Lymph directing prodrugs

Patent metadata

Field	Value
Publication number	US-11738087-B2
Application number	US-201615758633-A
Country	US
Kind code	B2
Filing date	Sep 8, 2016
Priority date	Sep 8, 2015
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

The present invention relates to compounds and their uses, in particular, compounds in the form of prodrugs that pro mote 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 residue of a C 2 -C 28 fatty acid;
—X— is selected from —O—, —NH— and —S—;

represents a pharmaceutical agent;
-L- is —X′—;
—Y— represents an optionally substituted —C 1 -C 2 alkylC(O)R 3 — group or a —C 2 alkenylC(O)R 3 — or —C 2 alkynylC(O)R 3 — group;
R 3 is a self-immolative group;
X′ is O, S, N(R 4 ) or N(H)S(O) 2 ; and
R 4 is H or C 1 -C 4 alkyl; or,
pharmaceutically acceptable salts thereof.

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

wherein denotes the point of attachment with the residue of a pharmaceutical agent and with the —Y— group.

3. A compound according to claim 1 , wherein the pharmaceutical agent is one that exhibits greater than 50% first pass metabolism.

4. A compound according to claim 1 , wherein the pharmaceutical agent is selected from testosterone, mycophenolic acid, estrogen, morphine, raloxifene, alphaxolone, atorvastatin, buprenorphine, pentazocine, propranolol, L-DOPA, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, isosorbidedinitrate, oxprenolol, labetalol, verapamil, salbutamol, epitiostanol, melphalan or lovastatin.

5. A compound according to claim 1 , wherein the pharmaceutical agent is testosterone and the compound is represented by the formula (V):

wherein R 1 , R 2 , R 3 , and X are as defined in claim 1 , and
R 5 and R 6 are individually selected from hydrogen and C 1 -C 4 alkyl; or
pharmaceutically acceptable salts thereof.

6. A compound according to claim 5 , wherein R 5 is methyl and R 6 is hydrogen.

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

8. A compound according to claim 5 , wherein X is oxygen.

9. A compound according to claim 5 , wherein R 1 and R 2 are residues of palmitic acid.

10. A compound according to claim 1 , wherein X is oxygen.

11. A compound according to claim 1 , wherein R 1 and R 2 are residues of palmitic acid.

12. A 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, cyclophosphamide, nitrosoureas, platinum, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, drugs acting on immunophilins, sulfasalazine, leflunomide, mycophenolate, opioids, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine mepesuccinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir, immunosuppressants and pharmaceutically active peptides.

13. A compound according to claim 1 , wherein R 1 and R 2 independently represent a residue of a C 2 -C 28 fatty acid.

14. A compound according to claim 1 , wherein —Y— represents an optionally substituted —C 1 -C 2 alkylC(O)R 3 —.

15. A compound according to claim 1 , wherein —Y— represents a —C 1 -C 2 alkylC(O)R 3 — group optionally substituted with methyl.

16. A compound according to claim 1 , wherein:
R 1 and R 2 independently represent a residue of a C 2 -C 28 fatty acid;
—X— is —O—; and
—Y— represents an optionally substituted —C 1 -C 2 alkylC(O)R 3 — group.

17. A compound according to claim 16 , wherein R 3 is selected from:

wherein denotes the point of attachment with the residue of a pharmaceutical agent and with the —Y— group.

18. A compound according to claim 16 , wherein the pharmaceutical agent is selected from testosterone, mycophenolic acid, cyclosporine, tacrolimus, sirolimus, celecoxib, rofecoxib, estrogen, morphine, tetrahydrocannabinol, cannabidiol, metoprolol, raloxifene, alphaxolone, atorvastatin, buprenorphine, pentazocine, propranolol, L-DOPA, lidocaine, chlorpromazine, amitriptyline, nortriptyline, oxprenolol, labetalol, salbutamol, epitiostanol, melphalan or lovastatin.

19. A compound according to claim 1 , represented by the formula (II):

wherein
R 1 , R 2 , R 3 , R 4 , X, X′, and

are as defined in claim 1 ; and
R 5 is selected from hydrogen and C 1 -C 4 alkyl; or
pharmaceutically acceptable salts thereof.

20. A compound according to claim 1 , represented by the formula (III):

wherein R 1 , R 2 , R 3 , R 4 , X, X′, and

are as defined in claim 1 ; and
R 5 and R 6 are individually selected from hydrogen and C 1 -C 4 alkyl; or
pharmaceutically acceptable salts thereof.

21. A compound according to claim 1 , wherein the compound is selected from those compounds listed in Table 1A and Table 3A:

TABLE 1A

Compound No.
R 1 & R 2
X
R 5
R 6
R 3
L
A

1
C(O)C 15 H 31
O
H
H
CASI 1
NMethyl
Sertraline

2
C(O)C 15 H 31
O
H

Assignees

• Univ Monash

Inventors

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

Classifications

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07C271/24

  with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07J1/0029

  Ethers · CPC title

• A61K47/542 Primary

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title