Lymph directing prodrugs

Patent metadata

Field	Value
Publication number	US-11311512-B2
Application number	US-201515502757-A
Country	US
Kind code	B2
Filing date	Aug 12, 2015
Priority date	Aug 12, 2014
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

The present invention relates to compounds and their uses, in particular, compounds in the form of prodrugs that promote transport of a pharmaceutical agent to the lymphatic system and subsequently enhance release of the parent drug.

First claim

We claim:

1. A compound of the formula (I):

wherein
R 1 and R 2 independently represent H or a C 2 -C 28 fatty acid;
—X— is selected from —O—, —NH—, and —S—;
—Y— represents a substituted —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group, wherein one or more of the carbon atoms in the alkyl, alkenyl, or alkynyl group may be replaced with NH, S, O, a C 5 -C 8 aromatic or aliphatic cyclic group, or a C 5 -C 8 aromatic or aliphatic heterocyclic group, provided that the alkyl, alkenyl, or alkynyl group does not exceed a length equivalent to a linear C 20 alkyl group;

represents a pharmaceutical agent;
—L— is —X′— or —X′ C(O)—;
X′ is O, S, N, N(R 4 ), or S(O) 2 NH;
represents a single bond when X′ is O, S, N(R 4 ), or S(O) 2 NH; or
represents two separate bonds when X′ is N;
—Z— is —C(O)— or —C(O)R 3 — when —L— is —X′—; or
—Z— is absent when —L— is —X′C(O)—;
R 3 is a self-immolative group; and
R 4 is H or C 1 -C 4 alkyl; or
a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 3 is selected from:

3. The compound of the formula (I) according to claim 1 , represented by the formula (II):

wherein
R 1 and R 2 independently represent H or a C 2 -C 28 fatty acid;
—X— is selected from —O—, —NH—, and —S—;
—Y— represents a substituted —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group, wherein one or more of the carbon atoms in the alkyl, alkenyl, or alkynyl group may be replaced with NH, S, O, a C 5 -C 8 aromatic or aliphatic cyclic group, or a C 5 -C 8 aromatic or aliphatic heterocyclic group, provided that the alkyl, alkenyl, or alkynyl group does not exceed a length equivalent to a linear C 20 alkyl group;

represents a pharmaceutical agent;
—L— is —X′— or —X′ C(O)—;
X′ is O, S, or N(R 4 );
R 4 is H or C 1 -C 4 alkyl; and
—Z— is —C(O)— when —L— is —X′—; or
—Z— is absent when —L— is —X′C(O)—; or
a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , represented by the formula (III):

wherein
R 1 , R 2 , —X—,

and —Z— are as defined in claim 1 ;
R 5 and R 6 are individually selected from hydrogen and C 1 -C 4 alkyl, provided that one or both of R 5 and R 6 are not hydrogen; and
n is from 1 to 18; or
a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 , wherein the pharmaceutical agent is selected from testosterone, mycophenolic acid, oestrogens (estrogen), morphine, metoprolol, raloxifene, alphaxolone, a statin, buprenorphine, pentazocine, propranolol, L-DOPA, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, isosorbidedinitrate, oxprenolol, labetalol, verapamil, salbutamol, epitiostanol, or melphalan.

6. The compound according to claim 5 , wherein the pharmaceutical agent is testosterone and the compound is represented by the formula (IV):

wherein R 1 , R 2 , and X are as defined in claim 1 ;
R 5 and R 6 are individually selected from hydrogen and C 1 -C 4 alkyl, provided that one or both of R 5 and R 6 are not hydrogen;
—Z— is —C(O)— or —C(O)R 3 —;
R 3 is a self-immolative group; and
n is from 1 to 18; or
a pharmaceutically acceptable salt thereof.

7. The compound according to claim 4 , wherein R 5 is methyl and R 6 is hydrogen.

8. The compound according to claim 4 , wherein R 5 is hydrogen and R 6 is methyl.

9. The compound according to claim 1 , wherein —X— and —X′— are oxygen.

10. The compound according to claim 1 , wherein —X— is —O— and R 1 and R 2 are independently selected from a C 2 -C 28 fatty acid.

11. The compound according to claim 1 , wherein the pharmaceutical agent is selected from non-steroidal anti-inflammatory medications (NSAIDS), COX-2 inhibitors, corticosteroid anti-inflammatory medications, anti-malarial medications, nitrosoureas, platinum, anthracyclines, drugs acting on immunophilins, opioids, immunosuppressants, and pharmaceutically active peptides.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.

13. The compound of claim 1 , wherein —X— is —O—.

14. The compound of claim 13 , wherein —Z— is —C(O)— or —Z— is absent.

15. The compound of claim 13 , wherein —Z— is —C(O)R 3 —.

16. The compound of claim 13 , wherein —Z— is —C(O)— or —Z— is absent; R 1 and R 2 are independently selected from a C 2 -C 28 fatty acid; and —Y— represents a substituted —C 8 -C 20 alkyl-, —C 8 -C 20 alkenyl-, or —C 8 -C 20 alkynyl- group, wherein one or more of the carbon atoms in the —C 8 -C 20 alkyl-, —C 8 -C 20 alkenyl-, or —C 8 -C 20 alkynyl- group of —Y— may be replaced with NH, S, or O.

17. The compound of claim 13 , wherein —Y— represents a —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group substituted with one or more groups selected from hydroxyl, alkyl, alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, acylamino, carboxy, cyano, halogen, nitro, sulfo, phosphono, phosphorylamino, phosphinyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocycloxy, trihalomethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl, amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl, and heterocyclyl, wherein one or more of the carbon atoms in the —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group of —Y— may be replaced with NH, S, or O.

18. The compound of claim 13 , wherein —Y— represents a —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group substituted with one or more C 1 -C 20 alkyl groups, wherein one or more of the carbon atoms in the —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group of —Y— may be replaced with NH, S, or O.

19. The compound of claim 13 , wherein —Y— represents a —C 3 -C 20 alkyl- group substituted with one or more C 1 -C 20 alkyl groups, wherein one or more of the carbon atoms in the —C 3 -C 20 alkyl- group of —Y— may be replaced with O.

20. The compound of claim 13 , wherein —Y— represents a —C 3 -C 20 alkyl- group substituted w

Assignees

• Univ Monash

Inventors

• Porter Chris
• Simpson Jamie
• Trevaskis Natalie
• Quach Tim
• Han Sifei
• Hu Luojuan

Classifications

• B01J20/291

  Gel sorbents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P5/24

  of the sex hormones · CPC title

• A61K31/365 Primary

  Lactones · CPC title

• C07J1/0029

  Ethers · CPC title