DE2237083A1 - Polymerisable reactive carboxylic and carbamic acid esters - for use as carriers for pharmaceuticals and enzymes - Google Patents

Abstract

Cpds of formula (I): (where R1 is OCH2Q (Q = 2-5C alkoxycarbonyl or CN), 2,4-dinitrophenoxy, 2,4,5-trichlorophenoxy, pentachlorphenoxy, phenylthio, p-nitrophenoxy, p-nitrophenylthio, piperidyl-N-oxy, succinimido-N-oxy, phthalimido-N-oxy or benzotriazolyl-N-oxy, R2 is H, Me, Cl, CN, Ph, MeOCO or EtOCO, R3 is H, Me, Et or Ph R4 is H or lower alkyl, A is a bond or NH, B is a bond, O, -O-CO-, 5-oxo-pyrrolidine-1,2-diyl, phenylene or pyridine-diyl, X is a single bond or -(CH2)m-Y-, m = 0-4, Y is O, S, NH, -O-CO, -NH-CI- or -NH-CO-O-CO-), with the exception of p-nitrophenyl (meth)acrylate, are new homo- and copolymerisable monomers useful as carriers for pharmaceuticals and enzymes. (I, A = bond) can be prepd. by reacting the corresp. carboxylic acid with R1OH, (I, A = NH) can be prepd. by reacting the corresp. isocyanate with R1OH.

Description

Reactive esters of monomeric, polymerizable carboxylic and carbamic acids, Their use and process for their production It is already known pharmaceuticals and to bind enzymes covalently to polymeric carriers, the binding often being via a so-called acid amide function takes place. The binding occurred either through implementation the monomeric acid or a reactive derivative thereof with the drug or Enzyme with subsequent polymerization Cs.S.I. Kotenko and Yu.

I. Lisunkin, Farm.Zh (Kiev) 26,17 (1971)) or - more often - by implementation the already polymerized acid or its reactive derivative with the enzyme or Pharmakon (see H. D. Ort and W. Brümmer, Angew. Chem. 82, 319 (1972)). As reactive derivatives so far mostly only acid chlorides and acid anhydrides have been used.

A third conceivable method is the polymerization of the reactive derivatives itself, has so far rarely been carried out, as uncrosslinked products rely on this Difficult to obtain and, moreover, because of the otherwise feared solvolysis the polymerization and also the subsequent conversion in the case of acid chlorides and anhydrides must run in organic solvents.

In addition, many pharmaceuticals and especially enzymes survive somewhat rough acylation method with acid chlorides or

-anhydrides only bad (this applies to all X methods described above). The usability of the two known methods as well as the third method is therefore drastically restricted by the use of acid chlorides and anhydrides. Liii special disadvantage of the use of acid anhydrides is, among other things, the fact that in the aminolysis of these compounds free carboxylate anions are formed which de give polymers an ion exchange character, which has a disruptive effect; ; aside from that Polymers with high proportions of carboxyl groups are often highly toxic.

tine in the literature (see II. Jatzkewitz, Z. saturforsch. 10b, 27 (1955); Y. Ohno and M.A. Stahmann, Macromolecules 4,350 (1971)) also mentioned The method for coupling amines to polymers is to convert the acid function of the finished polymer in the presence of dicyclohexyl carbodiimide or in formation of azides or mixed anhydrides as intermediates.

Since the intermediate products are only poorly or not at all cleaned can, however, be a hundred percent unsuccessful in reactions on polymers is very difficult to achieve, impure end products are obtained, their application is not possible in the pharmaceutical sector. So this method is convenient for the solution of the problem, a problem-free coupling of any amino groups containing Reaching pharmaceuticals or enzymes on polymeric carriers cannot be used.

The aim of the invention is to create monomeric and polymeric linkages to present suitable compounds with pharmaceuticals or enzymes, the described Do not have disadvantages. Such compounds should be very reactive, but at the same time gentle with nuclcophilic substances (e.g. amino, hydroxyl or mercapto groups load-bearing substances) react selectively. They should be polymerizable or copolymerizable, also stable and durable for a long time, both in monomeric and polymeric form be.

