CS217739B1 - Alternating block copolymers of synthetic polypeptides with linear structure - Google Patents

Abstract

The subject of the invention are alternating block copolymers of synthetic polypeptides with a linear structure of the type (A—B)n, where A is a polypeptide segment and B is the same or different segment of synthetic polyether, polyurethane or polyamide, where the molecular weight of the polypeptide segments ranges from 500 to 10,000. Alternating block copolymers of peptides according to the invention can be used in packaging technology, in consumer goods and, last but not least, for polymer medical devices, prostheses, implants, etc. The presence of peptide units with the spatial configuration L — is a basic condition for the given material to be sensitive to biodegradation by plant and animal organisms.

Description

The invention relates to alternating block copolymers of synthetic β linear polypeptides.

Synthetic polypeptides are a material that, both in composition and properties, is closest to natural materials such as wool, silk and / or collagen. Today, they are obtained by polymerizing N-carboxyanhydrides of α-amino acids and are produced in some countries for commercial and research purposes. The properties of synthetic polypeptides from various amino acids have been explored in detail, and some of them are very good materials for producing high quality fibers, films and artificial leather.

Synthetic pepites containing as monomer! The L-isomers of the N-amino acids have, besides various suitable technical properties, one specific property that is lacking in other technical polymers. It is biodegradability, guaranteed by the presence of units selectively cleavable by the enzyme machinery of living organisms. This implies a great potential for application in medicine, pharmacology and where plastic pollution is involved.

In the patent and scientific literature, we find a number of applications of synthetic polypeptides of N-carboxyanhydrides (NCAs), where known polymers are modified by copolymerization with N-carboxyanhydrides. Polyurethanes and / or polyurethanes are modified in this way. ethers and poles of epoxides as reported by Fujimoto Y., Masumura I., Tatsukawa K., Koshimoto S., and Doiuchi, T .: Ger. Offen. 2, 117, 982/28. 10. 1971; Fujimoto Y., Teranishi M .: Ger. Offen. 2, 124, 042 (December 2, 1971, Kyowa Fermentation. Industrial Co.); Tojima H., Hasegawa Y., Minami T .: Japan. Kokai 72 42,991 (December 28, 1972, Toycba Co.); Kajiyama S., Nakanishi T., Kusushita T .: Japan 74 74,118 (2 August 8, 1970, Matsushita Electric Industrial Co.), Hoshizumi S., Nakagoe Y .: Japan 73 23,882 (Jul 17, 1973, Honey Chemicals) other materials, such as vinyl polymers, have been modified, with polypeptides attached by chemical bonding as grafts [Kinoshita N .: Japan Koka! 75 12,189 (Feb. 7, 1975) Mitsubishi Monsanto Chem., Ebihara S., Akata A .: Japan Kokal 76 26,997) 05 May 1976, Agency of Ind. Sciences). Synthetic polypeptides have also been applied in the form of copolymers, and block copolymers are a prominent type. Previously known block copolymers of peptides were prepared by polymerizing N-carboxyanhydrides of amino acids in the presence of single amino terminal macroinitiators (Pearls A, Douy A., Gallot B .: Macromol. Chem. 1.976, 177, 2569; Douy A., Gallot B .: Polym Enig Sci 1977, 17, 523, Vlasov GP, Rudkovskaya GD, Ovsjannikova LA, Baranovskaya IA, Sokolova TA, Uljanova

N. N., Sixova N. V .: Vysokomol. Soed. 1980,

2B (216), optionally in part two terminal amino groups (Nakajima A., Hayashl T., Kugo K., Shinoda K .: Macromolecules 1979, 12, 84); Nakajima, A., Kugo, K., Hayashi, T .: Macromolecules' 1979, 12, 844; Nakajima, A., Kugo, K., Hayashi, T., Sato, H .: Biomedical Polymers, Academic Press 1980, 243-274). In particular, the latter work aims to bioapply synthetic block copolymers of peptides. There are a number of studies on the behavior of synthetic polypeptides implanted in a living organism, and the results appear promising in terms of both tolerance and gradual tissue replacement. (It should be pointed out that m, the aroinitiators enriched in the particles bearing the two amino groups reported by A. Nakajima and coworkers, have not been quantitatively analyzed for the ratio of monofunctional to bifunctional particles. This is impossible because other end groups are always formed - see H. Sek.iguchi: Pure and Applied Chemistry 53, 1689-1714 (1981)].

