WO2012013673A1

WO2012013673A1 - Biodegradable tissue adhesive

Info

Publication number: WO2012013673A1
Application number: PCT/EP2011/062828
Authority: WO
Inventors: Heike Heckroth; Christoph Eggert
Original assignee: Bayer Materialscience Ag
Priority date: 2010-07-29
Filing date: 2011-07-26
Publication date: 2012-02-02

Abstract

The invention relates to a compound of the formula (I), in which R₁, R₂ independently of each other are a C1-C6 alkyl radical or H or together are a C5-C7 alkyl radical, R₃, R₄ independently of each other are an organic radical containing no Zerewitinoff-active hydrogen, R5, R6 independently of each other are a CH₂-COOR₇radical, in which R₇ is an organic radical containing no Zerewitinoff-active hydrogen, a linear or branched C1-C4 alkyl, a cyclopentyl, a cyclohexyl radical or H, and X, Y independently of each other are a (CH₂)_p-0 radical, where p ≥ 2 ≤ 4, or a CH₂radical, and n, m independently of each other are ≥ 1 and ≤ 6 and o ≥ 1 and ≤ 10. The invention further relates to a polyurea system, in particular for bonding tissue, comprising a compound of the formula (I), and a dosing system for such a polyurea system.

Description

Biodegradable tissue adhesive

In recent years there has been an increasing interest in replacing or supporting surgical sutures through the use of suitable adhesives. Particularly in the area of plastic surgery, which emphasizes thin, invisible scars, adhesives are increasingly being used.

Tissue adhesives must have a number of properties to be accepted by surgeons as a suture replacement. These include ease of processing and sufficient viscosity so that the adhesive can not penetrate or run into deeper layers of fabric. In classical surgery, rapid curing is additionally required, whereas in plastic surgery a correction of the adhesive seam should be possible and thus the curing rate must not be too high. In addition, the adhesive must be biocompatible and have no histotoxicity, thrombogenicity or allergenic potential.

Various materials used as tissue adhesives are commercially available. These include cyanoacrylates Dermabond ^® (octyl-2-cyanoacrylate) and Histoacryl ^® Blue (butyl cyanoacrylate). However, the fast curing time, as well as the brittleness of the splice limit the use. Due to the poor biodegradability, cyanoacrylates are only suitable for external use.

As an alternative to cyanoacrylates, biological adhesives such as peptide-based substances (BioGlue ^® ) or fibrin glue (Tissucol) are available. In addition to the high costs, fibrin glue is characterized by a relatively low adhesive strength and a rapid degradation, so that they are only applicable for smaller cuts on unstressed skin.

EP 2 145 634 A1 discloses 2K adhesive systems based on polyurea. These are by reaction of isocyanate-functional prepolymers based on aliphatic

Isocyanates with special, structurally derived from amino acids, secondary diamines available. These adhesive systems are particularly suitable as haemostatic for hemostasis and also have advantageous adhesive property. Furthermore, with these systems, tissue pieces can again be joined together or connected to one another, in particular for larger injuries, which is advantageous for the wound healing process.

However, the polyurea-based adhesive known from EP 2 145 634 A1 is essentially designed for external use. So it is necessary for an application in the body manoeuvrable, that the adhesive degrades there after completion of the wound healing in a timely manner. This is not the case with the known adhesive.

The object of the present invention was therefore to specify a modified component for the polyurea system known from EP 2 145 634 A1, which accelerates the overall degradability of the system.

This object is achieved by the compound of formula (I)

O

(I)

solved, in the

R 1, R _{2 are} each independently a C 1 -C 6 -alkyl radical or H or together are a C 5 -C 7 -alkyl radical,

R ₃ , R _{4 are} each independently an organic radical which does not have Zerewitinoff active hydrogen,

R ₅ , each independently of one another represent a CH ₂ -COOR ₇ radical in which R _{7 is} an organic radical which has no Zerewitinoff-active hydrogen, a linear or branched C 1 - to C ₄ -alkyl radical, a cyclopentyl-, are a cyclohexyl radical or H,

X, Y are each, independently of one another, a (CH ₂ ) _p -O radical, where p> 2 <4, or are a CH ₂ radical,

n, m are each independently> 1 and <6 and o> l and <10.

It has been found that when a compound according to the invention of formula (I) is used instead of the secondary diamines described in EP 2 145 634 A1 as a component in the polyurea-based adhesive system, the resulting adhesive is significantly faster degradable and so that it can also be used for applications in the body.

Compounds according to the formula (I) can be prepared, for example, by the following route: The corresponding halogenated alkyl alcohol is converted to the azido-aldehyde using sodium azide. implemented. Subsequently, the diazidoketal is prepared, for example, by reaction with 2,2-dimethoxypropane, which is converted by conventional reduction by means of Pd / hydrogen in the diamine. The reaction to the aspartate is carried out as already described in EP 2 145 634 A1 by reaction of the diamine with a maleic acid ester.