It has now been found that reactive esters of monomeric polymerizable Carboxylic acids the desired; Have properties. Such esters are so far except for the nitrophenyl ester of acrylic and methacrylic acid, neither known nor been investigated. However, the two compounds mentioned above as being known were only in the context of an investigation into neighboring group effects on polymers shown and described (see H. Alorawetz, I.Amer.CIzem.Soc., 83, 1738 (1961)) about however, nothing has been said about the task at hand.

Suitable esters in the Rahlilen of the invention are substances of the general formula where R1 is the radical -OCIf2-Q (Q = -COO-lower alkyl with 1-4 carbon atoms, CN or pyridinium (-N #)) or the 2,4-dinitrophenoxy, 2,4,5-trichlorophenoxy, the pentachlorophenoxy, the phenylthio, the p-nitrophenoxy, the p-nitrophenylthio, the piperidyl-N-oxy-, the succinimide-N-oxy-, the phthalimide-N-oxy or the benzotriazole-N-oxy- Radical, R2 is hydrogen, methyl, chlorine, CN, phenyl or lower alkoxycarbonyl (the alkoxy radical of which has 1-2 carbon atoms).

R3 is hydrogen, lower alkyl with 1-2 C atoms or phenyl, R4 is hydrogen or lower alkyl, A is a single bond or the NH group and B is a single bond, an oxygen atom or a group of the sub-formulas X is a single bond (results in olefin) or - (Cll2) mY-, where m is one of the integers 0-4 and Y is oxygen, sulfur, or means.

Free-radically or ionically polymerizable ones are particularly suitable Esters of carboxylic or carbamic acids. The unsaturated or cyclic reactive urethanes are similar to the corresponding carboxylic acid esters Reaction, but different polymerization behavior, so that a broad Application range is achieved. In the field of free-radically polymerizable compounds comes the simple and cheap derivatives of acrylic and methacrylic acid as well as the Vinyl urethanes are of particular importance.

Important, particularly suitable individual substances are, for example, the following: The substances according to the invention are prepared starting from the respective monomeric acid by esterification processes known per se (for example conversion of the acid chloride, etc.)

anhydrides with the corresponding alcohol), in the case of urethanes Implementation of the corresponding isocyanate with the corresponding alcohol.

The following examples illustrate the invention without restricting it: 1. Hydroxysuccinimide acrylate MG 169 57.5 g (0.5 mol) of N-hydroxysuccinimide and 100 mg of dinitrobenzene are placed in a two-necked flask with 200 mol of absolutely dry methylene chloride. While stirring and cooling with ice, 69 ml (0.5 mol) of acryloyl chloride, dissolved in 60 ml of methylene chloride, are simultaneously added dropwise to separate dropping funnels with exclusion of moisture. After the end of the dropping in, the mixture is stirred for a further 6 hours at room temperature. The triethylamine hydrochloride formed is filtered off. The solution is extracted successively with water, saturated sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and evaporated. The crude product is dissolved in a little hot ethyl acetate and left to crystallize in a refrigerator using petroleum ether.

Yield: 55g = 65t mp 68-690C Analysis: calculated: 49.70% C 4.15% H 8.28 tN found: 49.39 tC 3.95 tH 8.12% N 2. Hydroxysuccinimide methacrylate f.iG 183 57.5 g (0.5 mol) of N-hydroxysuccinimide and 100 mg of dinitrobenzene are placed in a two-necked flask with 200 ml of absolutely dry methylene chloride. While stirring and cooling with ice, 69 ml (0.5 mol) of triethylamine dissolved in 31 ml of methylene chloride and 45.25 ml (0.5 mol) of methacryloyl chloride, dissolved in 55 ml of methylene chloride, were added dropwise simultaneously in separate dropping funnels with exclusion of moisture. After the end of the dropping in, the mixture is stirred for a further 6 hours at room temperature. The triethylamine hydrochloride formed is filtered off. The solution is shaken out successively with water, saturated sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated. The crude product is dissolved in a little hot ethyl acetate and left to crystallize out with petroleum ether in the refrigerator.

