DE3114428C2 - Polyurethanocarbamidoacylsemicarbazide for the manufacture of synthetic implants with temporary effects - Google Patents

Abstract

Polyurethanocarbamidoazylsemicarbazide for the production of synthetic implants with temporary effect with the following formula: (formula).

Description

-C H-CO-N H-CH- -CH-CO-NH-CH ₂ - —C H-CO-N HC H-

I I I i I

CH ₃ CH ₃ CH ₂ CH ₅ CH ₂ C ₆ H ₅ CH ₂ OCOCH ₃

-CH-CO-NH-CH-CO-Nh-CH ₂ -;

I I

²⁵ CH ₃ CH ₂ C ₆ H ₅

Rj = - (CHj) ₆ -C ₆ H ₄ -CH ₂ -C ₆ H ₄ -;

₃₀ R ₃ = I- (CHj) ₄ -OJ ₁₄ [- (CH ₂ J ₄ -OI ₂₁ .

The invention relates to novel chemical compounds based on isocyanate polymers, more specifically, Polyurethaneocarbamidoacylsemicarbazides.

The compounds according to the invention can be used in surgery as a starting material for the preparation of Temporary effective synthetic implants are used, which to avoid defects in Organs or tissues serve.

At present, synthetic implants are commonly used for this purpose, which are made from biological degradable synthetic polymers are made.

Synthetic implants of this type are intended to ensure the regeneration of the tissue in the tissue defect they fill in the course of a certain period of time, and then to be removed from the organism in the form of products of biodegradation to be excreted.

At present, the biodegradation of implants made of synthetic polymers is caused by the Introduction of a sufficient amount of labile links into the main chain of the polymer is achieved and regulated. The exact timing of the biodegradation is difficult because of the spectrum of the enzymes of the Tissue is not taken into account.

Attempts have been made to increase the biodegradation time of manufactured from synthetic polymers Implants by increasing the concentration of the labile links in the main polymer chain to control what one sought to achieve by chemical modification of the side chains. Furthermore, with the same goal the The ratio of hydrophylic and hydrophobic groups in the macromolecule of the polymer is controlled.

At present, the application of compounds based on polyurethanes in medicine great prospects, as their chemical and physical properties can be changed within wide limits. For example, a structured foam polyurethane is known (FR-PS 23 18 183), which by reaction an isocyanal blocked polyurethane prepolymer is prepared with water. However, its biodegradation occurs through hydrolysis of the ester group in the main chain of the original prepolymer, d. H. without the influence of the tissue's enzymes.

All of this shows that this problem has not yet been satisfactorily resolved.

The invention was based on the object, by introducing links of natural compounds into the main chain of the polymer, of such polyurethanes for the production of temporarily effective synthetic ones To create transplants, which by enzymatic hydrolysis both in aqueous Hn / ymlösung as well as in living organisms are broken down.

The polyurethaneocarbaniidoacylsemicarba / ide according to the invention are new compounds and have not yet been described in the literature.

According to the invention, the compounds mentioned have the following formula:

- (NH-R ₁ -CO-NH-NH-CO-NH-R ₂ -NH-CO-OR ₃ -CO-Nh-R ₂ -NH-CO) ,, -

where: η = 5-24; R, = -CH- -CH- - CH- - CH- —CH-

-CH

CH,

- CH-

(CH ₂ J ₂ SCH ₃

CH ₁ C ₄ H ₅ CH ₂ OCOCH, CH ₃ OH -CH ₂ -CO-NH-CH ₂ -

-CH-CO-CH-CH- -CH-CO-NH-CHr

CH ₃

CH ₃

CH ₂ C ₄ H ₅ CH ₂ CH (CH,), CHjC ₁₁ H ₄ OH - CH- CO- NH- CH-

—CH-CO-NH — CH-

- CH - CO - NH - CH - CO - NH - CHj-;

I I

CH ₃ CH ₂ C ₆ H ₅

R ₂ = - (CH ₂ ), -C ₆ H ₄ -CH ₂ -C ₄ H ₄ -; R ₃ = [- (CH ₂ J ₄ -OJ ₁₄ [- (CHA-OI ₂₁ .

The specified compounds are compiled in Table 1.

CH ₂ OCOCH ₃

Table 1 1 In the main chain of the polymer
built-in amino acid
or incorporated peptide R, Rj R, ι—] | _4th 1-k No. of
link 2 j 4th 5 I. 2 L-alanine - CH- - (CH ₂ ), - 1- (CHA-C 428 CH, jl L-phenylalanine - CH- the same the same CH ₂ C ₆ H ₅ 4th O-acetyl-L-serine - CH- the same the same 5 CH ₂ OCOCH, L-leucine - CH- the same the same 6th L-methtonine ( the same the same ZH ₂ CH (CHj) ₂ 7th L-tyrosine (CH ₂ ) JSCHj the same the same - CH-
I. 8th DL-phenylalanine CH ₂ C ₆ H ₄ OH the same the same 9 - CH- Glycylglycine CH ₂ C ₆ Hs the same the same L-alanyl-L-alanine -CH ₂ -CO-NH-CH ₂ - the same the same - CH- CO - NH- CH- CHj CHj

In the main chain of the polymer
built-in amino acid
or incorporated peptide R, R, R. 1-" the same continuation j 5 the same. j ^ No. of
link L-phenylalanyl-L-phenylalanine - CH-CO —NH-CH- - (CHj) ₆ - [- (CHj) ₄ -OJ ₁₄ N)
OO the same I. CHjC ₆ H, CH ₂ C ₆ H ₅ 10 L-phenylalanyl-O-acetyl-L-serine - CH-CO —NH-CH- the same the same CH ₂ C ₆ H ₅ CHjOCOCH ₃ 11th L-phenylalanylglycine - CH- CO - NH- CH ₂ - the same the same CH ₂ C ₆ H ₅ 12th L-alanyl-L-phenylalanylglycine - CH-CO -NH-CH-CO -NH-CHj the same CH ₃ CH ₂ C ₆ H ₅ ^ 13 L-alanine - CH- -C ₆ H ₄ -CH ₂ -C ₆ H ₄ - CH, 14th L-phenylalanine - CH- the same 15th

L-serine

O-acetyl-L-serine

CH ₂ C ₆ H ₅

- CH-CHjOH

- CH-CH ₂ OCOCH ₃

the same

the same

the same

the same

continuation No. of In the main chain of the polymer

Compound built-in amino acid or built-in peptide

L-alanyl-L-alanine

- (CH ₂ J ₆ -

the same

the same

—CH-CO —NH-CH-

CH, CH ₃

L-phenylalanyl-L-phenylalanine —CH-CO —NH-CH-

CH ₂ C ₆ H ₅ CH ₂ C ₆ H ₅

L-phenylalanylglycine -CH-CO-NH-CH ₂ -

C H2C6H5 L-Alanyl-L-phenylalanylglycine -CH-CO-NH-CH-CO-NH-Ch ₂ - desgl.

