, 1x10 ^{" 5} mol / l and 7.1x10 ^"6 mol / l were determined. A longer length of hydrophobic as well as the additional introduction of aromatic residues led to significantly low cmc values of <10 ^"5 mol / l, as for example for the amphiphilic Bz-CI 8- [G3.0] -OH (Example 2.4 ) with the cmc of 2.0x10 ^"6 mol / l.

Comparing the dendritic amphiphiles according to the invention with PEG-based representatives with otherwise the same hydrophobic radical, surprisingly significantly lower cmc values are found in the dendritic amphiphiles according to the invention. At comparable molecular weight, these values are ten times smaller.

In addition to the cmc, the molecular weight of the aggregates is of particular importance for a biological application. The aggregation numbers were determined by static light scattering measurements (photocorrelation spectroscopy). Surprisingly, the aggregation numbers are strongly dependent on the size of the dendritic head group in addition to the length of the hydrophobic moiety. Thus, the aggregation number for the compound according to Example 1.3 [G1]: 591, for the compound according to Example 1.6 [G2]: 60 and for the compound according to Example 1.7 [G3]: 21. Their hydrodynamic diameters are 11.5, 8.5 and 6.5 nm The aggregation numbers for the compounds according to Examples 2.1-2.10 are between 16-87 at molecular weights of the aggregates of 22,000-90000 g / mol. The hydrodynamic diameters of Examples 2.1-2.10 have values of 6-1 1 nm.

In addition to the polyglycerol dendron as a hydrophilic structural unit with its defined, perfectly branched structure, the choice of linker X and the structure of the hydrophobic moiety (e.g., chain length and composition) also have a major impact on the transport properties of the aggregates (micelles).

The amphiphiles of the general formulas (1), (2) and (3) are outstandingly suitable for the encapsulation, transport and thus for the solubilization of hydrophobic substances, such as, for example, active substances, signaling substances and other diagnostic markers. In particular, nonionic amphiphiles have a very good compatibility in vivo. The charge neutrality of the aggregates was verified by zeta potential measurements. Suitable active ingredients are all substances known per se which are known as sparingly soluble biologically active substances and are preferably used as medicaments. In principle, these include all substances intended to be used as active ingredients in the manufacture of medicinal products or to become medicinally active ingredients when used in the manufacture of medicinal products. These include natural and synthetic substances, such as, for example, known cytostatic agents, but also proteins, enzymes, glycoproteins, polypeptides, nucleosides, oligonucleotides, antibodies, lipids, liposomes, phospholipids, microorganisms, human cells. Signaling substances can be selected from the group of radioactively-labeled substances or the group of dyes, such as, for example, fluorophores and chromophores.

Various hydrophobic dyes and drugs have been successfully encapsulated as model compounds, and the transport capacity U VA / IS spectroscopically determined. Investigations on the encapsulation of hydrophobic substances showed a good solubilization of the water-insoluble dyes Nile Red and Pyrene, as well as the active ingredient nimodipine.

The encapsulation of Nile red and pyrene with the compounds of Examples 1.3, 1.6, 1.7, 1.4 and 1.5 showed that all compounds have the desired transport properties. The incorporation of aromatics into the amphiphilic structures leads to significantly higher transport capacities of complexed guest molecules. Compounds having biaromatic constituents (Compounds 1.3, 1.6 and 1.7) are even more effective than the compounds having only one aromatic constituent (1.4 and 1.5).

A uniform size distribution of the nanocarriers is also a prerequisite for an optimally controlled application. As a result of the purely physical binding (hydrophobic interaction) of the guest molecules in the micelles, the release at the site of action is much easier and faster than, for example, with dendrimers or other unimolecular, covalently linked transport systems.

Investigations with the known active ingredient nimodipine also confirmed the outstanding properties of the compounds according to the invention. Typical formulations of the water-insoluble active ingredient include large quantities of ethanolic polyethylene glycol solutions or phospholipids. It has been shown that the macromolecular linear dendritic amphiphiles, e.g. Bz-CI 8- [G2] -OH, solubilize up to 16 mg nimodipine per g amphiphile.

Outstanding water solubility characterizes the new dendritic polyglycerol amphiphiles. In particular, the compounds having a generation two and higher polyglycerol endonene are exceptionally well soluble in water irrespective of the group. Linear block copolymers with polyethylene glycol comparable molecular weight (PEG; such as at Pluronics ^®) are much worse to not water soluble.

As described, the nonionic, macromolecular amphiphiles described in this invention, in particular the compounds (1) and (2), are outstandingly suitable for solubilizing and transporting active ingredients and diagnostic agents (dyes, IR / MRI markers) in vivo. Tests with water-insoluble dyes and active ingredients have been successful performed (see also exemplary embodiments).

Not only is bioavailability and pharmacokinetics influenced by micellar nanotransport systems, but also the distribution of drugs in the body. The size of the aggregates results in passive accumulation, for example in tumor tissue, which has an expanded cell structure and a restricted lymphatic system in comparison to healthy tissue (enhanced permeability and retention, EPR effect). ⁵

It is noteworthy that the size of the micelles formed by the compounds of the invention with 5-12 nm, preferably 6-9 nm, on the one hand above the important renal threshold of about 5 nm, on the other hand, it is thus significantly lower than the polymeric micelles linear block copolymers (eg Pluronics ^®) with 30 to 100 nm and thus profits from the EPR effect, that there is a better tissue penetration.

The EPR effect can be used e.g. Achieve passive drug targeting of carcinomas or tissue with similar dilated structure as vascular tissue after balloon dilatation or massively inflamed tissue. This means a lower total burden of the organism with potentially toxic substances. The EPR effect occurs with macromolecules from 20 kDa on. For passive drug targeting, polymers between 20 and 200 kDa are generally used.

The amphiphilic compounds according to the invention can furthermore be used for the stabilization of emulsions, microemulsions and nanoemulsions as well as foams. They have a significant advantage over commonly used conventional low molecular weight stabilizers and linear block copolymers also used because of the low cmc. Due to the low cmc and low diffusion coefficients, they strongly absorb colloidal particles, thus providing good steric or electrosteric stabilization. On the other hand, block copolymers have the disadvantage that, as the molecular weight increases, the cmc often decreases, but the diffusion coefficient likewise decreases greatly. As a compromise, block copolymers with molecular weights of 1000-20000 g / mol are therefore used in industry.

The linear dendritic polyglycerol amphiphiles described in accordance with the invention have the great advantage that they have a very low cmc while having a low molecular weight of less than 1000 g / mol, depending on the compound and, at the same time, exceptionally good water solubility. Further fields of application of the amphiphiles described according to the invention are, for example, in use for the encapsulation of catalysts and for the formation of microreactors or for the adsorption on solid surfaces, for example of metal nanoparticles. Metal nanoparticles are interesting because of their special optical and electronic properties. Due to their small size, they can, after appropriate surface modification, react specifically with each other and with surfaces, such as molecules. They are used as nanomarkers, as catalysts but also as components in composite materials.

literature

(1) Croy, S.R.K., G.S. Current Pharmaceutical Design 2006, 12, 4669-4684.

(2) Kwon, G.S.F., M. Laird Drug Development Research 2006, 67, 15-22.

(3) Le Garrec, D.R., Maxime; Leroux, Jean-Christophe American Journal of Drug Delivery 2004, 2, 15-42.

(4) Monika L. Adams, A.L., Glen s. Kwon Journal of Pharmaceutical Sciences 2003, 92, 1343-1355.

(5) R. Haag, F.K. Angew. Chem. 2006, 118, 1218-1237.

(6) Noiret, N., Rivaux, Y., Brochette, P., Algarra, L., Patin, H, Polyglyceryl Amines as Surfactants 1: Symmetrical Polyglyceryl Amines and Aqueous Solution Properties. Journal of Surfactants and Detergents, 1999, Vol. 2, No.3.

(7) Wyszogrodzka, M., Mows, K., Kamlage, S., Wodzinska, J., Plietker, B., Haag, R., New approaches toward monoamino polyglycerol dendrons and dendritic triblock amphiphiles, Eur. J. Chem. Org., 2008, 53-63.

(8) H.C. KoIb, M.G. Finn, B.B. Sharpless, Click Chemistry: Various Chemical Function from a Few Good Reactions, Angew. Chem. Int. Ed., 2001, 40, 2004-2021

(9) W.H. Binder, R. Sachsenhofer, "Click" Chemistry in Polymer and Materials Science, Macromol., Rapid., Comm., 2007, 28, 15-54

(10) B. Rhomberg, WE Hennink, G. Storm; Pharmaceutical Research, 2008, 25, 55-71

In the following, the invention is explained in more detail by way of example without it being intended to be limited thereto.

embodiments

Synthesis and characterization of a library of novel amphiphiles based on dendritic architectures that self-assemble into spontaneously defined micelles in water. All amphiphiles consist of a hydrophobic block with a Cn, Ci _6, or Ciβ-alkyl chain and no or another aromatic unit (possibly next to the triazole ring). Polyglycerol dendrons of generations 1 to 3 were chosen as hydrophilic units. The coupling of hydrophobic and hydrophilic blocks has been accomplished by "click" chemistry, and the "click" chemistry introduced by Sharpless provides a synthetic concept consisting of some very reliable, almost perfect reactions that allow rapid synthesis of such compounds , The most widely used "click" reaction is the Cu (I) catalyzed version of the Huisgen 1, 3 cycloaddition of azides and alkynes, as well as generation 1 and 2 amphiphiles without an aromatic moiety, and a variety of compounds containing fluorine-containing alkyl side chains ,

example 1

Compounds of the general formula (1) - Amphiphiles with alkyl side chain and with alkyl chain and (central) aromatic unit in the vicinity of the dendritic polyglycerol

head group

The focus is on amphiphiles with an aromatic unit in the direct vicinity of the hydrophilic head group. In addition, amphiphiles without an aromatic unit were also shown. The selected hydrophobic and hydrophilic building blocks are exemplified as follows.

1

The hydrophobic units 1-3 are synthesized by esterification of the alkyl alcohol with the acid of the respective alkyne building block. For the coupling of the azide with the corresponding alkyne, "click" chemistry is used according to the protocol of Sharpless et al. ^[8] Since the synthesis is performed with acetal protected PG dendrons, the last step requires elimination of the acetal protecting groups The following retrosynthetic scheme illustrates the reaction:

The coupling of the azide with the corresponding alkyne is based on "click" chemistry. [G1] - and [G2] -PG dendrons will be functionalized with any of the three hydrophobic building blocks, generation 3 will be functionalized only with the aromatic compound 3. Generation 1 and 2, amide coupling derivatives without aromatic moiety were also synthesized, and Compound 7 shows an amide [G1] amphiphile without an aromatic moiety.

a) Representation of the hydrophobic alkyne building blocks

The hydrophobic alkynes 1, 2 and 3 are obtained by esterification of the alkyl alcohols 1-undecanol (8) or 1-hexadecanol (10) with propionic acid (9) or 4-ethynylbenzoic acid (11). The esterification is carried out azeotropically on a water separator. Toluene is a suitable solvent because it forms an azeotrope with the water liberated during the reaction and, moreover, all educts are soluble. To activate the carboxylic acid, catalytic amounts of PTSA are added. All esterifications are carried out with a 1.75-fold excess of alcohol. This ensures that the esterification equilibrium is shifted to the product side. The esters could be isolated by column chromatography separation of the unreacted starting materials. The yields were 68% for propionic acid undecyl ester (1), 58% for propionic acid hexadecyl ester (2) and 60% for 4-ethynylbenzoic acid hexadecyl ester (3). Due to the shorter chain of the alkyl alcohol 8 compared to 10, the steric hindrance in the preparation of the ester 1 is the lowest and thus the yield is greatest. All reactions could be carried out on a larger scale (3 - 1 O g) without difficulty. The synthesis scheme for the esterification is shown below:

General procedure for the preparation of the hydrophobic building blocks: The carboxylic acid (1 eq) and the alcohol (1, 75 eq) are dissolved in toluene. After adding catalytic amounts of PTSA, the reaction mixture is refluxed on a water separator until no more water separates (about 12 hours). It is then cooled to room temperature and the catalyst acid washed with water, aqueous sodium bicarbonate solution and water again. The organic phase is dried over sodium sulfate, the solvent is removed on a rotary evaporator and the crude product is then purified by column chromatography.

Propionic acid undecyl ester (1)

Approach: 3.00 g (42.8 mmol) of propionic acid (9), 12.91 g (74.9 mmol) of 1-undecanol (8), cat.

Amount of PTSA

Reaction time: 12 hours

Purification: flash column chromatography (3: 1 n-hexane / chloroform)

Yield: 6.52 g (29.1 mmol, 68%) of a colorless liquid

¹ H-NMR (CDCI _3, 500 MHz): (ppm) = 4.17 (2H, t, 3J6,5 = 7.0 Hz, H-6), 2.87 (1 H, s, H-9), 1.66

(2H, quin, 3J5.4 / 5.6 = 7.0Hz, H-5), 1.38-1.25 (16H, m, H-2, H-3, H-4), 0.87 (3H, t, 3J1, 2 = 7.0

Hz, H-1).

¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 152.8 (C-7), 74.8, 74.3 (C-8, C-9), 66.4 (C-6), 31.9,

29.5, 29.4, 29.3, 29.1, 28.3, 25.7 (C-3, C-4, C-5), 22.6 (C-2), 14.1 (C-1).

IR (KBr): (cm ^-1 ) = 3297 (m, CH (-C CH)), 2121 (m, CC (-C CH)), 2925, 2853 (s, CH (-CH ₂ , -CH ₃ )), 1714 (s, C = O), 1466, 1379 (w, CH (-CH ₂ , -CH ₃ )), 1239 (s, CO), MS (FAB ⁺ ): m / z = 224.8 [M + H] ⁺ '247.2 [M + Na] ⁺ .

Propionic acid hexadecyl ester (2)

Approach: 3.00 g (42.8 mmol) of propionic acid (9), 18.16 g (74.9 mmol) of 1-hexadecanol (10), cat.

Amount of PTSA

Reaction time: 12 hours

Purification: flash column chromatography (9: 1 n-hexane / chloroform)

Yield: 7.35 g (25.0 mmol, 58%) of a white solid

¹ H-NMR (CDCl ₃ , 500 MHz): (ppm) = 4.18 (2H, t, 3J6.5 = 7.0 Hz, H-6), 2.86 (1H, s, H-9), 1.67

(2H, quin, 3J5.4 / 5.6 = 7.0Hz, H-5), 1.37-1.25 (26H, m, H-2, H-3, H-4), 0.88 (3H, t, 3J1, 2 =

7.0 Hz, H-1).

¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 152.8 (C-7), 74.8, 74.3 (C-8, C-9), 66.5 (C-6), 31.9,

29.6, 29.5 (2x), 29.4, 29.2, 28.3, 25.7 (C-3, C-4, C-5), 22.7 (C-2), 14.1 (C-1).

IR (KBr): (cm ^-1 ) = 3298 (m, CH (-C CH)), 2121 (m, CC (-C CH)), 2925, 2854 (s, CH (-CH ₂ , -CH ₃ )), 1715 (s, C = O), 1467, 1379 (m, CH (-CH ₂ , -CH ₃ )), 1237 (s, CO) MS (El): m / z = 294.2 [M] ⁺ , 279.2 [M-CH ₃ ]. 4-Ethynylbenzoic acid hexadecyl ester (3)

Batch: 2.17 g (12.9 mmol) of 4-ethynylbenzoic acid (11), 5.47 g (22.6 mmol) of 1-hexadecanol

(10), cat. Amount of PTSA

Reaction time: 12 hours

Purification: flash column chromatography (9: 1 n-hexane / chloroform)

Yield: 2.85 g (7.7 mmol, 60%) of a white solid

¹ H-NMR (CDCl ₃ , 500 MHz): (ppm) = 8.00-7.54 (4H, m, H-9, H-10), 4.31 (2H, t, ³ J6.5 = 7.0 Hz,

H-6), 3.22 (1H, s, H-13), 1.76 (2H, quin, 3J5.4 / 5.6 = 7.0Hz, H-5), 1.46-1.25 (26H, m, H-2 , H-

3, H-4), 0.88 (3H, t, ³ JI, 2 = 7.0 Hz, H-1).

¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 166.0 (C-7), 132.0, 130.5, 129.4, 126.6, (C-8, C-9, C-)

10, C-1 1), 82.8, 79.9 (C-12, C-13), 65.4 (C-6), 31.9, 29.7, 29.6, 29.4, 29.3, 28.7, 26.0 (C-3,

C-4, C-5), 22.7 (C-2), 14.1 (C-1).

