Polymers, pharmaceutical compositions and methods of synthesizing the same

Patent metadata

Field	Value
Publication number	US-9969773-B2
Application number	US-201514688026-A
Country	US
Kind code	B2
Filing date	Apr 16, 2015
Priority date	Apr 16, 2014
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

Novel methods to prepare novel polymers are disclosed. Oxazolidinyl compounds according to formula IV:

are also disclosed as intermediate compounds that can be reacted with an acid to form a polymer of formula I.

First claim

What is claimed is:

1. A compound according to formula V:

or a pharmaceutically acceptable salt, stereoisomer, isotopic variant or tautomer thereof;
wherein
X is hydroxyl, alkoxy, amino or substituted amino;
Y is hydroxy, protected hydroxyl, amino or protected amino; or Y is —O—R 2 , —O—C(O)—R 2 , —NH—C(O)—R 2 or —NH—C(O)—O—R 2 ;
R 1 is H or methyl;
each R 2 is independently H, alkyl, or aryl;
each R 3 is independently selected from a group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
the subscript m is an integer from 2-200; and the subscript n is an integer from 2-1000;

provided that the compound is other than the compounds “Excluded Compounds 1-25” listed below:
Excluded Compound 1
CAS Registry Number: 1379581-54-0;
Excluded Compound 2
CAS Registry Number: 1353563-96-8;
Excluded Compound 3
CAS Registry Number: 1254174-69-0;
Excluded Compound 4
CAS Registry Number: 1254174-68-9;
Excluded Compound 5
CAS Registry Number: 1242240-17-0;
Excluded Compound 6
CAS Registry Number: 1242240-03-4;
Excluded Compound 7
CAS Registry Number: 1199579-48-0;
Excluded Compound 8
CAS Registry Number: 1199579-43-5;
Excluded Compound 9
CAS Registry Number: 1189539-31-8;
Excluded Compound 10
CAS Registry Number: 1189539-30-7;
Excluded Compound 11
CAS Registry Number: 1189539-29-4;
Excluded Compound 12
CAS Registry Number: 942119-12-2;
Excluded Compound 13
CAS Registry Number: 872611-89-7;
Excluded Compound 14
CAS Registry Number: 872611-87-5;
Excluded Compound 15
CAS Registry Number: 792954-90-6;
Excluded Compound 16
CAS Registry Number: 341990-80-5;
Excluded Compound 17
CAS Registry Number: 341552-34-9;
Excluded Compound 18
CAS Registry Number: 341552-26-9;
Excluded Compound 19
CAS Registry Number: 341552-14-5;
Excluded Compound 20
CAS Registry Number: 150439-04-6;
Excluded Compound 21
CAS Registry Number: 150439-01-3;
Excluded Compound 22
CAS Registry Number: 150438-98-5;
Excluded Compound 23
CAS Registry Number: 150438-96-3;
Excluded Compound 24
CAS Registry Number: 150438-95-2; and
Excluded Compound 25
CAS Registry Number: 150438-94-1.

2. A compound according to formula VIII:

or a stereoisomer, a tautomer, or an isotopic variant thereof;
wherein
X is hydroxyl, alkoxy, amino or substituted amino;
Y is hydroxy, protected hydroxyl, amino or protected amino; or Y is —O—R 2 , —O—C(O)—R 2 , —NH—C(O)—R 2 or —NH—C(O)—O—R 2 ;
R 1 is H or methyl;
each R 2 is independently H, alkyl, or aryl;
each R 3 is independently selected from a group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each R 4 is independently H or substituted or unsubstituted alkyl;
and

the subscript m is an integer from 2-200;
the subscript n is an integer from 2-1000;
the subscript t is 1, 2, 3, or 4.

3. The compound according to claim 1 , wherein Y is
i) —O—R 2 ; and R 2 is H, Me, Et, i-Pr, n-Pr, or Ph;
ii) —O—C(O)—R 2 ; and —C(O)—R 2 is lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, caproyl, benzoyl, cetyl, decyl, acetyl, phenyl acetyl, cyclohexyl acetyl, or valeroyl;
iii) —O—C(O)—R 2 ; and —C(O)—R 2 is glucuronyl;
iv) —O—C(O)-Me;
v) —NH—C(O)—R 2 ; and R 2 is Me, Et, i-Pr, or n-Pr; or
vi) NH-t-Boc or NH 2 .

4. The compound according to claim 1 , wherein Y is OH, OMe, —O—C(O)-Me, NH 2 , or NH-t-Boc.

5. The compound according to claim 1 , wherein R 1 is Me.

6. The compound according to claim 1 , wherein each R 3 is independently
i) Me, Et, n-Pr, i-Pr, n-Bu, sec-Bu, or i-Bu;
ii) phenyl or benzyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
iii) phenethyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
iv) 2-naphthyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
v) 2,2-diphenylethyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
vi) furanyl or thienyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
vii) aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, or 6-aminohexyl;
viii) guanidinomethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 5-guanidinopentyl, or 6-guanidinohexyl;
ix) imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, 4-imidazolylbutyl, 5-imidazolylpentyl, or 6-imidazolylhexyl; or
x) methyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, substituted with pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, triazolyl, or tetrazolyl.

7. The compound according to claim 1 , wherein R 3 is independently Me, i-Pr, i-Bu, sec-Bu, phenethyl, 4-hydroxyphenethyl, benzimidazol-3-ylmethyl, thiomethyl, methylthioethyl, hydroxymethyl, aminopropyl, guanadinopropyl, or imdazo-4-yl methyl.

8. The compound according to claim 2 , wherein t is 4; and each of R 4 is H; or t is 1 or 2, and each of R 4 is independently Me, Et, i-Pr or CF 3 .

9. The compound according to claim 1 , wherein X is —OH, —OMe, —OEt, or NH 2 .

10. The compound according to claim 1 , wherein m is an integer between 2-200.

11. The compound according to claim 1 , wherein n is an integer between 2-1000.

12. A pharmaceutical composition of a compound according to claim 1 .

13. The compound according to claim 2 , wherein Y is
i) —O—R 2 ; and R 2 is H, Me, Et, i-Pr, n-Pr, or Ph;
ii) —O—C(O)—R 2 ; and —C(O)—R 2 is lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, caproyl, benzoyl, cetyl, decyl, acetyl, phenyl acetyl, cyclohexyl acetyl, or valeroyl;
iii) —O—C(O)—R 2 ; and —C(O)—R 2 is glucuronyl;
iv) —O—C(O)-Me;
v) —NH—C(O)—R 2 ; and R 2 is Me, Et, i-Pr, or n-Pr; or
vi) NH-t-Boc or NH 2 .

14. The compound according to claim 2 , wherein R 1 is Me.

15. The compound according to claim 2 , wherein each R 3 is independently
i) Me, Et, n-Pr, i-Pr, n-Bu, sec-Bu, or i-Bu;
ii) phenyl or benzyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
iii) phenethyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
iv) 2-naphthyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
v) 2,2-diphenylethyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
vi) furanyl or thienyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy;
vii) aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, or 6-aminohexyl;
viii) guanidinomethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 5-guanidinopentyl, or 6-guanidinohexyl;
ix) imidazol

Assignees

• Kirshenbaum Kent
• Levine Paul
• Craven Timothy
• Univ New York

Inventors

• Kirshenbaum Kent
• Levine Paul
• Craven Timothy

Classifications

• C07K5/06165

  and Pro-amino acid; Derivatives thereof · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• C07K17/08

  the carrier being a synthetic polymer · CPC title

• C07K5/1024

  with the first amino acid being heterocyclic · CPC title