Heterobifunctional pan-selectin inhibitors

• US 20070054870A1
• Filed: 09/01/2006
• Published: 03/08/2007
• Est. Priority Date: 09/02/2005
• Status: Active Grant

• Current Assignee: GlycoMimetics Inc.
• Original Assignee: GlycoMimetics Inc.
• Inventors: Patton, John, Ernst, Beat, Sarkar, Arun, Magnani, John, Svarovsky, Sergei
• Granted Patent: US 7,728,117 B2
• Time in Patent Office: Days
• US Class Current: 514/35
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07H 15/22 : Cyclohexane rings, substituted by nitrogen atoms
• CPC Class Codes: C07H 15/26 : Acyclic or carbocyclic radicals, substituted by hetero rings
• CPC Class Codes: C07H 17/00 : Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals

Abstract

Compounds and methods are provided for modulating in vitro and in vivo processes mediated by selectin binding. More specifically, selectin modulators and their use are described, wherein the selectin modulators that modulate (e.g., inhibit or enhance) a selectin-mediated function comprise particular glycomimetics alone or linked to a member of a class of compounds termed BASAs (Benzyl Amino Sulfonic Acids) or a member of a class of compounds termed BACAs (Benzyl Amino Carboxylic Acids).

Claims

1. A compound or physiologically acceptable salt thereof, having the formula:

2. The compound or salt thereof according to claim 1 wherein R⁶ is

3. The compound or salt thereof according to claim 1 wherein R⁷ is H.

4. The compound or salt thereof according to claim 1 wherein R⁴ is

5. The compound or salt thereof according to claim 1 wherein R⁴ is

6. The compound or salt thereof according to claim 5, where R⁹ is cyclohexane.

7. The compound or salt thereof according to claim 1 wherein R⁶ is galactose.

8. The compound or salt thereof according to claim 1 wherein R⁸ is

9. The compound or salt thereof according to claim 1 wherein R² is —

[C(═

O)NH(CH₂)_nNHC(═

O)]_m(L)_mZ, where n, m, L and Z are defined according to claim 1.

10. The compound or salt thereof according to claim 9 wherein Z is a benzyl amino sulfonic acid, a benzyl amino carboxylic acid or a polyethylene glycol.

11. The compound or salt thereof according to claim 1 wherein R³ is —

O—

C(═

O)—

X or —

NH—

C(═

O)—

X, where X is defined according to claim 1.

12. The compound or salt thereof according to claim 11 wherein X is

13. The compound or salt thereof according to claim 1 wherein R⁵ is H.

14. The compound or salt thereof according to any one of claims 1-13 wherein L is a polyethylene glycol or a thiadiazole.

15. A composition comprising a compound or salt thereof according to claim 1 in combination with a pharmaceutically acceptable carrier or diluent.

16. A compound or physiologically acceptable salt thereof comprising a compound or salt thereof according to claim 1 further comprising a diagnostic or therapeutic agent.

17. A composition comprising a compound or salt thereof according to claim 16 in combination with a pharmaceutically acceptable carrier or diluent.

18. A method for modulating a selectin-mediated function, comprising contacting a cell expressing a selectin with a compound or salt thereof according to claim 1 in an amount effective to modulate the selectin'"'"'s function.

19. A method for modulating a selectin-mediated function, comprising contacting a cell expressing a selectin with a composition according to claim 15 in an amount effective to modulate the selectin'"'"'s function.

20. A method of treating a patient, comprising administering to the patient who is in need of having inhibited the development of a condition associated with an excessive selectin-mediated function, a compound or salt thereof according to claim 1 in an amount effective to inhibit the development of such a condition.

21. A method of treating a patient, comprising administering to the patient who is in need of having inhibited the development of a condition associated with an excessive selectin-mediated function, a composition according to claim 15 in an amount effective to inhibit the development of such a condition.

22. A method of inhibiting rejection of transplanted tissue, comprising administering to a patient who is the recipient of a transplanted tissue, a compound or salt thereof according to claim 1 in an amount effective to inhibit rejection of the transplanted tissue.

23. A method of inhibiting rejection of transplanted tissue, comprising administering to a patient who is the recipient of a transplanted tissue, a composition according to claim 15 in an amount effective to inhibit rejection of the transplanted tissue.

24. A method of targeting an agent to a selectin-expressing cell, comprising contacting a cell expressing a selectin with a compound or salt thereof according to claim 16 in an amount effective to target a diagnostic or therapeutic agent to the cell.

25. A method of targeting an agent to a selectin-expressing cell, comprising contacting a cell expressing a selectin with a composition according to claim 17 in an amount effective to target a diagnostic or therapeutic agent to the cell.