Known peptide copolymers are of type A-B or A-B-A, where A is a polypeptide segment, and very rarely after laborious laboratory separation block peptide copolymers of uniform type have been obtained.

The present invention provides alternate block copolymers of linear (A-B) type synthetic polypeptides, wherein n g s 2 and wherein A is a polypeptide segment and B is a synthetic polyether, polyurethane or polyamide segment, wherein the molecular weight of the polymers is linear. polypeptide segments ranging from 660 to 10,000.

It is a further feature of the invention that the individual B segments in the copolymer chains are selected from the group consisting of multiple species segments.

In the block copolymers of the invention, one of the segments A and B consists of a chain of α-amino acids, which may be either natural or synthetic. The second segment could also be composed of amino acid units, and its difference from the right segment could lie in a different kind of amino acids, but also in their number and sequence. The structure of the blocks A and B need not be uniform, but can consist of copolymers, both statistically and alternatively, respectively. and block. However, a significant case occurs when the other of the blocks is not a polypeptide but a different polymeric or oligomeric block of another synthetic polymer.

A similar type of alternating copolymers with a polypeptide component has hitherto been unknown.

Alternative block copolymers of the synthetic peptides of the invention can be prepared from telechelic polypeptides, the preparation of which is the subject of US Pat. Certificate No 217 238,

The subject of the cited Czechoslovak author's certificate No. 217 238 is lechelic polypeptides and copolypeptides, i.e. two-functional peptide polymers with terminal reactive groups, in this case ending with primary or secondary amino groups, i.e. of the type HzN - NH? or a polypeptide chain.

Telechelic polypeptides, prepared according to U.S. Pat. No. 217 238 can be advantageously used for the preparation of block copolymers of alternating type, for example polyadidia with other bivalent functional prepolymers terminated with suitable reactive end groups and amino groups according to the schemes n H 2 NH 2. + η X - X -> n H - N * - NH - X - X n HzN - NH - X - X -> H (HN - NH - X - Xj) whereby the resulting product is a copolymer of type (A - B) _n (Note: in this scheme, * a hydrogen atom at a terminal amino group originally bonded telechelic polypeptide segment X-X, provided polyaddition reaction. Therefore, it is not after the reaction scheme indicated).

The composition of the second block is related to the possibility of preparing soluble or preferably liquid polymers with groups which react rapidly and preferably to a high degree by converting with amino groups to form a covalent chemical bond. Such a condition is met, for example, by polyethers and other condensation polymers into which isocyanate end groups can be introduced and which are commonly used in polyurethane and polyurea technology. However, other polymers prepared by polycondensation meet this condition. Examples are polyamides. Advantageously, solution or interphase condensation of dicarboxylic acids such as aidipic acid with diamines such as hexamethylenediamine can be used in their preparation. In such polycondensation, terminal acyl chloride groups suitable for anchoring the polyamide block are already present. If the preparation of the polyamide prepolymer is carried out directly in situ in the presence of a telechelic polypeptide, block copolymers are also formed.

Another type of block alternating peptide copolymers claimed are those copolymers wherein the structure of the second block is not uniform and regular, as exemplified for a polyurethane with a peptide component.

Alternative block copolymers of peptides can be considered as chains of synthetic polymers, regularly interrupted by peptide bridges, according to their primary structure. This specific feature of their structure is of importance for the application of synthetic polymers in packaging, consumer goods and, last but not least, for polymer medical devices, prostheses, implants and the like. The presence of peptide units with a spatial configuration of L - is a prerequisite for the material to be susceptible to biedegradation by the action of plant and animal organisms. This type of degradation is characterized by high selectivity and speed and is conditioned by the action of enzymes. Technical synthetic polymers selectively cleave, elite is missing and products from them are often a difficult ballast, which contaminates nature after wear. Alternative block copolymers of polypeptides of defined structure and containing amino acids with L-configuration can therefore contribute significantly to solving environmental problems. To achieve a significant effect in this sense, even a small proportion by weight of the polypeptide in the blob copolymers may be sufficient, which is readily achieved by the molecular weight of the second copolymer component being higher than that of the polypeptide component.

The limit viscosity number (intrinsic viscosity) [yj] is given in dl / g in the following examples.

Example 1 (Block copolymer of a polypeptide "prepolymer" with a poly (oxyethylene) "prepolymer".

