IP Library › Granted Patent US 12,295,962
Granted Patent B2
US 12,295,962 · App. 18/624,982 · Granted May 13, 2025

Polymorphic compounds and uses thereof

Inventors: Alfredo C. Castro (Somerville, MA); David T. Jonaitis (Brookston, IN)
Assignee: AskAt Inc.
A61K31/64A61K31/44A61K39/3955A61P35/00C07D213/82C07D471/04C07B2200/13
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Quick Facts
Patent No.
US 12,295,962
App. No.
18/624,982
Granted
May 13, 2025
Kind
B2
Abstract

The present invention provides co-crystal and salt forms, and compositions and methods thereof, useful for treating various diseases, disorders or conditions in which EP4 prostaglandin receptors are implicated in the mediation of a proliferative disorder, by the administration of small molecule therapeutics acting as inhibitors of prostaglandin EP4 receptor activity.

Claims (68)

1. A compound selected from the group consisting of:

wherein the compound is crystalline.

2. The compound according to claim 1 , wherein said compound is a crystalline solid substantially free of amorphous compound.

3. The compound according to claim 1 , wherein said compound is substantially free of impurities.

4. A composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

5. A method of inhibiting or preventing prostaglandin EP4 receptor activity in a patient comprising administering to said patient the compound according to claim 1 or a composition thereof.

6. A method for treating a cancer in a patient comprising administering to the patient the compound according to claim 1 or a composition thereof, wherein the cancer is selected from the group consisting of basal cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, stomach cancer, intestinal cancer, colon cancer, gastric cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, prostate cancer, and renal cell carcinoma.

7. The method according to claim 6 , wherein the method comprises administration of the compound, or a composition thereof, in combination with an additional therapeutic agent.

8. The compound according to claim 1 , wherein:

(i) Compound 4 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 14.9, about 16.8 and about 24.5 degrees 2-theta;

(ii) Compound 1 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 13.0, about 15.2 and about 22.0 degrees 2-theta;

(iii) Compound 2 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 10.6, about 19.4 and about 22.4 degrees 2-theta;

(iv) Compound 3 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 8.2, about 9.5 and about 12.4 degrees 2-theta;

(v) Compound 5 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 4.9, about 15.8 and about 25.2 degrees 2-theta;

(vi) Compound 6 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 5.8, about 15.2 and about 22.1 degrees 2-theta;

(vii) Compound 7 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 15.6, about 19.1 and about 22.5 degrees 2-theta;

(viii) Compound 8 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 13.5, about 14.0 and about 21.7 degrees 2-theta;

(ix) Compound 9 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 16.6, about 17.5 and about 23.2 degrees 2-theta;

(x) Compound 10 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 3.6, about 9.4 and about 17.3 degrees 2-theta; and

(xi) Compound 11 is a crystalline solid form having one or more peaks in its XRPD selected from those at about 9.6, about 15.1 and about 15.7 degrees 2-theta.

9. The compound according to claim 1 , wherein:

(i) Compound 4 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 14.9, about 16.8 and about 24.5 degrees 2-theta;

(ii) Compound 1 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 13.0, about 15.2 and about 22.0 degrees 2-theta;

(iii) Compound 2 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 10.6, about 19.4 and about 22.4 degrees 2-theta;

(iv) Compound 3 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 8.2, about 9.5 and about 12.4 degrees 2-theta;

(v) Compound 5 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 4.9, about 15.8 and about 25.2 degrees 2-theta;

(vi) Compound 6 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 5.8, about 15.2 and about 22.1 degrees 2-theta;

(vii) Compound 7 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 15.6, about 19.1 and about 22.5 degrees 2-theta;

(viii) Compound 8 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 13.5, about 14.0 and about 21.7 degrees 2-theta;

(ix) Compound 9 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 16.6, about 17.5 and about 23.2 degrees 2-theta;

(x) Compound 10 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 3.6, about 9.4 and about 17.3 degrees 2-theta; and

(xi) Compound 11 is a crystalline solid form having at least two peaks in its XRPD selected from those at about 9.6, about 15.1 and about 15.7 degrees 2-theta.