IR (KBr): (cm-1) = 3245 (m, C-H (-CC-H)), 2105 (w, C C (-C C -H)), 2927, 2849 (s, C-H (-)

CH2, -CH3)), 1705 (s, C = O), 1471 (m, C-H (-CH2, -CH3)), 1606 (m, C = C (aromatic)), 1267 (s,

C-O).

MS (El): m / z = 369.8 [M] ⁺ , 128.8 [C9H5O] ⁺ .

b) Representation of the hydrophilic building blocks

As hydrophilic units, polyglycerol dendrons of generations 1 to 3 were synthesized. First, the corresponding OH-functionalized dendrons are represented by all generations, which can then be converted into the respective azides by a simple reaction sequence consisting of mesylation and azide formation. The synthesis of the OH-functionalized dendrons requires the incorporation of protecting groups for the vicinal OH free groups. Since acetal protecting groups protect only vicinal diols and are also stable under the conditions required for the preparation of the dendrons, they have been selected.

Starting from acetal-protected triglycerol (12), the higher generations 2 and 3 are synthesized i-iv in repetitive synthetic sequences. The next higher generation is obtained in each case by the reaction with methallyl dichloride. First, the chlorine atoms in methallyl dichloride are nucleophilically replaced by the oxygen atoms of the deprotonated alcohol 14. Deprotonation is achieved using NaH. To enhance the nucleophilic character also 15-crown-5 is added, which leads to the complexation of the sodium ion. By addition of Kl and 18-crown-6, the chloride is converted into a better leaving group and thus activated for the nucleophilic substitution reaction. The monosubstituted compound as well as unreacted methallyl dichloride and unreacted alcohol 14 are separated by HPLC. After HPLC separation, product 15 was obtained in 73% yield. In step iii and iv, the ozonolysis of the alkene 15 are carried out with subsequent reductive work-up. For this purpose, the alkene is dissolved in a mixture of DCM and methanol and cooled to -78 ⁰ C. At -78 ⁰ C, only the ozonation of C = C double bonds occurs, further side reactions can be ruled out. Ozone is introduced until the reaction mixture turns blue. The blue color indicates excess ozone in chlorinated solvents, which must then be removed by the introduction of oxygen, so that it can not lead to the formation of explosive mixtures. Since the ozonation proceeds very fast, only short reaction times of about 15 min. required. The reductive workup of the ozonides formed is achieved by addition of NaBH ₄ and 12 h stirring at room temperature. After quenching and aqueous work-up, product 16 was obtained. Since the reaction is complete, it was used without further purification for the subsequent mesylation. The mesylation of compounds 14 and 16 was carried out by adding methanesulfonyl chloride (MsCl) and triethylamine (Et ₃ N) as base. The progress of the reaction was monitored by thin-layer chromatography. First, 1 eq. MsCI and 1 eq. Et ₃ N used, after 2 h reaction time without further progress, another 0.5 eq. Et ₃ N was added and the reaction was complete within 1 h. The mesylate was converted to the azide without further work-up. 5 eq. NaN ₃ in DMF was added and the reaction mixture was heated at 120 ^° C. for 3 h. For purification, it was filtered through silica gel. The yield of the [G2] azide 18 was 94% over two stages, the yield of the [G3] azide 20 92% over three stages (including ozonolysis). [G1] -Azide 19 could be provided analogously.

Synthesis of the [G2] - and [G3] -OH dendrons; i) NaH, 15-crown-5 (cat), methallyl dichloride, THF, 2h, RT; ii) Cl, 18-crown-6 (cat), THF, 24 h, reflux, 75% overall yield of 15; iii) O _3, MeOH / DCM, ⁰ -78 C, 15 min; iv) NaBH ₄ , MeOH / DCM, RT, 12 h.

Synthesis of acetal-protected [G31-en (15)

9.00 g (12.9 mmol, 2.1 eq) of [G2] -OH (14), 1.48 g (61.5 mmol, 10 eq) 60% NaH in mineral oil, catalytic amounts of 18-crown-6 and absolute THF are placed in a dry round bottom flask under argon atmosphere. After the addition of 0.77 g (6.2 mmol, 1 eq) of methallyl dichloride, the reaction mixture is stirred for 2 hours at room temperature. Subsequently, catalytic amounts of potassium iodide and 15-crown-5 are added and the reaction mixture is refluxed for 12 hours. After cooling to Room temperature, the excess NaH is quenched with water and extracted three times with DCM. The combined organic phases are dried over sodium sulfate and the solvent is removed on a rotary evaporator. The crude product is over

Silica gel filtered (6: 1 ethyl acetate / n-hexane) and then purified by HPLC (1: 1

Isopropanol / n-hexane).

There was obtained 6.5 g (4.5 mmol, 73%) [G3] -en (15) as a light yellow, viscous oil.

¹ H-NMR (CDCl ₃ , 500 MHz): (ppm) = 5.15 (2H, s, H-1), 4.24-3.43 (74H, m, H- (3-10)), 1.39 /

1.33 (48H, 2s, H-12, H-13).

¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 143.1 (C-2), 109.3 (C-1 1), 78.4, 74.5, 72.4, 71.4, 70.6,

70.1, 66.9, 66.7 (C- (3-10)), 26.7, 25.4 (C-12, C-13).

IR (KBr): (cm-1) = 2988 (m, CH (-CH ₂ , -CH ₃ )), 1456, 1372 (m, CH (-CH ₂ , -CH ₃ )), 1082 (s,

C-O).

MS (TOF): m / z = 1467.8095 [M + Na] ⁺ , 745.3994 [M + 2Na] ²⁺ .

Synthesis of acetal-protected [G31-OH (16)

6.50 g (4.5 mmol) [G3] -en (15) are dry in 35 mL MeOH / DCM (1: 1) and cooled to -78 ⁰ C. As long as ozone is passed through the solution until a blue coloration occurs. Excess ozone is then removed by a strong flow of oxygen.

After the addition of 1.70 g (45 mmol) of NaBH ₄ , the reaction mixture is stirred for 12-15 hours while slowly warming to room temperature. After quenching with saturated ammonium chloride solution is stirred for an additional hour. The organic phase is separated and the aqueous extracted three times with DCM. The combined organic phases are washed three times with water, dried over sodium sulfate and the solvent is removed on a rotary evaporator.

Since the reaction proceeds completely and without by-products, [G3] -OH (16) was used in the next step without further purification and characterization.

There was obtained 6.52 g (4.5 mmol, 100%) of a light yellow, viscous oil.

Procedure for the preparation of PG-azides: 1 eq [G2] -OH (14) or [G3] -OH (16) and 1, 5 eq triethylamine are initially charged in toluene and cooled to 0 ⁰ C. Then it gets slow

1 eq methane sulfonyl chloride added dropwise. Reaction progress can be checked using DC.

After the end of the reaction, the precipitate is filtered off and the solvent on

Rotary evaporator removed. The mesylate is dissolved in DMF and 5 eq of sodium azide are added. The reaction mixture is stirred for 3 hours at 120 ⁰ C, the excess of Sodium azide is filtered off and the DMF is removed in vacuo. The crude product thus obtained is purified by filtration over silica gel (10: 1 ethyl acetate / n-hexane). Synthesis of the [G2] -azide:

Synthesis of acetal protected [G2] -N3 (18)

Preparation: 7.00 g (10.0 mmol) of [G 2] -OH (14), 1, 53 (15.1 mmol) of triethylamine, 1.15 g (10.0 mmol)

Methanesulfonyl chloride, 3.27 g (50.2 mmol) of sodium azide

Yield: 6.82 g (9.4 mmol, 94%) of a light yellow, viscous oil

¹ H-NMR (CDCl ₃ , 500 MHz): (ppm) = 4.25-3.45 (35H, m, H- (1-7)), 1.40 / 1.34 (24H, 2s, H-9, H-

10th

¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 109.3 (C-8), 78.7, 78.5, 74.7, 74.6, 72.5, 71.4, 70.3,

66.8, 66.7 (C- (2-7)), 61.1 (C-1), 26.7, 25.4 (C-9, C-10).

IR (KBr): (cm-1) = 2987 (s, CH (-CH ₂ , -CH ₃ )), 2101 (s, azide), 1456, 1371 (s, CH, (-CH ₂ , -

CH ₃ )), 1082 (s, CO).

MS (TOF): m / z = 722.4080 [M + H] ⁺ , 744.3897 [M + Na] ⁺ , 760.3638 [M + K] ⁺ .

Synthesis of acetal-protected [G31-N3 (20)

Preparation: 6.52 g (4.5 mmol) of [G3] -OH (16), 0.68 g (6.8 mmol) of triethylamine, 0.52 g (4.5 mmol)

Methanesulfonyl chloride, 1.46 g (22.5 mmol) of sodium azide

Yield: 6.1 1 g (4.1 mmol, 92%) of a pale yellow, viscous oil

¹ H-NMR (CDCl ₃ , 500 MHz): (ppm) = 4.24-3.43 (75H, m, H- (1-9)), 1.39 / 1.33 (24H,

2s, H-1 1, H-12).

¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 109.3 (C-10), 78.6, 78.4, 74.7, 74.5, 72.4, 71.6, 71.4,

71.2, 70.4, 66.9, 66.7 (C- (2-9)), 61.3 (C-1), 26.7, 25.4 (C-11, C-12).

IR (KBr): (cm ^-1 ) = 2987 (s, CH (-CH ₂ , -CH ₃ )), 2113 (m, azide), 1456, 1372 (s, CH, (-CH ₂ , -

CH ₃ )), 1082 (s, CO).

MS (TOF): m / z = 759.8986 [M + 2Na] ⁺ , 1474.8276 [M + H] ⁺ , 1496.8084 [M + Na] ⁺ , 1512.7832 [M + K] ⁺ .

Cleavage of Hydrophobic and Hydrophilic Building Blocks by Click Chemistry The conditions for successful synthesis published by Sharpless et al include the addition of 5 mol% CuSO ₄ -SH ₂ O and 10 mol% ascorbic acid as catalysts. NaOH was added as a base and surprisingly the increase of the base concentration from 10 mol% to 30 mol% led to the target reaction time of two [G1] azides and four days for [G2] azides and shortened to five days for the [G3] azides.

The general synthesis of the "click" chemistry carried out is shown in the following scheme:

Cleavage of the acetal protecting groups

In the last step, the acetal protecting groups were cleaved under acidic conditions. However, the pH should not be too low, since otherwise the esters are not stable and acid ester hydrolysis may occur. The Lewatit K 1131 ion exchanger in MeOH has proven to be suitable. The cleavage took place after 24 h stirring to 100%. All Products were purified by HPLC to give clean compounds for subsequent physicochemical characterizations that are very sensitive to any contaminants. Cleavage of the acetal protecting groups by the example of the [G1] amphiphiles:

The yields of the "click" reactions after acetal cleavage and HPLC separation are summarized in Table 1 below.

Table 1 :

Yielding the "click" reactions.

General working instructions for the "Click" reaction:

Azide (1 eq) and alkyne (1, 1 eq) are dissolved in 4 mL of THF / water (1: 1) mixture. CuSO4-5 H2O (5 mol%), ascorbic acid (10 mol%) and NaOH (30 mol%) are added and the reaction mixture is stirred for two to five days at room temperature. The solvent is removed in vacuo and the inorganic additives are passed through Filtration over silica gel removed. To cleave the protective groups, the crude product is dissolved in MeOH and about 100 wt.% Lewatit K 1131 ion exchanger are added. Stirred for 24 hours provides the deprotected amphiphile, which is purified by HPLC.

Example 1.1

Synthesis of 1 - [Gly-PG-1 H- [1,2,3triazole-4-carboxylic acid undecyl ester (22)

Approach: 750 mg (2.2 mmol) of [G1] -N3 (19), 534 mg (2.4 mmol) of undecyl propionate (1),

27 mg (0.11 mmol) CuSO ₄ -5 H ₂ O, 39 mg (0.22 mmol) ascorbic acid, 26 mg (0.66 mmol)

NaOH, 1.3 g of Lewatit K 1 131

Reaction time: 48 hours

Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)

Yield: 510 mg (1.0 mmol, 48%) of a yellow waxy solid

¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.61-8.56 (1H, m, H-9), 5.06 (1H, m, H-10), 4.28 (2H, t,

³ J6.5 = 7.0 Hz, H-6), 3.99-3.38 (14H, m, H- (1- 1-14)), 1.72 (2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H -5),

1.43-1.25 (16H, m, H- (2-4)), 0.85 (3H, t, 3J1, 2 = 7.0 Hz, H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.2 (C-7), 140.5 (C-9), 129.8 (C-8), 73.8, 72.1, 71.1,

66.3, 64.2, 62.9 (C-6, C- (10-14)), 33.1, 30.8, 30.5, 29.8, 27.0 (C- (3-5)), 23.8 (C-2), 14.5 (C-)

1 )-

IR (KBr): (cm ^-1 ) = 3387 (m, OH), 2927, 2856 (s, CH (-CH ₂ , -CH ₃ )), 1725 (m, C = O), 1543 (w,

C = C (aromatic)), 1466 (w, CH (-CH ₂ , -CH ₃ )), 1042 (m, CO).

TOF-MS: m / z = 490.3124 [M + H] ⁺ , 512.2945 [M + Na] ⁺ , 979.6180 [2M + H] ⁺ , 1001.6002

[2M + Na] ⁺ .

Example 1.2

Synthesis of 1- [G1l-PG-1 H- [1,2,3-triazole-4-carboxylic acid hexadecyl ester (21)

Approach: 587 mg (1.7 mmol) of [G1] -N3 (19), 551 mg (1.9 mmol) of hexadecyl propionate

(2), 21 mg (0.085 mmol) CuSO4-5 H2O, 30 mg (0.17 mmol) ascorbic acid, 20 mg (0.51 mmol) NaOH, 1.1 g Lewatit K1 131

Reaction time: 48 hours

Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)

Yield: 469 mg (0.84 mmol, 49%) of a white solid

¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.62-8.57 (1H, m, H-9), 5.06 (1H, m, H-10), 4.29 (2H, t,

³ J6.5 = 7.0 Hz, H-6), 4.00-3.39 (14H, m, H- (1- 1-14)), 1.73 (2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H -5),

1.44-1.25 (26H, m, H- (2-4)), 0.86 (3H, t, ³ JI, 2 = 7.0 Hz, H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.2 (C-7), 140.5 (C-9), 129.8 (C-8), 73.8, 72.1, 71.1,

66.3, 64.2, 62.9 (C-6, C- (10-14)), 33.1, 30.8, 30.7, 30.5 (2x), 29.8, 27.1 (C- (3-5)), 23.8 (C-2),

14.5 (C-1).

IR (KBr): (cm-1) = 3384 (s, OH), 2925, 2854 (s, CH (-CH2, -CH3)), 1724 (s, C = O), 1644, 1543 (w, C = C (aromatic)), 1466 (m, CH (-CH 2, -CH 3)), 1042 (m, CO).

TOF-MS: m / z = 560.3907 [IVH-H] ⁺ , 582.3722 [M + Na] ⁺ , 11 19.7751 [2M + H] ⁺ , 1141.7560

[2M + Na] ⁺ .

Example 1.3

Synthesis of 4- (1- [G1l-PG-1 H- [1,2,3-triazol-4-yl) benzoic acid hexadecyl ester (23)

Batch: 525 mg (1.5 mmol) of [G1] -N3 (19), 619 mg (1.7 mmol) of hexadecyl 4-ethynylbenzoate (3), 19 mg (0.075 mmol) of CuSO4-5 H2O, 26 mg (0 , 15 mmol)

Ascorbic acid, 18 mg (0.45 mmol) NaOH, 1.1 g Lewatit K 1131

Reaction time: 48 hours

Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)

Yield: 553 mg (0.87 mmol, 57%) of a yellowish-white solid

¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.62-8.57 (1H, m, H-13), 8.07-7.95 {AH, m, H-9, H-10),

5.08 (1H, m, H-14), 4.31 (2H, t, 3J6.5 = 7.0Hz, H-6), 4.06-3.45 (14H, m, H- (15-18)), 1.79

(2H, quin, 3J5,4 / 5,6 = 7.0Hz, H-5), 1.49-1.27 (26H, m, H- (2-4)), 0.89 (3H, t, 3J1.2 = 7.0Hz .

H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 167.7 (C-7), 147.4 (C-1 1), 136.5, 131.2, 131.0, 126.6,

123.4 (C- (8-13)), 73.9, 72.2, 71.3, 66.3, 64.3, 62.6 (C-6, C- (14-18)), 33.1, 30.8 (2x), 30.5

(2x), 29.9, 27.2 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).