L-phenylalanine - CH- - (CH ₂ J ₆ -

CH ₂ C ₆ H ₅ [- I,), - O—] ₁₄

desal.

the same

the same

[- (CH ₂ ) - O-h

The compounds listed are white, in flake or powder form, are in dimethylformamide, Dimethyl sulfoxide, Phosphosüurehexamethylamin, also in mixtures of these solvents with dioxane or F. acetic acid ethyl ester in the ratio I: I and soluble in pyridine and m-Crcsol. These swell in water Connections by 4 to 12%.

The chemico-physical properties of the compounds mentioned are given in Table 2.

Table 2 1 Sehmelxtempcralur-
berrcich, ⁰ C (iren / .viskositül
ι, in dl / g Molecular mass c
M, Polymcrisa-
degree η No. of
link
corresponding
Tab. I. 2 2 t 4th 5 I. 3 143-152 0.33 17 200 ! 2 4th 106-130 0.30 15,000 10 5 98-120 0.34 17 900 12th 6th 88-100 0.34 17 900 12th 7th 97-115 0.33 17 200 12th 8th 192-198 0.31 15 700 10 9 136-182 0.36 19 500 13th 10 205-220 0.27 12 900 9 Ii 193-197 0.35 18 700 12th 12th 167-171 0.22 9 600 6th 13th 115-141 0.25 11 600 7th 14th 112-146 0.57 37 500 24 15th 164-176 0.35 18 700 Il 16 195-201 0.31 15 700 10 17th 138-140 0.40 22 600 14th 18th 210-220 0.40 22 600 14th 19th 208-216 0.42 24 300 15th 20th 225-238 0.34 17 900 11th 21 200-201 0.38 21,000 12th 22nd 160-161 0.33 I7 2OO 10 166-167 0.22 9 600 5 140-142 0.50 31 100 15th

Note to Table 2

The basic viscosity I ₁ was determined in dimethylformamide solutions of the polymer at a temperature of 25 ° C. and at concentrations of 0.4 to 1.0% by weight.
The molecular mass M _{111 of} the specified compounds was calculated using the following formula:

= 3.58-10

1 (1.7

50

The frequencies of the! R spectrum of the specified polyurelhanocarbamidoacylsemicarba / ide in the range of 3800 cm 'to 700 cm' are listed in Table 3.

Table 3

No. of Stretching vibrations the O-C-O- the C = O- the C = O- the NH- Deforma Level defor- link Binding of Binding of Binding of Binding of motion speed mational correspond the ether Urethane, Urethane, Urea, Urclhans. the Schwin- corresponding binding. cm-' cm"' cm ¹ cm ' Urethane of the Tab. 1 cm " ¹ binding. Benzene ring, C-O j 4th 5 NH- cm " ¹ cm · ' I. 1 7th

1 1115 1250 1725 1660 1540 3320 2 1115 1250 1710 1660 1540 3320 1720

60

65

Vulon /. Curvatures the O -C-O- 31 14 428 Mumsloir, the nil- Deforma I. Level defor- I. continuation Binding des cm ¹ Binding of motion speed mational No. of the Alher lircthuns. Urclhans, the Schwin- link binding. cm ' S. cm ' Urethane of the 5 correspond cm ' the C = O- the C-O- binding, Bcnz.olrings, corresponding C-O Binding of ι, NH- cm " ¹ Tab. 1 Urethane, cm ' cm ' 7th IU, 4th

25th

40

45

50

3 1115 1250 1710
1720 1660 1540 3320 - 4th 1115 1250 1710
1720 1660 1540 3310 - 5 1115 1250 1710 1660 1540 3335 - 6th 1115 1250 1710
1720 1660 1540 3330 - 7th 1115 1250 1710
1720 1660 1540 3320 - 8th 1120 1255 1710
1720 1660 1570 3320
3340 - 9 1120 1255 1720 1665 1570 3325 - 10 1120 1255 1710
1720 1650 1570 3300 - 11th 1125 1250 1725 1660 1570 3330 - 12th 1120 1250 1720 1660 1570 3325
3340 - 13th 1115 1260 1705
1720 1660 1550 3280
3310 1600
1610 14th 1115 1230 1705
1725 1660 1540
1550 3300 1605 15th 1115 1225 1705
1730 1660 1540
1550 3300 1605 16 1115 1225 1730 1660 1540
1550 3300 1605 17th 1115 1230 1710
1730 1660 1550 3300 1605 18th 1120 1230 1730 1660 1550 3300 1605 19th 1115 1230 1705
1725 1660 1540
1550 3300 1605 20th 1115 1230 1730 1660 1540
1550 3300 1600 21 1115 1225 1710
1725 1660 1545
1555 3300 _ 22nd 1115 1250 1720 5 660 1560 3320

The mechanical properties of the specified Polyurethanocarbamidoacylsemicarbazide are in 55 Table 4 listed.

h0

65

Table 4 Tensile strength wedge Relative deformation, 200 Modulus of elasticity, Connection number N ■ in - · 10 ^h % 140 Nm ' ² x 10 " according to Tab. I. 5.70 890 5.35 1 5.57 440 5.44 2 7.39 170 3.33 3 2.17 2.04 4th 1.46 1.35 5

continuation

No. of the connection a ZerrciBfcsügkeil Relative deformation. 180 ! üasti / itätsmodul. according to Tab. 1 N ■ m - · 10 " % 720 Nm -10 * 6th 3.64 150 3.46 7th 4.25 120 1.81 8th 5.88 130 5.62 9 8.64 390 8.35 10 5.96 140 5.55 U 4.79 1280 3.70 12th 3.67 980 3.44 13th 7.87 1340 4.39 54 11.89 1570 5.65 15th 11.13 1040 3.53 16 21.12 633 5.39 17th 14.57 1150 7.28 18th 15.09 800 8.49 19th 16.04 330 6.89 20th 13.17 760 6, Ό 21 4.34 2.81 22nd 3.59 2.89

Note to Table 4

Samples of the specified compounds were tested using generally customary methodologies (See D. F. Williams, P. Rouf "Implantaly w chirurgii", Verlag "Medizina", Moscow, 1978, pages 68-71, 74-75).

To determine the stress, the relative deformation and the modulus of elasticity, the test samples, which represented pieces of film with the dimensions 30 x 4 x 0.3 mm, were tested mechanically in a tear machine at a tear speed of 10 mm / min.