10. The compound according to claim 1 , wherein:

(i) Compound 4 is of Form A;

(ii) Compound 1 is of Form A;

(iii) Compound 2 is of Form A;

(iv) Compound 3 is of Form A;

(v) Compound 5 is of Form A;

(vi) Compound 6 is of Form A;

(vii) Compound 7 is of Form A;

(viii) Compound 8 is of Form A;

(ix) Compound 9 is of Form A;

(x) Compound 10 is of Form A; and

(xi) Compound 11 is of Form A.

11. The compound according to claim 1 , wherein:

(i) Compound 4 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 7 ;

(ii) Compound 1 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 1 ;

(iii) Compound 2 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 3 ;

(iv) Compound 3 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 5 ;

(v) Compound 5 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 9 ;

(vi) Compound 6 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 11 ;

(vii) Compound 7 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 13 ;

(viii) Compound 8 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 15 ;

(ix) Compound 9 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 17 ;

(x) Compound 10 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 19 ; and

(xi) Compound 11 is a crystalline solid form having an XRPD substantially similar to that depicted in FIG. 21 .

12. The compound according to claim 1 , wherein:

(i) Compound 4 is a crystalline solid form having all three peaks in its XRPD selected from those at about 14.9, about 16.8 and about 24.5 degrees 2-theta;

(ii) Compound 1 is a crystalline solid form having all three peaks in its XRPD selected from those at about 13.0, about 15.2 and about 22.0 degrees 2-theta;

(iii) Compound 2 is a crystalline solid form having all three peaks in its XRPD selected from those at about 10.6, about 19.4 and about 22.4 degrees 2-theta;

(iv) Compound 3 is a crystalline solid form having all three peaks in its XRPD selected from those at about 8.2, about 9.5 and about 12.4 degrees 2-theta;

(v) Compound 5 is a crystalline solid form having all three peaks in its XRPD selected from those at about 4.9, about 15.8 and about 25.2 degrees 2-theta;

(vi) Compound 6 is a crystalline solid form having all three peaks in its XRPD selected from those at about 5.8, about 15.2 and about 22.1 degrees 2-theta;

(vii) Compound 7 is a crystalline solid form having all three peaks in its XRPD selected from those at about 15.6, about 19.1 and about 22.5 degrees 2-theta;

(viii) Compound 8 is a crystalline solid form having all three peaks in its XRPD selected from those at about 13.5, about 14.0 and about 21.7 degrees 2-theta;

(ix) Compound 9 is a crystalline solid form having all three peaks in its XRPD selected from those at about 16.6, about 17.5 and about 23.2 degrees 2-theta;

(x) Compound 10 is a crystalline solid form having all three peaks in its XRPD selected from those at about 3.6, about 9.4 and about 17.3 degrees 2-theta; and