IR (KBr): (cm-1) = 3415 (s, O-H), 2925, 2854 (m, C-H (-CH2, -CH3)), 1712 (w, C = O), 1616

(w, C = C (aromatic)), 1464 (w, C-H (-CH2, -CH3)), 1112 (w, C-O).

TOF-MS: m / z = 636.4228 [M + H] ⁺ , 658.4046 [M + Na] ⁺ , 1271.8383 [2M + H] ⁺ .

Example 1.4

Synthesis of 1- [G2l-PG-1 H- [1,2,3-triazole-4-carboxylic acid hexadecyl ester (24)

Approach: 902 mg (1.3 mmol) of [G2] -N3 (18), 405 mg (1.4 mmol) of hexadecyl propionate

(2), 16 mg (0.065 mmol) CuSO4-5 H2O, 23 mg (0.13 mmol) ascorbic acid, 16 mg (0.39 mmol) NaOH, 1.3 g Lewatit K1 131

Reaction time: 4 days

Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)

Yield: 630 mg (0.74 mmol, 59%) of a colorless wax

¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.71-8.66 (1H, m, H-9), 5.08 (1H, m, H-10), 4.34 (2H, t,

³ J6.5 = 7.0 Hz, H-6), 4.19-3.40 (34H, m, H- (1- 1-16)), 1.78 (2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H -5),

1.49-1.29 (26H, m, H- (2-4)), 0.90 (3H, t, ³ JI, 2 = 7.0Hz, H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.3 (C-7), 140.3 (C-9), 130.1 (C-8), 80.0, 73.9, 72.4,

72.2, 71.2, 70.2, 66.4, 64.4 (C-6, C- (10-16)), 33.1, 30.8, 30.5, 29.8, 27.1 (C- (3-5)), 23.8 (C-)

2), 14.5 (C-1).

IR (KBr): (cm-1) = 3385 (s, OH), 2925, 2854 (s, CH (-CH2, -CH3)), 1722 (m, C = O), 1643, 1543 (w, C = C (aromatic)), 1466 (m, CH (-CH 2, -CH 3)), 1 121 (m, CO). MS (TOF): m / z = 856.5390 [IVH-H] ⁺ , 878.5209 [M + Na] ⁺ .

Example 1.5

Synthesis of HG2l PG-1 H-H, 2,3-triazole-4-carboxylic acid undecyl ester (25)

Batch: 902 mg (1.3 mmol) of [G2] -N3 (18), 308 mg (1.4 mmol) of undecyl propionate (1),

16 mg (0.065 mmol) CuSO ₄ -5 H ₂ O, 23 mg (0.13 mmol) ascorbic acid, 16 mg (0.39 mmol)

NaOH, 1, 2 g l_ewatit K 1131

Reaction time: 4 days

Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)

Yield: 441 mg (0.56 mmol, 45%) of a colorless wax

¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.70-8.68 (1H, m, H-9), 5.08 (1H, m, H-10), 4.35 (2H, t,

3J6.5 = 7.0 Hz, H-6), 4.18-3.40 (34H, m, H- (11-16)), 1.78 (2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H-5 )

1.48-1.29 (16H, m, H- (2-4)), 0.90 (3H, t, ³ JI, 2 = 7.0Hz, H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.3 (C-7), 140.4 (C-9), 130.1 (C-8), 80.1, 73.9, 72.5,

72.2, 70.2, 66.4, 64.5, 63.5 (C-6, C- (10-16)), 33.1, 30.8, 30.5, 29.8 (C- (3-5)), 23.8 (C-2), 14.5

(C-1).

IR (KBr): (cm-1) = 3388 (s, O-H), 2924 (s, C-H (-CH2, -CH3)), 1720 (m, C = O), 1638 (m, C = C

(Aromat)), 1459 (w, C-H (-CH2, -CH3)), 1041 (m, C-O).

MS (TOF): m / z = 786.4608 [M + H] ⁺ , 808.4428 [M + Na] ⁺ .

Example 1.6

Synthesis of 4- (1-rG21-PG-1H-π, 2,31triazol-4-yl) -benzoic acid hexadecyl ester (26)

Batch: 752 mg (1.0 mmol) [G2] -N3 (18), 422 mg (1.1 mmol) 4

Ethylene benzoic acid hexadecyl ester (3), 12 mg (0.050 mmol) CuSO4-5 H2O, 18 mg (0.10 mmol) ascorbic acid, 12 mg (0.30 mmol) NaOH, 1.2 g Lewatit K 1131

Reaction time: 4 days

Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)

Yield: 423 mg (0.45 mmol, 44%) of a colorless wax

¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.64-8.60 (1H, m, H-13), 8.10-7.98 (4H, m, H-9, H-10),

5.07 (1H, m, H-14), 4.32 (2H, t, ³ J6.5 = 7.0Hz, H-6), 4.22-3.39 (34H, m, H- (15-20)), 1.79

(2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H-5), 1.50-1.28 (26H, m, H- (2-4)), 0.89 (3H, t, ³ JI, 2 = 7.0 Hz,

H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 167.8 (C-7), 147.2 (C-1 1), 136.5, 131.3, 131.0, 126.6,

123.7 (C- (8-13)), 80.1, 73.9, 72.5, 72.2, 70.5, 66.3, 64.4 (2x) (C-6, C- (14-20)), 33.1, 30.8,

30.7 (2x), 30.5, 29.9, 27.2 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).

IR (KBr): (cm-1) = 3381 (s, O-H), 2923, 2853 (s, C-H (-CH2, -CH3)), 1716 (m, C = O), 1615

(w, C = C (aromatic)), 1466 (m, CH (-CH 2, -CH 3)), 1112 (s, CO). MS (TOF): m / z = 932.571 1 [IVH-H] ⁺ , 954.5531 [M + Na] ⁺ .

Example 1.7

Synthesis of 4- (1- [G31-PG-1 H- [1, 2,31triazol-4-yl) benzoic acid hexadecyl ester (27)

Preparation: 1.00 g (0.68 mmol) [G3] -N3 (20), 276 mg (0.75 mmol) 4

Ethinylbenzoesäurehexadecylester

(3), 8 mg (0.034 mmol) CuSO 4 .5H 2 O, 12 mg (0.068 mmol) ascorbic acid, 8 mg (0.20 mmol) NaOH,

1.3 g of Lewatit K 1 131

Response time: 5 days

Purification: HPLC (MeOH / DCM 1: 5, flow 64 mL / min)

Yield: 604 mg (0.40 mmol, 58%) of a colorless wax

¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.66-8.65 (1H, m, H-13), 8.12-8.01 {AH, m, H-9, H-10),

5.27 (1H, m, H-14), 4.33 (2H, t, ³ J6.5 = 7.0Hz, H-6), 4.21-3.42 (74H, m, H- (15-22)), 1.80

(2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H-5), 1.51-1.28 (26H, m, H- (2-4)), 0.90 (3H, t, ³ JI, 2 = 7.0 Hz,

H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 167.8 (C-7), 147.1 (C-1 1), 136.5, 131.3, 131.0, 126.7,

124.0 (C- (8-13)), 80.5, 79.8, 74.0, 72.9, 72.2, 71.0, 70.4, 66.4, 64.5, 63.5 (C-6, C- (14-22)),

33.1, 30.8, 30.5, 29.8, 27.2 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).

MS (TOF): m / z = 1524.8621 [M + H] ⁺ , 1546.8432 [M + Na] ⁺ .

c) Synthesis of amide amphiphiles

The amide amphiphiles 7 and 33 were synthesized as shown below. The hydrogenation with Pd / C was carried out in an autoclave at 8 bar hydrogen pressure and was complete after 24 h. After filtration through silica gel, 99% [GI] -NH ₂ 28 or 96% [G ₂ ] -NH ₂ 29 were obtained. The coupling of 28 and 29 to 30 with DCC and NHS was carried out in two steps. After activation of the acid as NHS ester, the resulting DCU could be filtered off for the most part and then amine 28 or 29 were added. The progress of the coupling reaction was monitored by TLC.

General procedure for amide coupling:

Hexadecanoic acid (1 eq) and DCC (1.1 eq) are dissolved in THF and after addition of NHS (1.05 eq) is stirred for 24 hours at room temperature. The DCU precipitate is filtered off and a portion of the solvent removed. After further crystallization of DCU overnight in the refrigerator is filtered again. The filtrate is taken up in a THF / DMF (1: 1) mixture and, after addition of the amine (1 eq), stirred again for 2-5 days. After completion of the reaction, the solvent mixture is removed under reduced pressure. To cleave off the protective groups, the crude product is dissolved in methanol and about 100 wt.% Ion exchange Lewatit K 1 131 are added. Stirred for 24 hours provides the deprotected amphiphile, which is purified by HPLC.

Example 1.8

Synthesis of hexadecanoic acid [G11-PG amide (7)

Batch: 0.80 g (2.5 mmol) of [G1] -NH2 (28), 641 mg (2.5 mmol) of hexadecanoic acid (30), 567 mg

(2.8 mmol) DCC, 302 mg (2.6 mmol) NHS, 1.4 g Lewatit K 1131

Reaction time: 48 hours

Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)

Yield: 289 mg (0.61 mmol, 24%) of a white solid

¹ H NMR (MeOD, 500 MHz): (ppm) = 4.14 (1H, m, H-8), 3.76-3.40 (14H, m, H (9-12)), 2.17

(2H, t, 3J6.5 = 7.5Hz, H-6), 1.57 (2H, m, H-5), 1.29-1.26 (24H, m, H- (2-4)), 0.87 (3H, t , 3J1,2 = 7.0 Hz, H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 174.9 (C-7), 72.5, 72.2, 70.9, 69.9, 63.0 (C- (8-12),

35.8, 31.8, 29.5, 29.3, 29.2, 29.0, 25.8 (C- (3-6)), 22.4 (C-2), 13.1 (C-1).

IR (KBr): (cm-1) = 3357 (m, O-H), 2974, 2926 (m, C-H (-CH2, -CH3)), 1267 (m, C-O).

MS (TOF): m / z = 478.3738 [M + H] +, 500.3557 [M + Na] +, 516.3260 [M + K] +.

Example 1.9

Synthesis of hexadecanoic acid [G21-PG amide (33)

Preparation: 1.00 g (1.4 mmol) of [G2] -NH2 (29), 359 mg (1.4 mmol) of hexadecanoic acid (30), 318 mg

(1, 5 mmol) DCC, 177 mg (1, 5 mmol) NHS, 1, 4 g Lewatit K 1 131

Response time: 5 days

Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)

Yield: 479 mg (0.62 mmol, 44%) of a colorless wax

¹ H-NMR (MeOD, 500 MHz): (ppm) = 4.13 (1H, m, H-8), 3.79-3.46 (34H, m, H- (9-14)), 2.22

(2H, t, 3J6.5 = 7.5Hz, H-6), 1.61 (2H, m, H-5), 1.33-1.29 (24H, m, H- (2-4)), 0.90 (3H, t , 3J1,2

= 7.0 Hz, H-1).

¹³ C-NMR (MeOD, 125 MHz): (ppm) = 176.3 (C-7), 79.8, 74.0, 73.0, 72.2, 71.3, 70.0, 64.5,

63.0 (C- (8-14), 37.2, 33.1, 30.9, 30.5, 30.4, 27.1 (C- (3-6)), 23.8 (C-2), 14.5 (C-1).

IR (KBr): (cm-1) = 3398 (m, O-H), 2925 (m, C-H (-CH2, -CH3)), 1643 (w, C = O (amide)), 1265

(s, C-O).

MS (TOF): 774.5222 [M + H] +, 796.5036 [M + Na] +.

Example 2

Compounds of general formula (1) - Alkyl side chain amphiphiles and aromatic

Unit at the end of the hydrophobic moiety with dendritic polyglycerol head group

The synthesis of non-ionic, linear dendritic polyglycerol amphiphiles with terminal aromatics is shown using the example of biphenyl octadecanyl polyglycerol compound - Bi-CI 8-PG [G2.0] -OH. Similarly, short alkyl chain amphiphiles (C1 1), benzoyl (Bz), or naphthoyl (Na) structures (instead of the biphenyl moiety in the compound presented herein) and amphiphiles with generation 1.0 and 3.0 polyglycerol endo-dides were also prepared.

Examples 2.1 to 2.10

Bz-CI 1-PG [GlO] -OH Bz-CI 1-PG [G2.0] -OH Bz-CI 8-PG [G2.0] -OH Bz-CI 8-PG [G3.0] -OH

Na-CI 1-PG [G2.0] -OH Na-CI 8-PG [G2.0] -OH Na-CI 8-PG [G3.0] -OH

Bi-CI 1-PG [G2.0] -OH Bi-CI 8-PG [G2.0] -OH Bi-CI 8-PG [G3.0] -OH Synthesis of Bi-CI 8-PG [G2.0] -OH

Structure of biphenyl octadecanyl polyglycerol:

1 1- (4 - ((6,12-bis ((2,3-dihydroxypropoxy) methyl) -1,2,16,17-tetrahydroxy-4,7,11,14-tetraoxaheptadecan-9-yloxy) methyl) -1 H -1, 2,3-triazol-1-yl) undecylbiphenyl-4-carboxylate

Chemical formula: C ₅₅ H ₉₁ N ₃ Oi ₇ Exact mass: 1065.63485 Molecular weight: 1066.32094

a) Representation of the hydrophobic amphiphile building block

18-azido-1-octadecanol

With gentle heating, 1,1,8-octadecanediol (18.80 g, 65.62 mmol, 1.5 equiv.) In abs. Dissolved THF (800 ml) and treated with triethylamine (18.75 mL, 13.61 g, 134.50 mmol, 3.1 equiv.). Over a period of 90 minutes, methanesulfonyl chloride (3.35 mL, 4.96 g, 43.28 mmol) was added. After 18 hours, the precipitated in the reaction colorless solid was separated and the solvent removed on a rotary evaporator. There were obtained 33.80 g of a colorless, waxy solid, which was reacted without further purification to the azide.

The crude product was in abs. Dissolved DMF (250 mL), treated with sodium azide (14.19 g, 218.25 mmol) and the suspension stirred at 120 ⁰ C for three hours. After separating off the excess sodium azide, the solvent was removed in vacuo and the residue was purified by column chromatography (hexane / EA 1: 0, 8: 1 to 3: 1). There were obtained 8.25 g (61% based on mesyl chloride) of a colorless, waxy solid,

¹ H-NMR (250 MHz, CDCl 3): δ = 3.62 (t, 2H, 1-H), 3.25 (t, 2H, 18-H), 1.85 (OH), 1.58 (m, 6H,

2/3/17-H), 1.26 (26H, 4-16H) ppm

¹³ C-NMR (250 MHz, CDCl 3): δ = 62.94 (1-C), 51.45 (18-C), 32.76 (2-C), 29.61 - 28.79,

26.67, 25.71 (3-17-C) ppm

HR-MS (ESI-TOF): calcd for C18H37N3ONa +: 334.2834, found: 334.2807 [M + Na] +

esterification

Alcohol and carboxylic acid (1.4-2 equiv.) Are dissolved in toluene and the reaction mixture after addition of p-toluenesulfonic acid (PTSA, 1 1-15 mol%) at 118-125 ⁰ C on a water ("Dean-Stark") under reflux After the TLC has been checked, it is washed with water, saturated sodium bicarbonate solution and once more with water, and the organic phase is dried over sodium sulphate After removal of the solvent on a rotary evaporator, purification by column chromatography is carried out.