For the definition of Zerewitinoff-active hydrogen, reference is made to Römpp Chemie Lexikon, Georg Thieme Verlag Stuttgart. Preferably, groups having Zerewitinoff-active hydrogen are OH, NH or SH.

It is particularly preferred if, in the case of the compound of the formula (I), R 1 and R _{2 are} each independently of the other or simultaneously a methyl radical or a hydrogen radical. Thus, the lower steric hindrance of the radicals leads to a higher curing rate of the polyurea system.

But it is also possible that Ri and R ₂ together are a sterically demanding C4 to C6 alkyl radical. ie a cyclic acetal structure is present in which the C4 to C6 alkyl radical together with the carbon atom carrying it forms a five- to seven-membered ring. In this way, the curing speed of the adhesive can be slowed down.

It is furthermore advantageous if R ₅ , Rg are each a CH ₂ -COOR ₇ radical in which R _{7 is} an organic radical which has no Zerewitinoff-active hydrogen. As a result, the adhesive strength can be increased due to the additional ester function by forming hydrogen bonds to the tissue.

R ₃ , R ₄ and optionally R ₇ may in each case in each case independently of one another or simultaneously be a C 1 to C 10 -alkyl radical and preferably a methyl and / or an ethyl radical. Very particular preference is given to an ethyl radical since non-toxic ethanol can be released on hydrolysis.

It is likewise preferred if X and Y are each simultaneously a CH ₂ radical.

According to a further preferred embodiment, it is provided that n and m are each independently or simultaneously> 1 and <6, preferably> 1 and <4 and particularly preferably 1 or 2.

It is also preferred if o> 1 and <10, in particular> 1 and <4 and particularly preferably 1 or 2. Another aspect of the present invention relates to a polyurea system which is particularly suitable for use as an adhesive for fabrics.

The polyurea system of the invention comprises

as component A) isocyanate-functional prepolymers obtainable by reaction of

aliphatic isocyanates AI) with

Polyols A2) having a number average molecular weight of> 400 g / mol and an average OH functionality of 2 to 6, and

as component B) at least one compound according to formula (I).

The isocyanate-functional prepolymers used in A) can be obtained by reacting isocyanates with polyols, if appropriate with the addition of catalysts and auxiliaries and additives.

In AI) can be used as isocyanates, for example, monomeric aliphatic or cycloaliphatic diesters triisocyanates such as 1,4-butylene diisocyanate (BDI), 1,6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), 2,2,4- and / or 2,4, 4-trimethylhexamethylene diisocyanate, the isomeric bis (4,4'-isocyanatocyclohexyl) methanes or mixtures thereof of any isomer content, 1,4-cyclohexylene diisocyanate, 4-isocyanatomethyl-1,8-octane diisocyanate (nonanetriisocyanate), and also alkyl-2, 6-diisocyanatohexanoate (lysine diisocyanate) with C1-C8 alkyl groups are used.

In addition to the abovementioned monomeric isocyanates, it is also possible to use their relatively high molecular weight secondary products with uretdione, isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione or oxadiazinetrione structure and mixtures thereof.

Isocyanates of the abovementioned type with exclusively aliphatically or cycloaliphatically bound isocyanate groups or mixtures thereof are preferably used in Al). The use of aliphatic isocyanates in comparison to the aromatic systems does not involve the risk that hydrolysis in the body gives rise to aromatic amines which have a toxicologically unfavorable profile.

The isocyanates or isocyanate mixtures used in Al) preferably have an average NCO functionality of 2 to 4, particularly preferably 2 to 2.6 and very particularly preferably 2 to 2.4. In a particularly preferred embodiment, hexamethylene diisocyanate is used in Al).

For the prepolymer structure, it is possible to use in principle all the polyhydroxy compounds having 2 or more OH functions per molecule which are known to the person skilled in the art in A2). These may be, for example, polyester polyols, polyacrylate polyols, polyurethane polyols, polycarbonate polyols, polyether polyols, polyester polyacrylate polyols, polyurethane polyacrylate polyols, polyurethane polyester polyols, polyurethane polyether polyols, polyurethane polycarbonate nopolymers, polyester polycarbonate polyols or any desired mixtures thereof.

Polyetherpolyols of the abovementioned type are preferably used for the prepolymer structure.

The polyols used in A2) preferably have a mean OH functionality of 3 to 4.

The polyols used in A2) furthermore preferably have a number-average molecular weight of from 400 to 20 000 g / mol, particularly preferably from 2000 to 10 000 g / mol and very particularly preferably from 4000 to 8500 g / mol. When such polyols are used, a prepolymer is obtained which, because of its viscosity, can easily be mixed with component B.

Polyether polyols are preferably polyalkylene oxide polyethers based on ethylene oxide and optionally propylene oxide.

These polyether polyols are preferably based on di- or higher-functional starter molecules such as dihydric or higher-functional alcohols or amines.

