HK1187635A - Tissue adhesive based on trifunctional aspartates - Google Patents

Description

Tissue adhesives based on trifunctional aspartates

The present invention relates to amino-functional compounds for use in polyurea systems which are provided in particular for sealing, bonding (verbinden), adhering (verkleben) or covering cellular tissue. The invention further provides polyurea systems comprising the compounds according to the invention, and metering systems for the polyurea systems according to the invention.

Various materials are commercially available for use as tissue adhesives. They comprised cyanoacrylate Dermabond (2-octyl cyanoacrylate) and Histoacrryl Blue (butyl cyanoacrylate). However, the primary condition for effective adhesion of cyanoacrylates is a dry substrate. Such adhesives can fail where there is significant bleeding.

As an alternative to cyanoacrylate, bioadhesives such as BioGlue, a mixture of glutaraldehyde and bovine serum albumin, various collagen-and gelatin-based systems (FloSeal) and fibrin adhesives (Tissucol) are available. This system is mainly used to stop bleeding (hemostasis). In addition to being costly, fibrin adhesives are also distinguished by relatively weak adhesive strength and rapid degradation, making them useful only in relatively minor injury situations on non-tensioned tissue. Collagen-and gelatin-based systems such as FloSeal are only used for hemostasis. In addition, since fibrin and thrombin are obtained from human materials and collagen and gelatin are obtained from animal materials, there is always a risk of infection of biological systems. The biological materials must additionally be stored in a cooled condition, making them impossible to use in emergency supplies, such as in disaster areas, in military activities, etc. In this case QuikClot or QuikClot +ACS +^TMTraumatic wounds, which are mineral particles, are treated, placed in the wound in first aid and blood coagulation is produced by removing water. In the case of QuikClot, this is a strong exothermic reaction, which can lead to burns. QuikClot ACS +^TMIs gauze with salt embedded inside. The system must be pressed tightly against the wound to stop bleeding.

The preparation and use of polyurea systems as tissue adhesives is known from WO 2009/106245 a 2. The system disclosed therein comprises at least two components. The components are an amino-functional aspartate and an isocyanate-functional prepolymer, which is obtainable by reacting an aliphatic polyisocyanate with a polyester polyol. The described 2-component polyurea systems can be used as tissue adhesives for closing wounds in human and animal cell structures. Very good bonding results can thus be achieved.

In order to ensure good miscibility of the two components of the polyurea system, the viscosity of said components at 23 ℃ should be as low as possible less than 10,000 mPas. Prepolymers with NCO functionality of less than 3 exhibit correspondingly low viscosities. When using such prepolymers, it is necessary to use aspartates having amino functionalities greater than 2 as second component, since otherwise it is not possible to produce a polymer network. However, this is necessary in order for the polyurea system or the bonding lines (Klebnaht) composed thereof to have the required mechanical properties, such as elasticity and strength. In addition, when difunctional aspartates are used, there is the disadvantage that curing times of up to 24 hours are obtained, wherein the polyurea systems in many cases remain tacky even after the curing time, that is to say the tack is not eliminated.

It is therefore an object of the present invention to provide an isocyanate-reactive component for polyurea systems which can be mixed easily with prepolymers having an NCO functionality of less than 3, has an amino functionality of greater than 2 and can react rapidly with prepolymers to form a three-dimensional polyurea network. A further condition to be considered is the absence of cytotoxicity of the curing system according to ISO 10993 when used in humans or animals.

According to the invention, this object is achieved by a compound of the general formula (I),

wherein

R₁、R₂ Independently of one another, identical or different organic radicals which do not contain Zerewitinoff active hydrogen, and

R₄、R₅、R₆independently of one another, are saturated, linear or branched organic radicals which contain no zerewitinoff-active hydrogen and can optionally also be substituted in the chain by heteroatoms.

