4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase

• US 10,752,581 B2
• Filed: 03/01/2019
• Issued: 08/25/2020
• Est. Priority Date: 10/10/2013
• Status: Active Grant

• Current Assignee: Eastern Virginia Medical School, US Department of Health and Human Services (Government of the United States of America), Thomas Jefferson University (Main Line Health System)
• Original Assignee: Eastern Virginia Medical School
• Inventors: Maloney, David J., Luci, Diane K., Jadhav, Ajit, Holman, Theodore, Nadler, Jerry L., Holinstat, Michael, Taylor-Fishwick, David, Simeonov, Anton, Yasgar, Adam, McKenzie, Steven
• Primary Examiner(s): Pagonakis, Anna
• Application Number:
  US16/289,994
• Publication Number:
  US 20190276395A1
• Time in Patent Office: 543 Days
• Field of Search: None
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07C 311/44 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 211/28 to which a second hetero atom is attached
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 217/02 with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 217/22 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 235/30 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 239/69 Benzenesulfonamido-pyrimidines
• CPC Class Codes: C07D 261/16 Benzene-sulfonamido isoxazoles
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 277/52 to sulfur atoms, e.g. sulfonamides
• CPC Class Codes: C07D 277/82 Nitrogen atoms
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 333/36 Nitrogen atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

Claims

1. A compound of Formula (I)

2. The compound of claim 1, wherein R₁ is selected from the group consisting of methoxy and Cl when R₂ is H;

R₂ is selected from the group consisting of Br, and Cl when R₁ is H; and

R₃ is selected from the group consisting of 2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 4-methyl-2-benzothiazole, thiophene, phenyl, 1-naphthalene, 2naphthalene, 1, 4-bi-phenyl, 3-piperazine-phenyl, 4-piperidine-phenyl, 4-piperazine-3-pyridine, 6-methyl-3-pyridine, 3-quinoline, 8-isoquinoline, 2-pyridine, 3-pyridine, 3-tertbutyl-phenyl, 6-methoxy-2-benzothiazole, 6-fluro-2-benzothiazole, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, 3-piperidine-phenyl, 3-isopropyl-phenyl, and 4-bi-phenyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein R₁ is methoxy and R₂ is H.

4. The compound of claim 3, wherein R₃ is thiophene.

10. The compound of claim 1, wherein R₁ is methoxy and R₂ is H.

11. The compound of claim 1, wherein R₃ is phenyl, optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, F, Cl, Br, hydroxyl, amine, alkoxy, phenyl, cycloalkyl, aryl, piperazine, piperidine, pyridine, morpholine, pyrrolidine, pyrazolidine, imidazolidine, and thiomorpholine.

12. The compound of claim 11, wherein R₃ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl and Br.

13. The compound of claim 12, wherein R₃ is phenyl substituted with F.

5. A compound of Formula (I)

6. The compound of claim 5 wherein R₃ is pyridine.

7. A compound of formula (II)

8. A compound of formula (III)

9. A compound of formula (IV)