3-(5-SUBSTITUTED-4-OXOQUINAZOLIN-3(4H)-YL)-3-DEUTERO-PIPERIDINE-2,6-DIONE DERIVATIVES AND COMPOSITIONS COMPRISING AND METHODS OF USING THE SAME

• US 20190330124A1
• Filed: 12/17/2018
• Published: 10/31/2019
• Est. Priority Date: 01/14/2013
• Status: Active Grant

• Current Assignee: Salarius Pharmaceuticals, Inc.
• Original Assignee: Deuterx, Llc
• Inventors: DeWitt, Sheila
• Granted Patent: US 11,040,925 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/515 Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 51/0459 having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 27/16 Otologicals
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• 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 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 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07B 59/002 : Heterocyclic compounds
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides 3-deuterium-enriched 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same, such as in the treatment of cancer, an immune-related disease, or an inflammatory disease.

Claims

1. A deuterium-enriched compound of Formula I:

7. The deuterium-enriched compound of claim 1, wherein the compound is

12. The deuterium-enriched compound of claim 1, wherein the compound is a deuterium-enriched compound of Formula Ia or Ib:

13. The deuterium-enriched compound of claim 1, wherein the compound is a deuterium-enriched compound of Formula Ic or Id:

14. The deuterium-enriched compound of claim 1, wherein the compound is a deuterium-enriched compound of Formula Ie or If:

15. A deuterium-enriched compound of claim 12, wherein R¹⁰=R^10a and pharmaceutically acceptable salts and solvates thereof.

16. The deuterium-enriched compound of claim 1, wherein the compound is a deuterium-enriched compound of Formulae IIa or IIb:

17. The deuterium-enriched compound of claim 1, wherein the compound is selected from:

18. The deuterium-enriched compound of claim 1, wherein the compound is a deuterium-enriched compound of Formulae IIIa or IIIb:

19. The deuterium-enriched compound of claim 1, wherein the compound is selected from:

20. The deuterium-enriched compound of claim 1, wherein the compound is a deuterium-enriched compound of Formulae IVa or IVb:

21. The deuterium-enriched compound of claim 1, wherein the compound is selected from:

22. The deuterium-enriched compound of claim 1, wherein the abundance of deuterium in Z is selected from:

(a) at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e) at least 80%, (f) at least 90%, (g) at least 95%, (h) at least 97%, and (i) about 100%.

24. The deuterium-enriched compound of claim 12, wherein the enantiomeric excess, with respect to the C—

Z carbon, is at least 90%.

26. The deuterium-enriched compound of claim 12, wherein the enantiomeric excess, with respect to the C—

Z carbon, is at least 97%.

27. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1.

28. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 22.

29. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 24.

30. A method for treating, preventing, and/or managing angiogenesis and/or a cytokine related disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

2-6. -6. (canceled)

8-11. -11. (canceled)

23. (canceled)

25. (canceled)