The compound according to the invention can be easily mixed with the prepolymer since it has a viscosity of less than 10,000mPas at 23 ℃. In addition, it has an amino functionality of 3 and is therefore capable of rapidly forming a three-dimensional polyurea network with prepolymers having an NCO functionality of 2. The network is characterized by high elasticity, strength, adhesive strength and lack of cytotoxicity. In addition, the network is no longer tacky, that is to say the tack is eliminated, only after a short time.

In the general formula (I), the radical R₄、R₅、R₆Independently of one another, they can be linear or branched, in particular saturated, aliphatic C1-C12, preferably C2-C10, particularly preferably C3-C8 and most preferably C3-C6 hydrocarbon radicals. Such amino-functional compounds are characterized in that they cure particularly rapidly with prepolymers, forming highly adhesive, elastic and strong polyurea networks.

According to a further preferred embodiment of the compounds according to the invention, the radical R₁、R₂Independently of one another, are linear or branched organic C1-C10, preferably C1-C8, particularly preferably C2-C6, most particularly preferably C2-C4 groups and in particular aliphatic hydrocarbon groups. This compound is also characterized by rapid network formation upon reaction with the prepolymer.

Preference is likewise given to the radical R₁And R₂Are each the same and/or a group R₄、R₅、R₆Each being identical.

Most particularly preferred are compounds of the formula (I) wherein R₁And R₂Each simultaneously being methyl or ethyl and R₄、R₅、R₆Each simultaneously being ethyl, propyl or butyl.

The invention further provides a polyurea system comprising

-component a): isocyanate-functional prepolymers obtainable by reacting aliphatic polyisocyanates A1) with polyols A2), which in particular may have a number-average molecular weight of ≥ 400g/mol and an average OH functionality of from 2 to 6,

-component B): according to the invention, the amino-functional compounds of the general formula (I),

-optionally component C): an organic filler, which may in particular have a viscosity of 10 to 6000mPas at 23 ℃ measured according to DIN 53019,

-optionally component D): reaction products of isocyanate-functional prepolymers according to component A) with amino-functional compounds according to component B) and/or organic fillers according to component C), and

-optionally component E): water and/or a tertiary amine.

The polyurea systems according to the invention are obtained by mixing the prepolymer A) with the amino-functional compound B) and optionally components C), D) and/or E). The ratio of free or blocked amino groups to free NCO groups is preferably 1:1.5, particularly preferably 1:1. Whereby water and/or an amine are added to components B) or C).

Isocyanate-functional prepolymers a) are obtainable by reacting polyisocyanates a1) with polyols a2), optionally with the addition of catalysts and auxiliaries, and additives.

As polyisocyanates A1), it is possible to use, for example, monomeric aliphatic or cycloaliphatic di-or triisocyanates, such as 1, 4-Butylidene Diisocyanate (BDI), 1, 6-Hexamethylene Diisocyanate (HDI), isophorone diisocyanate (IPDI), 2, 4-and/or 2,4, 4-trimethylhexamethylene diisocyanate, bis (4,4' -isocyanatocyclohexyl) methane isomers or mixtures thereof with any desired isomer content, 1, 4-cyclohexylene diisocyanate, 4-isocyanatomethyl-1, 8-octane diisocyanate (nonane triisocyanate), and also alkyl 2, 6-diisocyanatohexanoate with C1-C8 alkyl (lysine diisocyanate).

In addition to the monomeric polyisocyanates a1) mentioned above, it is also possible to use their higher molecular weight secondary products having a uretdione, isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione or oxadiazinetrione structure and mixtures of these secondary products.

Preference is given to using polyisocyanates A1) of the type mentioned above or mixtures thereof, A1) having exclusively aliphatically or cycloaliphatically bonded isocyanate groups.

Preference is likewise given to using polyisocyanates A1) of the type mentioned above having a functionality with an average NCO functionality of from 1.5 to 2.5, preferably from 1.6 to 2.4, more preferably from 1.7 to 2.3, most particularly preferably from 1.8 to 2.2 and in particular 2).

Hexamethylene diisocyanate is most preferably used as polyisocyanate A1).