Examples of such initiators are water (considered as a diol), ethylene glycol, propylene glycol, butylene glycol, glycerol, trimethylolpropane (TMP), sorbitol, pentaerythritol, triethanolamine, ammonia or ethylenediamine.

Preferred polyalkylene oxide polyethers are those of the abovementioned type and have an ethylene oxide-based content of from 50 to 100%, preferably from 60 to 90%, based on the total amount of alkylene oxide units present, thereby ensuring a particularly high adhesive performance.

Preferred polyesterpolyol are the known polycondensates of di- and optionally tri- and tetraols and di- and optionally tri- and tetracarboxylic acids or hydroxycarboxylic acids or lactones. Instead of the free polycarboxylic acids and the corresponding polycarboxylic anhydrides or corresponding polycarboxylic acid esters of lower alcohols are used to prepare the polyesters.

Examples of suitable diols are ethylene glycol, butylene glycol, diethylene glycol, triethylene glycol, polyalkylene glycols such as polyethylene glycol, furthermore 1,2-propanediol, 1,3-propanediol, butanediol (1,3), butanediol (1,4), hexanediol (I, 6) and isomers, neopentyl glycol or hydroxypivalic acid neopentyl glycol esters, with hexanediol (1,6) and isomers, butanediol (1,4), neopentyl glycol and neopentyl glycol hydroxypivalate being preferred. In addition, it is also possible to use polyols, such as trimethylolpropane, glycerol, erythritol, pentaerythritol, trimethylolbenzene or trishydroxyethyl isocyanurate.

Suitable dicarboxylic acids are phthalic acid, isophthalic acid, terephthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, cyclohexanedicarboxylic acid, adipic acid, azelaic acid, sebacic acid, glutaric acid, tetrachlorophthalic acid, maleic acid, fumaric acid, itaconic acid, malonic acid, suberic acid, 2-methylsuccinic acid, 3,3-diethylglutaric acid and / or 2,2-dimethylsuccinic acid. The acid source used may also be the corresponding anhydrides.

If the mean functionality of the polyol to be esterified is greater than 2, monocarboxylic acids, such as benzoic acid and hexanecarboxylic acid may additionally be used.

Preferred acids are aliphatic or aromatic acids of the abovementioned type. Particular preference is given to adipic acid, isophthalic acid and phthalic acid.

Hydroxycarboxylic acids which can be used as reactants in the preparation of a hydroxyl-terminated polyester polyol include hydroxycaproic acid, hydroxybutyric acid, hydroxydecanoic acid, hydroxystearic acid and the like. Suitable lactones are caprolactone, butyrolactone and homologs. Preference is given to caprolactone.

It is likewise possible to use hydroxyl-containing polycarbonates, preferably polycarbonatediols, having number-average molecular weights M of from 400 to 8000 g / mol, preferably from 600 to 3000 g / mol. These are obtainable by reaction of carbonic acid derivatives, such as diphenyl carbonate, dimethyl carbonate or phosgene, with polyols, preferably diols.

Examples of suitable 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-bis-hydroxymethylcyclohexane, 2-Methyl-l, 3-propanediol, 2,2,4-Trimethylpentandiol-l, 3, dipropylene glycol, polypropylene glycols, dibutylene glycol, polybutylene glycols, bisphenol A and lactone-modified diols of the aforementioned type in question.

The polyols A2) may very particularly preferably contain polyester polyols and / or polyester-polyether polyols and / or polyether polyols, in each case in particular with an ethylene oxide proportion of between 60 and 90% by weight, thereby ensuring a particularly high adhesive performance.

To prepare the prepolymer, the compounds of component AI) can be reacted with those of component A2) at an NCO / OH ratio of preferably 4: 1 to 20: 1, more preferably 8: 1, and then the proportion of unreacted compounds of the component AI) separated by suitable methods. Usually, the thin-film distillation is used for this purpose, low-monomer products having a residual monomer content of less than 1% by weight, preferably less than 0.5% by weight, very particularly preferably less than 0.1% by weight, being obtained.

Optionally, stabilizers such as benzoyl chloride, isophthaloyl chloride, dibutyl phosphate, 3-chloropropionic acid or methyl tosylate may be added during or after preparation.

The reaction temperature in the prepolymer preparation may be 20 to 120 ° C, preferably 60 to 100 ° C.

According to a further embodiment, it is provided that the polyurea system according to the invention comprises as component C) organic fillers. This makes it possible to compensate for fluctuations in the NCO content occurring during prepolymer production. Thus, an increased NCO content in the prepolymer can be leveled by adding a larger amount of filler. Conversely, if the NCO content of the prepolymer is determined to be lower than expected, the content of filler can be reduced.

The organic fillers used in C) are preferably not cytotoxic according to a cytotoxicity measurement according to ISO 10993 and thus do not impair wound healing.