Bi-C18-N3 (59) Preparation: 1 1-azido-octadecan-i-ol (3) (4.00 g, 12.84 mmol), 4-biphenylcarboxylic acid (8)

(3.82 g, 19.26 mmol, 1.5 equiv.), PTSA (370 mg, 1.92 mmol, 15 mol%), toluene (14 mL)

Reaction: 120 ^° C., 20 h

Purification: silica gel chromatography column, hexane / chloroform 1: 1

Yield: 5.02 g (10.50 mmol, 82%) of a colorless, loose crystalline solid

1 H-NMR (250 MHz, CDCl 3): δ = 8.13 (d, 2H, 2/12-H), 7.65 (4H, 6/7/9/10-H), 7.44 (3H,

3/8/11-H), 4.35 (t, 2H, 14-H), 3.25 (t, 2H, 31-H), 1.80 (m, 2H, 15-H), 1.60 (m, 2H, 30- H), 1.28

(28H, 16-29-H) ppm

13 C-NMR (250 MHz, CDCl 3): δ = 166.44 (13-C), 145.44 (1-C), 140.00 (4-C), 129.99, 129.27,

128.84, 128.02, 127.19, 126.92 (2/3/5/6/7/8/9/10/11/12-C), 65.08 (14-C), 51.43 (31-C),

29.63-26.02 (15-30-C) ppm

HR-MS (ESI-TOF): calcd for C31 H45N3O2Na +: 514.3409, found: 514.3421

b) Synthesis of the hydrophilic dendritic polyglycerol building block

Acetal protected alkynyl triglycerol

Triglycerol (11:51 g, 47.91 mmol) was heated to 90-100 ⁰ C, until it assumed a transparent liquid consistency. After addition of 2,2-dimethoxypropane (30 ml, 26.04 g, 250.00 mmol), PTSA (913 mg, 4.8 mmol, 10 mol%) was slowly added with vigorous stirring, and the homogeneous, orange mixture was stirred at 40 ^° C. for 18 hours. After neutralization of the orange-black solution with triethylamine (0.7 mL, 0.51 g, 5.00 mmol), the solvent was removed in vacuo and the orange crude oil was purified by column chromatography on silica gel (hexane / EtOH 3: 1). 11.44 g (35.71 mmol, 75%) of a golden yellow oil were obtained. 1 H-NMR (250 MHz, CDCl 3): δ = 4.19-3.46 (15H, PG-H), 1.34-1.27 (2 s, 8H, acetal-H) ppm

Acetal Protected Polyglycerol [G2.0] - propargyl

To represent the second generation polyglycerol dendron, the acetal-protected polyglycerol is reacted with methallyl dichloride. Addition of NaH results in deprotonation (addition of 15-crown-5 to complex the sodium ion). Addition of Kl and 18-crown-6 converts the chloride into a better leaving group.

In the further steps, the ozonolysis of the double bond followed by reductive workup with sodium borohydride (for more details, see also Example 1).

Subsequently, the introduction of the alkyne functionality by reaction with Propargyl. To this was added sodium hydride (3 equiv.) To the hydroxy compound in THF and the suspension was stirred at 40 ° C for 2 h. At 0 ° C, propargyl bromide (2.5 equiv.) Was added to the reaction and allowed to thaw slowly to RT over 18 h.

Coupling by the "click" reaction

Alkyne and azide (1.1 equiv.) Are dissolved in a little THF and diisopropylethylamine (DIPEA, 10-20 mol%) added. After a few minutes, aqueous solutions of sodium ascorbate (20-40 mol%) and copper (II) sulfate pentahydrate (10-20 mol%) are added. After setting a THF / water solvent ratio of 1: 1, the reaction mixture is stirred at RT for 12 hours to seven days. For workup, the batch is diluted with water, the phases are separated and the aqueous phase washed three times with DCM. The The combined organic phases are dried over sodium sulfate, the solvent removed in vacuo and the crude product purified by column chromatography on silica gel. The "click" reaction occurs here, unlike the synthesis of the linear dendritic amphiphiles with central aromatics (see Example 1) with copper (II) sulfate pentahydrate, sodium ascorbate, and DIPEA as the base, where lower reaction times and higher yields can be observed become.

Bi-CI 8- [G21 batch: [G2] -Propargyl 14 (1.54 g, 2.10 mmol), Bi-C18-N3 59 (1.14 g, 2.31 mmol,

1.1 equiv), DIPEA (54.9 μL, 0.32 mmol, 15 mol%), sodium ascorbate

(0.63 mmol, 30 mol%), copper sulfate pentahydrate (0.32 mmol, 15 mol%),

THF / water (1: 1, 8.1 ml_)

Reaction: 4 d

Purification: silica gel flash column, hexane / THF 3: 1, 1.5: 1

Yield: 2.27 g (1.85 mmol, 88%) of viscous oil

1 H-NMR (400 MHz, CDCl 3): δ = 8.07 (d, 2H, 2/12-H), 7.63-7.55 (5H, 6/7/9/10/18-H), 7.42 (t, 2H , 3/11-H), 7.35 (1H, 8-H), 4.77 (2H, 20-H), 4.30 (4H, 14/17-H), 4.20-3.45 (35H, PG-H), 1.85 (2H, 15-H), 1.75 (2H, 16-H), 1.37-1.22 (44H, alkyl, acetal-H) ppm 13 C-NMR (400 MHz, CDCl 3): δ = 166.36 (13-C), 145.34 (19-C), 139.88 (1-C), 129.90, 129.14, 128.76, 127.95, 127.10, 126.84, 122.20 (2/3/4/5/6/7/8/9/10/11/12 / 18-C),) 109.18 (acetal-C), 78.31, 74.51, 74.48, 72.36, 66.61, 64.99, 63.87 (14 / PG-C), 50.13 (17-C), 30.22-25.28 (alkyl, acetal) H) ppm HR-MS (ESI-TOF): calcd for C67H107N3O17Na +: 1248.7498, found: 1248.7456

Remove the acetal protecting group

To cleave the acetal protecting groups of the polyglycerol endpoints, the protected product is dissolved in methanol and, after addition of 100% by weight of Lewatit K 1 131, stirred for 24 hours at RT. Subsequently, the ion exchanger is separated and washed with methanol.

Bi-C18 [G21-OH] (51)

Yield: 1.79 g (1.68 mmol, 91%) wax

1 H-NMR (400 MHz, MeOD): δ = 8.06 (d, 2H, 2/12-H), 8.00 (1H, 18-H), 7.71 (d, 2H, 3/1 1-H),

7.65 (2H, 6/10-H), 7.45 (2H, 7/9-H), 7.38 (1H, 8-H), 4.79 (2H, 20-H), 4.37-4.31 (4H, 14/17 -H),

3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.24 (28H, alkyl-H) ppm

13 C-NMR (400 MHz, MeOD): δ = 167.90 (13-C), 147.00 (1-C), 141.05 (19-C), 131.10,

130.10, 128.22, 125.13 (2/3/4/5/6/7/8/9/10/1 1/12/18-C), 79.91, 74.00, 72.21, 66.26, 64.49,

(14 / PG-C), 51.38 (17-C), 31.38-27.17 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd for C55H91 N3O17Na +: 1088.6246, found: 1088.6192

Spectroscopic data of all amphiphiles with terminal aromatics

Bz-C1 1 - [GI] -OH (46)

1 H-NMR (400 MHz, MeOD): δ = 7.99 (3H, 2/6/12-H), 7.59 (1H, 4-H), 7.47 (m, 2H, 3/5-H),

4.78 (2H, 14-H), 4.38 (t, 2H, 8-H), 4.30 (t, 2H, 11-H), 3.75-3.49 (15H, PG-H), 1.88 (2H, 8-H )

1.76 (2H, 9-H), 1.45-1.29 (14H, alkyl-H) ppm

13 C-NMR (400 MHz, MeOD): δ = 168.09 (7-C), 134.21 (13-C), 131.63, 130.45, 129.61,

125.14 (1/2/3/4/5/6/12-C), 78.76, 73.98, 72.42, 66.24, 64.44 (8-C / PG-C), 51.37 (11-C),

31.32-27.13 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd. For C30H49N3O9Na +: 618.3366, found: 618.3358

Bz-C1 1- [G21-OH (47)

1 H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (m, 1H, 4-H), 7.48 (m, 2H,

3/5-H), 4.79 (2H, 14-H), 4.39 (2H, 8-H), 4.31 (t, 2H, 11-H), 3.77-3.49 (35H, PG-H), 1.90 ( 2H,

9-H), 1.77 (2H, 10-H), 1.46-1.31 (14H, alkyl-H) ppm

13 C-NMR (400 MHz, MeOD): δ = 168.1 1 (7-C), 146.40 (13-C), 134.23, 131.62, 130.49,

129.62, 125.17 (1/2/3/4/5/6/12-C), 79.88, 74.00, 72.45, 66.25, 64.49, 63.02 (8-C, PG-C),

51.39 (11C), 33.67-26.96 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd. For C42H73N3O17Na +: 914.4838, found: 914.4853

1 H-NMR (400 MHz, MeOD): δ = 8.58 (1H, 10-H), 8.02-7.98 (3H, 2/8/16-H), 7.93 (d, 2H, 3/5-H) , 7.63-7.56 (2H, 6/7-H), 4.78 (2H, 18-H), 4.36 (4H, 12/15-H), 3.76-3.49 (35H, PG-H), 1.87-1.78 (4H , 13/14-H), 1.47-1.28 (14H, alkyl chain) ppm 13 C-NMR (400 MHz, MeOD): δ = 168.18 (1 1-C), 137.00, 133.93, 131.89, 130.39, 129.54, 128.88, 127.97, 126.04 (1/2/3/4/5/6/7 / 8/9/10/16/17-C), 79.87, 74.00, 72.45, 66.40, 65.1 1, 64.49 (12 / PG-C), 51.36 (15-C), 30.56-26.95 (alkyl-C) ppm HR MS (ESI-TOF): calcd for C46H75N3O17Na +: 964.4994, found: 964.5013

Bi-CI HG21-OH (49)

1 H-NMR (400 MHz, MeOH): δ = 8.07 (d, 2H, 2/12-H), 7.99 (1H, 18-H), 7.73 (d, 2H, 3/1 1-H),

7.67 (2H, 6/10-H), 7.48 (2H, 7/9-H), 7.39 (1H, 8-H), 4.78 (2H, 20-H), 4.37-4.32 (4H, 14/17 -H),

3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.29 (14H, alkyl-H) ppm

13C-NMR (400 MHz, MeOD): δ = 167.96 (13-C), 147.04 (1-C), 141.07 (19-C), 131.10,

130.35, 130.1 1, 128.24, 127.98, 128.10 (2/3/4/5/6/7/8/9/10/1 1/12/18-C),), 79.88, 74.01,

72.47, 72.21, 66.27, 64.49, (14 / PG-C), 51.37 (17-C), 30.60-26.96 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd for C48H77N3O17Na +: 990.5151, found: 990.511 1

Bz-C18- [G21-OH (45)

1 H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (1H, 4-H), 7.47 (m, 2H, 3/5

H), 4.79 (2H, 14-H), 4.39 (2H, 8-H), 4.31 (t, 2H, 11-H), 3.77-3.50 (35H, PG-H), 1.90 (2H, 9-

H), 1.77 (2H, 10-H), 1.46-1.27 (28H, alkyl-H) ppm

13 C NMR (400 MHz, MeOD): δ = 168.02 (7-C), 146.37 (13-C), 134.20, 131.60, 130.45,

129.60, 125.16 (1/2/3/4/5/6/12-C), 79.90, 73.97, 72.44, 66.22, 64.46 (8-C, PG-C), 51.37 (1)

C), 30.81-27.16 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd for C49H87N3O17Na +: 1012.5933, found: 1012.5951

Na CI 8- [G21-OH (50)

1 H-NMR (400 MHz, MeOD): δ = 8.57 (1H, 10-H), 8.02-7.96 (3H, 2/8/16-H), 7.91 (d, 2H, 3/5-H) , 7.62-7.53 (2H, 6/7-H), 4.78 (2H, 18-H), 4.37-4.35 (4H, 12/15-H), 3.76-3.49 (35H, PG-H), 1.86-1.79 (4H, 13/14-H), 1.47-1.22 (28H, alkyl chain) ppm 13 C-NMR (400 MHz, MeOD): δ = 168.12 (11-C), 136.97, 133.89, 131.87, 130.35, 129.49, 128.84, 127.91, 126.02 (1/2/3/4/5/6/7 / 8/9/10/16/17-C), 79.84, 73.96, 72.27, 66.37, 64.45 (12 / PG-C), 51.35 (15-C), 30.76-27.15 (alkyl-C) ppm HR-MS ( ESI-TOF): calcd for C53H89N3O17Na +: 1062.6090, found: 1062.6030

1 H-NMR (400 MHz, MeOD): δ = 8.06 (d, 2H, 2/12-H), 8.00 (1H, 18-H), 7.71 (d, 2H, 3/1 1-H),

7.65 (2H, 6/10-H), 7.45 (2H, 7/9-H), 7.38 (1H, 8-H), 4.79 (2H, 20-H), 4.37-4.31 (4H, 14/17 -H),

3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.24 (28H, alkyl-H) ppm

13 C-NMR (400 MHz, MeOD): δ = 167.90 (13-C), 147.00 (1-C), 141.05 (19-C), 131.10,

130.10, 128.22, 125.13 (2/3/4/5/6/7/8/9/10/11/12/18-C), 79.91, 74.00, 72.21, 66.26, 64.49,

(14 / PG-C), 51.38 (17-C), 31.38-27.17 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd for C55H91 N3O17Na +: 1088.6246, found: 1088.6192

Bz-C18- [G31-OH (52)

1 H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (1H, 4-H), 7.48 (m, 2H, 3/5

H), 4.81 (2H, 14-H), 4.40 (t, 2H, 8-H), 4.31 (t, 2H, 11-H), 3.76-3.50 (75H, PG-H), 1.91 (2H, 9-

H), 1.78 (2H, 10-H), 1.46-1.28 (28H, alkyl-H) ppm

13 C-NMR (400 MHz, MeOD): δ = 168.12 (7-C), 146.58 (13-C), 134.22, 131.65, 130.46,

129.62 (1/2/3/4/5/6/12-C), 79.89, 74.03, 72.23, 66.26, 64.54 (8-C, PG-C), 51.42 (1 1 -C),

30.81-27.15 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd for C73H135N3O33Na +: 1604.8876, found: 1604.8855

1 H-NMR (400 MHz, MeOD): δ = 8.59 (1H, 10-H), 8.03-8.01 (3H, 2/8/16-H), 7.94 (d, 2H, 3/5

H), 7.64-7.55 (2H, 6/7-H), 4.81 (2H, 18-H), 4.39-4.37 (4H, 12/15-H), 3.77-3.49 (75H, PG-H),

1.88-1.82 (4H, 13/14-H), 1.49-1.25 (28H, alkyl chain) ppm

13 C-NMR (400 MHz, MeOD): δ = 168.21 (1 1-C), 146.56, 137.03, 133.96, 131.90, 130.40,

129.55, 128.88, 127.97, 126.05 (1/2/3/4/5/6/7/8/9/10/16/17-C), 79.87, 74.03, 72.45, 66.42,

64.55 (12 / PG-C), 51.41 (15-C), 31.43-24.76 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd for C77H137N3O33Na +: 1654.9032, prepared: 1654.9035

1 H-NMR (400 MHz, MeOD): δ = 8.08 (d, 2H, 2/12-H), 8.01 (s, 1H, 18-H), 7.73 (d, 2H, 3/1 1-

H), 7.67 (2H, 6/10-H), 7.48 (2H, 7/9-H), 7.39 (1H, 8-H), 4.80 (2H, 20-H), 4.39 (t, 2H, 14-H),

4.32 (t, 2H, 17-H), 3.77-3.49 (75H, PG-H), 1.89 (2H, 15-H), 1.78 (2H, 16-H), 1.47-1.26 (28H,

Alkyl H) ppm

13 C-NMR (400 MHz, MeOD): δ = 167.95 (13-C), 147.04 (1-C), 141.07 (19-C), 131.10,

130.1 1, 128.23 (2/3/4/5/6/7/8/9/10/11/12/18-C), 79.86, 74.02, 72.43, 66.27, 64.53, (14 / PG-

C), 51.41 (17-C), 31.43-27.15 (alkyl-C) ppm

HR-MS (ESI-TOF): calcd for C79H139N3O33Na +: 1680.9189, found: 1680.9251 Overview of linear dendritic polyglycerol amphiphiles, Examples 2.1-2.10

Example 3

Compounds of the general formula (2) - Amphiphiles with alkyl radicals and partially fluorinated

Alkyl side chains and dendritic polyglycerol head groups

1. Experimental part

1.1. General

Preparative methods:

All reactions requiring dry conditions were carried out under argon atmosphere in dried glassware. The compounds (x), (x), (x) and (x) were prepared and purified within the Haag group, the solvents for the column chromatography were purified by distillation. All other chemicals and reagent grade dry solvents were commercially purchased and used without further purification. Column and flash chromatography were performed on silica gel 60 (230-400 mesh).

spectroscopy:

The ¹ H NMR and ¹³ CN MR spectra were recorded with BRUKER AC 250 (250 MHz), BRUKER DRX 500 (500 MHz) and JOEL ECLIPSE 400 (400 MHz), with the proton and carbon signals taken from residual solvent for calibration CDCl ₃ (δ = 7.26 ppm for ¹ H and δ = 77.0 ppm for ¹³ C) and CD ₃ OD (δ = 4.84 ppm for ¹ H). The ¹³ C NMR spectra were recorded with ¹ H broadband decoupling. The chemical shifts are given in parts per million (ppm) and the coupling constants in Hertz (Hz).