The polymeric film was prepared from the 20prozcntigcn pimcthylformamidlösungcn Polyurethancarbamidoacylsemicarbazide indicated by evaporating the solvent at 40-60 ⁰ C and a pressure of 6-10 h Pa (hectopascals) on a polished Fluorpolymeruntcrlage over the course of 6 to 8 hours made.

The specified compounds can be produced by protein-splitting enzymes or in the living organism are biodegradable.

The enzymes trypsin and chymotrypsin were selected to investigate the peculiarities of the effect of protein-cleaving enzymes on the stated polyurethaneocarbamidoacylsemicarbazides.

Two polyurethaneocarbamidoacylsemicarbazides were selected as test substances which were subjected to the action of the enzymes mentioned. One polyurethane contains the dipeptide in the main chain Glycylglycine, the other the dipeptide L-phenylalanine-O-acelyl-L-serine.

The polymers mentioned were ground in a ball mill at the temperature of liquid nitrogen. Comparative measurements of the viscosity of the polymers mentioned showed no changes during exposure lower temperatures on the polymers.

The ground polymers were placed in two cans for each polymer. The initial weight was in each can I g. Then the polymers were mixed with 25 ml of 0.005% Irish-prepared trypsin or chymotrypsin solution which, by adding phosphate buffer, had a pH of 7.8. The samples were kept in a thermostat at 37 ° C. Twice a day at intervals of 12 hours the Solutions of the enzymes mentioned renewed. The experiment lasted 14 days. After that, the basic viscosity became of the polymers treated with enzymes as described above.

The results of the determination of the viscosity of the polymers mentioned, the molecular masses calculated according to this and the degree of polymerization are shown in Table 5.

.10 40

55

Table p

Influence of solutions of protein-splitting enzymes on the change in the basic viscosity> /, on the molecular mass M _m and the degree of polymerization η of the tested polyurethanes.

enzyme Dipeptide in the main polymer chain
L-phenylalanyl-O-acctyl-L-scrin
I ₁ in dl / g M " η 11500 7
7 200 4 Glycylglycine
ι / in dl / g M " π Trypsin
Chymotrypsin 0.25
0.18 0.26
0.27 12 200
12 900 8th
9

As can be seen from Table 5, the chymotrypsin solution has a noticeable effect on the reduction of the Molecular weight of the polyurethane which contains L-phenylalanyl-O-accyl-L-serine in the main polymer chain. This is fully consistent with the specific effects of chymotrypsin on aromatic amino acid containing substrates. Chymotrypsin primarily splits Pcptidbindungen, which through the carboxyl group aromatic natural e-L-amino acids are formed.

On the other hand , the effect of the described trypsin solution on this polymer is small because this enzyme primarily cleaves peptide bonds which are formed by the carboxyl group of lysine or arginine, and therefore does not act specifically on this polymer.

For the same reason, the influence of the specified trypsin and chymotrypsin solutions on the polymers containing glycylglycine in the main chain is small. For comparison, the effect of phosphate buffer solutions with pH values of 4.0; 7.8; 8.0 on foils made from Polyurethanocarbamidoacylsemicarbaziden im Examined over a period of 3 months with daily renewal of the buffer solutions. This experiment did not lead to any changes in the samples tested. It is also known that the action of protein-splitting enzymes on polyurethanes, which do not contain any labile links such as peptides or amino acids in the main polymer chain, do not lead to hydrolytic cleavage (see T. E. Lipatowa, G. A. Pchakadse, Primenentje polymerow w chirurgii ", Kiev, publishing house" Naukowa Dumka ", 1977, pages 60-61).

The biological degradation of the specified polyurethanes in the living organism was tested with Chinchilla rabbits weighing 2-3 kg studied.

The sample - pieces of film with the dimensions 20 x 10 x 0.3 mm, which are made as described above were - implanted under the skin of rabbits. In each test series (for each polymer sample) 12 animals were used. After implantation, the animals were after one week, two weeks, one Month and three months removed from the test series (three Rabbit removed). The implant and the surrounding tissue were removed and placed in 10 percent, fixed to neutral formalin. After fixation, tissue sections 10-12 μm thick were stained with hematoxylinposin. Under the microscope was the morphological response of the tissues to the implanted Pattern determined by the Van Gieson method. The tissues responded moderately to the implantation developed, germ-free inflammation, which subsided over the course of two weeks to a month. That testifies of the fact that the tested polymer implants have no tissue-sealing properties.

The intrinsic viscosity of the samples implanted in the test animals was determined based on them then the molecular weights and degree of polymerisation of the polymers were calculated. These results are listed in Table 6.

Table 6

Effect of the living organism of test animals on the change in the basic viscosity »/, the molecular mass M _m and the degree of polymerization η of the polyurethanes according to the invention.

No. of Duration of the implantation sample after 2 weeks sample after a month sample after 3 Months Connect manure Initial sample '; dl / g M _n , η ., dl / g M _m π ., dl / g M " η correspond corresponding ι, dl / g M _n , η Tab. 1

11 0.25 11 500 7 0.25 11 500

8 0.27 12 900 9 0.25 11900

2 0.30 15,000 10 0.24 10 900

3 0.340 17 900 12 0.30 14 700

7 0.15 5 500 4

8 0.220 9 600 7
7 0.230 10 200 7

IO 0.280 13 200 9

0.130 4,500 3

0.210 9 000 6

0.220 9 600 6

0.240 11 000 7

Comment on Tubelle 6

For the rest of the specified connections, the specified characteristics decrease with analogous to the increasing duration of the implantation of synthetic implants. As can be seen from Table 6, the molecular mass of the tested polyurethaneocarbamidoacylsemicarba-

duration of implantation No. of the connection according to Tab. I. relative Elasticity 8th relative Elasticity 11th deformation module Tear deformation module Shredding % N m ^} strength % N-m ' ² fesligkcit 390 3.70 Nm ² 150 5.62 N m ' ² 150 3.34 5.88 - - Initial sample 4.75 130 3.18 - - - 1 week 3.52 100 2.94 - 50 - 2 weeks 3.36 150 _ 3.62 was destroyed 1 month 3.04 The sample 3 months 2.80

zide noticeably with increasing length of stay of the synthetic'implants in the animal organism. That testifies to the biological degradation processes of the samples mentioned.

It should be added that the biodegradation of the specified Polyurcthanocarbamidoacylscmicarbazide runs at different speeds.

That depends on the type of amino acids or peptides in the main chain of the poly and on the spectrum of enzymes that act on the synthetic implants in the biological object.

The degradation of the specified compounds in the living organism is also confirmed by the electron microscope examination of the morphology of the compounds according to the invention.

The listed polymer samples were mechanically tensioned after implantation in test animals, relative deformation and modulus of elasticity checked.

