US-12622915-B2 - Methods of treating PDE IV-mediated diseases or conditions

Abstract

The disclosure provides methods and compositions for the treatment of PDE IV-mediated diseases or conditions, including inflammatory diseases or conditions, using a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

Inventors

• Vuk Koprivica

Assignees

• VANDA PHARMACEUTICALS INC.

Dates

Publication Date

20260512

Application Date

20210910

Claims (20)

1. 1 . A method for treatment of a patient with a phosphodiesterase IV (PDEIV)-mediated disease or condition that is psoriasis, atopic dermatitis, contact dermatitis, seborrheic dermatitis, stasis dermatitis, morphea, Behçet's Syndrome, lupus, alopecia, vitiligo, acne, lichen planus, uveitis, Prurigo nodularis, or discoid lupus erythematosus, comprising administering to said patient an amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, effective to treat said disease or condition.
2. 2 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is psoriasis.
3. 3 . The method of claim 2 , wherein the PDEIV-mediated disease or condition is plaque psoriasis.
4. 4 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is atopic dermatitis.
5. 5 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is contact dermatitis.
6. 6 . The method of claim 1 , wherein the patient is a human.
7. 7 . The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition comprising said compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
8. 8 . The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered topically, orally, perorally, as a suppository, intravenously, parenterally, intraperitoneally, intramuscularly, intralesionally, intrathecally, intranasally, or subcutaneously.
9. 9 . The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered topically.
10. 10 . The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.
11. 11 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is seborrheic dermatitis.
12. 12 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is stasis dermatitis.
13. 13 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is morphea.
14. 14 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is Behçet's Syndrome.
15. 15 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is lupus.
16. 16 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is alopecia.
17. 17 . The method of claim 16 , wherein the PDEIV-mediated disease or condition is frontal fibrosing alopecia.
18. 18 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is vitiligo.
19. 19 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is acne.
20. 20 . The method of claim 1 , wherein the PDEIV-mediated disease or condition is lichen planus.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is the U.S. National Phase Application under 35 U.S.C. § 371 of International Application No. PCT/US2021/049870, filed on Sep. 10, 2021, which claims the benefit of U.S. Provisional Application No. 63/076,774, filed on Sep. 10, 2020, the entireties of which incorporated by reference herein. TECHNICAL FIELD The disclosure is directed to methods and compositions for the treatment of PDE IV-mediated diseases or conditions. BACKGROUND Phosphodiesterase IV (PDEIV) is a family of cAMP-specific phosphodiesterase enzymes comprised of four distinct gene products, A-D. See D P Rotella, Phosphodiesterases, Comprehensive Medicinal Chemistry II, 2007, 919-957. PDE4 enzymes are expressed in the CNS and other nervous system tissues, smooth muscle, inflammatory and endothelial cells, and in the heart. PDEIV is responsible for cAMP catabolism and regulation of inflammation in many types of cells. Some small molecule inhibitors of PDEIV have demonstrated anti-inflammatory properties. See. e.g., Sekut, L., et al., (1995), Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. Clinical & Experimental Immunology, 100:126-132. Inflammatory diseases or disorders, and other diseases and disorders having an inflammatory component, represent a significant portion of the conditions afflicting modern populations. Given the large number of conditions in which inflammation is an undesireable aspect, there exists a need for methods of treating patients suffering from inflammation related disorders. SUMMARY The disclosure is directed to, among other things, methods for treatment of a patient with a phosphodiesterase IV (PDEIV)-mediated disease or condition comprising administering to said patient an amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, effective to treat the disease or condition. In other aspects, the disclosure is directed to methods of inhibiting release of an inflammatory cytokine from mammalian inflammatory cell by contacting the mammalian inflammatory cells with an amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, effective to inhibit the release of an inflammatory cytokine from mammalian inflammatory cells. In yet other aspects, the disclosure is directed to methods of inhibiting PDE IV activity in mammalian inflammatory cells by contacting the mammalian inflammatory cells with an amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, that is effective to inhibit the PDE IV activity. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the post randomization body weight by group in Example 1. FIG. 2 shows body weight by group at 6 hours in Example 1. FIG. 3 shows body weight by group at 24 hours in Example 1. FIG. 4 shows the right ear thickness by group at 6 hours in Example 1. FIG. 5 shows the left ear thickness by group at 6 hours in Example 1. FIG. 6 shows the right ear thickness by group at 24 hours in Example 1. FIG. 7 shows the left ear thickness by group at 24 hours in Example 1. FIG. 8 shows the change in right ear thickness by group from 0-6 hours in Example 1. FIG. 9 shows the change in left ear thickness by group from 0-6 hours in Example 1. FIG. 10 shows the change in right ear thickness by group from 0-24 hours in Example 1. FIG. 11 shows the change in left ear thickness by group from 0-24 hours in Example 1. FIG. 12 shows the right ear weight by group at 6 hrs in Example 1. FIG. 13 shows the left ear weight by group at 6 hrs in Example 1. FIG. 14 shows the right ear weight by group at 24 hrs in Example 1. FIG. 15 shows the left ear weight by group at 24 hrs in Example 1. FIG. 16 shows the ear tissue MPO by group at 6 hrs in Example 1. FIG. 17 shows the ear tissue MPO by group at 24 hrs in Example 1. FIG. 18 shows the ear tissue total protein by group at 6 hours in Example 1. FIG. 19 shows the ear tissue total protein by group at 24 hours in Example 1. FIG. 20 shows G-CSF and eotaxin in ear tissue homogenate by group in Example 1. FIG. 21 shows GM-CSF and IL-1ß in ear tissue homogenate by group in Example 1. FIG. 22 shows IL-2 and IL-5 in ear tissue homogenate by group in Example 1. FIG. 23 shows IL-6 and IL-10 in ear tissue homogenate by group in Example 1. FIG. 24 shows KC (keratinocyte chemotactic-like) and MCP-1 (Monocyte Chemotactic Protein-1) in ear tissue homogenate by group in Example 1. FIG. 25 shows MIP-1β and TNF-α in ear tissue homogenate by group in Example 1. FIG. 26 shows plasma and ear tissue concentrations of the compound of Formula (I) in Example 1 FIG. 27 shows the body weight by group in Example 2. FIG. 28 shows the percent change in body weight by group in Example 2. FIG. 29 shows the ear thickness by group in Example 2. FIG. 30 shows back skin thickness by group in Example 2. FIG. 31 shows erythema by group in Example 2. FIG. 32 shows scales by group in Example 2. FIG. 33 shows skin