According to a preferred embodiment of the polyurea system according to the invention, it is provided that polyol A2) is a polyester polyol and/or a polyester-polyether polyol and/or a polyether polyol. Particular preference is given to polyester-polyether polyols and/or polyether polyols having an ethylene oxide content of from 60 to 90% by weight.

It is also preferred that the polyol A2) has a number average molecular weight of 4000-8500 g/mol.

Suitable polyetherester polyols are preferably prepared according to the prior art by polycondensation of polycarboxylic acids, anhydrides of polycarboxylic acids and esters of polycarboxylic acids with readily volatile alcohols, preferably C1-C6 monoalcohols, such as methanol, ethanol, propanol or butanol, with a molar excess of low molecular weight and/or higher molecular weight polyols; wherein the ether group-containing polyol is optionally used as a polyol in a mixture with other ether group-free polyols.

Of course, mixtures of higher molecular weight polyols with lower molecular weight polyols can also be used for the polyetherester synthesis.

This molar excess of low molecular weight polyol is a polyol having a molar mass of from 62 to 299 daltons, having from 2 to 12 carbon atoms and a hydroxyl functionality of at least 2, which may further be branched or unbranched and whose hydroxyl groups are primary or secondary hydroxyl groups. These low molecular weight polyols may also contain ether groups. Typical representatives are ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 1, 4-butanediol, 2, 3-butanediol, 2-methyl-1, 3-propanediol, 1, 5-pentanediol, 1, 6-hexanediol, 3-methyl-1, 5-pentanediol, 1, 8-octanediol, 1, 10-decanediol, 1, 12-dodecanediol, cyclohexanediol, diethylene glycol, triethylene glycol and higher homologues, dipropylene glycol, tripropylene glycol and higher homologues, glycerol, 1,1, 1-trimethylolpropane, and oligo-tetrahydrofuran with hydroxyl end groups. Mixtures within this group can of course also be used.

The molar excess of the higher molecular weight polyol is a polyol having a molar mass of 300-3000 daltons, which can be obtained by ring-opening polymerization of epoxides, especially ethylene oxide and/or propylene oxide, and by acid-catalyzed ring-opening polymerization of tetrahydrofuran. Either alkali metal hydroxide or double metal cyanide catalysts can be used for epoxide ring-opening polymerization.

As starter for the epoxide ring-opening polymerization it is possible to use all molecules which are at least difunctional and are selected from the group consisting of amines and the low molecular weight polyols mentioned above. Typical representatives are 1,1, 1-trimethylolpropane, glycerol, o-TDA, ethylenediamine, 1, 2-propanediol and the like, and water, including mixtures thereof. Mixtures within the group of higher molecular weight polyols in excess may of course also be used.

The synthesis of higher molecular weight polyols can be carried out in random or block fashion, as far as hydroxy-terminated polyalkylene oxides of ethylene oxide and/or propylene oxide are concerned, wherein mixed blocks may also be present.

Polycarboxylic acids are aliphatic or aromatic carboxylic acids which may be cyclic, linear, branched or unbranched and may contain from 4 to 24 carbon atoms.

Examples are succinic acid, glutaric acid, adipic acid, azelaic acid, sebacic acid, 1, 10-decanedicarboxylic acid, 1, 12-dodecanedicarboxylic acid, phthalic acid, terephthalic acid, isophthalic acid, trimellitic acid, pyromellitic acid. Succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, phthalic acid, terephthalic acid, isophthalic acid, trimellitic acid, pyromellitic acid are preferred. Succinic, glutaric and adipic acids are particularly preferred.

The group of polycarboxylic acids also includes hydroxycarboxylic acids or their internal anhydrides, such as caprolactone, lactic acid, hydroxybutyric acid, ricinoleic acid and the like. Also included are monocarboxylic acids, in particular those having more than 10 carbon atoms, such as soya oil fatty acid, palm oil fatty acid and peanut oil fatty acid, where their proportion in the overall reaction mixture which constitutes the polyetherester polyol is not more than 10% by weight and, in addition, the accompanying low functionality is compensated by the simultaneous use of at least trifunctional polyols, whether the functionality is on the low molecular weight polyol side or on the higher molecular weight polyol side.