For example, as organic fillers, liquid polyethylene glycols such as PEG 200 to PEG 600, their mono- or dialkyl ethers such as PEG 500 dimethyl ether, liquid polyether and polyester polyols, liquid polyesters such as Ultramoll (Lanxess AG, Leverkusen, DE) and glycerol and its liquid derivatives such as triacetin (Lanxess AG, Leverkusen, DE) are used.

The organic fillers of component C) are preferably hydroxy- or amino-functional, preferably purely hydroxy-functional compounds. Preferred purely hydroxy-functional compounds are polyethers and / or polyester polyols, more preferably polyether polyols.

The organic fillers of component C) preferably have average OH functionalities of from 1.5 to 3, particularly preferably from 1.8 to 2.2, very particularly preferably from 2.0.

The organic fillers of component C) preferably have repeating units derived from ethylene oxide. Such fillers are particularly compatible with the other components of the polyurea system and therefore do not adversely affect the adhesive strength of the overall system.

The viscosity of the organic fillers of component C) is preferably 10 to 20,000 mPas at 23 ° C measured according to DIN 53019, which makes it easier to mix component C with component B.

The polyurea system according to the invention can furthermore contain, as component D), water and / or tertiary amine.

Thus, it was found that even by the sole addition of either water or tertiary amine, the reaction rate of the prepolymer A) with the component B) significantly increased and thus the curing time is reduced. Surprisingly, the curing time increases even more when both water and tertiary amine are added together. Thus, the reaction rate is increased again by about 1.3 times, if a combination of water and tertiary amine is used instead of a corresponding amount of only one of the two substances.

According to a preferred embodiment, the polyurea system contains tertiary amines of the general formula

^R 10

^N \

R ₈ ^R 9

(Π), where R ₈ , R ₉ , R 1 independently of one another may be alkyl or heteroalkyl radicals having heteroatoms in the alkyl chain or at the end thereof, or R ₈ and R ₉ together with the nitrogen atom carrying them may form an aliphatic, unsaturated or aromatic heterocycle, optionally may contain other heteroatoms.

Particularly preferred is when the tertiary amine in particular from the group triethanolamine, tetrakis (2-hydroxyethyl) ethylenediamine, N, N-dimethyl-2- (4-methylpiperazin-l-yl) ethanamine, 2 - {[2- (2- Dimethylamino) ethyl] (methyl) amino} ethanol and 3,3 ', 3 "- (1,3,5-triazinane-1,3,5-triyl) tris (N, N-dimethyl-propane-1-amine) is selected.

The concentration of water in the polyurea system may be in particular 0.2 to 2.0% by weight. With the addition of 0.2% by weight of water, the average conversion rate increases by a factor of 2. If 2.0% by weight of water are added, an increase in the conversion rate by a factor of 8 occurs.

In particular, from 0.1 to 1.0% by weight of tertiary amine can be added to the polyurea system. An addition of 0.1% by weight causes a doubling of the average reaction rate and the addition of 1.0% by weight leads to an increase of

Factor 2.5.

Furthermore, it is likewise possible for the polyurea system according to the invention to comprise, as component E), pharmacologically active compounds, in particular analgesics with or without anti-inflammatory action, anti-inflammatory agents, antimicrobially active substances or antimycotics.

Pharmacologically active compounds are generally understood to mean substances and preparations of substances intended for use on or in the human or animal body in order to heal, alleviate, prevent or recognize diseases, suffering, bodily injury or pathological complaints. This also includes substances and preparations derived therefrom in order to repel, eliminate or render harmless pathogens, parasites or exogenous substances.

Analgesics are analgesic substances of different chemical structure and mode of action.

Antiphlogistics are anti-inflammatory substances. Antimicrobially active substances / antiseptics are compounds which inhibit the growth of certain microorganisms such as. B. bacteria, fungi, algae and protozoa inhibited and / or these can die off.

Antifungals are medicines used to treat fungal infections.

Antiparasitic compounds are active substances that kill parasites or inhibit their growth and nesting in human or animal tissue.

The pharmacologically active compound should preferably be soluble at room temperature in component B), but may also be used suspended in B).

The concentration of the pharmacologically active compound depends on the therapeutically necessary doses and is generally from 0.001 wt .-% to 10 wt .-%, preferably from 0.01 wt .-% to 5 wt .-% based on the total amount of all non-volatile components of the polyurea system.

All pharmacologically active compounds which can be used are distinguished by the fact that they preferably do not have NCO-reactive functional groups or that the reaction of any functional groups present with the isocyanate prepolymer is significantly slower than the reaction of components A) and B).

Suitable analgesics are local anesthetics such as ambucaine, amylocaine, arecaidin, benoxinate, benzocaine, betoxycaine, butacaine, butethamine, bupivacaine, butoxycain, chloroprocaine, coceanthene, cocaine, cyclomethycaine, dibucaine, dimethocaine, dimethisoquine, etidocaine, fomacaine, isobutyl p-aminobenzoate , Leucinocaine, lidocaine, meperidine, mepivacaine, metabutoxycaine, octacaine, orthocaine, oxethazain, phenacaine, piperocaine, piridocaine, pramoxin, procaine, procainamide, proparacaine, propoxycaine, pseudococaine, pyrrocain, ropivacaine, tetracaine, tolcain, tricaine, trimecaine , Tropacocaine, amolanone, cinnamoylcocaine, paracetocaine, propiocaine, myrtaincaine and propanocaine.