The results of the tests mentioned are listed in Table 7. Table 7

From Table 7 it can be seen that the mechanical parameters produced from the specified polymers :> o Implants decrease with increasing length of stay in the organism of the test animals, which is evidence of their biological degradation. It is believed that the marked reduction in the relative deformation of the test specimens is related to the decrease in the molecular mass of the specified polymers and consequently with the decrease in the dimensions of the macromolecules, which reduces the elasticity of the latter and, at the same time, the elasticity of the test specimen.

To compare the biological degradation of the specified polymers under the action of protein-splitting Enzymes and in the living organism were the IR spectra of those treated with trypsin and chymotrypsin Samples as well as the IR spectra of the samples implanted in the rabbits were determined.

The IR spectral analysis of the compounds mentioned was carried out in the absorption range from 3800 to 700 cm " ¹ .

When comparing the IR spectra of the polymer samples listed, certain differences in the change in intensity of the absorption band of the carbony group were found in the range from 1620 to 1720 cm " ^1. The quantitative calculation of the absorption bands in the range from 1750 to 1600 cm" was carried out according to the method with "internal standard" taking into account the half-height range of the bands and the scattering through the sample pattern.

The band of CH stretching vibrations was selected as the “internal standard”. The relative absorption intensity of the carbonyl groups R was determined as the ratio of the optical density of the examined band to the optical density of the CH stretching vibrations.

The values of the relative absorption intensity of the carbonyl groups are shown in Table 8. Table 8

Influence of aqueous solutions of protein-splitting enzymes and of the living organism on the relative absorption intensity of the carbonyl groups of the polyurethaneocarbamidoacylsemicarbazides investigated

Type of to the number of the connection according to Tab. I.

Connections of the acting medium 11 K

RR R RRR

1720 cm ■ '1660 cm' 1720 cm '1660 cm' 1640 cm '1620 cm' _{6 (1}

Starting compound 2.5 1.74 1.92 1.51 1.29 1.14 Water Trypsin solution 2.5 1.75 2.01 1.56 1.38 1.12 Water Chymotrypsin 2.46 1.4S 1.92 1.56 1.27 1.15 ^

continuation . No. of the release indication according to Tab. 1 8th R. R. R. Kind of on the R. 1660 cm ' 1640 cm " ¹ 1620 cm " ¹ Connections a P. 1720 cm ' acting medium R. K 1720 cm ' 1660 cm ' In the organism of 1.54 1.23 1.12 Guinea pigs 2.Ü1 1.54 1.12 1.0 after 2.48 1.70 2.0 1.46 1.06 0.87 2 weeks 1.08 1.50 1.8 one month 1.39 1.21 3 months 6 months

As can be seen from Table 8, the effect of chymotrypsin on the polyurethane, which is in the polymer main chain Contains L-phenylalanyl-O-acetyl-L-serine, due to a decrease in the relative absorption intensity of the carbonyl groups in the range of 1660 cm ', which corresponds to the range of the stretching vibrations of the Amide groups (of the peptide bond) corresponds (cf. Infrared Absorption Spectra Hydrazides. IV. Some Monoaeid Hydrazides, M. Mashima. Bull. Chem. Soc. Japan, 35, 1882-1889, 1962).

When trypsin acts on the L-phenylalanyl-O-acetyl-L-serine contained in the main polymer chain Polyurethane did not change its IR spectrum.

The same applies to the action of trypsin and chymotrypsin on a glycylglycine in the main polymer chain containing polyurethane.

The values contained are in full agreement with the specific effect of the enzymes mentioned on substrates. -M) and correspond to the measured values of the characteristic viscosity of these polymer samples.

As can be seen from Table 8, L-phenylalanyl-O-acetyl-L-serine is used for the polyurethane that is in the main polymer chain contains, manufactured synthetic implants after implantation in test animals for different Periods of time a decrease in the relative absorption intensity in the region of the 1660 cm "'band (Peptide bond) and the 1720 cm 'band (urethane bond), which is characteristic of the splitting of the peptide or urethane bond.

After implantation for different periods of time in test animals, the synthetic implant, which contained glycylglycine in the polyurethane main chain, a decrease in the absorption intensity in the Area of the 1620 cm '' band (semicarbazide bond) and the 1640 cm '' band (peptide bond) observed, which corresponds to the splitting of the semicarbazide and peptide bonds (see Infrared Absorption Spectra Hydrazides. IV. Some Monoacid Hydrazides, M. Mashima. Bull. Chem. Soc. Japan, 35, 1882-1889, 1962).

The decrease in the absorption intensity of the latter polymer in the region of the 1720 cm 'band (urethane bond) and the 1660 cm 'band (peptide bond) is less pronounced than that of the polyurethane contained in the Polymer backbone contains L-phenylalanyl-O-acetyl-L-serine.

It should be pointed out that in the IR spectrum of the polyurethane with L-phenylalanyl-O-acetyl-L-serine in the Polymer backbone the 1620 cm 'band is absent, which is believed to be due to the intramolecular interaction the esterified hydroxyl group of serine and the hydrazine grouping.

On the basis of the cited results, one can conclude that the biological degradation of the cited compounds takes place primarily through enzymatic hydrolysis of the peptide bonds.

Synthetic implants with temporary effect in direct contact with the blood must be a prerequisite that they do not cause thrombosis during their use.

It became the influence of the polyurethane with L-phenylalanyl-O-aetyl-L-serine and of the polyurethane with L-phenylalanine examined for blood coagulation in the main polymer chain. The influence of the polyurethanes mentioned Blood coagulation was assessed using the prothrombin index.

In the following, a method for determining the prothrombin value is given, which is a modification the well-known Lindholm method.

In order to apply this methodology, an institute for micromolecular chemistry at the Academy of Sciences device created by the CSSR (see J. Drobnik, M. Stol, J. Dvorakova, J. KaIaI and Z. Vozlova, Thrombogenicity of alloplastic materials: in vitro testing in a planeravcd chamber (17th microsymposium of makromoleculy Medical Polymers, Prague, 63, 1977)). The device consists of a tube for the liquid supply and sectis removable containers, which are provided with shut-off nozzles with connected to the tube mentioned.

A linden of the named tube is used to connect to the blood donor. The other is with one Provide a shut-off device and serve / to control the oil process of the device. All metal parts of the device are covered with silicone rubber.

h> 18 hours before the start of the experiment, the samples to be tested were placed in the containers. After that it was the device is filled with Ringerscher's solution.

Immediately before the start of the experiment, the device was connected to the blood donor. The donor blood entered the container and displaced clabui the Ringerschc solution from the device. After filling the container

these were removed and kept at a temperature of 37 ° C. for 4 hours. The blood was then centrifuged and the serum obtained was used for further investigations. The serum was placed in test tubes with a polypropylene syringe and centrifuged at 2000 rpm. The liquid above the sediment was cooled with ice and used again. The liquid used further contained 0.1 ml of serum and 0.1 ml of tissue thromboplastin. This mixture was kept for 1 min at 37 ^° C. and then 0.2 ml of prothrombin-free blood plasma was added. The time until / around the appearance of the first fibrin thread was determined, which is referred to as the prothrombin time or prothrombin index. The lower the prothrombin index, the less the material affects blood coagulation.