According to the prior art, the preparation of the polyetherester polyols is carried out at elevated temperatures of 120-250 ℃ initially under normal pressure and subsequently with the application of a vacuum of 1 to 100mbar, preferably but not necessarily using an esterification or transesterification catalyst, wherein the reaction is carried out until the acid number has fallen to a value of 0.05 to 10mg KOH/g, preferably 0.1 to 3mg KOH/g and particularly preferably 0.15 to 2.5mg KOH/g.

An inert gas may additionally be used during the atmospheric stage prior to the application of the vacuum. Of course, liquid or gaseous entrainers may also be used as an alternative or in a separate esterification stage. For example, when nitrogen is used as the carrier gas, the water of reaction can be vented as when azeotropic entrainers, such as benzene, toluene, xylene, dioxane, and the like, are used.

Mixtures of polyether polyols and polyester polyols in any ratio can of course also be used.

Preferred polyether polyols are polyalkylene oxide polyethers based on ethylene oxide and optionally propylene oxide.

Such polyether polyols are preferably based on difunctional or higher-functional starter molecules such as difunctional or higher-functional alcohols or amines.

Examples of such starters are water (understood as glycol), ethylene glycol, propylene glycol, butylene glycol, glycerol, TMP, sorbitol, pentaerythritol, triethanolamine, ammonia or ethylenediamine.

It is likewise possible to use hydroxyl-containing polycarbonates, preferably polycarbonate diols, which have a number-average molecular weight Mn of 400-8000g/mol, preferably 600-3000 g/mol. They can be obtained by reaction of carbonic acid derivatives, such as diphenyl carbonate, dimethyl carbonate or phosgene, with polyhydric alcohols, preferably diols.

Examples of such diols are ethylene glycol, 1, 2-and 1, 3-propanediol, 1, 3-and 1, 4-butanediol, 1, 6-hexanediol, 1, 8-octanediol, neopentyl glycol, 1, 4-dimethylolcyclohexane, 2-methyl-1, 3-propanediol, 2, 4-trimethylpentane-1, 3-diol, dipropylene glycol, polypropylene glycol, dibutylene glycol, polybutylene glycol, bisphenol A and lactone-modified diols of the type mentioned above.

To prepare prepolymer A), polyisocyanate A1) can be reacted with polyol A2) in an NCO/OH ratio of preferably 4:1 to 12:1, particularly preferably 8:1, and the unreacted polyisocyanate present can then be separated off by suitable methods. Thin film distillation is often used for this purpose, wherein the resulting prepolymer has a residual monomer content of less than 1% by weight, preferably less than 0.1% by weight, most preferably less than 0.03% by weight.

During the preparation, stabilizers such as benzoyl chloride, isophthaloyl dichloride, dibutyl phosphate, 3-chloropropionic acid or methyl tosylate may optionally be added.

The reaction temperature in the preparation of the prepolymer A) is preferably from 20 to 120 ℃ and more preferably from 60 to 100 ℃.

The prepolymers prepared have an average NCO content, measured in accordance with DIN EN ISO 11909, of from 2 to 10% by weight, preferably from 2.5 to 8% by weight.

According to a further embodiment of the polyurea system according to the invention, the prepolymer A) may have an average NCO functionality of 1.5 to 2.5, preferably 1.6 to 2.4, more preferably 1.7 to 2.3, most particularly preferably 1.8 to 2.2 and in particular a functionality of 2 is used.

The organic filler of component C) may preferably be a hydroxy-functional compound, in particular a polyether polyol having repeating units of ethylene oxide.

It is also advantageous for the fillers of component C) to have an average OH functionality of from 1.5 to 3, preferably from 1.8 to 2.2 and particularly preferably 2.