Also useful are opioid analgesics such as morphine and its derivatives (eg, codeine, diamorphine, dihydrocodeine, hydromorphone, oxycodone, hydrocodone, buprenorphine, nalbuphine, pentazocine), pethidine, levomethadone, tilidine, and tramadol.

Likewise, non-steroidal anti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid, acemeta-, dexketoprofen, diclofenac, aceclophenac, diflunisal, piritramide, etofenamate, felbinac, flurbiprofen, flufeamic acid, ibuprofen, indomethacin, ketoprofen, lonazolac, lornoxicam, Mefenamic acid, meloxicam, naproxen, piroxicam, tiaprofenic acid, tenoxicam, phenylbutazone, propyphenazone, phenazone and etoricoxib. Other analgesics such as azapropazone, metamizol, nabumetone, nefopam, oxacephrol, paracetamol and the analgesic amitriptyline can of course also be used.

In addition to the mentioned analgesics, which have an anti-inflammatory effect, in addition purely anti-inflammatory compounds can be used. This includes the class of glucocorticoids such. Cortisone, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, budesonide, allotetrahydro-cortisone, fludrocortisone, fluprednisolone, fluticasone propionate, etc.

As antiseptics, among others, the following compounds can be used: triclosan (2,4,4'-trichloro-2'hydroxydiphenyl ether), chlorhexidine and its salts, octenidine, chloramphenicol, florfenicol, chloroquinazole, iodine, povidone-iodine, He xachlorophene, merbromin, PHMB, nanocrystalline silver, and silver and copper salts.

Furthermore, as antimicrobial substances, antibiotics from the class of β-lactams (eg, penicillin and its derivatives, cephalosporins), tetracyclines (eg, demeclocycline, doxycycline, oxytetracycline, minocycline, tetracycline), macrolides (e.g. B. erythromycin, josamycin, spiramycin), the lincosamides (eg, clindamycin, lincomycin), the oxazolidinones (eg, linezolid), the gyrase inhibitors (eg, danofloxacin, difloxacin, aerofloxacin, ibafloxacin, marbofloxacin , Nahdixic acid, pefloxacin, fleroxacin, levofloxacin) and the cyclic peptides (eg bicozamycin). Also used may be rifamycin, rifaximin, methenamine; Mupirocin, fusidic acid, flumechin, and the derivatives of nitroimidazole (eg, metronidazole, nimorazole, tinidazole), nitrofuran (furaltadone, nifurpirinol, nihydrazone, nitrofurantoin), sulfonamide (eg, sulfabromo-methazine, sulfacetamide, sulfachlorpyridazine, Sulfadiazines, etc.) as well as β-lactamase inhibitors such as clavulanic acid.

As antifungal substances can all azole derivatives that inhibit the biosynthesis of ergosterol, such as. Clotrimazole, fluconazole, miconazole, bifonazole, econazole, feniconazole, isoconazole, oxiconazole, etc. are used. Other locally applicable antifungals include amorolfine, ciclopirox, thymol and its derivatives, and naftifine. Likewise, the class of the alkyl parabens can be used. Suitable antiparasitic compounds include, but are not limited to, the ectoparasiticides cyfluthrin and lindane, various azole derivatives, such as, e.g. As dimetridazole and metronidazole and quinine.

The polyurea system according to the invention is particularly suitable for sealing, bonding, gluing or covering cell tissue, in particular for arresting the escape of blood or tissue fluids or closing leaks in cell tissue. It is advantageous, in particular, that the cured system is not cytotoxic (ISO 10993-5: 2009 with L 929 cells).

The stoppage of the fluid or blood outlet or the closure of leaks in cell tissue can be carried out both in vivo and in vitro.

In the context of the present invention, tissue or cell tissue is understood in particular to be cell aggregates which consist of cells of the same shape and power as covering tissue (skin), epithelial tissue, myocardium, connective or supporting tissue, muscles, nerves and cartilage. These include, among other things, all organs composed of cell associations such as liver, kidney, lung, heart, etc.

It is also possible to use the polyurea system according to the invention for the preparation of an agent for stopping the escape of blood (haemostatic agent) or tissue fluids or the occlusion of leaks in cell tissues.

The invention likewise relates to a metering system with two chambers for a polyurea system according to the invention, in which component A) in one chamber and components B) in the other chamber and optionally components C), D) and E) are included. Such a metering system can be used in particular to easily apply a polyurea system according to the invention to tissue.

The invention further provides the adhesive films obtainable from the polyurea system according to the invention and composite parts produced therefrom.