Comparative tests were carried out using the following test material: glass as Thrombogenic material, and glass coated with a mixed polymer of methacrylamide and 2-Hydroxypropylaerylamide, as a non-thrombotic material.

The results of the determination of the prothrombin index are listed in Table 9.

Table 9

No. Type of material tested Λη / uhl der Prothroma try binindex in Seconds I. 2 .1 1 Polyurethanocarbamidoaeylsemi- 3 37.8 ± 1.6 carbazid No. 11 according to Tab. 1 2 Polyurethanocarbamidoaeylsemi- 3 45.3 ± 3.8 carbazid No. 2 according to Tab. 1 3 Glass 6th 180 4th Mixed polymer made from methacrylamide 6th 31.4 ± 2.5 and 2-hydroxypropyl acrylamide

The specified polyurethanes are in the reaction of a prepolymer whose molecules at least carry two isocyanate groups, with an amino acid hydrazide or a hydrazide of a peptide in solution obtained at an equimolar ratio of the starting materials and a temperature of 20 to 25 ° C.

The procedure is carried out as follows.

Hydrazides of amino acids or peptides are used as starting materials.

These compounds are prepared from hydrazides of N-carbobenzoxyamino acids and hydrazides of N-carbobenzoxypeptides by cleavage of the N-carbobene / oxy groups by normal hydrogen bromide solution in anhydrous acetic acid. The hydrazides can also be prepared differently, namely by reacting hydrazine with N-trifluoroacetylamino acid ester. In this way, the hydrazides of ^ -leucine and α- valine were obtained with yields of 15-40% (see, for example, F Wcygand, W. Swodenk, N-TFA amino acid hydrazides from the methyl esters and diketopipcrazine formation from N-TFA dipeptide methyl esters with Hydrazin. Chem. Ber., 93, 1693-1696, 1960).

In addition, a dichlorohydral of a triglycine hydrazide is known (K. Hofmann, A. Lindenmann, M. Z. Magee, N. H. Khan. Studies on Polypeptides. 111 Novel Routes to σ-Aminoacid and Polypeptide Hydrazides. J. At the. Chem. Soc, 470-475, 1952), which starting from a hydrazide of N-carbobenzoxytriglycine by removing the N-carbobenzoxy group is produced by means of hydrogen over a palladium catalyst, however with higher costs of the hydrazide to be produced.

The inventive method for the preparation of hydrazides of amino acids and peptides by Treatment of the hydrazides of N-carbobenzoxyamino acids and of peptides with hydrogen bromide ^ acetic acid has the advantages of a high yield of 95-100% and a simple one over the prior art Procedural conduct on.

The process for producing the polyurethanes according to the invention is carried out as follows: The hydrazide will be solved. Dimethylformamide, hexamethylformamide or dimethyl sulfoxide can be used as the solvent will. A mixture of these solvents with dioxane or ethyl acetate in a ratio of 1: 1 is also applicable. The solution of the hydrazide of the amino acid or of the peptide in one of the specified Solvent is prepared as follows.

The dibromohydrate of the hydrazide of the amino acid or of the peptide (0.1-0.2 mol) is in 20-30 ml of one of the Solvent specified solvent Triethylamine (0.2-0.4 mol) is used as the acceptor of the hydrogen bromide given. The precipitate of triethylamine bromide is filtered off and 15-20 ml of the used Solvent washed. The resulting solution of the amino acid or peptide hydrazide is added dropwise while mixing the prepolymer solution in the same solvent (80-160 ml) added. The temperature should be the reaction mixture in the range of 20 to 25 ° €.

For the production of the specified polyurethanes prepolymers can be used:

- based on polyoxytetramethylene glycol with a molecular mass of 1000 and hexamethylene diisocyanate or diphenylmethane diisocyanate;

- on the basis of polyoxyletramethylene glycol with a molecular mass of 1500 and hexamethylene diisocyanate.

13th

The prepolymers are obtained from the reaction of compounds containing hydroxyl groups (simple polyethers) and diisocyanates in a molar ratio of 1: 2 to 70 ^° C. under a moisture-free atmosphere. The completion of the reaction is determined by checking whether the content of isocyanate groups in the prepolymer corresponds to the theoretical value.

The isocyanate group content of the reaction mixture is determined by the method of S. Stagg (p. Stagg. Analyst, 71, 5571, 1946). This method is based on the reaction of the sample (weight 0.1-0.2 g) with an excess of a 0.1 normal solution of an aliphatic amine in toluene or chlorobenzene. The excess the amine is titrated with an aqueous 0.1 normal hydrochloric acid solution. The percentage of isocyanate groups of the prepolymer is determined using the following formula:

_% NCO - 0-

g where the following applies:

Ki - volume of 0.1 η hydrochloric acid, titrating the aliquot of the 0.1 η solution of the aliphatic Amine is needed in toluene, ml;

V \ - volume of 0.1 η hydrochloric acid which is used to titrate the aliquot amount of the 0.1 η solution of the aliphatic amine in toluene with the weight of the sample to be analyzed dissolved in it, ml;

g - weight of the sample to be analyzed, g.

The polyurethaneocarbamidoacylsemicarbazide solution obtained is kept under the above-mentioned conditions for 18 hours. Then it is poured into a vessel with cold water with constant mixing. The end product is in the form of white crumbs or flakes. The precipitated end product is filtered off, then washed with water until there is no odor of solvent and ^{dried at 40 °} C. until the mass is constant.

The yield of the end product is 90.1-97.9%.

In this way, polyurethanes were produced, which are natural links in the main polymer chain Contain compounds (o-L-amino acids and peptides). Such hybrid polymers are specifically by protein-splitting enzymes and tissue cathepsins are broken down.

In the presence of a selection of the specified polyurethanes with certain speeds of the biological degradation it is possible by mechanical mixing in certain proportions a precise control of the biodegradation of synthetic implants on the basis of the proposed To achieve polyurethanes taking into account the enzyme spectrum of the tissues.

For a better understanding of the invention, the following illustration examples of the specified compounds are provided specified.

example 1

The polyurethaneocarbamidoacyl semi-arbazide No. 1 shown in Table 1 was made as follows in accordance with the invention obtain.

1.35 g (0.00505 niol) of L-alanine hydra / .iddihydrobromide were dissolved in 10 ml of dimethylformamide.

1.41 ml (0.0101 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained L-alanine hydrazide solution was added dropwise with mixing into a solution of 6.75 g (0.00505 mol) of a prepolymer in 40 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate made in 40 ml of dimethylformamide.