For example, polyethylene glycols which are liquid at 23 ℃, such as PEG200-PEG600, their mono-or dialkyl ethers, such as PEG500 dimethyl ether, liquid polyether-and polyester polyols, liquid polyesters, such as Ultramoll (Lanxess AG, Leverkusen, germany), and glycerol and its liquid derivatives, such as triacetin (Lanxess AG, Leverkusen, germany), can be used as organic fillers.

The viscosity of the organic fillers, measured at 23 ℃ in accordance with DIN 53019, is preferably from 50 to 4000mPas, particularly preferably from 50 to 2000 mPas.

In a preferred embodiment of the polyurea system according to the invention, polyethylene glycol is used as organic filler. They preferably have a number average molecular weight of 100-.

In order to further reduce the average equivalent weight of all compounds used for crosslinking the prepolymer, based on NCO-reactive groups, it is additionally possible to prepare the reaction products of the prepolymer A) with the amino-functional compounds B) and/or the organic fillers C) in a separate preliminary reaction, provided they are amino-or hydroxy-functional, and then to use them as higher molecular weight curing agent component.

Preferably, the ratio of isocyanate-reactive groups to isocyanate groups is determined in the pre-growth (vorverlaengegung) to be from 50:1 to 1.5:1, particularly preferably from 15:1 to 4: 1.

This modification by pre-growth is advantageous in that the equivalent weight and equivalent volume of the curing agent component can be improved within wider limits. Commercially available 2-chamber metering systems can therefore be used for this application to give adhesive systems which can be adjusted to the desired ratio of NCO-reactive groups to NCO groups by means of the existing chamber volume ratios.

According to a further preferred embodiment of the polyurea system according to the invention, it is provided that component E) comprises a tertiary amine of the general formula (II)

Wherein

R₇、R₈、R₉Independently of one another, may be alkyl or heteroalkyl having a heteroatom in the alkyl chain or at its terminus, or R₇And R₈Together with the nitrogen atom bearing them, may form an aliphatic, unsaturated or aromatic heterocyclic ring, which may optionally contain further heteroatoms.

These polyurea systems are characterized by particularly rapid curing.

The compounds used in component E) may most particularly preferably be tertiary amines selected from: triethanolamine, tetrakis (2-hydroxyethyl) ethylenediamine, N-dimethyl-2- (4-methylpiperazin-1-yl) ethylamine, 2- { [2- (dimethylamino) ethyl ] (methyl) amino } -ethanol, 3',3"- (1,3, 5-triazine (triazinan) -1,3, 5-triyl) tris (N, N-dimethyl-propan-1-amine).

Very particularly high curing speeds can also be achieved if component E) comprises from 0.2 to 2.0% by weight of water and/or from 0.1 to 1.0% by weight of a tertiary amine.

It is, of course, also possible to introduce pharmaceutically active ingredients such as analgesics with and without anti-inflammatory activity, anti-inflammatory agents, substances with antibacterial activity, antifungal agents, substances with antiparasitic activity into the polyurea system.

The polyurea systems according to the invention are particularly suitable for sealing, adhering, bonding or covering cellular tissue and in particular for preventing the outflow of blood or interstitial fluid or for sealing leaks in cellular tissue. Most particularly preferably, it can be used or used for the preparation of a medicament for sealing, adhering, bonding or covering human or animal cell tissue. By means of the polyurea system according to the invention, a fast-curing, transparent, flexible and biocompatible adhesive line can be produced which adheres closely to the tissue.

The present invention further provides a metering system for the polyurea system according to the invention having two chambers, wherein one chamber contains component A) of the polyurea system and the other chamber contains component B) and optionally components C), D) and E). Such a metering system is particularly suitable for applying the polyurea system as an adhesive to tissue.

Example (b):

the invention is explained in more detail below with the aid of examples.