(xi) Compound 11 is a crystalline solid form having all three peaks in its XRPD selected from those at about 9.6, about 15.1 and about 15.7 degrees 2-theta.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 25, 2024
From: TRICLINIC LABS
To: ARRYS THERAPEUTICS, INC.
Reel/Frame 068685/0239 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 25, 2024
From: JONAITIS, DAVID T.
To: TRICLINIC LABS
Reel/Frame 068685/0243 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 25, 2024
From: CASTRO, ALFREDO C.
To: ARRYS THERAPEUTICS, INC.
Reel/Frame 068685/0247 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 25, 2024
From: ARRYS THERAPEUTICS, INC.
To: ASKAT INC.
Reel/Frame 068685/0268 →
Continuity (5)
Continuation 17258534
Provisional Application 62834539 · Apr 16, 2019
Provisional Application 62737273 · Sep 27, 2018
Provisional Application 62696463 · Jul 11, 2018
Related Publication 20240358723A1 · Oct 31, 2024
References Cited (97)
US 6710054B2 · Nakao et al. · 2004 [cited by applicant]
US 6864265B2 · Bridger et al. · 2005 [cited by applicant]
US 7141580B2 · Nakao et al. · 2006 [cited by applicant]
US 7238714B2 · Nakao et al. · 2007 [cited by applicant]
US 7354934B2 · Bridger et al. · 2008 [cited by applicant]
US 7479564B2 · Nakao et al. · 2009 [cited by applicant]
US 7960407B2 · Haruta et al. · 2011 [cited by applicant]
US 7998505B2 · Thoorens et al. · 2011 [cited by applicant]
US 8921391B2 · Take et al. · 2014 [cited by applicant]
US 9265756B2 · Newbold et al. · 2016 [cited by applicant]
US 9457084B2 · Kanazawa et al. · 2016 [cited by applicant]
US 9688674B2 · Take et al. · 2017 [cited by applicant]
US 9708258B2 · Modi et al. · 2017 [cited by applicant]
US 10342785B2 · Ohtani et al. · 2019 [cited by applicant]
US 10391086B2 · Okumura · 2019 [cited by applicant]
US 10583129B2 · Ohtani et al. · 2020 [cited by applicant]
US 10611761B2 · Take et al. · 2020 [cited by applicant]
US 10947235B2 · Take et al. · 2021 [cited by applicant]
US 10973834B2 · Manfredi et al. · 2021 [cited by applicant]
US 11065226B2 · Yoshida et al. · 2021 [cited by applicant]
US 20090018158A1 · Haruta et al. · 2009 [cited by applicant]
US 20090036495A1 · Audoly · 2009 [cited by applicant]
US 20120088723A1 · Take et al. · 2012 [cited by applicant]
US 20150004175A1 · Kaech et al. · 2015 [cited by applicant]
US 20150250773A1 · Rausch-Derra et al. · 2015 [cited by applicant]
US 20170253595A1 · Take et al. · 2017 [cited by applicant]
US 20170360764A1 · Okumura · 2017 [cited by applicant]
US 20190269663A1 · Ohtani et al. · 2019 [cited by applicant]
US 20190365680A1 · Ohtani et al. · 2019 [cited by applicant]
US 20220073510A1 · Take et al. · 2022 [cited by applicant]
CA 3029611A1 · 2018 [cited by applicant]
EP 2422779A1 · 2012 [cited by applicant]
WO WO2000056729A1 · 2000 [cited by applicant]
WO WO200232422A2 · 2002 [cited by applicant]
WO WO2002032900A2 · 2002 [cited by applicant]
WO WO2003086371A2 · 2003 [cited by applicant]
WO WO2005021508A1 · 2005 [cited by applicant]
WO WO2006095268A1 · 2006 [cited by applicant]
WO WO2011102149A1 · 2011 [cited by applicant]
WO WO2013090552A1 · 2013 [cited by applicant]
WO WO2014148053A1 · 2014 [cited by applicant]
WO WO2015134792A1 · 2015 [cited by applicant]
WO WO2015134797A1 · 2015 [cited by applicant]
WO WO2015179615A1 · 2015 [cited by applicant]
WO WO2018008711A1 · 2018 [cited by applicant]
WO WO2018039197A1 · 2018 [cited by applicant]
WO WO2018084230A1 · 2018 [cited by applicant]
WO WO2019204257A1 · 2019 [cited by applicant]
WO WO2020014445A1 · 2020 [cited by applicant]
WO WO2020014465A1 · 2020 [cited by applicant]
WO WO2006009288A1 · 2020 [cited by applicant]
WO WO2020069288A1 · 2020 [cited by applicant]
WO WO2021205367A1 · 2021 [cited by applicant]