The reaction mixture thus prepared was allowed to stand for 18 hours.

It was then placed in a vessel with 0.6 l of cold water with constant mixing.

The end product was precipitated in the form of white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the final product was 6.5 g (91.2%).

Example 2

The polyurethaneocarbamidoacylsemicarbazide No. 2 according to Table 1 was made according to the invention as follows obtain.

3.51 g (0.0103 mol) of L-phenylalanine hydrohromide were dissolved in 25 ml of dimethylformamide. 2.88 ml (0.0206 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 15 ml of dimethylformamide washed.

The obtained L-phenylalanine hydrazide solution was added dropwise with mixing into a solution of 13.82 g (0.0103 mol) of a prepolymer in 75 ml of dimethylformamide. The prepolymer was made from polyoxyttramethylene glycol with a molecular mass of 1000 and from hexa-

14th

methylene diisocyanate produced.

The rejection mixture prepared in this way was left to stand for 18 hours.

It was then placed in a vessel with 1.0 l of cold water with constant mixing.

The end product was precipitated in the form of white flakes.

The completed final product was abfillriert, formamide washed with water to / by the disappearance of the odor of dimethyl 5 and to Massekonslanz at a temperature of 40 ⁰ C dried.

The yield of the final product was 14.5 g (92.5%).

Example 3

The polyurethaneocarbamidoacylsemicarba / .id no. 3 according to Table 1 was according to the invention as follows obtain.

7.31 g (0.0248 mol) of O-acetyl-L-serine hydra / .iddihydrobromide were dissolved in 25 ml of dimethylformamide.

6.92 ml (0.0496 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and 15 ml of dimethylformamide 15 washed.

The obtained O-acetyl-L-scrinhydrazide solution was added dropwise with mixing into a solution of 33.18 g (0.0248 mol) of a prepolymer in 120 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate manufactured. 20th

The reaction mixture prepared in this way was left to stand for 18 hours.

It was then placed in a jar with 1.5 liters of cold water with constant mixing.

The end product was filled in in the form of white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor had disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.} 25th

The yield of the final product was 32.8 g (90.1%).

Example 4

The Polyurethanocarbamidoacylsemicarbuzid No. 4 according to Table 1 was according to the invention as follows- M) so received.

3.08 g (0.01 mol) of L-leucine hydrazide dihydrobromide was dissolved in 20 ml of dimethylformamide.

2.78 ml (0.02 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed. 35

The obtained L-leucine hydrazide solution was added dropwise with mixing into a solution of 13.36 g (0.01 mol) of a prepolymer in 70 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate manufactured.

The reaction mixture thus prepared was left to stand for 18 hours. 40

It was then placed in a vessel with 1.0 l of cold water with constant mixing.

The end product of white flakes was filled in.

The precipitated end product was filtered off, washed with water until the odor of dimethylformamide had disappeared and dried ^{at a temperature of 40 ° C. until it was solid.}

The yield of the final product was 13.4 g (90.4%). 45

Example 5

The polyurethaneocarbamidoacyl semicarbazide No. 5 according to Table 1 was made as follows in accordance with the invention obtain. 50

6.80 g (0.02 mol) of L-methionine hydrazide dihydrobromide were dissolved in 25 ml of dimethylformamide.

5.56 ml (0.0400 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 15 ml of dimethylformamide washed.

The obtained L-methionine hydrazide solution was added dropwise with mixing into a solution of 26.72 g of 55 (0.02 mol) of a prepolymer in 130 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate manufactured.

The reaction mixture thus prepared was left to stand for 18 hours.

It was then placed in a vessel containing 1.5 liters of cold water, with constant mixing. 60

The end product was filled in in the form of white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the final product was 28.8 g (93.2%).

Example 6
The Polyurethanqcarbamidoacylsemicarbazid No. 6 according to Table 1 was according to the invention as follows

15th

so received.

1.85 g (0.00518 mol) of L-tyrosine hydrazide dihydrobromide was dissolved in 15 ml of dimethylformamide.

1.44 ml (0.01036 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained L-tyrosine hydrazide solution was added dropwise with mixing into a solution of 6.97 g (0.00518 mol) of a prepolymer in 55 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate.
K) The reaction mixture prepared in this way was left to stand for 18 hours.

It was then placed in a vessel with 1.0 l of cold water with constant mixing.

The end product was precipitated in the form of white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.} The yield of the end product was 6.8 g (90.5%).

Example 7

The polyurethaneocarbamidoacyl semi-arbazide no. 7 according to Table I was made according to the invention as follows obtain.

3.58 g (0.02 mol) of DL-phenylalanine hydrazide were dissolved in 50 ml of dimethylformamide.

The resulting solution was added dropwise with mixing into a solution of 26.72 g (0.02 mol) of a prepolymer given in 100 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate manufactured.

The reaction mixture thus prepared was left to stand for 18 hours.

It was then placed in a vessel containing 1.5 liters of cold water, with constant mixing.

The end product of white flakes was precipitated.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the final product was 18.9 g (95.3%).

Example 8

The polyurethaneocarbamidoacylsemicarbazide No. 8 shown in Table 1 was made as follows in accordance with the invention obtain.

6.12 g (0.02 mol) of glycylglycine hydra / iddihydrobromide were dissolved in 25 ml of dimethylformamide. 5.54 ml (0.04 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 25 ml of dimethylformamide washed.

The obtained L-alanine hydrazide solution was added dropwise with mixing into a solution of 26.72 g (0.02 mol) of a prepolymer in 70 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate manufactured.

The reaction mixture thus prepared was left to stand for 18 hours. It was then placed in a vessel with 1.5 l of cold water with constant mixing. The end product was precipitated in the form of white crumbs.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor had disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.} The yield of the final product was 27.7 g (93.0%).

Example 9

The polyurethaneocarbamidoacylsicarbazide No. 9 shown in Table 1 was made as follows in accordance with the invention obtain.

8.81 g (0.0263 mol) of L-alanyl-L-alanine hydrazide dihydrobromide were dissolved in 25 ml of dimethylformamide. 7.28 ml (0.0526 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the triethylamine hydrobromide which had precipitated was filtered off and mixed with 15 ml of dimethylformamide washed.

M) The obtained L-alanyl-L-alanine hydrazide solution was added dropwise with mixing into a solution of 35.0 g (0.0263 mol) of a prepolymer in 200 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate manufactured.

The reaction mixture thus prepared was left to stand for 18 hours. It was then placed in a vessel with 2.0 liters of cold water with constant mixing. The end product was filled in in the form of white crumbs.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

16

The yield of the final product was 36.4 g (92.0%). Example 10

The polyurethaneocarbamidoacyisemicarbazide No. 10 shown in Table 1 was obtained according to the following earth method.

