Nylon-3 co-polymers and synthetic lung surfactant compositions containing same

Patent metadata

Field	Value
Publication number	US-9925213-B2
Application number	US-201514701775-A
Country	US
Kind code	B2
Filing date	May 1, 2015
Priority date	Mar 19, 2010
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

Non-natural oligomers have recently shown promise as functional analogs of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Presented herein an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of β-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers affords further improvements by reducing the percent surface area compression to reach low minimum surface tension.

First claim

What is claimed is:

1. An artificial lung surfactant composition comprising a nylon-3 homopolymer, a nylon-3 random copolymer, or a nylon-3 non-random copolymer, whose monomers are selected from the group consisting of:

wherein:
R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; or
one of R 3 and R 4 combined with one of R 5 and R 6 , together with the carbon atoms to which they are attached, define a cyclic moiety “A”

wherein “A” is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
provided that at least two of R 3 , R 4 , R 5 , or R 6 are not hydrogen; and
wherein “n” is a positive integer,
wherein the nylon-3 homopolymer, nylon-3 random copolymer, or nylon-3 non-random copolymer comprises a lipophilic alkanoyl end group capable of inserting into a lipid film.

2. The artificial lung surfactant composition of claim 1 , wherein:
in at least one of the monomers, R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
in at least one of the monomers:
one of R 3 and R 4 combined with one of R 5 and R 6 , together with the carbon atoms to which they are attached, define a cyclic moiety “A”

wherein “A” is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

3. The artificial lung surfactant composition of claim 2 , wherein “A” is substituted or unsubstituted C 5 -C 12 cycloalkyl.

4. The artificial lung surfactant composition of claim 2 , wherein “A” is substituted or unsubstituted C 5 -C 12 cycloalkenyl.

5. The artificial lung surfactant composition of claim 2 , wherein “A” is substituted or unsubstituted five- to twelve-membered heterocyclic.

6. The artificial lung surfactant composition of claim 2 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl, aryl, and C 1 -C 6 -alklyaryl.

7. The artificial lung surfactant composition of claim 2 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of substituted or unsubstituted amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

8. The artificial lung surfactant composition of claim 1 , wherein the nylon-3 homopolymer, nylon-3 random copolymer, or nylon-3 non-random copolymer is present in the artificial lung surfactant composition as an artificial lung surfactant in an amount effective to treat a respiratory distress syndrome or pulmonary disorder involving deficient or dysfunctional lung surfactant in a mammalian subject.

9. The artificial lung surfactant composition of claim 1 , wherein at least some of the monomers are cationic monomers, at least one of R 3 , R 4 , R 5 , and R 6 in each of the cationic monomers is amino or amino-C 1 -C 6 -alkyl, and the cationic monomers are present in the polymer in a proportion of less than 67% of the monomers.

10. The artificial lung surfactant composition of claim 1 , wherein the alkanoyl end group is an octadecanoyl end group.

11. An artificial lung surfactant composition comprising a polymer, wherein the polymer comprises monomers and an end group, wherein the monomers comprise a first set of monomers and a second set of monomers, wherein:
each monomer in the first set has a structure of:

wherein R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
each monomer in the second set has a structure of:

wherein:
one of R 3 and R 4 combined with one of R 5 and R 6 in each monomer in the second set, together with the carbon atoms to which they are attached, define a cyclic moiety “A”

A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the other of R 3 and R 4 and the other of R 5 and R 6 in each monomer in the second set are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
the end group is a lipophilic alkanoyl end group capable of inserting into a lipid film.

12. The artificial lung surfactant composition of claim 11 , wherein:
at least some of the monomers in the first set of monomers are cationic monomers;
at least one of R 3 , R 4 , R 5 , and R 6 in each of the cationic monomers is amino or amino-C 1 -C 6 -alkyl; and
the cationic monomers are present in the polymer in a proportion of less than ⅔ of all of the monomers in the polymer.

13. The artificial lung surfactant composition of claim 11 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 in the second set of monomers are independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

14. The artificial lung surfactant composition of claim 11 , wherein:
R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl, wherein at least one of R 3 , R 4 , R 5 , and R 6 is amino or amino-C 1 -C 6 -alkyl;
A together with the carbon atoms to which it is attached in each monomer in the second set is selected from the group consisting of substituted or unsubstituted C 8 -C 12 cycloalkyl, C 8 -C 12 cycloalkenyl, and eight- to twelve-membered heterocyclic; and
the polymer yields:
an average surface tension no higher than 35 mN m −1 with 0.40-mm radius bubbles composed of 1,2-diacyl-sn-glycero-3-phosphocholine (DPPC):1-palmitoyl-2-oleoyl-sn-glycero-

Assignees

• Wisconsin Alumni Res Found
• Univ Northwestern

Inventors

• Gellman Samuel H
• Stahl Shannon S
• Mowery Brendan P
• Barron Annelise
• Dohm Michelle

Classifications

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• A61K31/785 Primary

  Polymers containing nitrogen · CPC title

• A61K9/0082

  Lung surfactant, artificial mucus · CPC title

• C08L77/02

  Polyamides derived from omega-amino carboxylic acids or from lactams thereof (C08L77/10 takes precedence) · CPC title

• C08G69/22

  Beta-lactams · CPC title