Mass spectrometry was performed on an Agilent 6210 ESI-TOF instrument.

1.2. General procedure

General Procedure for the Synthesis of C _n -N ₃ : The azide (x) was dissolved in DMSO and KOH powder (4 equivalents per OH) was added all at once to give a brown suspension. After stirring at room temperature for 10 min, the olefinic bromide (2 equiv. Per OH) was added via syringe and the reaction mixture was then stirred for a further 40 min. The reaction was quenched with H ₂ O and then extracted with DCM. The combined organic layers were washed with H ₂ O and dried over anhydrous Na ₂ SO ₄ . The DCM was evaporated in vacuo and the residual DMSO was removed by cryogenic distillation. The resulting liquid was purified by column chromatography on silica gel with 2% EA in hexane as eluent to give the desired product.

General procedure for the synthesis of C _n -G0-Ck-G _m : propargyl G _m (1, 0 equivalents) and the azide C _n -N ₃ (1, 1 equivalents) were dissolved in very small amounts of THF to give a clear to give concentrated solution. Subsequently, catalytic amounts of DIPEA (10-30 mol%) and freshly prepared aqueous solutions of sodium ascorbate (10-30 mol%) and CuSO ₄ -5H ₂ O (5-15 mol%) were added successively with Eppendorf pipettes. Additional amounts of H ₂ O were added to give a total THF / H ₂ O ratio of 1: 1. Subsequently, the reaction mixture was vigorously stirred for 3 to 5 days at room temperature until the TLC analysis indicated that the propargyl G _{m was} completely consumed. H ₂ O was added for dilution and then extracted with DCM. The combined organic layers were washed with small amounts of saturated EDTA solution and dried over anhydrous Na ₂ SO ₄ . The DCM was evaporated in vacuo and the residual oil was purified by column chromatography or filtration on silica gel with a mixture of EA or isopropanol and hexane as eluent to give the desired product.

General procedure for the synthesis of RfC _n -G0-Ck-G _{m: n} C _-G0-Ck-m G was dissolved in RfC ₂ H ₄ SH (4 equivalents per C = C) and heated under reflux at 9O ⁰ C , A spatula tip AIBN was added and after stirring for 2 hours a second. The reaction mixture was stirred at 9O ⁰ C for at least 22 more hours until TLC analysis indicated that the C _n -G0-Ck-G _{m was} completely consumed. A large part of the unused RfC ₂ H ₄ SH was (if appropriate) removed by means of cryogenic distillation. The residual oil was purified by filtration through silica gel with a mixture of PE and DCM (7: 1) and a subsequent mixture of EE or isopropanol and hexane as eluent to give the desired product.

1.3. Reaction method and analytical characteristics

2-azidopropane-1,3-diol (xx):

Acetal deprotection on azide (x1) to give the azide (x2): The azide (x1) (9.57 g, 47.57 mmol) was dissolved in ethanol (100 ml). After addition of 2.5 equivalents of K ₂ CO ₃ (16.44 g, 199 mmol) in one portion, the suspension was stirred for 30 min at room temperature. The precipitate formed was filtered off separated and washed with ethanol. The solvent of the combined filtrates was evaporated under vacuum and the remaining liquid was dried under high vacuum to give the azide (x2) as a pale yellow oil (5.699 g, 47.57 mmol, 99%).

¹ H-NMR (CD ₃ OD, 400 MHz, 2.5 ⁰ C): δ = 3.51 (m, 4 H, 2-H), 3.42 to 3.36 (m, 1H, 1- H) ppm.

C ₆ -N ₃ (XX):

Synthesis of C ₆ -N ₃ : The reaction was carried out with the azide (x) (1. 871 g, 15.98 mmol), KOH powder (7.17 g, 128 mmol), and 6-bromohex-1-ene ( x) (10.0 g, 61 mmol) in 50 ml of DMSO as described above. Extraction with DCM (3 x 100 ml) and purification by column chromatography gave C ₆ -N ₃ (x) as a colorless liquid (4.05 g, 14.39 mmol, 90%).

¹ H-NMR (CDCI _3, 500 MHz, 26 ⁰ C): δ = 5.79 (tdd, J = 16.95, 10.20, 6.66 Hz, 2 H, 2-H), 5.01 , 4.98 (2 dd, J = 3.62, 1.59 Hz, each 1 H, 1-H), 4.95, 4.93 (2 td, J = 2.16, 1, 21 Hz, 1 H, 1-H), 3.66 (tt, J = 6.62, 4.61 Hz, 1 H, 8-H), 3.51, 3.45 (2 m, 4 H, 6, respectively) -H, 7-H), 2.06 (m, 4H, 3-H), 1.58 (m, 4H, 5-H), 1.45 (m, 4H, 4-H) ppm ,

¹³ C-NMR (CDCI _3, 400 MHz, 26 ⁰ C): δ = 138.58 (s, C-2), 114.48 (s, C-1), 71, 36 (s, C-6) , 70.34 (s, C-7), 60.56 (s, C-8), 33.41 (s, C-3), 28.96 (s, C-5), 25.23 (s , C-4) ppm.

MS (ESI-TOF): calculated for C ₁₅ H ₂₇ N ₃ O ₂ : (281, 2103); Found: m / z = 304,2001 [M + Na] ⁺ . C ₁₁ -N ₃ (XX):

Synthesis of C ₁₁ -N ₃ : The reaction was carried out with the azide (x) (1.018 g, 9.23 mmol), KOH powder (4.14 g, 73.8 mmol) and 1 l -bromoundec-i -en (x) (8.61 g, 36.9 mmol) in 15 ml of DMSO as described above. Extraction with DCM (3 x 70 ml) and purification by column chromatography gave C ₁₁ -N ₃ (x) as a colorless liquid (3.41 g, 8.09 mmol, 88%).

¹ H-NMR (CDCI _3, 500 MHz, 26 ⁰ C): δ = 5.80 (tdd, J = 16.93, 10.18, 6.68 Hz, 2 H, 2-H), 5.00 , 4.96 (2 dd, J = 3.72, 1.60 Hz, each 1 H, 1-H), 4.93, 4.91 (2 td, J = 2.28, 1, 21 Hz, 1 H, 1-H), 3.67 (tt, J = 6.55, 4.61 Hz, 1 H, 13-H), 3.51 (ddd, J = 16.65, 10.04, 5.60Hz, 4H, 12H), 3.43 (m, 4H, 11H), 2.03 (m, 4H, 3H), 1, 56 (qd, J = 13, 42, 6.59 Hz, 4H, 10-H), 1, 36 (m, 4H, 4-H), 1, 27 (s, 20H, H-5, H-6, H- 7, H-8, H-9) ppm.

¹³ C-NMR (CDCI _3, 500 MHz, 2.5 ⁰ C): δ = 139.13 (s, C-2), 114.05 (s, C-1), 71, 64, 70.37 ( 2s, C-1 1, C-12), 60.60 (s, C-13), 33.76 (s, C-3), 29.55, 29.48, 29.38, 29.08 , 28.89 (6s, C-4, C-5, C-6, C-7, C-8, C-9, C-10) ppm.

MS (ESI-TOF): calculated for C ₂₅ H ₄₇ N ₃ O ₂ : (421, 3668); Found: m / z = 444.3574 [M + Na] ⁺ , 460.3318 [M + K] ⁺ .

Example 3.1

C ₆ -GO-Ck-GLO (XX):

Synthesis of C ₆ -Go-Ck-GLO: The reaction was treated with propargyl GLO (x) (1.392 g, 3.83 g of mmol), C ₆ -N ₃ (x) (1.20 g, 4.272 mmol), DIPEA (100 mg, 0.777 mmol), sodium ascorbate (154 mg, 0.777 mmol) and CuSO ₄ -OH ₂ O (97 mg, 0.388 mmol) in 3 mL of THF as described above. Extraction with DCM (3 x 75 ml) and Purification by column chromatography on silica gel with a mixture of EA and hexane (1: 1, then 2: 1) gave C ₆ -GO-Ck-GLO (x) as a pale yellow oil (1, 941 g, 3.029 mmol, 78%).

The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 26 ⁰ C): δ = 7.69 (s, 1 H, 9-H), 5.74 (tdd, J = 16.95, 6.66, 10, 18 Hz, 2 H, 2-H), 4.98, 4.94 (2 dd, J = 3.40, 1.74 Hz, each 1 H, 1-H), 4.93, 4.92 ( 2 m, each 1 H, 1-H), 4.83 (tt, J = 9.84, 4.84 Hz, 1 H, 8-H), 4.76 (t, J = 1.74 Hz, 2 H, 1 1-H), 4.21 (m, 2 H, 15-H), 4.00 (ddd, J = 10.55, 6.35, 4.16 Hz, 2 H, 16-H ), 3.79 (d, J = 3.79 Hz, 4H, 7-H), 3.69, 3.57, 3.52, 3.46, 3.40 (5 br m, 15 H, 6-H, 12-H, 13-H, 14-H, 16-H), 2.00 (dd, J = 7.22, 14.29 Hz, 4H, 3-H), 1, 37 ( m, 4 H, 4-H), 1, 38, 1, 32 (2 s, 12 H, 18-H, 19-H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 28 ⁰ C): δ = 144.75 (s, C-10), 138.45 (s, C-2), 122.70 (s, C-9) , 14.55 (s, C-1), 109.24 (s, C-17), 78.55 (s, C-12), 74.54 (s, C-15), 72.40 ( s, C-14), 71, 47, 71, 28 (m, C-6, C-13), 69.30 (s, C-7), 66.66 (s, C-16), 63, 83 (t, J = 3.85 Hz, C-1 1), 60.51 (s, C-8), 32.29 (s, C-3), 28.77 (s, C-5), 26.68, 25.32 (2 s, C-18, C-19), 25.12 (s, C-4) ppm.

MS (ESI-TOF): calculated for C ₃₃ H ₅₇ N ₃ O ₉ : (639.4095); Found: m / z = 640.4175 [M + H] ⁺ , 662.3999 [M + Na] ⁺ , 678.3738 [M + K] ⁺ . Example 3.2

C ₆ -G0-Ck-G2.0 (XX):

Synthesis of C ₆ -Go-Ck-G2.0: The reaction was carried out with propargyl G2.0 (x) (2.391 g, 3.256 010101), C ₆ -N ₃ (x) (1.008 g, 3.581 mmol). , DIPEA (126 mg, 0.977 mmol), sodium ascorbate (194 mg, 0.977 mmol) and CuSO ₄ -5H ₂ O (122 mg, 0.488 mmol) in 3 mL THF as described above. Extraction with DCM (3 × 75 ml) and purification by column chromatography on silica gel with a mixture of EA and hexane (1: 1, then 6: 1) gave C ₆ -G 0 -Ck-G 2 O (x) as a pale yellow oil ( 2.538 g, 2.497 mmol, 76%).

¹ H-NMR (CDCI _3, 500 MHz, 26 ⁰ C): δ = 7.68 (s, 1 H, 9-H), 5.75 (tdd, J = 16.92, 10.19, 6, 66 Hz, 2 H, 2-H), 4.98, 4.95 (2 dd, J = 3.45, 1.64 Hz, each 1 H, 1-H), 4.93, 4.91 ( 2 td, J = 2.04, 1, 09 Hz, each 1 H, 1-H), 4.82 (dp, J = 5.70, 1.60 Hz, 1 H, 8-H), 4, 75 (s, 2H, 11H), 4.21 (m, 4H, 17H), 4.00 (m, 4H, 18H), 3.79 (d, J = 5 , 69 Hz, 4H, 7-H), 3.68, 3.64, 3.53, 3.46 (4 br, 27H, 12H, 13H, 14H, 15H , 16-H, 18-H), 3.41 (m, 4H, 6-H), 2.01 (dd, J = 14.29, 7.20 Hz, 4H, 3-H), 1 , 52 (m, 4H, 5-H), 1, 35 (m, 4H, 4-H), 1, 37, 1, 32 (2 s, each 12 H, 20-H, 21-H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 25 ⁰ C): δ = 144.86 (s, C-10), 138.44 (s, C-2), 122.70 (s, C-9) , 1 14.58 (s, C-1), 109.24 (s, C-19), 78.40, 78.34 (2 s, C-12, C-14,), 74.52 (s , C-17), 72.40 (s, C-15, C-16), 71, 40, 71, 27 (m, C-6, C-13), 69.30 (s, C-7) , 66.67 (s, C-18), 63.83 (d, J = 4.41 Hz, C-1), 60.46 (s, C-8), 33.31 (s, C-3), 28.76 (s, C-5), 26.70, 25 , 34 (2s, C-20, C-21), 25.18 (C-4) ppm.

MS (ESI-TOF): calculated for C ₅₁ H ₈₉ N ₃ O ₁₇ : (1015.6192); Found: m / z = 1016.6282 [M + H] ⁺ , 1038.6099 [M + Na] ⁺ , 1054.5840 [M + K] ⁺ .

Example 3.3 C ₆ -G0-Ck-G3.0 (XX):

Synthesis of C ₆ -Go-Ck-G3.0: The reaction was carried out with propargyl G3.0 (x) (1.53 g, 1.032 mmol), C ₆ -N ₃ (x) (0.320 g, 1 , 137 mmol), DIPEA (40 mg, 0.310 mmol), sodium ascorbate (61 mg, 0.310 mmol) and CuSO ₄ -OH ₂ O (39 mg, 0.155 mmol) in 3 mL THF as described above. Extraction with DCM (3 x 75 mL) and purification by filtration over silica gel with 5% EA in hexane, then 35% isopropanol in hexane gave C ₆ -G 0 C k -G 3 O (x) as a pale brown oil (1050 g , 0.594 mmol, 58%).

The resulting from the click coupling regioisomers ratio is 87:13 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 27 ⁰ C): δ = 7.68 (s, 1 H, 9-H), 5.75 (tdd, J = 16.93, 10.23, 6, 65, Hz, 2H, 2-H), 4.99 (dd, J = 3.31, 1.66Hz, 1H, 1-H), 4.95 (dd, J = 3.39, 1 , 74 Hz, 1 H, 1-H), 4.94, 4.91 (2 m, each 1 H, 1-H), 4.82 (qd, J = 11, 28, 5.53 Hz, 1 H, 8-H), 4.76 (s, 2H, 11-H), 4.21 (m, 8H, 19-H), 4.01 (dd, J = 12.82, 6, 21Hz, 8H, 20-H), 3.80 (m, 4H, 7-H), 3.69 (m, 8H, 20-H), 3.62, 3.57, 3.53 , 3.47 (4brm, 51H, 12H, 13H, 14H, 15H, 16H, 17H, 18H), 3.39 (m, 4H, 6-H), 2.02 (dd, J = 14.39, 7.1 1 Hz, 4H, 3-H), 1, 53 (td, J = 14.64, 6.63 Hz, 4H , 5-H), 1, 38 (s, 24 H, 23-H), 1, 36 (m, 4 H, 4-H), 1, 32 (s, 24 H, 23-H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 25 ⁰ C): δ = 144.93 (s, C-10), 138.43 (s, C-2), 122.71 (s, C-9) , 1 14.59 (s, C-1), 109.23 (s, C-21), 78.55, 78.30, 78.28 (3 s, C-12, C-14, C-16 ), 74.53 (s, C-19), 72.41 (s, C-15, C-17, C-18), 71, 36, 71, 28 (m, C-6, C-13) , 69.33 (s, C-7), 66.71 (s, C-20), 63.93 (s, C-1 1), 60.43 (s, C-8), 33.33 ( s, C-3), 28.79 (s, C-5), 26.73, 25.36 (2 s, C-22, C-23), 25.20 (C-4) ppm.

MS (ESI-TOF): calculated for C ₈₇ H ₁₅₃ N ₃ O ₃₃ : (1768.0386); Found: m / z = 907.0101 [M + 2 Na] ²⁺ , 1791, 0324 [M + Na] ⁺ .

Example 3.4 C ₁₁ -GO-Ck-GLO (Xx):

Synthesis of C ₁₁ -GO-Ck-GLO: The reaction was carried out with propargyl GLO (x) (0.762 g, 2.126 mmol), C ₁₁ -N ₃ (x) (0.990 g, 2.338 mmol), DIPEA (55 mg, 0.425 mmol), sodium ascorbate (84 mg, 0.425 mmol) and CuSO ₄ -OH ₂ O (53 mg, 0.213 mmol) in 3 mL THF as described above. Extraction with DCM (3 × 75 ml) and purification by column chromatography on silica gel with a mixture of EA and hexane (5:95, then 1: 1) gave C ₁₁ -GO-Ck-GLO (x) as a colorless oil (1, 335 g, 1.711 mmol, 80%).