Yield: 70 g = 76.5% mp 103 ° C. Analysis: Calculated: 52.46 tC 4.92 ii 7.65 t; Found: 52.59% C 5.08% H 7.74% N 3. Acrylic acid hydroxybenzotriazol ester MG 189 1) 67.5 g (0.5 mol) 1-hydroxybenzotriazole are dissolved in 200 μl of methanol. 20 g (0.5 mol) of sodium hydroxide dissolved in 50 ml of water are added. The solution is evaporated to dryness and the hydroxybenzotriazole sodium salt is dried at 140 ° C. in a water jet vacuum until the final weight is a constant 78.5 g.

2) To 78.5 g (0.5 lol) of hydroxybenzotriazole sodium salt add 300 ml given absolutely dry methylene chloride and 100 n r dinitrobenzene. While stirring and ice cooling, 39.75 nl (0.5 lol) acryloyl chloride are dissolved in 60: l methylene chloride added dropwise with exclusion of moisture. It works for 6 hours at room temperature stirred and boiled a @ reflux for 2 hours. The solution is formed from Aiatriunchlor i decanted off, the methylene chloride stripped off and the Rohpro @ @kt in hot Bssigester solved. After adding petroleum ether leaves to crystallize in the freezer. It is then again by dissolving in ethyl acetate / chloroform 1: 1 and adding recrystallized from petroleum ether.

Yield: 28 g = 30% mp 122-125 ° C. Analysis:. Calculated: 57.14% C 3.65 tli 22.22 tN found: 55.90 tC 4.08 at 22.06% N 4. Ethacrylic acid lydroxybenzotriazol ester MW 203 1) 67.5 g (0.5 mol) of 1-hydroxybenzotriazole are dissolved in 200 ml of methanol. 20 g (0.5 mol) of sodium hydroxide dissolved in 50 ml of water are added. The solution is evaporated to dryness and the hydroxybenzotriazole sodium salt is dried at 140 ° C. in a water jet vacuum until the final weight is a constant 78.5 g.

2) To 78.5 g (0.5 mol) of hydroxybenzotriazole sodium salt are 300 ml of absolutely dry methylene chloride and 100 mg of dinitrobenzene are added. While stirring and ice cooling, 45.25 ml (0.5 mol) of methacryloyl chloride are dissolved in 60 ml of methylene chloride dripped in with exclusion of moisture. It is stirred for 6 hours at room temperature and refluxed for 2 hours. The solution is formed from the sodium chloride decanted off, the methylene chloride stripped off and the crude product in hot ethyl acetate solved. After the addition of petroleum ether, the mixture is left to crystallize in the refrigerator (3 days).

Yield: 31 g = 30% mp 400 C Analysis: calculated: 59.11 tC 4.43 tH 20.65% N found: 59.32 tC 4.55% H 21.03% N 5. Acrylic acid-2,4 , 5-trichlorophenyl ester MW 251.5 98.75 g (0.5 mol) 2,4,5-trichlorophenol and 100 mg dinitrobenzql are placed in a two-necked flask with 200 ml absolutely dry methylene chloride. While stirring and cooling with ice, 69 ml (0.5 mol) of triethylamine, dissolved in 31 ml of methylene chloride, and 39.75 ml (0.5 mol) of acryloyl chloride, dissolved in 60 ml of methylene chloride, are simultaneously added dropwise to separate dropping funnels with exclusion of moisture. After the end of the dropping in, the mixture is stirred for a further 6 hours at room temperature. The triethylamine hydrochloride formed is filtered off. The solution is shaken out successively with aqueous, saturated sodium hydrogen carbonate solution and again with water, dried with anhydrous sodium sulfate and evaporated. The crude product is recrystallized with a little petroleum ether.