The method comprises the following steps:

molecular weight: molecular weights were determined by Gel Permeation Chromatography (GPC) as follows: calibration was performed with polystyrene standards with molecular weights Mp 1,000,000-162. Tetrahydrofuran p.a. was used as eluent. The following parameters were followed during the double measurement: an online degasser; flow rate: 1 ml/min; analysis time: 45 minutes; a detector: a refractometer and a UV detector; injection volume: 100 to 200. mu.l. Mean molar mass value M_w、M_nAnd M_pAnd polydispersity M_w/M_nSoftware is used to assist the computation. The baseline points and evaluation limits were fixed according to DIN 55672 part 1.

NCO content: the NCO content is determined volumetrically according to DIN-EN ISO 11909, unless otherwise mentioned.

Viscosity: the viscosity was determined according to ISO 3219 at 23 ℃.

Residual monomer content: the residual monomer content was determined in accordance with DIN ISO 17025.

NMR spectra were recorded using a Bruker DRX 700 apparatus.

Substance (b):

polyethylene glycol 600 (Aldrich)

Synthesis of 2,2' - (4- (3- (1, 4-diethoxy-1, 4-dioxobut-2-ylamino) propyl) hept-1, 7-diyl) bis (azanediyl) tetraethyl disuccinate (3)

4- (2-cyanoethyl) pimelitrile (1)

A mixture of 12.2g (55.4 mmol) of 4- (2-cyanoethyl) -4-nitroheptanedinitrile and 18ml of tributyltin hydride is heated with 2.78g of azo-bis- (isobutyronitrile) (AIBN) in 250ml of acetonitrile at reflux overnight. After removal of the solvent in vacuo, the product is stirred with n-hexane and crystallized from a mixture of n-hexane and dichloromethane. 8.25g (85%) of the product are obtained in the form of a colorless solid.

4- (3-aminopropyl) hepta-1, 7-diamine (2)

8g (45.7 mmol) of 4- (2-cyanoethyl) heptadinitrile are hydrogenated in 100ml of 7N methanolic ammonia solution at 130 ℃ and a hydrogen pressure of 100 bar for 5 hours. After cooling to room temperature, the reaction mixture was filtered over celite and washed with methanol. After removal of the solvent in vacuo, 7.5g of crude product were obtained and used in the next stage without further purification.

2,2' - (4- (3- (1, 4-diethoxy-1, 4-dioxobut-2-ylamino) propyl) hept-1, 7-diyl) bis (azanediyl) tetraethyl disuccinate (3)

25.7g (150 mmol) of diethyl maleate are added to a solution of 7.5g (40 mmol) of 4- (3-aminopropyl) hepta-1, 7-diamine in 100ml of ethanol. The reaction mixture was stirred at 60 ℃ for 3 days. After removal of the solvent in vacuo, the product was purified by column chromatography (hexane/ethyl acetate 1:1, then dichloromethane/methanol 10: 1). 15.5g (39%) of the product are obtained as a yellow oil.

Synthesis of prepolymer A

212.5g (1.8 mol) of succinic acid and 1591.5g of polyethylene glycol 600 (2.6 mol) were heated to 235 ℃ with stirring. The water formed was distilled off over 8.5 hours. 100 ppm of tin (II) chloride were then added and heated further in a water separator under vacuum (15 mbar) at 235 ℃ for 9 hours.

672g of HDI (4 mol) and 0.1% by weight of benzoyl chloride were placed in a reaction vessel and heated to 80 ℃. 788g of polyester were then metered in over a period of 1 hour with stirring, and stirring was continued at 80 ℃ until a constant NCO content was reached. Excess HDI was removed by means of a thin-film evaporator at 140 ℃ and 0.13 mbar. The prepolymer obtained had an NCO content of 3.5% and a viscosity of 4700mPas/23 ℃. Residual monomer content < 0.03% HDI.