Finally, the present invention also relates to a method for closing or joining cell tissues in which the polyurea system according to the invention is used. Examples:

The invention will be explained in more detail below with reference to examples.

Unless otherwise indicated, all percentages are by weight.

methods:

NCO contents were determined volumetrically in accordance with DIN-EN ISO 11909, unless expressly stated otherwise.

The determination of the residual monomer content was carried out according to DIN ISO 17025.

Synthesis of ethyl 7,7-dimethyl-6,8-dioxa-3,10-diazatridone-1,12,13-tetracarboxylate

2-azidoethanol (1)

A suspension of 25 g (310 mmol) of 2-chloroethanol, 40.4 g (621 mmol) of sodium azide and 2.2 g (7.8 mmol) of tetrabutylammonium bromide was heated to 110 ° C for 16 h. After cooling to room temperature, the reaction mixture was added to 400 ml of diethyl ether. The precipitate was filtered off and discarded. After removal of the solvent in a rotary evaporator, 24.3 g of 1 were obtained as a yellow oil.

[1] HR Pfaendler, V. Weimar, Synthesis 1996, 1345-1349. 2,2 ^" bis (2-azidoethoxy) propane (2)

10.5 g (101 mmol) of 2,2-dimethoxypropane and 0.86 g (5 mmol) of p-toluenesulfonic acid were added to a solution of 17.5 g (201 mmol) of 1 in 150 ml of toluene. The reaction mixture was heated at 130 ° C. for 16 hours on a water separator. After cooling to room temperature, the solvent was removed on a rotary evaporator and purified by column chromatography (eluent hexane / ethyl acetate in the ratio 2: 1). 1 lg (51%) of 2 was obtained as a yellow liquid.

2,2 ^" - (Propane-2,2-diylbis (oxy) diethanolamine (3)

To a solution of 8.1 g (37.8 mmol) of 2 in 50 ml of methanol, 400 mg of palladium on activated carbon (5w / w%) were added and hydrogenated in an autoclave for 16 h at room temperature and 15 bar. After filtration, the solvent was removed on a rotary evaporator. There was obtained 5.3 g (86%) of 3 as a yellow liquid.

7,7-dimethyl-6,8-dioxa-3, ll-diazatridecan-l, 2,12,13-tetracarboxylic acid ethyl ester (4)

8 g (49.3 mmol) of 3 were initially charged in 80 ml of anhydrous ethanol and added dropwise with 17 g

(98.6 mmol) of diethyl maleate. The reaction mixture was stirred for 16 h at room temperature. After removal of the solvent in a rotary evaporator, the reaction mixture was purified by column chromatography. (Eluent hexane / ethyl acetate in the ratio 1: 1, then dichloromethane 5: 1). This gave 6.4 g (26%) of 4 as a yellow liquid.

Ή NMR (CDC1 ₃ , 400 MHz): δ = 1.27 (t, 6H), 1.29 (t, 6H), 1.32 (s, 6H), 2.66 (m, 6H), 2.82 (m, 2H), 3.49 (t, 4H), 3.69 (t, 2H), 4, 10 (q, 4H), 4, 19 (q, 4H).

1 C-NMR (CDC1 ₃ , 400 MHz): δ = 14.2, 24.9, 38.0, 47.7, 57.9, 60.4, 60.6, 61.2, 99.9, 170, 9

173.5.

Synthesis of tetraethyl 8,8-dimethyl-7,9-dioxa-3,13-diazapentadecane-1,2,1,15,15-tetracarboxylate

2- (3-hydroxypropyl) -1H-isoindole-1,3-2-dione (5)

25 g (169 mmol) of phthalic anhydride were heated to 140 ° C. with 12.7 g (168 mmol) of 3-amino-1-propanol for 4 h. After cooling to 110 ° C, the reaction mixture was added to 200 ml of ice water, whereby a solid precipitated, which was dissolved in dichloromethane. After washing with sodium carbonate solution and water, the organic phase was dried over sodium sulfate. After removal of the solvent in vacuo, 33.5 g of the product (97%) were obtained as a colorless solid.

2,2 '- [propane-2,2-diylbis (oxypropane-3,1-diyl)] bis (1H-isoindole-1,3 (2H) -dione) (6)

20 g (97.5 mmol) of 5 were dissolved in 150 ml of toluene. Successively, 5. 1 g (48.7 ml) of dimethoxypropane and 255 mg (0.49 mmol) of p-toluenesulfonic acid were added. The reaction mixture was heated on a Claisen condenser so that the azeotrope formed in the reaction from methanol and toluene distilled off at 63.degree. After lowering the head temperature, another 1.53 g (14.6 mmol) of dimethoxypropane were added. It was heated for a further 2 h at 140 ° C while distilling off toluene. After cooling to room temperature, it was neutralized with 50 ml of ammonia-toluene solution. After filtration, the solvent was removed in vacuo and the residue was crystallized from ethyl acetate. There were obtained 11.2 g (51%) of the product as a colorless solid.