Yield: 93 g = 74 t mp 650C Analysis: calculated: 42.94 tC 1.99 tH 42.35% Cl found: 43.21 tC 2.19% H 42.46% Cl 6. methacrylic acid-2,4, 5-trichlorophenyl ester MG 265.5 98.75 g (0.5 mol) 2,4,5 trichlorophenol and 100 mg dinitrobenzene are placed in a two-necked flask with 200 ml absolutely dry methylene chloride. While stirring and cooling with ice, 69 ml (0.5 mol) of triethylamine, dissolved in 31 ml of methylene chloride, and 45.25 ml (0.5 mol) of methacryloyl chloride, dissolved in 55 ml of ethylene chloride, are simultaneously added dropwise to separate dropping funnels with exclusion of moisture. When the dropwise addition is complete, the mixture is stirred for a further 6 hours at room temperature. The triethylamine hydrochloride formed is filtered off. The solution is shaken out in succession with saturated sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and evaporated. The crude product is recrystallized with a little petroleum ether.

Yield: 87 g = 65% mp 600C Analysis: calculated: 45.25% C 2.64% H 40.11% Cl found: 45.11% C 2.81% H 40.22% Cl 7.N-vinyl- Carbamic acid hydroxysuccinimide ester MG 184 57.5 g (0.5 mol) N-IIydroxysuc, cinimid are dissolved in 300 ml absolutely dry tetrahydrofuran. 36.7 ml (0.5 lol) of vinyl isocyanate dissolved in 60 ml of tetrahydrofuran are added dropwise with stirring and ice-cooling with exclusion of moisture. The mixture is stirred for a further 6 hours at room temperature, half of the solvent is drawn off, petroleum ether is added and the mixture is left to crystallize in the refrigerator.

Yield: 78 g = 85% mp 111 ° C analysis: calculated: 45.65% C 4.35% H 15.22% N found: 46.50% C 4.74% H 14.81 0N 8th N- Vinyl carbamic acid 1-hydroxybenzotriazol ester MW 204 67.5 g (0.5 mol) of 1-hydroxybenzotriazole are dissolved in 300 μl of absolutely dry tetrahydrofuran. 36.7 inl (0.5 mol) of vinyl isocyanate dissolved in 60 ml of tetrahydrofuran are added dropwise with stirring and ice-cooling with exclusion of moisture.

The solvent is stirred for a further 6 hours at room temperature Half of it is drawn off, cooled and the crude product is sucked off. It is made from tetrahydrofuran recrystallized.

Yield: 79 g = 77 ° b. Mp 135-1400C (decomposition) Analysis: calculated: 52.94% C 3.92% h $ 27.45% N found: 50.79 ° aC 3.65 ° * i 27.83 % W 9. N-vinyl-carbamic acid 2,4,5-trichlorophenyl ester MW 266.5 98.75 g (0.5 mol) 2,4,5-trichlorophenol are dissolved in 300 ml absolutely dry methylene chloride. 36.7 ml (0.5 mol) of vinyl isocyanate dissolved in 60 ml of methylene chloride are added dropwise with stirring and ice-cooling with exclusion of moisture. The mixture is stirred for a further 6 hours at room temperature, the solvent is drawn off and the crude product is recrystallized from petroleum ether.

Yield: 90 g s 68 to mp 1300C Analysis: calculated: 40.53% C 2.25 % H 5.25% N 39.97% Cl found: 40.66% c 1.75% H 5.94% N 40.42% Cl 10. Hydroxysuccinimide polyacrylate 3.38 g (0.02 mol) of acrylic acid hydroxysucciniid ester and 10 mg of azoisobutyrodinitrile are kept at 60 ° C. for 4 hours in 40 ml of absolutely dry tetrahydrofuran. The precipitated polymer is filtered off with suction and washed with tetrahydrofuran.

Yield: 2.2 g "65% 11. Polymethacrylic acid hydroxysuccinimide ester 3.66 g (0.02 Io 1) flol): hydroxysuccinimide methacrylate and 10 mg g of azoisobutyrodinitrile are kept at 600 ° C. for 4 hours in 40 cll of absolutely dry tetrahydrofuran. The precipitated polymer is filtered off with suction and washed with tetrahydrofuran.

Yield: 1.67 g = 46% 12. Poly-N-vinyl-carbamic acid hydroxysuccinimide ester 3.68 g (0.02 mol) of N-vinyl carbamic acid hydroxysuccinimide ester and 10 mg of azoisobutyrodinitrile are kept at 60 ° C. for 4 hours in 40 ml of absolutely dry tetrahydrofuran. That precipitated polymers are filtered off with suction and washed with tetrahydrofuran.