Synthesis of prepolymer B

A prepolymer was prepared analogously to prepolymer A from 263g (1.8 mol) of adipic acid and 1591.5g of polyethylene glycol 600 (2.6 mol). The prepolymer obtained had an NCO content of 5.93% and a viscosity of 1450mPas/23 ℃. Residual monomer content < 0.03% HDI.

Synthesis of prepolymer C

465g of HDI and 2.35g of benzoyl chloride were placed in a1 l four-necked flask. 931.8g of a polyether having an ethylene oxide content of 71% and a propylene oxide content of 29%, based in each case on the total alkylene oxide content, were added at 80 ℃ over a period of 2 hours and stirred for 1 hour. Excess HDI was then distilled off by thin-film distillation at 130 ℃ and 0.13 mbar. 980g (71%) of a prepolymer were obtained having an NCO content of 2.37% and a viscosity of 4500mPas/23 ℃. Residual monomer content < 0.03% HDI.

Preparation of tissue adhesives

4g of the prepolymer was vigorously stirred in a beaker with an equivalent amount (equivalent amount) of amino-functional compound 3 already prepared. Immediately thereafter, the polyurea system is applied as a thin layer to the muscle tissue to be bonded. The polyurea system was determined to still have a sufficiently low viscosity such that it could be applied to tissue without difficulty as a processing time.

The time for which the polyurea system is no longer tacky (tack free time) is measured by an adhesion test using a glass rod. For this purpose, the glass rod is brought into contact with a layer of the polyurea system. When the stick is no longer adhered, the system is considered tack free. In addition, adhesion was determined by coating two muscle tissues (l = 4 cm, h = 0.3 cm, b = 1 cm) 1cm from the tip with a polyurea system and bonding them one over the other. The adhesion of the polyurea systems was tested separately by the pull-off method.

	Curing agent	Working time	Tack free time	Adhesive force
					Prepolymer A	3	1 minute and 30 seconds	2 minutes	++
Prepolymer B	3	1 minute	2 minutes	+
					Prepolymer B (comparative example 1)	4	8 minutes	>30 minutes	+
Prepolymer A	5	3 minutes	5 minutes	++

Good ++, good.

Comparative example 1 difunctional prepolymer + difunctional curing agent

Instead of the amino-functional compound 3 which has been prepared, tetraethyl 2,2' - [ (2-methylpent-1, 5-diyl) diimido ] disuccinate (4) described in EP 2145634 is reacted with prepolymer B. The processing time here was 8 minutes. The polyurea system showed no removal of the tack even after 10 minutes.

Measurement of cytotoxicity of adhesive prepared in (3)

Prepolymer C was reacted with an equivalent of 3. Cytotoxicity was measured with L929 cells according to ISO 10993-5: 2009. Cell survival rate was not reduced. Therefore, polyurea systems are not classified as cytotoxic.

Comparative example 2 cytotoxicity of structurally similar trifunctional curing Agents

Diethyl 2- [ (8- [ (1, 4-diethoxy-1, 4-dioxobut-2-yl) amino ] -4- { [ (1, 4-diethoxy-1, 4-dioxobut-2-yl) amino ] methyl } octyl) amino ] succinate (5)

346g (2 mol) of diethyl maleate are added dropwise to 115.3g (0.6 mol) of triaminononane. The reaction mixture was heated at 60 ℃ for 3 days until no further maleate was detectable (Bayer reagent).

Measurement of cytotoxicity of cured adhesive

4g of prepolymer C were vigorously stirred in a beaker with an equivalent amount of (5) and cured. The adhesives were measured with L929 cells according to ISO 10993-5: 2009. The cell survival rate is reduced to 4% (high cytotoxicity).

Claims (16)

1. A compound of the general formula (I)

Wherein

R₁、R₂Independently of one another, identical or different organic radicals which do not contain zerewitinoff-active hydrogen, and

R₄、R₅、R₆independently of one another, saturated, linear or branched organicA group that does not contain zerewitinoff-active hydrogen and is also optionally substituted in the chain by heteroatoms.