13.39 g (0.0266 mol) of L-phenylalanyl-L-phenylalanine hydrazide dihydrobromide were dissolved in 25 ml of dimethylformamide

7.65 ml (0.0532 mol) of triethylamine were added to the resulting solution.

After 15 min, the precipitated triethylamine hydrobromide was filtered off and washed with 20 ml of dimethylformamide washed.

The obtained L-phenylalanyl-L-phenylalanine hydrazide solution was added dropwise with mixing into a Given a solution of 37.0 g (0.0266 mol) of a prepolymer in 130 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate

The reaction mixture thus prepared was left to stand for 18 hours. It was then placed in a jar of 2.0 liters of cold water with constant mixing. The end product was precipitated in the form of white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the final product was 43.5 g (97.9%). Example Il

The polyurethaneocarbamidoacylsemicarbazide No. 11 shown in Table I was obtained according to the invention as follows.

17.71 g (0.0396 mol) of L-phenylalanyl-O-acetyl-L-serine hydrazide dihydrobromide were dissolved in 30 ml of dimethylformamide

11.0 ml (0.0792 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and treated with 20 ml of dimethylformamide 3 « washed.

The obtained L-phenylalanyl-O-acetyl-L-serine hydrazide solution was added dropwise with mixing into a Given a solution of 53.0 g (0.0396 mol) of a prepolymer in 270 ml of dimethylformamide.

The prepolymer was prepared from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate.

The reaction mixture thus prepared was left to stand for 18 hours. It was then placed in a vessel with 3.0 l of cold water with constant mixing. The end product of white crumbs was precipitated.

The precipitated end product was filtered off, washed with water until the odor of dimethylformamide and to constant weight at a temperature of 4O ⁰ C dried. -40

The yield of the final product was 55.8 g (91.2%). Example 12

The polyurethaneocarbamidoacylsemicarbazide No. 12 according to Table I was obtained according to the invention as follows.

2.11 g (0.00532 mol) of L-phenylalanyl glyein hydrazide dihydrobromide were dissolved in 15 ml of dimethylformamide.

1.48 ml (0.01064 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained L-phenylalanylglycine hydrazide solution was dropwise into a solution with mixing 7.11 g (0.00532 mol) of a prepolymer were placed in 65 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylcnglycol with a molecular weight of 1000 and from hexamethylene diisocyanate.

The reaction mixture thus prepared was left to stand for 18 hours. It was then placed in a basin with 1.0 L of cold water with constant mixing. The end product was precipitated in the form of white crumbs.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the final product was 7.6 g (91.6%). Example 13

The polyurethaneocarbamidoacylsemicarbazide No. 13 according to Table I was obtained according to the invention as follows.

2.35 g (0.005 mol) of L-alanyl-L-phenylalanylglycine hydrazide dihydrobromide were dissolved in 20 ml of dimethylformamide.

17th

1.39 m! (0.01 mo!) Triethylamine added.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained L-alanyl-L-phenylalanylglycine hydrazide solution was added dropwise with mixing into a Solution of 6.68 g (0.05 mol) of a prepolymer in 40 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from hexamethylene diisocyanate

The reaction mixture thus prepared was left to stand for 18 hours.

After that, it was placed in a gel with OJI cold water with constant mixing. The end product was precipitated in the form of white crumbs.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the final product was 8.2 g (99.3%).

15 Example 14

The polyurethaneocarbamidoacylsemicarbazide No. 14 according to Table 1 was obtained according to the invention as follows.

0.80 g (0.003 mol) of L-alanine hydrazide dihydrobromide were dissolved in 20 ml of dimethylformamide which had been freshly distilled over.

0.84 ml (0.006 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained L-alanine hydrazide solution was added dropwise over 30 minutes at 25 ° C with mixing in added a solution of 4.50 g (0.003 mol) of a prepolymer in 30 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from diphenylmethane diisocyanate.

The reaction mixture thus prepared was allowed to stand for 12 hours. It was then placed in a vessel with 0.6 l of cold water with constant mixing. The end product was precipitated in the form of large white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.} The yield of the final product was 4.4 g (91.54).

35 Example 15

The polyurethaneocarbamidoacylsicarbazide No. 15 according to Table 1 was obtained according to the invention as follows.

6.60 g (0.0193 mol) of L-phenylalanine hycirozide dihydrobromide were dissolved in 50 ml of dimethylformamide. 5.36 ml (0.0386 mol) of triethylamine were added to the resulting solution.

After 10 minutes the precipitated triethylamine hydrobromide was filtered off and mixed with 25 ml of dimethylformamide washed.

The obtained L-phenylalanine hydrazide solution was added dropwise with mixing into a solution of 28.95 g (0.0193 mol) of a prepolymer in 100 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from dimethylmethane diisocyanate.

The reaction mixture thus prepared was allowed to stand for 12 hours. It was then placed in a vessel with 2.0 l of cold water with constant mixing. The end product was precipitated in the form of white flakes.

The precipitated end product was abfillriert, washed with water until the odor of dimethylformamide and to constant weight at a temperature of 4O ⁰ C dried.

The yield of the final product was 29.5 g (91.0%). Example 16

The polyurethaneocarbamidoacyl semicarbazide No. 16 according to Table 1 was obtained according to the invention as follows.

2.0 g (0.0071 mol) of L-serine hydrazide dihydrobromide were dissolved in 20 ml of dimethylformamide. 1.98 ml (0.0142 mol) of triethylamine were added to the resulting solution.

M) After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained L-serine hydrazide solution was added dropwise over 30 minutes at 25 ° C with mixing in added a solution of 10.65 g of a prepolymer in 40 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from diphenylmethane diisocyanate.

The reaction mixture thus prepared was allowed to stand for 12 hours. It was then placed in a vessel with 0.7 l of cold water with constant mixing.

18th

The end product was precipitated out in the form of white flakes.

The precipitated end product was filtered off, washed with water until the odor of dimethylformamide disappeared and ^{dried to constant mass at a temperature of 40 °} C. The yield of the end product was 10.8 g (93.9%).

Example 17

The polyurethaneocarbamidoacylsicarbazide No. 17 shown in Table 1 was obtained according to the invention as follows.

3.23 g (0.01 mol) of O-acetyl-L-serine hydrazide dihydrobromide were dissolved in 20 ml of dimethylformamide.

2.78 ml (0.02 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained O-acetyl-L-serine hydrazide solution was added dropwise with mixing into a solution of 15.0 g (0.01 mol) of a prepolymer in 100 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from diphenyl methane diisocyanate.

The reaction mixture thus prepared was allowed to stand for 12 hours. It was then placed in a vessel with 1.5 l of cold water with constant mixing. The end product was precipitated in the form of white flakes.