The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 25 ⁰ C): δ = 7.70 (s, 1 H, 14-H), 5.77 (tdd, J = 16.92, 10.17, 6, 67 Hz, 2 H, 2-H), 4.97, 4.94 (2 dd, J = 3.64, 1, 62 Hz, each 1 H, 1-H), 4.90, 4.88 ( 2 td, J = 2.24, 1, 19 Hz, each 1 H, 1-H), 4.84 (tq, J = 9.78, 4.82 Hz, 1 H, 13-H), 4, 76 (t, J = 1.70 Hz, 2H, 16H), 4.21 (m, 2H, 20H), 4.00 (m, 2H, 21H), 3.78 (d, J = 5.67 Hz, 4H, 12H), 3.69 (m, 2H, 21H), 3.60 (m, 1H, 17H), 3.57, 3.46 (2 br, 8H, 18H, 19H), 3.37 (m, 4H, 1H), 2.00 (m, 4H, 3H), 1 , 49 (m, 4H, 10-H), 1, 38 (s, 6H, 24-H), 1, 34 (m, 4H, 4-H) 1, 32 (s, 6H, 23 -H), 1, 23 (s, 20H, 5H, 6H, 7H, 8H, 9H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 27 ⁰ C): δ = 144.72 (s, C-15), 139.04 (s, C-2), 122.72 (s, C-14) , 114.05 (s, C-1), 109.25 (s, C-22), 78.56 (s, C-17), 74.55 (s, C-20), 72.40 (s , C-19), 71, 54, 71, 48 (m, C-11, C-18), 69.27 (s, C-12), 66.67 (s, C-21), 63.83 (s, C-16), 60.51 (s, C-13), 33.70 (s, C-3), 29.43, 29.35, 29.29, 29.02, 28.82 ( 5s, C-5, C-6, C-7, C-8, C-9, C-10), 26,69 (s, C-23), 25,93 (s, C-4), 25.33 (s, C-24) ppm.

MS (ESI-TOF): calculated for C ₄₃ H ₇₇ N ₃ O ₉ : (779.5660); Found: m / z = 780.5767 [M + H] ⁺ , 802.5585 [M + Na] ⁺ , 818.5335 [M + K] ⁺ .

Example 3.5 C ₁₁ -G0-Ck-G2.0 (XX):

Synthesis of C ₁₁ -G0-Ck-G2.0: The reaction was carried out with propargyl G2.0 (x) (1.442 g, 1.962 mmol), C ₁₁ -N ₃ (x) (0.910 g, 2.158 mmol), DIPEA (76 mg, 0.589 mmol), sodium ascorbate (17 mg, 0.589 mmol) and CuSO ₄ -OH ₂ O (73 mg, 0.294 mmol) in 3 mL THF as described above. Extraction with DCM (3 × 75 ml) and purification by filtration through silica gel with a mixture of EA and hexane (1: 2, then 1: 6) gave C ₁₁ -G 0 -Ck-G 2 O (x) as a brown oil ( 1, 953 g, 1, 689 mmol, 86%).

The resulting from the click coupling regioisomers ratio is 89: 7 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 28 ⁰ C): δ = 7.69 (s, 1 H, 14-H), 5.79 (tdd, J = 16.96, 10.17, 6, 68 Hz, 2 H, 2-H), 4.99, 4.95 (2 td, J = 2.04, 1.58 Hz, each 1 H, 1-H), 4.92, 4.90 ( 2 td, J = 2.33, 1, 21 Hz, each 1 H, 1-H), 4.83 (m, 1 H, 13-H), 4.76 (s, 2 H, 16-H) , 4.27 (m, 4H, 22H), 4.01 (ddt, J = 7.35, 4.07, 2.37Hz, 4H, 23H), 3.80 (m, 4 H, 12-H), 3.70 (m, 4 H, 23-H), 3.64, 3.54, 3.46 (3 br m, 23 H, 17-H, 18-H, 19 -H, 20-H, 21-H), 3.40 (m, 4H, 11-H), 2.01 (m, 4H, 3-H), 1, 51 (p, J = 6 , 72 Hz, 4 H, 10-H), 1, 39 (s, 12 H, 25-H), 1, 35 (m, 4 H, 4-H), 1, 33 (s, 12 H, 26 -H), 1, 25 (s, 20H, 5H, 6H, 7H, 8H, 9H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 2.5 ⁰ C): δ = 144.87 (s, C-15), 139.09 (s, C-2), 122.72 (s, C 14), 1 14.09 (s, C-1), 109.28 (s, C-24), 78.57, 78.42 (2 s, C-17, C-19), 74.57 ( s, C-22), 72.45 (s, C-20, C-21), 71, 59, 71, 45, (m, C-1 1, C-18), 69.32 (s, C -12), 66.72 (s, C-23), 63.83 (s, C-16), 60.49 (s, C-13), 33.74 (s, C-3), 29, 48, 29.40, 29.34, 29.07, 28.88, (5s, C-5, C-6, C-7, C-8, C-9, C-10), 26.74 (s, C-25), 25.96 (s, C-4), 25.37 (s, C-26) ppm.

MS (ESI-TOF): calculated for C ₆₁ H ₁₀₉ N ₃ O ₁₇ : (1 155.7757); Found: m / z = 1 156.7920 [M + H] ⁺ , 1 178.7736 [M + Na] ⁺ , 1194.7622 [M + K] ⁺ , 1218.7144 [M + Cu] ⁺ . Example 3.6 C ₁₁ -GO-Ck-O-GS (XX):

Synthesis of C ₁₁ -GO-Ck-O-GS: The reaction was treated with propargyl-G3.0 (x) (2,204 g, 1, 481 mmol), C ₁₁ -N ₃ (X) (0.687 g, 1, 629 mmol), DIPEA (57 mg, 0.444 mmol), sodium ascorbate (88 mg, 0.444 mmol) and CuSO ₄ -5H ₂ O (55 mg, 0.222 mmol) in 5 mL THF as described above. Extraction with DCM (3 x 75 ml) and purification C gave ₁₁ -GO-Ck-GS-O (x) as a colorless oil (1, 472 g of purified by column chromatography on silica gel with 5% EE in hexane, then 25% isopropanol in hexane , 0.771 mmol, 52%).

The resulting from the click coupling Regioisomerenverhältnis is 32: 1 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 25 ⁰ C): δ = 7.68 (s, 1 H, 14-H), 5.78 (tdd, J = 16.95, 10.19, 6, 67 Hz, 2 H, 2-H), 4.98, 4.94 (2 dd, J = 3.65, 1, 61 Hz, each 1 H, 1-H), 4.91, 4.89 ( 2 td, J = 2.24, 1, 18 Hz, each 1 H, 1-H), 4.81 (p, J = 5.85 Hz, 1 H, 13-H), 4.75 (s, 2H, 16H), 4.21 (m, 8H, 24H), 4.00 (m, 8H, 25H), 3.79 (m, 4H, 12H), 3.68 (m, 8H, 25-H), 3.62, 3.57, 3.52, 3.45 (4 br, 51H, 17H, 18H, 19H, 20 -H, 21-H, 22-H, 23-H), 3.39 (m, 4H, 1 1-H), 2.00 (m, 4 H, 3-H), 1, 51 (p, J = 6.82 Hz, 4 H, 10-H), 1, 38 (s, 24 H, 27-H), 1, 34 (m, 4 H, 4-H), 1, 32 (s, 24 H, 28-H), 1, 24 (s, 20 H, 5-H, 6-H, 7-H, 8-H, 9-H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 3O ⁰ C): δ = 144.91 (s, C-15), 139.06 (s, C-2), 122.68 (s, C-14) , 1 14.08 (s, C-1), 109.23 (s, C-26), 78.59, 78.35, 78.04 (3 s, C-17, C-19, C-21 ), 74.55 (s, C-24), 72.48 (s, C-20, C-22, C-23), 71, 57, 71, 39 (m, C-1 1, C-18 ), 69.33 (s, C-12), 66.88 (s, C-25), 63.92 (s, C-16), 60.43 (s, C-13), 33.71 ( s, C-3), 29,48, 29,38, 29,34, 29,05, 28,85, (5s, C-5, C-6, C-7, C-8, C-9 , C-10), 26.74 (s, C-27), 25.95 (s, C-4), 25.37 (s, C-28) ppm.

MS (ESI-TOF): calculated for C ₉₇ H ₁₇₃ N ₃ O _33: (1908.1951); Found: m / z = 977.0871 [M + 2 Na] ²⁺ , 1931, 1844 [M + Na] ⁺ .

Example 3.7 Rf-C ₆ -GO-Ck-GLO (XX):

Synthesis of ₆ RfC -GO-Ck-GLO: The reaction was charged with C ₆ -GO-Ck-GLO (x) (1, 299 g, 2.030 mmol) in RfC ₂ H ₄ SH (7.80 g, 16 , 24 mmol) as described above. Purification by filtration over silica gel with a mixture of PE and DCM (1, 5 1, 7: 1) and a subsequent mixture of EE and hexane (1, 5 1, 2: 1) gave Rf-C ₆ -GO-Ck -GLO (x) as a colorless oil (2.619 g, 1.637 mmol, 81%) which formed a milky wax after storage in the refrigerator.

The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 2.5 ⁰ C): δ = 7.70 (s, 1 H, 19-H), 4.84 (m, 1 H, 18-H), 4, 77 (t, J = 1.70Hz, 2H, 21H), 4.23 (m, 2H, 25H), 4.01 (m, 2H, 26H), 3.81 (d, J = 5.62 Hz, 4H, 17H), 3.71 (m, 2H, 26H), 3.61, 3.58, 3.47 (3 br, 9H , 22-H, 23-H, 24-H), 3.40 (m, 4H, 16-H), 2.70 (m, 4H, 10-H), 2.52 (t, J = 7.35Hz, 4H, 11H), 2.34 (m, 4H, 9H), 1.54 (m, 8H, 12H, 15H), 1, 38 ( s, 6H, 28H), 1, 35 (m, 4H, 14H), 1, 33 (s, 6H, 29H), 1, 29 (m, 4H, 13H ) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 25 ⁰ C): δ = 144.82 (s, C-20), 122.75 (s, C-19), 121-107 (m, CF), 109 , 33 (s, C-27), 78.61 (s, C-22), 74.59 (s, C-25), 72.45 (s, C-24), 71, 53, 71, 37 (2s, C-16, C-23), 69.40 (s, C-17), 66.70 (s, C-26), 63.88 (s, C-21), 60.55 ( s, C-18), 32.25 (s, C-11), 31, 81 (t, J = 21, 90 Hz, C-9), 29.27, 29.19 (2 s, C-12 , C-15), 28.47 (s, C-13), 26.70 (s, C-28), 25.59 (s, C-14), 25.32 (s, C-19), 22.54 (s, C-10) ppm.

¹⁹ F-NMR (CDCI _3, 400 MHz, 24 ⁰ C): δ = -80.80 (t, J = 9.94 Hz, 6 F, 1-F), -1 14.31 (m, 4 F , 2-F), -121, 70, -121, 92 (2 s, 12 F, 3-F, 4-F, 5-F), -122.72 (s, 4 F, 6-F), -123.35 (s, 4F, 7-F), -126.13 (m, 4F, 8-F) ppm.

MS (ESI-TOF): calculated for C ₅₃ H ₆₇ F ₃₄ N ₃ O ₉ S _2: (1599.3776); found: m / z = 1 120.4051 [(M - RfC ₂ H ₄ SH) + H] ⁺ , 1142.3867 [(M - RfC ₂ H ₄ SH) + Na] ⁺ , 1158.3623 [(M - RfC ₂ H ₄ SH) + K] ⁺ , 1600.3901 [M + H] ⁺ , 1622.3717 [M + Na] ⁺ , 1638.3469 [M + K] ⁺ .

Example 3.8

Rf-C ₆ -G0-Ck-G2.0 (xx):

Synthesis of ₆ RfC -G0-Ck-G2.0: The reaction was charged with C ₆ -G0-Ck-G2.0 (x) (1, 510 g, 1, 486 mmol) in RfC ₂ H ₄ SH ( 5.70 g, 11, 89 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1.5 I, 7: 1) followed by a mixture of EE and hexane (1 L, 5: 1) gave Rf-C ₆ -Go-Ck-G2 .0 (x) as a colorless oil (2.421 g, 1.224 mmol, 82%), which when stored in the refrigerator, formed a milky wax.

¹ H-NMR (CDCI _3, 500 MHz, 22 ⁰ C): δ = 7.69 (s, 1 H, 19-H), 4.83 (m, 1 H, 18-H), 4.76 ( s, 2H, 21H), 4.22 (m, 4H, 27H), 4.01 (m, 4H, 28H), 3.80 (d, J = 5.61 Hz , 4 H, 17-H), 3.69 (m, 4 H, 28-H), 3.64, 3.56, 3.53, 3.46 (4 br m, 23 H, 22 H, 23-H, 24-H, 25-H, 26-H), 3.40 (m, 4H, 16-H), 2.70 (m, 4H, 10-H), 2.52 (t , J = 7.35 Hz, 4H, 11H), 2.34 (m, 4H, 9H), 1, 53 (m, 8H, 12H, 15H), 1 , 38 (s, 12H, 30H), 1.35 (m, 4H, 14H), 1.32 (s, 12H, 31H), 1.29 (m, 4H , 13-H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 2.5 ⁰ C): δ = 144.95 (s, C-20), 122.68 (s, C-19), 121-107 (m, CF) , 109.29 (s, C-29), 78.59, 78.47 (2 s, C-22, C-24), 74.59 (s, C-27), 72.47 (s, C -25, C-26), 71, 46, 71, 37 (m, C-16, C-23), 69,42 (s, C-17), 66,72 (s, C-28), 63 , 89 (s, C-21), 60.50 (s, C-18), 32.14 (s, C-1 1), 32.06 (t, J = 21, 90 Hz, C-9) , 29.27, 29.20 (2 s, C-12, C-15), 28.47 (s, C-13), 26.70 (s, C-30), 25.58 (s, C -14), 25.32 (s, C-31), 22.56 (s, C-10) ppm.

¹⁹ F-NMR (CDCI _3, 400 MHz, 25 ⁰ C): δ = -80.74 (t, J = 9.99 Hz, 6 F, 1-F), -1 14.30 (m, 4 F , 2-F), -121, 66, -121, 88 (2 s, 12 F, 3-F, 4-F, 5-F), -122.68 (s, 4 F, 6-F), -123.31 (s, 4F, 7-F), -126.08 (m, 4F, 8-F) ppm.

MS (ESI-TOF): calculated for C ₇₁ H ₉₉ F ₃₄ N ₃ O ₁₇ S ₂ : (1975, 5873); Found: m / z = 1010.7823 [M + 2 Na] ²⁺ , 1518.5926 [(M-RfC ₂ H ₄ SH) + Na] ⁺ , 1998.5762 [M + Na] ⁺ . Example 3.10

Rf-C ₁₁ -GO-Ck-GLO (Xx):

Synthesis of RfC ₁₁ -GO-Ck-GLO: The reaction was charged with C ₁₁ -GO-Ck-GLO (x) (0.681 g, 0.873 mmol) in RfC ₂ H ₄ SH (3.35 g, 6.98 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1 L, 7: 1) followed by a mixture of EE and hexane (1 L, 1: 1) gave Rf-C ₁₁ -GO-Ck-GLO (x ) as a colorless oil (1.335 g, 0.767 mmol, 88%) which formed a milky wax in the refrigerator after storage.