0.40 g of copolymers of D, L-phenylalanine with L-leucine [- NIH2] = 2,558 mol / kg and 0,495 g of poly (oxyethylene), [containing 2,065 mol / kg of isocyanate end groups prepared from poly (oxyethylene j) : polyethylene glycol having a mass of 600 and hexamethylenediisocyanate at a molar ratio of [—NCO] / [- OH] of 2: 1 and 60 ° C for 40 hours; [η] = 0.13 dichloroacetic acid (DCAj, 25 ° C) was dried 16 hours at a pressure of 0.07 Pa at 25 ° C and dissolved in 14 ml of chloroform free of acidic impurities and traces of water After 6 hours of reaction in the presence of 0.66 μibut of dibutyltin dilaurate at 25 ° C, excluding air humidity, the solution was clear. filtered and freely evaporated in a glass dish for 48 hours, the residue extracted 3 times 4 hours at 40 ° C with cyclohexane and dried at 50 ° C under vacuum to constant weight.

The sample thus obtained was extracted with water for 3 hours at 40 ° C and the undissolved fraction in the form of a rigid flexible film weighed 0.891 g and contained 44.8 wt. percent of the polypeptide component. The intrinsic viscosity [η] of this alternating block copolymer was 6.89 (DCA, 25 ° C). The sample contained 12.1 wt. ° / o water (25 ° C).

Example 2

Telechelic poly (D, L-f-enylanine-co-L-leucine) block copolymer with polyphoxyethylene

0.379 g of peptide copolymers, [—NH2] =

217 = 2,558 mol / kg, and 2,647 g of a poly (oxyethylene) prepolymer with isocyanate groups (prepared in poly (oxyethylene) of mass 4000 by reaction with hexamethylene diisocyanate at an initial molar ratio of —NCO and —OH of 2: 1 at 60 ° C / 40 hours and containing 0.353 mol NCO / kg [η = 0.42] was dissolved in 32 ml of chloroform The reaction at 25 ° Ό for 72 hours was carried out in a sealed vessel under nitrogen. as well as the reaction mixture of Example 1, and 3.020 g of water-soluble block copolymers having an intrinsic viscosity of 4.93 (DCA, 25 ° C) were obtained.

Example 3

Polyurethane of telechelic poly (L-alanine-co-γ-benzyl-L-glutamate). 8.74 g of poly (oxytetramethylene) having terminal OH groups having a molecular weight of 1000, an intrinsic viscosity of 0.10 (DCA, 25 ° C) was heated to 80 ° C under a nitrogen atmosphere with the addition of 2.97 g of hexamethylene diisocyanate for 5 hours After cooling, 30 g of dichloromethane, 3 g of 3,6-dioxa-1,8-octanediol and 2 g of telechelic copolymers of L-alanine and χ-benzyl L-glutamate, [—NH] = 0.332 mol / kg, were added, After 12 hours of reaction at 80 ° C, the film was removed, extracted with water and dried.The polyurethane-type copolymers weighed 16.50 g, an intrinsic viscosity of 4.20 (DCA, 25 ° C). C).

Example 4

Block copolymer containing poly (D, L-phenylalanine-co-L-leucine] and polyfhexamethylene adpamiid). Solution of 1 g of telechelic "prepolymer" of D, L-phenylalanine and L-leucine (content - skupin2 groups: 2,558 mol / kg, —COOH groups: 0,0140 mol / kg [η] = 0,12 (25 ° C) (DCA) in 50 ml of acid-free chloroform is added dropwise over 2 hours to a solution of 3.5 g of freshly distilled adipoyl chloride in 50 ml of chloroform, with vigorous stirring, after 2 hours at room temperature. hexamethylenediamine in water (70 g water and 30 g ice) After 20 minutes the product was filtered off, washed with hot ethanol (309 ml) and dried at 0.13 Pa at 70 ° C to give 6.6 g of a white powder. η] = 1.8 (25 ° C, DCA).

Claims (2)

Alternative block copolymers of synthetic polypeptides of linear structure type (A-B) _n > where ng 2a wherein A is a polypeptide segment and B is a segment of synthetic polyether, polyurethane or polyamide, wherein the molecular weight of the polypeptide segments ranges from 600 to 10,000 . 2. Alternative block copolymers according to item 1, wherein the individual B segments in the copolymer chains are arbitrarily selected from the group consisting of multiple species segments. Severography, n. P. Zívod 7 Most