3,3 '- [Proan-2,2-diylbis (oxy)] dipropane-1-amine (7)

A solution of 14.5 g (32.2 mmol) of 6 was heated to 140 ° C in 150 ml of 6N NaOH overnight. After cooling to room temperature, the separated yellow oil was separated. There were obtained 3, 15 g (68%) of the product.

Ή NMR (CDC1 ₃ , 400 MHz): δ = 1.36 (s, 6H), 1.72 (m, 4H), 2.81 (t, 4H), 3.51 (t, 4H). ¹ C-NMR (CDC1 ₃ , 400 MHz): δ = 24.9, 30.7, 39.8, 58.9, 99.6. Tetraethyl 8,8-dimethyl-7,9-dioxa-3,13-diazapentadecane-1,2,14,15-tetracarboxylate (8)

To 3 g (15.7 mmol) of 7 were added dropwise 6.02 g (35 mmol) of diethyl maleate. The reaction mixture was heated to 60 ° C for three days. The product was then purified by column chromatography (eluent hexane / ethyl acetate in the ratio 1: 1, then dichloromethane 5: 1). 5.04 g (60%) of the product were obtained as a yellow oil.

Ή NMR (CDC1 ₃ , 400 MHz): δ = 1.27 (t, 6H), 1.29 (t, 6H), 1.32 (s, 6H), 1.7 (m, 4H), 1.79

(br, 2NH), 2.66 (m, 4H), 2.72 (m, 4H), 3.42 (t, 4H), 3.62 (t, 2H), 4, 19 (q, 4H) , 4,21 (q, 4H). ¹ C-NMR (CDC1 ₃ , 400 MHz): δ = 14.2, 24.9, 31.4, 38.4, 45.6, 57.8, 58.9, 60.4, 61.2, 99.7, 170.8, 174.1.

Synthesis of Prepolymer A

465 g of HDI and 2.35 g of benzoyl chloride were placed in a 1 liter four-necked flask. Within 2 h, 931.8 g of a polyether having an ethylene oxide content of 71% and a propylene oxide content of 29% (based on the total alkylene oxide content) started at 80 ° C. were added to trimethylolpropane (3-functional) and stirred for 1 h. Subsequently, the excess HDI was distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. This gave 980 g (71%) of the prepolymer with an NCO content of 2.37%. The residual monomer content was <0.03% HDI.

Preparation of the tissue adhesive with 4

4 g of the prepolymer A were stirred well with an equivalent amount of 4, based on the functionality of 4, in a beaker. The reaction mixture was then applied thinly to the tissue to be adhered immediately thereafter. A curing to a transparent film with a strong bond associated therewith had taken place within 4 minutes. The surface of the adhesive was no longer tacky after 6 minutes.

Preparation of tissue adhesive with 8

4 g of the prepolymer A were stirred well with an equivalent amount of 8, based on the functionality of 8, in a beaker. The reaction mixture was then applied thinly to the tissue to be adhered immediately thereafter. A cure to a transparent film with an associated strong bond had taken place within 5 minutes. The surface of the adhesive was no longer tacky after 7 minutes. The processing time was 7 min.

Determination of biodegradability

The adhesives of 4 and 8 were in a tube (diameter 0.5 cm, length 2 cm) for

Cured brought. The resulting 2.7 g each test specimen was shaken in 10 ml buffer solution (pH 7.4, Aldrich P-5368) at 60 ° C or 37 ° C in a shaking incubator at 150 U / min until the material completely, ie without sediment had dissolved.

The samples were completely degraded after the following periods:

Adhesive from 4:

60 ° C: 2 days

37 ° C: 7 days

Adhesive from 8:

60 ° C: 2 days

37 ° C: 7 days

Cytotoxizitätsmessung

The cured adhesive was tested for cytotoxicity according to ISO 10993-5: 2009 with L 929 cells. The material has proven to be non-cytotoxic.

Example:

Synthesis of prepolymer B

465 g of HDI and 2.35 g of benzoyl chloride were placed in a 1 liter four-necked flask. Within 2 h, 931.8 g of a polyether having an ethylene oxide content of 71% and a propylene oxide content of 29% (in each case based on the total alkylene oxide content) started at 80 ° C. were added to TMP (3-functional) and stirred for 1 h. Subsequently was distilled off by thin-film distillation at 130 ° C and 0, 13 mbar, the excess HDI. This gave 980 g (71%) of the prepolymer with an NCO content of 2.37%. The residual monomer content was <0.03% HDI.

Aspartate NH1220

To 2 mol of diethyl maleate was slowly added dropwise under nitrogen atmosphere 1 mole of 2-methyl-l, 5-diaminopentane, so that the reaction temperature did not exceed 60 ° C. The mixture was then heated to 60 ° C until no more diethyl maleate was detectable in the reaction mixture by HPLC.