The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 27 ⁰ C): δ = 7.72 (s, 1 H, 24-H), 4.85 (m, 1 H, 23-H), 4.78 ( t, J = 1, 63 Hz, 2H, 26H), 4.25 (m, 2H, 30H), 4.03 (m, 2H, 31H), 3.81 (i.e. , J = 5.69 Hz, 4H, 22H), 3.72 (m, 2H, 31H), 3.62, 3.59, 3.48 (3 br m, 9H, 27 -H, 28-H, 29-H), 3.40 (m, 4H, 21-H), 2.72 (m, 4H, 10-H), 2.53 (t, J = 7, 5Hz, 4H, 11-H), 2.34 (m, 4H, 9-H), 1.58 (td, J = 14.99, 7.35Hz, 4H, 12-H), 1, 51 (m, 4H, 20H), 1.40 (s, 6H, 33H), 1.37 (m, 4H, 14H), 1.34 (s, 6H , 34-H), 1, 25 (s, 24 H, 13-H, 15-H, 16-H, 17-H, 18-H, 19-H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 27 ⁰ C): δ = 144.81 (s, C-25), 122.80 (s, C-24), 109.35 (s, C-32) , 78.65 (s, C-27), 74.63 (s, C-30), 72.50 (s, C-29), 71, 64, 71, 39 (2 s, C-21, C -28), 69.38 (s, C-22), 66.76 (s, C-31), 63.92 (s, C-26), 60.61 (s, C-23), 32, 27 (s, C-11), 31, 46 (t, J = 32.15 Hz, C-9), 29.56, 29.53, 29.48, 29.45, 29.39, 29.35 , 29.19, 28.79 (8s, C-12, C-13, C-15, C-16, C-17, C-18, C-19, C-20), 26.75 (s , C-33), 26.01 (s, C-14), 25.38 (s, C-34), 22.58 (s, C-10) ppm. ¹⁹ F-NMR (CDCI _3, 400 MHz, 27 ⁰ C): δ = -80.70 (t, J = 9.85 Hz, 6 F, 1-F), -1 14.27 (m, 4 F , 2-F), -121, 63, -121, 88 (2 s, 12 F, 3-F, 4-F, 5-F), -122.65 (s, 4 F, 6-F), -123.31 (s, 4F, 7-F), -126.04 (m, 4F, 8-F) ppm.

MS (ESI-TOF): calculated for C ₆₃ H ₈₇ F ₃₄ N ₃ O ₉ S ₂ : (1739.5341); found: m / z = 1298.5322 [(M - RfC ₂ H ₄ SH) + K] ⁺ , 1740.5399 [M + H] ⁺ , 1762.5205 [M + Na] ⁺ , 1778.51 10 [M + K] ⁺ .

Example 3.1 1

Rf-C ₁₁ -G0-Ck-G2.0 (xx):

Synthesis of RfC ₁₁ -G0-Ck-G2.0: The reaction was charged with C _ir G0-Ck-G2.0 (x) (1, 346 g, 1, 164 mmol) in RfC ₂ H ₄ SH (4 , 47 g, 9.31 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1.5 l, 7: 1) followed by a mixture of EE and hexane (1 l, 5: 1) gave Rf-C ₁₁ -GO-Ck-G2 .0 (x) as a pale yellow oil (2.170 g, 1.029 mmol, 88%) that formed a milky wax in the refrigerator after storage.

The resulting from the click coupling Regioisomerenverhältnis is 23: 1 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 22 ⁰ C): δ = 7.70 (s, 1 H, 24-H), 4.84 (m, 1 H, 23-H), 4.76 ( s, 2H, 26H), 4.22 (m, 4H, 32H), 4.01 (m, 4H, 33H), 3.80 (d, J = 5.60 Hz , 4H, 22H), 3.70 (m, 4H, 33H), 3.64, 3.57, 3.54, 3.47 (4 br, 23H, 27H, 28-H, 29-H, 30-H, 31-H), 3.40 (m, 4H, 21-H), 2.70 (m, 4H, 10-H), 2.53 (t , J = 7.5 Hz, 4H, 11-H), 2.35 (m, 4H, 9-H), 1, 57, 1, 51 (2 m, each 4 H, 12-H, 20) -H), 1, 39 (s, 12H, 35-H), 1, 36 (m, 4H, 14-H), 1, 33 (s, 12H, 36-H), 1, 24 ( s, 24H, 13H, 15H, 16H, 17H, 18H, 19H) ppm.

¹³ C-NMR (CDCl ₃ , 400 MHz, 29 ⁰ C): δ = 144.89 (s, C-25), 122.73 (s, C-24), 121-107 (m, CF), 109 , 21 (s, C-34), 78.59, 78.41 (2 s, C-27, C-29), 74.60 (s, C-32), 72.47 (s, C-30 , C-31), 71, 59, 71, 46 (2s, C-21, C-28), 69.35 (s, C-22), 66.73 (s, C-33), 63, 88 (s, C-26), 60.52 (s, C-23), 32.32 (s, C-1 1), 32.10 (t, J = 22.33 Hz, C-9), 29.53, 29.50, 29.45, 29.42, 29.36, 29.31, 29.15, 28.75 (8s, C-12, C-13, C-15, C-16 , C-17, C-18, C-19, C-20), 26.71 (s, C-35), 25.97 (s, C-14), 25.34 (s, C-36) , 22.53 (s, C-10) ppm.

¹⁹ F-NMR (CDCI _3, 400 MHz, 2.5 ⁰ C): δ = -80.77 (t, J = 9.81 Hz, 6 F, 1-F), -1 14.32 (m, 4F, 2-F), -121, 67, -121, 90 (2S, 12F, 3-F, 4-F, 5-F), -122.70 (s, 4F, 6-F ), -123.35 (s, 4F, 7-F), -126.10 (s, 4F, 8-F) ppm.

MS (ESI-TOF): calculated for C ₈₁ H ₁₁₉ F ₃₄ N ₃ O ₁₇ S ₂ : (21, 15.7438); Found: m / z = 1658.7513 [(M - RfC ₂ H ₄ SH) + Na] ⁺ , 21 16.7520 [M + H] ⁺ , 2138.7349 [M + Na] ⁺ .

Example 3.12

Rf-C ₁₁ -GO-Ck-O-GS (XX):

Synthesis of RfC ₁₁ -GO-Ck-O-GS: The reaction was charged with C ₁₁ -GO-Ck-O-GS (x) (0.860 g, 0.450 mmol) in RfC ₂ H ₄ SH (1, 73 g , 3.60 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1.5 l, 7: 1) and a subsequent mixture of isopropanol and hexane (1.5 l, 1: 4) gave Rf-C ₁₁ -GO-Ck -GS-O (x) as a colorless oil (0.863 g, 0.301 mmol, 60%) which formed a milky wax after storage in the refrigerator. Unused C ₁₁ -GO-Ck-GS.0 (x) was also obtained (6%).

The resulting from the click coupling Regioisomerenverhältnis is 32: 1 (calculated from ¹ H-NMR).

¹ H-NMR (CDCI _3, 500 MHz, 25 ⁰ C): δ = 7.69 (s, 1 H, 24-H), 4.81 (m, 1 H, 23-H), 4.76 ( s, 2H, 26H), 4.21 (m, 8H, 34H), 4.01 (m, 8H, 35H), 3.79 (m, 4H, 22H ), 3.69 (m, 8H, 35H), 3.63, 3.58, 3.53, 3.40 (4 br m, 51H, 27H, 28H, 29H , 30-H, 31-H, 32-H, 33-H) 3.39 (m, 4H, 21-H), 2.70 (m, 4H, 10-H), 2.53 (t , J = 7.5 Hz, 4H, 11-H), 2.35 (m, 4H, 9-H), 1.57 (td, J = 15.00, 7.38 Hz, 4H, 12-H), 1, 52 (m, 4H, 20-H), 1, 38 (s, 24H, 37-H), 1, 36 (m, 4H, 14-H), 1, 32 (s, 24H, 38H), 1.25 (s, 24H, 13H, 15H, 16H, 17H, 18H, 19H) ppm.

¹³ C-NMR (CDCI _3, 400 MHz, 3O ⁰ C): δ = 144.93 (s, C-25), 122.70 (s, C-24), 121-107 (m, CF), 109 , 26 (s, C-36), 78.61, 78.33 (m, C-27, C-29 C-31), 74.56 (s, C-34), 72.46 (s, C -30, C-32, C-33), 71, 59, 71, 41 (m, C-21, C-28), 69.36 (s, C-22), 66.76 (s, C-) 35), 63.93 (s, C-26), 60.44 (s, C-23), 32.32 (s, C-1 1), 32.10 (t, J = 22.17 Hz, C-9), 29.53, 29.48, 29.41, 29.32, 29.17, 28.78 (6s, C-12, C-13, C-15, C-16, C- 17, C-18, C-19, C-20), 26.74 (s, C-37), 25.98 (s, C-14), 25.37 (s, C-38), 22, 54 (s, C-10) ppm. ¹⁹ F-NMR (CDCI _3, 400 MHz, 22 ⁰ C): δ = -80.70 (t, J = 9.57 Hz, 6 F, 1-F), -1 14.33 (m, 4 F , 2-F), -121, 68, -121, 89 (2 s, 12 F, 3-F, 4-F, 5-F), -122.68 (s, 4 F, 6-F), -123.34 (s, 4 F, 7-F), -126.08 (m, 4 F, 8-F) ppm.

MS (ESI-TOF): calculated for C ₁₁₇ H ₁₈₃ F ₃₄ N ₃ O ₃₃ S _2: (2868.1632); Found: m / z = 1217.5799 [(M-RfC ₂ H ₄ SH) + Na] ²⁺ , 1457.0717 [M + 2 Na] ²⁺ , 2412.1465 [(M-RfC ₂ H ₄ SH) + Na] ⁺ , 2891, 1572 [M + Na] ⁺ .

Example 4

Compounds of the general formula (2) - amphiphiles with partially fluorinated

Alkyl side chains and dendritic polyglycerol head groups

Experimental part

General: All reactions in which dry conditions are required were performed in Schlenk glassware under argon. Dry and reagent grade solvents were purchased from Acros or Aldrich and used as supplied. The ¹ H NMR and ¹³ C NMR spectra were recorded at 25 ^° C. using the Bruker AB 250 spectrometers (250 and 67.5 MHz for ¹ H and ¹³ C, respectively), ECX 400 (400 and 100 MHz for ¹ H or ¹³ C) and Delta JEOL ECLIPSE 500 (500 and 125 MHz for ¹ H and ¹³ C, respectively).

The ECX 400 was used to record high-resolution ¹³ C NMR. The spectra were calibrated for the solvent peak (CDCl ₃ : 7.26 ppm for ¹ H and 77.0 ppm for ¹³ C, CD ₃ OD: 4.84 ppm for ¹ H and 49.05 ppm for ¹³ C). Flash chromatography was performed on silica gel 60 (230-400 mesh) using compression pressure with the aid of compressed air. For the ESI-TOF measurements, an Agilent 6210 ESI-TOF, Agilent Technologies, Santa Clara, USA, was used. HPLC was performed on a Knauer HPLC (K-1800 pump) using a Knauer RI detector K-2401 and a Nucleosil 50-5 column (32 x 240).

General procedure for the coupling of propargyl donors with the [G1.5] azide: 1, 0 equivalents of [Gn] propargyl and 1.1 equivalents of [G1.5] azide per triple bond dissolved in THF were mixed with 15 mol% DIPEA (diisopropylethylamine) added per triple bond. After stirring for 5 min, 30 mol% sodium ascorbate per triple bond was added, followed by 15 mol% CuSO ₄ -OH ₂ O per triple bond. The THF / H ₂ O mixture must be 1: 1 (v / v). The heterogeneous mixture became to the point stirred vigorously, where the TLC analysis showed that the starting material was completely consumed. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with a small amount of a saturated EDTA solution, dried with Na ₂ SO ₄ and concentrated in vacuo. Purification by column chromatography gives the desired product (a stock solution of sodium ascorbate and CuSO ₄ - 5H ₂ O in water was prepared at a concentration of 100 mg / ml).

[G1.0] -Propargyl-click- [G1.5] -azide (2): Reaction conditions and workup were as described above with [G1.0] -propargyl (0.385 g, 1.107 mmol, 1.0 equivalents ), [G1.5] azide (0.518 g, 1, 218 mmol, 1:05 equivalents), DIPEA (27.45 μl, 0.166 mmol, 0.15 equivalents), sodium ascorbate (65.8 mg, 0.332 mmol, 0.3 equiv) and copper (II) sulfate pentahydrate (41.5mg, 0.166mmol, 0.15equi.) In THF / H ₂ O (6mL). Purification by column chromatography (10% isopropanol in n-hexane and 20% isopropanol in n-hexane) gave the desired product 2 (0.468 g, 54%).

¹ H NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 7.71 (s, 1 H, H-3), 5.84 (m, 4 H, H-10), 5.28 to 5 , 08 (m, 8H, H-1 1), 4.86 (m, 1H, H-4), 4.74, 4.60 (s, 2H, H-1), 4.22 ( m, 2H, H-15), 4.05 (m, 4H, H-6), 4.00 (m, 2H, H-7), 3.94 (m, 4H, H-8 ), 3.87 (m, 4H, H-5), 3.82 - 3.30 (br m, 21H, H-16, H-14 - H-12, H-9), 1, 38 , 1, 32 (2 xs, 12 H, H-19, H-18) ppm. ^{1 3} C-NMR (500 MHz, CDCl 3, 25 ⁰ C): δ = 144.78 (C-2), 134.90, 134.51 (C-10), 122.75 (C-3), 116 , 98, 116.89 (C-11), 109.23 (C-17), 77.18, 76.70, 72.42, 71, 56, 69.60 (C-16, C-14 - C-12, C-9, C-8), 74.55 (C-15), 72.26 (C-9), 71, 22 (C-6), 70, 12 (C-5), 66 , 67 (C-7, C-16), 63.85 (C-1), 60.40 (C-4), 26.72, 25.35 (C-19, C-18) ppm.

ESI-TOF-MS: calculated for C ₃₉ H ₆₅ N ₃ O ₁₃ : (783.4517); found: 784.4553 [M + H] ⁺ , 806.4374 [M + Na] ⁺ , 822.4114 [M + K] ⁺ .

[G3.0] -Propargyl-click- [G1.5] -azide (3): Reaction conditions and workup were as described above, with [G3.0] propargyl (1.0 g, 0.672 mmol, 1.0 equivalents ), [G1.5] azide (0.314 g, 0.739 mmol, 1.1 equivalents), DIPEA (16.65 μl, 0.101 mmol, 0.15 equivalents), sodium ascorbate (39.9 mg, 0.202 mmol, 0, 3 equivalents) and copper (II) sulfate pentahydrate (25.2 mg, 0.101 mmol, 0.15 equiv.) In THF / H ₂ O (10 mL). Purification by column chromatography (ethyl acetate / n-hexane 8: 1 and 2% MeOH in CH ₂ Cl ₂ ) gave the desired product 3 (0.96 g, 75%).

¹ H-NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 7.69 (s, 1 H, H-3), 5.90 to 5.80 (m, 4 H, H-10), 5.26-5.10 (m, 8H, H-1 1), 4.84 (m, 1H, H-4), 4.74 (s, 2H, H-1), 4.25 -4.16 (m, 8H, H-19), 4.12-3.97 (m, 12H, H-20, H-9), 3.95, 3.94 (m, 4H, H-9), 3.88, 3.86 (m, 4H, H-5), 3.75-3.40 (br m, 69 H, H-20, H-18 - H-12, H -8 - H-6), 1, 37, 1, 32 (2 xs, 48 H, H-23, H-22) ppm.

13 C-NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 144.95 (C-2), 134.96, 134.55 (C-10), 122.69 (C-3), 116.93, 1.163 (C-11), 109.23 (C-21), 74.69, 74.54 (C-19), 70.52, 70.12 , 69.97 (C-5), 78.58, 78.30, 72.43, 72.25, 71, 61, 71, 19, 69.66 (C-18 - C-12, C-9 - C-6), 66.86, 66.73 (C-20), 63.89 (C-1), 60.32 (C-4), 26.73, 25.36 (C-23, C-) 22) ppm.

ESI-TOF-MS: calculated for C ₉₃ H ₁₆₁ N ₃ O ₃₇ : (1912.0809); found: 1936.0733 [M + H + Na] ⁺ , 1951, 0452 [M + K] ⁺ , 979.5307 [M + H + Na] ²⁺ .

General procedure for the thiol coupling to the "click" compounds: The click compounds (2-4) were mixed with 4 equivalents of RfCH ₂ CH ₂ SH per allyl group. The solution was stirred under reduced pressure (3 mbar) to remove the oxygen from the solution. After heating at 8O ⁰ C a catalytic amount of AIBN (azobisisobutyronitrile) was added under an argon atmosphere, and the reaction mixture was stirred for 2 h. After further addition of the same amount of AIBN, the mixture was stirred at 8O ⁰ C for a further 24 h, and then the solvent was evaporated. Further purification was achieved by column chromatography.

Example 4.1

[G1.0] -propargyl-click [G1.5] -azid-thiol (5):

Reaction conditions and workup were as described above, with 2

(0.46 g, 0.611 mmol, 1.0 equivalents), RfCH ₂ CH ₂ SH (4.70 g, 9.799 mmol, 16

Equivalents) and a catalytic amount of AIBN. Cleaning by means of a flash column

(Petroleum ether (40-60 ° C) / CH ₂ Cl ₂ 7: 1 and ethyl acetate / n-hexane 1: 2) gave the desired

Product 5 (0.66 g, 40%).