Yield: 0.5 g = 14 -t 13. 2,4,5-trichlorophenyl polyacrylate 5.03 g (0.02 mol) of 2,4,5-trichlorophenyl acrylate and 10 mg of azoisobutyrodinitrile are kept at 60 ° C. for 4 hours in 40 ml of absolutely dry tetrahydrofuran. The polymer formed is then precipitated in petroleum ether and filtered off with suction.

Yield: Z g = 40% 14. Polymethacrylic acid-2,4,5-trie @@@ lester 5.31 g (0.02 mol) of 2,4,5-trichlorophenyl methacrylate and 10 mg of azoisobutyrodinitrile are kept at 60 ° C. for 4 hours in 40 ml of absolutely dry tetrahydrofuran. then the formed polymer is precipitated in petroleum ether and sucked off.

Yield: 1.25 g = 24% 15. Poly-N-vinyl-carbamic acid 2,4,5-trichlorophenyl ester 5.33 g (0.02 mol) of N-vinyl-carbamic acid-2,4,5-trichlorophenyl ester and 10 mg of azoisobutyrodinitrile are kept in 40 nil absolutely dry tetrahydrofuran for 4 hours at 60.degree. Then the polymer formed is precipitated in petroleum ether and filtered off with suction.

Yield: 0.53 g = 10% 16. hydroxybenzotriazole ester 3.78 g (0.02 lol) acrylic acid hydroxybenzotriazol ester and 10 mg azoisobutyrodinitrile are kept at 60 ° C. for 4 hours in 40 ml of absolutely dry tetrahydrofuran. The precipitated polymer is filtered off with suction and washed with tetrahydrofuran.

Yield: 2.35 g = 62% 17. Polymethacrylic acid hydroxybenzotriazol ester 4.06 g (0.02 mol) of hydroxybenzotriazole methacrylate and 10 mg of azoisobutyrodinitrile are kept at 60 ° C. for 4 hours in 40 ml of absolutely dry tetrahydrofuran. The polymer formed is then precipitated in petroleum ether and filtered off with suction.

Yield: 1.35 g = 33 z 18. Poly-N-vinyl-carbamic acid hydroxybenzotriazol ester 4.08 g (0.02 mol) of N-vinyl carbamic acid hydroxybenzotriazol ester and 10 mg of azoisobutyrodinitrile are kept at 60 ° C. for 4 hours in 40 ml of absolutely dry tetrahydrofuran. That precipitated polymers are filtered off with suction and washed with tetrahydrofuran.

Yield: 0.5 g W 12.2 t 19. Methacrylic acid cyclohexylamide C + oH16N0; MC 166 3.66 g (20 mblol) of methacrylic acid hydroxysuccinimide ester are mixed with a spatula tip of hydroquinone in 25 ml of dioxane / water at 0 ° C. Then 1.72 ml (20 mmol) of cyclohexylamine are added dropwise. After stirring for 6 hours at room temperature, a complete conversion can be seen in the thin-layer chromatogram. It is shaken out several times with ethyl acetate. The ethyl acetate solutions are combined and the ethyl acetate is stripped off in a vacuum when dried.

The remaining product is recrystallized from ethyl acetate / petroleum ether.

Yield: 2.6 g = 78.5% analysis: calculated: 72.3 tC 9.65% H 8.43 0N found: 71.76% C 9.65% H 8.28% N 20. a) Polymethacrylic acid cyclohexylamide Hydroxysuccinimide polymethacrylate 1.69 g (10 mmoles) of hydroxysuccinimide polymethacrylate are slurried in 25 ml of absolute methylene chloride.

2.26 ml (20 mmol) of cyclohexylamine are added with stirring. After 3-5 days - at room temperature - the polymer has settled and dissolved. 5 "l of methanol are then added in order to dissolve the hydroxysuccinimide formed.