The precipitated end product was filtered off, washed with water until the odor of dimethylformamide disappeared and dried at a temperature of 40 ° C. until the mass was constant.

The yield of the final product was 16.7 g (96.3%). Example 18

The polyurethaneocarbamidoucylsemicarbazide No. 18 according to Table I was prepared according to the invention as follows.

1.00 g (0.0029 mol) of L-alanyl-L-alanine hydrazide dihydrobromide was dissolved in 15 ml of dimethylformamide.

0.80 ml (0.0058 mol) of triethylamine were added to the resulting solution. ίο

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The obtained L-alanyl-L-alanir.hydrazide solution was added dropwise to a solution at 25 ° C with mixing from 4.34 g (0.0029 mol) of a prepolymer in 30 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from diphenylmethane diisocyanate.

The reaction mixture thus prepared was allowed to stand for 12 hours. It was then placed in a vessel with 0.5 l of cold water with constant mixing. The final product was precipitated out in the form of white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the final product was 4.4 g (90.6%). Example 19

The polyurethanocarbamidoacyl semicarbazide No. 19 according to Table 1 was obtained according to the invention as follows.

7.0 g (0.0143 mol) of L-phenylalanyl-L-phenylalanine hydrazide dihydrobromide were dissolved in 30 ml of dimethylformamide.

3.98 ml (0.0286 mol) of triethylamine were added to the resulting solution. so

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 20 ml of dimethylformamide washed.

The obtained L-phenylalanine hydrazide solution was added dropwise over 30-40 minutes with mixing in added a solution of 21.47 g (0.0143 mol) of a prepolymer in 100 ml of dimethylformamide.

The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1000 and from diphenylmethane diisocyanate.

The reaction mixture thus prepared was allowed to stand for 12 hours. It was then placed in a vessel containing 1.5 liters of cold water, with constant mixing. The end product was precipitated in the form of white flakes.

The precipitated end product was filtered off, washed with water until the odor of dimethylformamide disappeared and dried at a temperature of 40 ° C. until the mass was constant.

The yield of the final product was 23.7 g (90.7%). Example 20

The polyurethaneocarbamidoacylsemicarbazide No. 20 according to Table 1 was obtained according to the invention as follows. 2.50 g (0.0063 mol) of L-phenylalanylglycine hydrazide dihydrobromide was dissolved in 20 ml of dimethylformamide.

19th

1.74 g (0.0126 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 10 ml of dimethylformamide washed.

The L-phenylalanyl glycol hydrazide solution obtained was (drop by drop over the course of 30 min at 25 ° C. Mix in a solution of 9.42 g (0.0063 mol) of a prepolymer in 35 ml of dimethylformamide.

The prepolymer was made from polyuxytetramethylene glycol with a molecular weight of 1000 and from diphenylmethane diisocyanate manufactured.

The reaction mixture thus prepared was allowed to stand for 12 hours.

It was then placed in a GcIaB with 0.7 l of cold water with constant mixing. The end product was precipitated in the form of white flakes.

The precipitated end product was filtered off, washed with water until the dimethylformamide odor disappeared and dried ^{at a temperature of 40 ° C. until the mass was constant.}

The yield of the end product was 10.5 g (96.04%).

15 Example 21

Polyurethanocarbamidoacylsicarbazide No. 21 according to Table I was made according to the invention as follows obtain.

2.00 g (0.0048 mol) of L-alanyl-L-rocnylalanylglycine hydrazide dihydrobromide were dissolved in 20 ml of dimethylformamide solved.

1.32 ml (0.0096 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 15 ml of dimethylformamide washed.

The obtained L-Alanyl-L-phenylalanylglycine hydrazide solution was added dropwise from 40 min at 25 ° C under Mix into a solution of 7.16 g (0.0048 mol) of a prepolymer in 50 ml of dimethylformamide.

The prepolymer was made from polyoxyttramethylene glycol with a molecular weight of 1000 and from diphenylmethundiisocyanate manufactured.

The reaction mixture thus prepared was allowed to stand for 12 hours.

It was then placed in a vessel with 1.0 l of cold water with constant mixing. jo The end product was precipitated in the form of white flakes.

The precipitated end product was filtered off, washed with water until disappearance of the odor /.um of dimethylformamide and to constant weight at a temperature of 4O ⁰ C dried.

The yield of the final product was 8.0 g (92.8%).

35 B c i s ρ i c I 22

Polyurethanocarbamidoacylsicarbazide No. 22 shown in Table 1 was made as follows in accordance with the present invention obtain.

2.37 g (0.0069 mol) of L-phenylalanine hydrazide dihydrobromide were dissolved in 20 ml of dimethylformamide. 2.93 ml (0.0138 mol) of triethylamine were added to the resulting solution.

After 15 minutes, the precipitated triethylamine hydrobromide was filtered off and mixed with 15 ml of dimethylformamide washed.

The obtained L-phenylalanine hydrazide solution was added dropwise over 30 min at 20-25 ° C Mix in a solution of 12.74 g (0.0069 mol) of a prepolymer in 50 ml of dimethylformamide. The prepolymer was made from polyoxytetramethylene glycol with a molecular weight of 1500 and from hexamethylene diisocyanate manufactured.

The reaction mixture thus prepared was allowed to stand for 12 hours.

It was then placed in a basin with 1.0 L of cold water with constant mixing.

The end product was precipitated in the form of white flakes that stuck together.

The precipitated end product was filtered off, washed with water until the odor of dimethylformamide and to constant weight at a temperature of 4O ⁰ C dried.

The yield of the end product was 13.3 g (95.1%).

Specific examples of the implementation of the invention are given above, but with various modifications and allow additions which are apparent to those skilled in the relevant field. Therefore, the invention is not limited to the examples described, but can be used within the scope of The spirit and scope of the invention, which are determined by the claims, modified and can be added.

20th

Claims (1)

Claim. Polyurethanocarbamidoacylsemicarbazide for the manufacture of synthetic implants with temporary effect with the following formula: - (NH-R ₁ -CO-NH-NH-CO-NH-R ₂ -NH-CO-OR ₃ -CO-NH-R ₂ -NH-CO) _n where: η = 5-24; R ₁ - —CH- -CH- -CH- —CH- —CH- - CH- I I I Il I CH ₃ CH ₂ C ₄ H ₅ CH ₂ OCOCH ₃ CH ₂ OH CH ₂ CH (CH ₃ ) Z CH ₂ C ₆ H ₄ OH - CH- -CH ₂ -CO-NH-CH ₂ - _CH - CO — NH- CH- I Il (CH ₂ J ₂ SCH ₃ CH ₂ C ₆ H ₅ CH ₂ C ₄ H ₅