¹ H-NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 7.70, 7.67 (s, 1 H, H-3), 4.86 (m, 1 H, H-4), 4.77,

4.63 (s, 2H, H-1), 4.24 (m, 2H, H-7), 4.02 (m, 2H, H-25), 3.88 (d, 4H , J = 4.63 Hz,

H-5), 3.80 (m, 1H, H-22), 3.76-3.32 (br m, 28H, H-26, H-24, H-23, H-9, H -8, H-6), 2.70

(m, 8H, H-12), 2.61 (t, 8H, J = 6.94Hz, H-1 1), 2.35 (m, 8H, H-13), 1, 81 (m, 8H, H-10),

1, 39, 1, 33 (2xS, 12H, H-29, H-28) ppm.

¹³ C-NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 144.92 (C-2), 122.73 (C-3), 109.36 (C-27), 77.84 (C -22), 74.77, 74.63 (C-7), 70.25 (C-5), 66.71 (C-25), 64.91, 63.89 (C-1), 60, 53 (C-4), 31, 99 (C-13), 29,60, 29,32 (C-10), 28,81, 22,46 (C-12, C-1 1), 26,70 , 25, 32 (C-29, C-28), 78, 65, 77, 86, 72, 50, 71, 50, 71, 38, 70, 64, 69, 57, 68, 42 (C-26, C-24, C-23, C-9 - C-6), 122.00-107.00 (C-21 - C-14) ppm.

¹⁹ F-NMR (400 MHz, CDCl _3, 25 ⁰ C): δ = -1 14.41 (F-20), -121, 79, -122.00 (F-17, F-19, F-18 ), -122.82 (F-16), -123.39 (F-15), -126.24 (F-14) ppm. ESI-TOF-MS: calculated for C ₇₉ H ₈₅ F ₆₈ N ₃ O ₁₃ S _4: (2703.3879); Found: 2726.3645 [M + Na] ⁺ , 2742.3448 [M + K] ⁺ .

Example 4.2

[G2.0] -propargyl-click- [G1.5] -azidethiol (6):

Reaction conditions and work-up were as described above, with 4

(0.5 g, 0.431 mmol, 1.0 equivalents), RfCH ₂ CH ₂ SH (3.31 g, 6.894 mmol, 16

Equivalents) and a catalytic amount of AIBN. Cleaning by means of a flash column

(Petroleum ether (40-60 ° C) / CH ₂ Cl ₂ 7: 1 and ethyl acetate / n-hexane 4: 1) gave the desired

Product 6 (0.80 g, 69%).

¹ H-NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 7.68 (s, 1 H, H-3), 4.86 (m, 1 H, H-4), 4.77 ( s, 2 H,

H-1), 4.23 (m, 4H, H-28), 4.03 (m, 4H, H-27), 3.89, 3.88 (d, 4H, J = 5, 6 Hz, H-5), 3.82-

3.30 (br m, 45 H, H-28, H-26 - H-22, H-9 - H-6), 2.72 (m, 8 H, H-12), 2.62 (t , 8 H, J =

7.2 Hz, H-1 1), 2.36 (m, 8H, H-13), 1, 83 (m, 8H, H-10), 1, 40, 1, 34 (2 xs, 24H, H-31,

H-30) ppm.

¹³ C NMR (500 MHz, CDCl _3, 25 ⁰ C): δ =

¹⁹ F-NMR (400 MHz, CDCl _3, 25 ⁰ C): δ = -80.79 (F-21), -1 14.34 (F-20), -121, 70, -121, 93

(F-19, F-18, F-17), -122.73 (F-16), -123.32 (F-15), -126.14 (F-14) ppm.

ESI-TOF-MS: calculated for C ₉₇ H ₁₁₇ F ₆₈ N ₃ O ₂₁ S _4: (3079.3879); found: 3103.6002 [M + H + Na] ^+, 3081, 6176 [M + 2H] ^+,

1552.3016 [M + 2H + Na] ²⁺ , 1512.7896

Example 4.3

[G3.0] propargyl click [G1.5] azide thiol (7):

Reaction conditions and workup were as described above, with 3

(0.6 g, 0.313 mmol, 1.0 equivalents), RfCH ₂ CH ₂ SH (2.41 g, 5.017 mmol, 16

Equivalents) and a catalytic amount of AIBN. Cleaning by means of a flash column

(Petroleum ether (40-60 ° C) / CH ₂ Cl ₂ 7: 1 and ethyl acetate / n-hexane 10: 1) gave the desired

Product 7 (0.89 g, 74%).

¹ H-NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 7.65 (s, 1 H, H-3), 4.82 (m, 1 H, H-4), 4.74 ( s, 2H, H-1), (m, 2H, H-7), 4.21 (m, 8H, H-30) 4.01 (m, 8H, H-29), 3, 88 (m, 4H, H-5), 3.75-3.34 (br m, 75H, H-30, H-28 -H-22, H-9, H-8, H-6) , 2.70 (m, 8H, H-12), 2.60 (m, 8H, H-1 1), 2.34 (m, 8H, H-13), 1, 82 (m, 8H, H-10), 1, 38-1, 32 (2 xs, 48H, H-32, H-33) ppm.

¹³ C-NMR (500 MHz, CDCl _3, 25 ⁰ C): δ = 144.95 (C-2), 122.63 (C-3), 109.27 (C-31), 77.83 (C -22), 74.70, 74.55 (C-7), 70.01 (C-5), 66.73 (C-29), 63.87, 63.74 (C-1), 60, 28 (C-4), 31, 90 (C-13), 29,60 (C-10), 28,79, 28,68 (C-12, C-1 1), 26,75, 25,33 (C-33, C-32), 78, 82, 78, 58, 78, 30, 77, 20, 72, 44, 71, 43, 71, 15, 70, 71, 69, 53, 68, 40 66.71 (C-30, C-28 - C-23, C-9, C-8, C-6), 122.00-107.00 (C-21 - C-14) ppm.

¹⁹ F-NMR (400 MHz, CDCl _3, 25 ⁰ C): δ = -80.85 (F-21), -1 14.40 (F-20), -121, 76, -121, 98 (F -19, F-18, F-17), -122.79 (F-16), -123.35 (F-15), -126.21 (F-14) ppm.

QFT-ESI-MS: calculated for C ₁₃₃ H ₁₈₁ F ₆₈ N ₃ O ₃₇ S _4: 3832.0171; Found: 3834.0390 [M + 2H] ⁺ .

General procedure for the deprotection of the alcohol function: 1, 0 equivalents of the acetal protected compounds (5-7) dissolved in a mixture of dichloromethane / methanol 1: 3 (. Vol.A / ol) was treated with the ion exchange resin Dowex ^® 50WX2- 100 and stirred for 12-24 h at room temperature. Thereafter, the Dowex ^® 50WX2-100 was removed by filtration, and the residue was concentrated under vacuum to give the desired compounds (8-10).

Example 4.4

[G1.0] -propargyl-click [G1.5] -azide-OH (8):

Reaction conditions and workup were as described above, with 5

(0.6 g, 0.222 mmol) in CH ₂ Cl ₂ / MeOH (30 ml). Evaporation of the solvent gave the desired product 8 (0.28 g, 0.1067 mmol, 48%).

Example 4.5

[G2.0] -propargyl-click- [G1.5] -azide-0H (9):

Reaction conditions and workup were as described above, with 6

(0.8 g, 0.259 mmol) in CH ₂ Cl ₂ / MeOH (30 mL). Evaporation of the solvent gave the desired product 9 (0.59 g, 0.2020 mmol, 78%).

Example 4.6

[G3.0] -propargyl-click [G1.5] -azide-0H (10):

Reaction conditions and workup were as described above, with 7

(0.89 g, 0.232 mmol) in CH ₂ Cl ₂ / MeOH (30 mL). Evaporation of the solvent gave the desired product 10 (0.76 g, 0.2163 mmol, 93%).

Example 5

Investigations of suitability as a nanotransporter / Determination of the transport capacity of selected linear dendritic polyglycerol compounds according to the invention according to Examples 1 and 2 on the basis of the dyes Nile Red and Pyrene and of the active ingredient nimodipine (the latter in comparison to PEG-based surfactants known per se)

a) Transport investigations of the amphiphiles with aromatics at the end of the hydrophobic radical according to Example 2

Table 2

Results of dye transport measurements with Nile Red and 1 g / L of PG-Dendron-based

Amphiphiles ³

Table 4

Results of dye transport measurements with Nile Red (and Pyrene) and 1 g / L of PG-

Dendron-based amphiphiles ^a

Filtration (PTFE, 0.45 μM, Rotilabo) after 24 h. [Amphiphile] = 1.0 g / L. ^b mg transported Nile red per g amphiphile. ° mmol transported Nile red per mole of amphiphile. ^d Centrifuged.

c) Encapsulation and transport capacity of nimodipine with compounds according to Example 2. Nimodipine is an active ingredient of the dihydropyridine class. It is used under the trade names Nimotop ^® and Periplum ^® as a calcium antagonist for the treatment of heart disease and nerve damage in the central and peripheral nervous system.

Table 5

Results of drug delivery measurements with nimodipine ⁸

In summary, it has been found that the encapsulation of Nile red, pyrene and nimodin with the compounds according to the invention showed that the new compounds have the desired transport properties. All PG amphiphiles according to the invention spontaneously form micelles in water. The micelles have a small size between 5 and 12 nm, preferably from 5.6 to 8.2 nm. Surprisingly, the incorporation of aromatics into the amphiphilic structures leads to significantly higher transport capacities of complexed guest molecules.

The advantages of the linear dendritic polyglycerol amphiphiles in comparison to the PEG amphiphiles also investigated here are their defined structure (monodispersed), the small size of the micelles formed, which ensure better tissue penetration and above all the outstanding water solubility in comparison with the known structures with PEG as a hydrophilic unit (eg, Pluronics ^®). In particular, all second generation polyglycerol amphiphiles (PG [G2.0]) are exceptionally soluble in water. Here presented PEG amphiphiles with mPEG750 (comparable molecular weight to PG [G2.0] are poor, amphiphiles with mPEG1100 only satisfactorily water-soluble.

Claims

claims

1. linear dendritic polyglycerol compounds characterized by the general formulas (1), (2) or (3)

in which mean

PG a polyglycerol dendron generation 0 to 10 [G0-G10] of repeating glycerol units, wherein R ³ = H, -C (CHs) _2, -CH _3, -SO ₃ Na, PO ₃ Na, or - (CH), CO-ONa with I = 1 -36,

Y - (bond) or a polyglycerol-dendron [G0-G10] other than PG of repeating glycerol units, wherein the number n of the surface group (- Z - R ¹ - Z - R ² ) _n of the generation of the dendron depends 1 - 2048

is selected from: - (bond), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-, -S-S-,

in the case of several radicals Z these may be the same or different,

X is a linker which in the case of several radicals X may be identical or different and is selected from -O-, -CH ₂ -O-, -S-, -CH ₂ -S-, -COO-, -OOC-, - CH ₂ OOC, -NH-CO-, -NH-COO-, -OOC-NH-, -NH-CO-, -CH ₂ NH-CO-, -CO-NH-, -SS, -CH ₂ - SS,

or a cleavable linker,

R ¹ - (bond), a linear, saturated and unsaturated alkyl chain with 1 to 36 C

Atoms, an aryl and / or heteroaryl radical and / or a perfluoroalkyl or partially fluorinated alkyl radical (C1 - C16), and R ² corresponds to the meaning of R ¹ , wherein R ¹ and R ^{2 may be the} same or different, but not both - or can only represent an aryl radical,

with the proviso that compounds of formula (1) in which

PG is a polyglycerol dendron of generation O or 1 [G0-G1] with R ³ = H, X = -OOC, Z = - and

R ¹ , R ^{2 represent} an alkyl chain (C1 to C72) are excluded.

2. Polyglycerolverbindungen according to claim 1, characterized in that the polyglycerol Dendron PG is a PG from the 1st generation, preferably from the 2nd generation.

3. Polyglycerolverbindungen according to any one of claims 1 or 2, characterized in that the linker

X selected from -S-. Is -OOC-, -COO-, -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or a triazole radical

represents.

4. Polyglycerolverbindungen according to one of claims 1 to 3, characterized in that

Z is selected from -, -S-S-, -S-, -COO, or -OOC-.

5. Polyglycerolverbindungen according to one of claims 1 to 4, characterized in that

R ¹ = -, aryl and / or a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms.

6. Polyglycerolverbindungen according to one of claims 1 to 5, characterized in that

R ² = linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, aryl radical and / or partially fluorinated alkyl (C 1 -C 16).

7. Polyglycerolverbindungen according to any one of claims 1 to 6, characterized in that R ¹ and / or R ² = include an aryl radical, preferably a phenyl, biphenyl or naphthyl radical.

8. Polyglycerolverbindungen according to any one of claims 1 to 7, characterized by the formula (1), wherein mean

PG = a second generation PG dendron, where R 3 _ = H,

X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = -, aryl and / or a linear, saturated and unsaturated alkyl chain having 1 to 36 C atoms,

Z = -, -S-, -COO-, -OOC- and

R ² = a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, aryl and / or partially fluorinated C 1 to C 16 alkyl.

9. Polyglycerolverbindungen according to any one of claims 1 to 7, characterized by the formula (2), wherein mean

PG = PG dendron from the 1st generation (G1-G10), where R ³ = H, or -C (CH _{3) 2,}

Y = a polyglycerol-dendron differing from PG from the O. generation (G0-G10) from repeating glycerol units, n in (-Z-R ¹ -Z-R ² ) _n corresponds to the number of surface groups of the generated dendron where is valid

n = 2-2048

X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 C atoms,

Z = -, -S-, and

R ² = a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, and / or a partially fluorinated alkyl radical C1-C16.

10. Polyglycerol compounds according to claim 9, characterized in that

X =

means.

1 1. Polyglycerolverbindungen according to any one of claims 1 to 7, characterized by the formula (3), wherein mean

Is PG = PG dendron from the 1st generation, wherein R ³ is H,

Y = - (bond) or glycerol unit GO, where

n = 1 or 2

X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, vzw. C8 to C36 alkyl,

Z = is selected from - (bond), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-

R ² = a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms and / or a C 1 -C 16 partially fluorinated alkyl.

12. Polyglycerolverbindungen according to any one of claims 1 to 1 1, characterized in that R ¹ and / or R ² = include an aryl radical.

13. Polyglycerolverbindungen according to any one of claims 1 to 12, characterized in that the aryl radical is a phenyl, biphenyl or Naphthylrest, which adjoins directly to X or which is present in R ² terminal.

14. Polyglycerolverbindungen according to any one of claims 1 to 13, characterized in that they are perfectly branched and form in aqueous solutions aggregates, preferably micelles.

15. Aggregates comprising polyglycerol compounds according to any one of claims 1 to 14, characterized in that they have a critical micelle formation concentration

<10 ^{"have 5} mol / l.

16. Aggregates according to claim 15, characterized in that they are micelles having a diameter of on average 5 to 12 nm.

17. Aggregates according to any one of claims 14 to 16, characterized in that they are loaded or bound with signal substances from the group of radioactively-labeled derivatives or from the group of dyes.

18. Aggregates according to one of claims 14 to 17, characterized in that they are loaded or bound with a diagnostic or therapeutic agent, optionally in combination with a signaling agent.

19. A process for the preparation of a compound of general formula (1), (2) or (3) according to any one of claims 1 to 13, characterized in that using the click chemistry, the target compound via 1, 3-dipolar cycloaddition an alkyne and azide functionality, which is optionally generated at the hydrophobic and hydrophilic building block, wins.

20. The method according to claim 19, characterized in that the central coupling step of the two components of different polarity as Cu-catalyzed cycloaddition of alkyne and azide functionality in THF and / or a water / THF two-phase system with the addition of CuSO ₄ -SH ₂ O and ascorbic acid or its salts as catalysts and NaOH or DIEPA (diisopropylethylamine) takes place.

21. Use of a polyglycerol compound according to any one of claims 1 to 13 for the preparation of water-soluble and isolatable aggregates comprising at least one substance.

22. Use of a polyglycerol compound according to claim 21 for the encapsulation and solubilization of hydrophobic substances.

23. Use according to claim 21 or 22, characterized in that the substance is an active ingredient, color and / or signaling material.

24. Use of a polyglycerol compound according to any one of claims 1 to 13 for the stabilization of emulsions, micro- and nanoemulsions and of foams.

25. Use of a polyglycerol compound according to any one of claims 1 to 13 for the encapsulation of catalysts, for the formation of microreactors, for adsorption on solid surfaces.