LYMPH DIRECTING PRODRUGS

• US 20170326103A1
• Filed: 08/12/2015
• Published: 11/16/2017
• Est. Priority Date: 08/12/2014
• Status: Active Grant

• Current Assignee: Monash University
• Original Assignee: Monash University
• Inventors: Porter, Chris, Simpson, Jamie, Trevaskis, Natalie, Quach, Tim, Han, Sifei, Hu, Luojuan
• Granted Patent: US 11,311,512 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: B01J 20/291 Gel sorbents
• CPC Class Codes: C07J 1/0025 Esters
• CPC Class Codes: C07J 1/0029 Ethers
• CPC Class Codes: C07J 31/00 Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
• CPC Class Codes: C07J 31/006 not covered by C07J31/003
• CPC Class Codes: C07J 5/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
• CPC Class Codes: C07J 7/002 not substituted in position 16
• CPC Class Codes: C07J 9/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
• CPC Class Codes: C09J 5/00 Adhesive processes in general; Adhesive processes not provided for elsewhere, e.g. relating to primers

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.

Claims

1. A compound of the formula (I):

2. A compound according to claim 1, wherein R³ is selected from:

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

4. A compound according to claim 1, wherein Y and Z are selected to facilitate stable transport of the pharmaceutical agent to the intestinal lymph.

5. A compound according to claim 4, wherein Y and Z are selected to facilitate release of the pharmaceutical agent in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, tumours, the liver or in the systemic circulation.

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

7. A compound according to claim 6, wherein the pharmaceutical agent is one that exhibits greater than 50% first pass metabolism or has highly variable first pass metabolism after oral administration.

8. A compound according to claim 7, wherein the pharmaceutical agent is selected from testosterone, mycophenolic acid, oestrogens (estrogen), morphine, metoprolol, raloxifene, alphaxolone, statins such as atorvastatin, buprenorphine, pentazocine, propranolol, L-DOPA, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, isosorbidedinitrate, oxprenolol, labetalol, verapamil, salbutamol, epitiostanol, melphalan or lovastatin.

9. A compound according to claim 8 wherein the pharmaceutical agent is testosterone and the compound is represented by the formula (IV):

10. A compound according to claim 6, wherein R⁵ is methyl and R⁶ is hydrogen.

11. A compound according to claim 6, wherein R⁵ is hydrogen and R⁶ is methyl.

12. A compound according to claim 1, wherein X and X′

are oxygen.

13. A compound according to claim 1, wherein R¹ and R² are residues of palmitic acid.

14. A method of treating or preventing a disease or disorder in which increased testosterone levels are beneficial, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to claim 9.

15. A method according to claim 14 wherein the disease or disorder is hypogonadism, anaemia due to bone marrow failure, anaemia due to renal failure, chronic respiratory failure, chronic cardiac failure, steroid-dependent autoimmune disorders, AIDS wasting, hereditary angioedema or urticaria, terminal breast cancer or menopause.

21. A compound according to claim 1 wherein the compound is selected to facilitate targeted delivery of the pharmaceutical agent within the lymphatic system.

22. A compound according to claim 21 wherein the pharmaceutical agent is selected from non-steroidal anti-inflammatory medications (NSAIDS, such as aspirin, ibuprofen, naproxen), COX-2 inhibitors (such as celecoxib, rofecoxib), corticosteroid anti-inflammatory medications (such as prednisolone, dexamethasone), anti-malarial medications (such as hydroxychloroquine), cyclophosphamide, nitrosoureas, platinum, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracyclines (such as daunarubicin), mitomycin C, bleomycin, mithramycin, drugs acting on immunophilins (such as ciclosporin, tacrolimus, sirolimus), sulfasalazine, leflunomide, mycophenolate, opioids, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinibmesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxinemepesuccinate, 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 such as mycophenolic acid, cyclosporine, tacrolimus, sirolimus and pharmaceutically active peptides.

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

16. A method of promoting lymphatic transport and systemic release of a pharmaceutical agent comprising conjugating to the pharmaceutical compound a prodrug residue of the formula (VI):

17. A method according to claim 16, wherein R³ is selected from:

18. A method according to claim 16, wherein the compound is administered orally with food to promote transport to the intestinal lymph.

19. A method according to claim 16, wherein the compound is co-administered orally with a lipid based formulation to promote transport to the intestinal lymph.

20. A method according to claim 16, wherein the compound is co-administered orally with an enzyme inhibitor.