“Grapiprant and Pembrolizumab in Patients with Advanced or Progressive MSS Colorectal Cancer,” https://clinicaltrials.gov/ct2/show/NCT03658772. Accessed May 18, 2022. [cited by applicant]
Adams et al., “Big opportunities for small molecules in immuno-oncology,” Nat Rev Drug Discov, 2015; 14(9):603-22. [cited by applicant]
Albu et al., “EP4 Antagonism by E7046 diminishes Myeloid immunosuppression and synergizes with Treg reducing IL-2-Diphtheria toxin fusion protein in restoring anti-tumor immunity”, Oncoimmunology. Jun. 28, 2017;6(8):e13… [cited by applicant]
An et al., “Solution phase combinatorial chemistry. Discovery of 13- and 15-membered polyazapyridinocyclophane libraries with antibacterial activity,” Tetrahedron. 1998;54(16):3999-4012. [cited by applicant]
Arndt and Kleinebudde, “Influence of binder properties on dry granules and tablets”, Powder Technology, 2018;337:68-77. [cited by applicant]
Bao et al., “Combination of EP4 antagonist and checkpoint inhibitors promotes anti-tumor effector T cells in preclinical tumor models”, J Immunother Cancer. Nov. 2015;3(Suppl2):p. 350. [cited by applicant]
Berge et al., “Pharmaceutical Salts,” J Pharm Sci, 1977;66(1):1-19. [cited by applicant]
Caira, “Crystalline Polymorphism of Organic Compounds,” Topics in Current Chemistry. 1998;198:163-208. [cited by applicant]
Golub et al., “Molecular classification of cancer: class discovery and class prediction by gene expression monitoring,” Science. Oct. 15, 1999;286(5439):531-7. [cited by applicant]
Hilfiker et al., “Relevance of Solid-state Properties for Pharmaceutical Products”, Polymorphism in the Pharmaceutical Industry; 2006; Chapter 1, pp. 1-19. [cited by applicant]
Hua et al., “Topical Loperamide-Encapsulated Liposomal Gel Increases the Severity of Inflammation and Accelerates Disease Progression in the Adjuvant-Induced Model of Experimental Rheumatoid Arthritis,” Front Pharmacol.… [cited by applicant]
Ji et al., “Modified toxicity probability interval design: a safer and more reliable method than the 3+3 design for practical phase I trials,” J Clin Oncol 2013; 31(14):1785-91. [cited by applicant]
Knych et al., “Detection and pharmacokinetics of grapiprant following oral administration to exercised Thoroughbred horses,” Drug Test Anal. 2018; 10(8):1237-1243. [cited by applicant]
Lala and Orucevic, “Role of nitric oxide in tumor progression: lessons from experimental tumors,” Cancer Metastasis Rev. Mar. 1998;17(1):91-106. [cited by applicant]
Majumder et al., “EP4 as a Therapeutic Target for Aggressive Human Breast Cancer”, Int J Mol Sci. Mar. 29, 2018;19(4):1019. [cited by applicant]
Medlineplus, “Cancer”, National Library of Medicine, last updated May 18, 2017, www.nlm.nih.gov/medlineplus/cancer.html. [cited by applicant]
Mohen et al., “Propionic Acid—an Overview, Process Design and Optimization for Platform Chemical Biorefinery”, Platform Chemical Biorefinery, 2016, Section 25.2.1. [cited by applicant]
Nagahisa et al., “Pharmacology of Grapiprant, a Novel EP4 Antagonist: Receptor Binding, Efficacy in a Rodent Postoperative Pain Model, and a Dose Estimation for Controlling Pain in Dogs,” J Vet Pharmacol Ther. 2016; 40(… [cited by applicant]
Nair and Jacob, “A simple practice guide for dose conversation between animals and human”, J Basic Clin Pharm, 2016;7(2):27-31. [cited by applicant]
Okumura et al., “Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist”, Bioorg Med Chem Lett. Mar. 1, 2017;27(5):1186-1192. [cited by applicant]
Partial International Search Report and Provisional Opinion of the International Searching Authority in PCT/US2019/027603, dated Aug. 14, 2019 (15 pages). [cited by applicant]
PCT International Search Report for PCT Application No. PCT/US19/41378, mailed by the U.S. Patent and Trademark Office on Nov. 14, 2019, 4 Pages. [cited by applicant]