2. A compound according to claim 1, characterized in that the group R₄、R₅、R₆Independently of one another, they can be linear or branched, in particular saturated, aliphatic C1-C12, preferably C2-C10, particularly preferably C3-C8 and most preferably C3-C6 hydrocarbon radicals.

3. Compound according to claim 1 or 2, characterized in that the group R₁、R₂Independently of one another, are linear or branched organic C1-C10, preferably C1-C8, particularly preferably C2-C6, most particularly preferably C2-C4 groups and in particular aliphatic hydrocarbon groups.

4. A compound according to one of claims 1 to 3, characterized in that the radical R₁And R₂Are each the same and/or a group R₄, R₅, R₆Are respectively the same.

5. A polyurea system comprising

-component a): isocyanate-functional prepolymers obtainable by reacting aliphatic polyisocyanates A1) with polyols A2), which in particular may have a number-average molecular weight of ≥ 400g/mol and an average OH functionality of from 2 to 6,

-component B): an amino-functional compound according to any one of claims 1 to 4,

-optionally component C): an organic filler, which may in particular have a viscosity of 10 to 6000mPas at 23 ℃ measured according to DIN 53019,

-optionally component D): reaction products of isocyanate-functional prepolymers according to component A) with amino-functional compounds according to component B) and/or organic fillers according to component C), and

-optionally component E): water and/or a tertiary amine.

6. Polyurea system according to claim 5, characterized in that the polyol A2) comprises a polyester polyol and/or a polyester-polyether polyol and/or a polyether polyol, in particular a polyester-polyether polyol and/or a polyether polyol having an ethylene oxide content of 60 to 90% by weight.

7. Polyurea system according to claim 5 or 6, characterized in that the polyol A2) has a number average molecular weight of 4000-.

8. Compound according to any of claims 5 to 7, characterized in that the prepolymer A) has an average NCO functionality of 1.5 to 2.5, preferably 1.6 to 2.4, more preferably 1.7 to 2.3, most particularly preferably 1.8 to 2.2 and in particular 2.

9. Polyurea system according to any one of claims 5 to 8, characterized in that the organic filler of component C) is a hydroxyl-functional compound, in particular a polyether polyol having ethylene oxide repeating units.

10. Polyurea system according to claim 9, characterized in that the filler of component C) has an average OH functionality of 1.5 to 3, preferably 1.8 to 2.2 and particularly preferably 2.

11. Polyurea system according to any one of claims 5 to 10, characterized in that component E) comprises a tertiary amine of the general formula (II)

Wherein

R₇、R₈、R₉Independently of one another, may be alkyl or heteroalkyl having a heteroatom in the alkyl chain or at its terminus, or R₇And R₈And beltTogether with their nitrogen atoms, may form an aliphatic, unsaturated or aromatic heterocyclic ring, which may optionally contain additional heteroatoms.

12. Polyurea system according to any one of claims 5 to 11, characterized in that the tertiary amine is selected from: triethanolamine, tetrakis (2-hydroxyethyl) ethylenediamine, N-dimethyl-2- (4-methylpiperazin-1-yl) ethylamine, 1- { [2- (dimethylamino) ethyl ] (methyl) amino } -ethanol, 3',3"- (1,3, 5-triazine-1, 3, 5-triyl) tris (N, N-dimethyl-propan-1-amine).

13. Polyurea system according to any one of claims 5 to 12, characterized in that component E) comprises 0.2 to 2.0 wt.% of water and/or 0.1 to 1.0 wt.% of a tertiary amine.

14. Polyurea system according to any one of claims 5 to 13 for closing, adhering, bonding or covering cellular tissue, in particular for preventing blood or interstitial fluid from flowing out or for closing leaks in cellular tissue.

15. Polyurea system according to claim 14 for use in closing, adhering, bonding or covering human or animal cell tissue.

16. Metering system with two chambers for a polyurea system according to any of claims 5 to 15, characterized in that one chamber contains component a) of the polyurea system and the other chamber contains component B) and optionally components C), D) and E).