Tissue adhesive made of prepolymer B and aspartate NH1220, biodegradability study

0.53 g of aspartate NH1220 was mixed well with 4 g of the prepolymer B and cured in a tube (diameter 0.5 cm, length 2 cm). The resulting test specimens were in each case 10 ml of buffer solution (pH 7.4, Aldrich P-5368) 48 h at 60 ° C in

Shaking incubator swollen at 150 rpm. Subsequently, the samples were rinsed with completely deionized water and dabbed dry. The weight of the samples was registered as start weight. The samples were further shaken in 10 ml of buffer solution (pH 7.4, Aldrich P-5368) at 60 ° C or 37 ° C in the shaking incubator under the same conditions. The weight of the samples was determined weekly.

After 18 weeks, no change in the weight of the sample was measured.

The above experiments show that the polyurea systems according to the invention in comparison to the known from EP 2 145 634 AI known systems degrade much faster and thus are also suitable for use in the body.

Claims

claims:

1. Compound of formula (I)

(I)

in the

R 1, R _{2 are} each independently a C 1 to C 6 alkyl radical or H or together are a C 5 to C 7 alkyl radical,

R ₃ , R 4 are each independently an organic radical which does not have any

Zerewitinoff-active hydrogen,

R5, R6 each independently represent a CH ₂ -COOR ₇ radical in which R _{7 is} an organic radical which has no Zerewitinoff-active hydrogen, a linear or branched C 1 - to C 4 -alkyl radical, a cyclopentyl-, are a cyclohexyl radical or H,

n, m are each independently> 1 and <6 and

o> l and <10.

A compound according to claim 1, characterized in that Ri and R ₂ are each independently of one another or simultaneously are a methyl residue or H.

Compound according to one of claims 1 or 2, characterized in that R ₅ , 5 are each a CH ₂ -COOR ₇ radical in which R _{7 is} an organic radical which has no Zerewitinoff-active hydrogen.

A compound according to any one of claims 1 to 3, characterized in that R ₃ , R ₄ and optionally R _{7 are} each independently or simultaneously a C 1 to C 10 alkyl radical and preferably a methyl and / or an ethyl radical.

5. A compound according to any one of claims 1 to 4, characterized in that X and Y are each simultaneously a CH ₂ radical.

6. A compound according to any one of claims 1 to 5, characterized in that n and m are each independently or simultaneously> 1 and <6, preferably> 1 and <4 and particularly preferably 1 or 2.

7. A compound according to any one of claims 1 to 6, characterized in that o> 1 and <10, preferably> 1 and <4 and particularly preferably 1 or 2.

8. Polyurea system comprising

as component A) isocyanate-functional prepolymers obtainable by reaction of

aliphatic isocyanates AI) with

as component B) at least one compound according to one of claims 1 to 7.

9. polyurea system according to claim 8, characterized in that the polyols A2) polyesterpolyols and / or polyester-polyether polyols and / or Polyetherpolyo- le, each in particular with an ethylene oxide content between 60 and 90 wt .-%, containing.

10. polyurea system according to one of claims 8 or 9, characterized in that the polyols used for the preparation of component A) have a number average molecular weight of 4000 to 8500 g / mol.

11. polyurea system according to one of claims 8 to 10, characterized in that it comprises as component C) organic fillers which have in particular a measured viscosity according to DIN 53019 at 23 ° C in the range of 10 to 20,000 mPas.

12. Polyurea system according to claim 11, characterized in that the organic fillers of component C) are hydroxy-functional compounds, more preferably polyether polyols.

13. polyurea system according to claim 12, characterized in that the fillers of component C) have an average OH functionality of 1.5 to 3, preferably from 1.8 to 2.2 and more preferably from 2.

14. polyurea system according to one of claims 12 or 13, characterized in that the fillers of the component C) have repeating ethylene oxide units.

15. polyurea system according to one of claims 8 to 14, characterized in that it contains as component D) water and / or tertiary amine, wherein the tertiary amine in particular from the group triethanolamine, tetrakis (2-hydroxyethyl) ethyl-endiamin, N, N-dimethyl-2- (4-methylpiperazin-1-yl) ethanamine, 2- {[2- (dimethylamino) ethyl] (methyl) amino} ethanol and 3,3 ', 3 "- (l, 3,5-triazinane-1,3,5-triyl) tris (N, N-dimethyl-propane-1-amine).

16. polyurea system according to one of claims 8 to 15, characterized in that it comprises as component E) pharmacologically active compounds, in particular analgesics with or without anti-inflammatory action, anti-inflammatory drugs, antimicrobial active substances or antimycotics.

17. polyurea system according to one of claims 8 to 16 for closing, connecting, bonding or covering of cell tissue, in particular for stopping the escape of blood or tissue fluids or the closure of leaks in cell tissue.

18. dosing system with two chambers for a Polyhamstoff system according to one of claims 8 to 17, characterized in that in one chamber, the component A) and in the other chamber, the components B) and optionally the components C), D) and E) of the polyurea system are included.