PCT International Search Report for PCT Application No. PCT/US19/53413, mailed Dec. 2, 2019 by the ISA/US; 3 Pages. [cited by applicant]
PCT International Search Report for PCT Appllication No. PCT/US2019/041351, mailed by the ISA/US on Oct. 1, 2019, 3 Pages. [cited by applicant]
PubChem-CID-11677589, Create Date: Oct. 26, 2006; entire document, especially p. 2 Figure, p. 6: 3.2.1 Melting Point, Grapiprant Hydrochloride; p. 10: 6.1 Drug Indication. [cited by applicant]
Rausch-Derra et al., “Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs,” J Vet Pharamacol Ther. 2016;39(6):… [cited by applicant]
Rojas et al., “Functional assessment of four types of disintegrants and their effect on the spironolactone release properties”, AAPS PharmSciTech, 2012;13(4):1054-62. [cited by applicant]
Saal and Becker, “Pharmaceutical salts: a summary on doses of salt formers from the Orange Book”, Eur J Pharm Sci. Jul. 16, 2013;49(4):614-23. [cited by applicant]
Shaw et al., “Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation”, Vet Med Sci . Dec. 21, 2015;2(1):3-9. [cited by applicant]
Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorg Med Chem Lett, 2018;28(3):319-329. [cited by applicant]
Watson, “Are We Close to a Cure for Chronic Lymphocytic Leukemia?”, Healthline, last updated Jan. 12, 2023, https://www.healthline.com/health/cll/cll-cure-are-we-close. [cited by applicant]
Yurdakul et al., “Axial Spondyloarthritis and Autosomal Dominant Polycystic Kidney Disease in Two Siblings: a Rare Cooccurrence.” Case Rep Rheumatol. 2018; 6150875. [cited by applicant]
Lee et al., Differential expression of E prostanoid receptors in murine and human non-melanoma skin cancer, J Invest Dermatol. Oct. 2005;125(4):818-25. [cited by applicant]
Piazuelo et al., “Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus”, Prostaglandins Other Lipid Mediat. Dec. 2006;81(3-4): 150-61, Abstract. [cited by applicant]
Sapienza et al. “EP4-mediated prostanoid signalling promotes oral cancer progression”, BMC Proc. Sep. 24, 2010;4 (Suppl 2):p. 35. [cited by applicant]
Chell et al., “Increased EP4 Receptor Expression in Colorectal Cancer Progression Promotes Cell Growth and Anchorage Independence”, Cancer Res. Mar. 15, 2006;66(6):3106-13. [cited by applicant]
Xia et al., “Prostaglandin E2 promotes the cell growth and invasive ability of hepatocellular carcinoma cells by upregulating c-Myc expression via EP4 receptor and the PKA signaling pathway”, Oncol Rep. Oct. 2014;32(4):… [cited by applicant]
Kashiwagi et al., “Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression” Br J Cancer. 2018; 118(2):213-223. [cited by applicant]
Charo et al., “Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor”, Pancreas. Apr. 2013;42(3):467-74. [cited by applicant]
Obermajer et al., “PGE2-Induced CXCL12 Production and CXCR4 Expression Controls the Accumulation of Human MDSCs in Ovarian Cancer Environment”, Cancer Res. Dec. 15, 2011;71(24):7463-70. [cited by applicant]
Sales et al., “Cyclooxygenase-2 Expression and Prostaglandin E2 Synthesis Are Up-Regulated in Carcinomas of the Cervix: A Possible Autocrine/Paracrine Regulation of Neoplastic Cell Function via EP2/EP4 Receptors”, J Cli… [cited by applicant]
Sung et al., “Lack of Expression of the EP2 but not EP3 Receptor for Prostaglandin E2 Results in Suppression of Skin Tumor Development”, Cancer Res. Oct. 15, 2005;65(20):9304-11. [cited by applicant]
Simper et al., “The tumor promoting activity of the EP4 receptor forprostaglandin E2 in murine skin”, Mol Oncol. Dec. 2014;8(8):1626-39. [cited by applicant]
Wu et al., “Prostaglandin E2 regulates renal cell carcinoma invasion through the EP4 receptor-Rap GTPase signal transduction pathway”, J Biol Chem. Sep. 30, 2011;286(39):33954-62. [cited by applicant]