The polymer is then precipitated by dropping it into acetone and then reprecipitated from methanol / water. According to the infrared spectrum, the product still contains hydroxysuccinimide in free or esterified form of the starting compound. Its share is after Elemental analysis 20-40%.

b) Polyacrylsäurecyclohexylamid from Polyacrylsäurebenzotriazolester 1.89 g (10 mmol) of polyacrylic acid benzotriazol ester are dissolved in 25 ml of absolute methylene chloride slurried. 2.26 ml (20 mmol) of cyclohexylamine are added with stirring. After brief stirring at room temperature, the solution becomes homogeneous.

The product is precipitated after 24 hours by dropping it into ether. and reprecipitated from methanol / water. The polyacrylic acid cyclohexylamide obtained contains nor the infrared spectrum, no more benzotriazole. By titration with sodium hydroxide solution in Methanol / water can detect 3% of the starting compound or the resulting acid will.

21. Poly-N-vinyl-N-cyclohexylurea 1.84 g (10 mmoles) of poly-N-vinyl-carbamic acid hydroxysuccinimide ester are slurried in 25 ml of absolute methylene chloride. With stirring, 2.26 ml (20 mmol) of cyclohexylamine were added. To 4-5 days has become the polymer unset and dissolved. 5 inl ethanol are then added to the to dissolve resulting hydroxysuccinimide. It is precipitated by dropping it into acetone and reprecipitated from methanol / water. The obtained poly-N-vinyl-N-cyclohexylurea According to the infrared spectrum and elemental analysis, it still contains 20-40 9 hydroxysuccinimide or output connection.

21. Polymethacryloyl ethanolamide 5.6 g (30 mmol) of polymethacrylic acid hydroxysuccinimide ester are dissolved in 40 nil of dimethyl sulfoxide. 3.6 g (60 mmol) of ethanolamine in 10 liii l) of methyl sulfoxide are added dropwise to this solution with stirring.

It is stirred for 24 hours at room temperature. The resulting product is now precipitated by dropping in methylene chloride. Then from methanol / acetone recirculated. The resulting product is strongly hygroscopic and contains according to the infrared spectrum even larger amounts of hydroxysuccinimide. This is made by dialysis in aqueous Separated solution. The purified polymethacryloyl / ethanolamide is again through Dropping in acetone precipitated. The polymer obtained is readily soluble in water.

Yield: 2.5 g = 71.5 z By reacting equimolar amounts of the Starting compounds and heating to 80-100 ° C. become partially cross-linked polymers obtain.

22. Water-soluble copolymers N-vinylpyrrolidone (901) / N-vinyl-carbamic acid benzotriazol ester (10%) 2.244 g (11 mmol) N-vinyl-carbamic acid benzotriazol ester, 24.42 g (220 -tol) N-vinylpyrrolidone and 115.5 mg (0.3 mol%) azoisobutyrdinitrile are with absolute dry tetrahydrofuran dissolved in a 110 ml dilatometer vessel (monomer concentration : 2 mol / 1). The solution is made oxygen-free by passing nitrogen through it, a 2 ml capillary is attached and the dilatometer is suspended in a water bath at 600C. After 24 hours, cooling is interrupted and another 115.5 g of azotsobutyrdinitrile are added admitted. The demolition occurs with a contraction of 1.84 ml by failures in ether. It is reprecipitated from chloroform / ether.

Yield: 11.21 g = 42% conversion 23. Acrylamide (90%) / acrylic acid hydroxysuccinimide ester (10%) 4.23 g (25 mmoles) of acrylic acid hydroxysccinimide ester, 14.2 g (200 mmoles) of acrylamide and 56.4 mg (0.15 mol%) of azoisobutyrdinitrile with absolutely dry tetrahydrofuran dissolved in a 110 ml dilatometer vessel. (Monomer concentration: 2.05 mol / 1). the The solution is made oxygen-free by passing nitrogen through it, a 2 ml capillary put on and the dilatometer hung in a water bath of 60 0C. The demolition takes place with a contraction of 2 ml (after approx. 1 h) by cooling in ice. That Polymer is transferred to a beaker with methanol and suctioned off. It will be out Water / methanol reprecipitated.

