Water‐Soluble polyamides as potential drug carriers. I. Poly(α,β‐D,L‐asparthydrazide‐CO‐D,L‐ornithine)

Abstract

The polycondensation of D,L-aspartic acid with N,-phthaloyl-L-ornithine in phosphoric acid at 185 "C gives rise to the formation, in 60-75% yield, of random copolymers of the poly(D,L-succinimide-co-N,-phthaloyl-D,L-ornithine) type 6 possessing inherent viscosities (DMF) in the range of 5 -15 ml g-l. Copolyimides of the same compositions 6 and comparable chain lengths are obtained from aspartic acid and the copper chelate of the phthaloylornithine. Treatment of copolymers 6 with hydrazine hydrate in DMF leads to N-deprotection and opening of the intrachain succinimide rings with formation of hydrazide side groups. The resultant polyamides are of the poly(a,bD,L-asparthydrazide-co-D,L-ornithine) type 7. Shorter reaction periods give incomplete hydrazinolytic ring opening, and the remaining succinimide units are cleaved hydrolytically during the subsequent aqueous workup, thereby transforming into aspartic acid units. The polyamides so formed possess the general poly(a,bD,basparthydrazide-co-a,bD,L-aspartic acid-co-D,L-ornithine) structure 8. Both types 7 and 8 are soluble in water and, in this medium, give inherent viscosities of 5 -14 ml g-'. The potential drug-anchoring capabilities of these amine-functionalized polyamides are demonstrated by coupling reactions with model carboxylic acids. ZUSAMMENFASSUNG: Bei der Polycondensation von D,L-Asparaginsaure mit N,-phthaloyl-L-ornithin in Phosphorsaure bei 185 "C entstehen statistische Copolymere (Ausbeute 60-70%) aus Poly(D,L-succinimid-co-N,-p~thaloyl-D,L-ornithin), Formel 6, mit inharenten Viskositaten (DMF) von 5 bis 15 ml g-'. Copolyimide der selben Zusammensetzung 6 und vergleichbarer Kettenlange werden aus AsparaginsLure und dem Kupferchelat des Phthaloylornithins erhalten. Die Behandlung des Copolymeren 6 mit Hydrazinhydrat fiihrt zur Offnung der Succinimid-Kettenglieder unter Bildung von Hydrazid-Seitengruppen. Die resultierenden Polyamide sind Poly(a,bD,L-asparaginsaurehydrazid-co-D,L-ornithin), Formel 7. Kurzere Reaktionszeiten bedingen unvollstandige Ring-Offnung, und die verbleibenden Succinimid-Gruppen werden bei der folgenden Aufarbeitung hydrolytisch gespalten unter Bildung von Asparagindure-Gruppen; die so 0 1990 Hiithig & Wepf Verlag, Base1 CCC 0003-3146/90/$03.00

Synthesis of Biodegradable Amphoteric Poly[(aspartic acid)-co-lysine] by Thermal Polycondensation

“…From their insoluble characteristic, it may be concluded that the water-insoluble species are the crosslinking products which were generated by the nucleophilic reaction of the pendant amino groups presented in lysine units with succinimides in the polymer main chain during polymerization. [8] The water-soluble parts were precipitated into methanol to give a yellowish viscous product.…”

“…In addition, other amino acids, such as glysine, ornithine and x-amino acid can also be incorporated to the polymer main chain by simple copolycondensation. [5][6][7][8] However, to our knowledge, there are few reports on the co-polycondensation of aspartic acid and lysine to give biodegradable amphoteric poly-[(aspartic acid)-co-lysine] [P(ASP-co-LYS)] (Scheme 1). Such biodegradable polyampholytes are promising for the preparation of absorbable polyelectrolyte complexes with high pH-sensitivity for controlled protein release by complexation with polyanions.…”

On the synthesis of sequence-controlled poly(vinyl benzyl amine-co-N-substituted maleimides) copolymers

“…After copolymerization, the phthalimide protecting groups were removed in order to afford sequencecontrolled primary-amine containing copolymers. However, this later step is not trivial because it can potentially also lead to ring opening [46] or complete deimidation [47] of the succinimide units in the copolymer as shown in Scheme 3. Thus, the deprotection step was carefully studied using 1 H and 13 …”

Synthesis of Biodegradable Amphoteric Poly[(aspartic acid)-co-lysine] by Thermal Polycondensation

“…From their insoluble characteristic, it may be concluded that the water-insoluble species are the crosslinking products which were generated by the nucleophilic reaction of the pendant amino groups presented in lysine units with succinimides in the polymer main chain during polymerization. [8] The water-soluble parts were precipitated into methanol to give a yellowish viscous product. It should be noted that the two monomers could dissolve in methanol/water mixed solution (90 : 10, v/v), ensuring the purity of the precipitated products.…”

“…In addition, other amino acids, such as glysine, ornithine and x-amino acid can also be incorporated to the polymer main chain by simple copolycondensation. [5][6][7][8] However, to our knowledge, there are few reports on the co-polycondensation of aspartic acid and lysine to give biodegradable amphoteric poly-[(aspartic acid)-co-lysine] [P(ASP-co-LYS)] (Scheme 1). Such biodegradable polyampholytes are promising for the preparation of absorbable polyelectrolyte complexes with high pH-sensitivity for controlled protein release by complexation with polyanions.…”