Yield: 12.07 g = 65.5% conversion 24. N # -Polymethacryloyl-N # -tert. Butyloxycarbonyl-Lysyl-Alanyl-Amide / Polymethacryloyl-Ethanolamide 1.85 g (10 mmol) of polymethacrylic acid hydroxysuccinimide ester are dissolved in 20 ml of dimethyl sulfoxide. 3 mmol of the dipeptide are added to this solution with stirring. It is stirred for 2 days at room temperature. Then 1.2 g (20 mmol) of ethanolamine are added and the mixture is stirred for a further 24 hours. The product is precipitated by dropping it into methylene chloride. Then it is reprecipitated from methanol @ ether. According to the nuclear magnetic resonance spectrum (tert. Butyl peak at 1.5 ppm, comparison with the spectra of the starting compounds), the polymeric product contains about 15-20% of the dipeptide.

25. Polymethacryloyl cycloserine / polymethacryloyl ethanolamide To 5.6 g (30 mmol) of polymethacrylic acid hydroxysuccinimide ester, dissolved in 40 ml of dimethyl sulfoxide, 1 g (10 mmol) of cycloserine, dissolved in 10 ml of dimethyl sulfoxide, is added. It will Stirred for 3 days at room temperature. Then 2.4 g (40 ml / vol) of ethanolamine are added. After stirring for a further 24 hours, it is precipitated by dropwise addition into methylene chloride and reprecipitated from methanol / acetone. The polymeric product contains according to the infrared spectrum Polymethacryloyl cycloserine (bands at 1190 and 1280, comparison with propionyl cycloserine).

26. Polymethacryloyl-glycyl-emetine / polymethacryloyl-ethanolamide 1.85 g (10 xíol) of polymethacrylic acid hydroxysuccinimide ester are dissolved in 20 ml of dimethyl sulfoxide. 1 mmol glycylemetine is added to this solution with stirring. It is stirred for 2 days at room temperature. Then 1.2 g (20 mmol) of ethanolamine are added and the mixture is stirred for a further 24 hours. The product is precipitated by dropwise addition into methylene chloride / ether (50:50) and reprecipitated from methanol / ether. According to the nuclear magnetic resonance spectrum, the polymeric product contains about 2-4 z Glycyl-EmetintPeak at 3.95 ppm of the methoxy groups).

Claims (1)

Claims Monomer substances of the general formula wherein R1 is the radical -OCH2-Q (Q = -COO-lower alkyl with 1-4 carbon atoms or CN) or the 2,4-dinitrophenoxy-, 2,4,5-trichlorophenoxy-, the pentachlorophenoxy-, the phenylthio- , p-nitrophenoxy, p-nitrophenylthio, piperidyl-N-oxy, succinimide-N-oxy, phthalimide-N-oxy or benzotriazole-N-oxy radical R2 is hydrogen, methyl, chlorine , CN, phenyl or lower alkyloxycarbonyl (the alkoxy radical of which has 1-2 C atoms). R3 is hydrogen, lower alkyl with 1-2 C atoms or phenyl, R4 is hydrogen or lower alkyl A is a single bond or the NH group and B is a single bond, an oxygen atom or a group of the partial formulas or X is a single bond (gives olefin) or where m is one of the integers 04 and # oxygens sulfur, -NH-, #, # or -NH- #, with the exception of the p-nitrophenyl ester of acrylic and methacrylic acid. 2. Use of the monomer substances of the general formula I for the preparation of corresponding polymeric reactive esters by free-radical or ionic polymerization. 3. Use of the monomer substances of the general formula I for the preparation of pharmaceuticals or enzymes covalently bound to polymers. 4. Production of monor0eren carboxylic acid esters of the general formula I, characterized in that acids of the general formula in which R2 to R4, B and n have the meanings given above and A is a single bond, are reacted by methods known per se with alcohols of the general formula R1 - OH III in which R1 has the meaning given above. 5. Production VO "of monomeric carbamic acid esters of the general formula I, characterized in that isocyanates of the general formula in which R2 to R4, B and n have the abovementioned meaning, are reacted in a manner known per se with alcohols of the general formula III.