IP Library › Granted Patent US 12,396,992
Granted Patent B2
US 12,396,992 · App. 17/421,303 · Granted Aug 26, 2025

Organic compounds

Inventors: Gretchen Snyder (New York, NY); Lawrence P. Wennogle (Hillsborough, NJ); Jennifer O'Brien (New York, NY); Joseph Hendrick (New York, NY); Robert Davis (San Diego, CA)
Assignee: INTRA-CELLULAR THERAPIES, INC.
A61K31/519A61P35/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,396,992
App. No.
17/421,303
Granted
Aug 26, 2025
Kind
B2
Abstract

The disclosure relates to the use of phosphodiesterase 1 (PDE1) inhibitors for the treatment of cancers and tumors, including for inhibiting tumor recruitment of macrophages and other cells to the tumor or cancer, for complementing and enhancing checkpoint inhibitor therapies, and for mitigating the side effects (i.e., inflammatory-related adverse events) associated with checkpoint inhibitor therapies.

Claims (54)

1. A method of treating a cancer or tumor by inhibiting one or more of

(A) cancer or tumor recruitment of immune cells;

(B) tumor or cancer metastasis;

(C) tumor or cancer angiogenesis;

(D) disruption of immune surveillance;

comprising administering a pharmaceutically effective amount of a PDE1 inhibitor, optionally in combination or association with a checkpoint inhibitor or an immunotherapy, to a subject in need thereof, wherein the PDE1 inhibitor is a compound of Formula Ia

wherein

(i) R 2 and R 5 are independently H or hydroxy and R 3 and R 4 together form a tri- or tetra-methylene bridge; or R 2 and R 3 are each methyl and R 4 and R 5 are each H; or R 2 , R 4 and R 5 are H and R 3 is isopropyl;

(ii) R 6 is (optionally halo-substituted) phenylamino, (optionally halo-substituted) benzylamino, C 1-4 alkyl, or C 1-4 alkyl sulfide;

(iii) R 10 is C 1-4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl, or thiadiazolyl; and

X and Y are independently C or N,

in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.

2. The method according to claim 1 , wherein the condition is a tumor.

3. The method according to claim 1 , wherein the tumor is selected from one or more of acoustic neuroma, astrocytoma, chordoma, lymphoma, craniopharyngioma, gliomas, subependymoma, medulloblastoma, meningioma, metastatic brain tumors, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET), schwannoma, adenomas, fibroids, fibromas, hemangiomas, lipomas, myxoma, osteoma, preleukemias, rhadomyoma, papilloma, seborrheic keratosis, skin adnexal tumors, hepatic adenomas, renal tubular adenoma, bile duct adenoma, transitional cell papilloma, hydatidiform moles, ganglioneuroma, meningioma, neurilemmoma, neurofibroma, C cell hyperplasia, pheochromocytoma, insulinoma, gastrinoma, carcinoids, chemodectoma, paraganglioma, nevus, actinic keratosis, cervical dysplasia, metaplasia, leukoplakia, hemangioma, lymphangioma, carcinoma, sarcoma, blastoma, germ cell tumor, mesothelioma, malignant skin adnexal tumors, hypernephroma, seminoma, glioma, malignant meningioma, malignant schwannoma, malignant pheochromocytoma, malignant paraganglioma, melanoma, mercell cell neoplasm, cystosarcoma phylloides, or Wilms tumor.

4. The method according to claim 1 , comprising administering a checkpoint inhibitor, wherein the checkpoint inhibitor is selected from one or more of inhibitors of CTLA-4, PD-1 and/or PD-L1.

5. The method according to claim 1 , comprising administering a checkpoint inhibitor, wherein the checkpoint inhibitor comprises one or more members selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, avelumab, durvalumab, atezolizumab, and spartalizumab.

6. The method according to claim 1 , wherein the subject is suffering from a systemic inflammatory response, a gastrointestinal inflammation-related disorder, an endocrine inflammation-related disorder, a dermatologic inflammation-related disorder, an ophthalmologic inflammation-related disorder, a neurologic inflammation-related disorder, a hematologic inflammation-related disorder, a genitourinary inflammation-related disorder, a respiratory inflammation-related disorder, a musculoskeletal inflammation-related disorder, a cardiac inflammation-related disorder, or a defined systemic inflammation-related disorder.

7. A method of mitigation of a disease, disorder or adverse effect consequent to administration of a checkpoint inhibitor therapy, the method comprising administering a pharmaceutically acceptable amount of a PDE1 inhibitor to a subject in need thereof, wherein the PDE1 inhibitor is a compound of Formula Ia

wherein

(i) R 2 and R 5 are independently H or hydroxy and R 3 and R 4 together form a tri- or tetra-methylene bridge; or R 2 and R 3 are each methyl and R 4 and R 5 are each H; or R 2 , R 4 and R 5 are H and R 3 is isopropyl;

(ii) R 6 is (optionally halo-substituted) phenylamino, (optionally halo-substituted) benzylamino, C 1-4 alkyl, or C 1-4 alkyl sulfide;

(iii) R 10 is C 1-4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl, or thiadiazolyl; and

X and Y are independently C or N,

in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.

8. The method according to claim 7 , wherein the checkpoint inhibitor therapy is administered for the treatment of a cancer or tumor.

9. The method according to claim 7 , wherein the checkpoint inhibitor is an inhibitor of CTLA-4, PD-1 and/or PD-L1.

10. The method according to claim 7 , wherein the disease, disorder or adverse effect consequent to administration of a checkpoint inhibitor therapy is a systemic inflammatory response, a gastrointestinal inflammation-related disorder, an endocrine inflammation-related disorder, a dermatologic inflammation-related disorder, an ophthalmologic inflammation-related disorder, a neurologic inflammation-related disorder, a hematologic inflammation-related disorder, a genitourinary inflammation-related disorder, a respiratory inflammation-related disorder, a musculoskeletal inflammation-related disorder, a cardiac inflammation-related disorder, or a defined systemic inflammation-related disorder.

11. A method of suppressing macrophage or microglial recruitment to metastatic cells comprising administering a pharmaceutically acceptable amount of a PDE1 inhibitor to a subject in need thereof, wherein the PDE1 inhibitor is a compound of Formula Ia

wherein

(i) R 2 and R 5 are independently H or hydroxy and R 3 and R 4 together form a tri- or tetra-methylene bridge; or R 2 and R 3 are each methyl and R 4 and R 5 are each H; or R 2 , R 4 and R 5 are H and R 3 is isopropyl;

(ii) R 6 is (optionally halo-substituted) phenylamino, (optionally halo-substituted) benzylamino, C 1-4 alkyl, or C 1-4 alkyl sulfide;

(iii) R 10 is C 1-4 alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl, or thiadiazolyl; and

X and Y are independently C or N,

in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.

12. The method according to claim 11 , wherein the macrophage or microglial recruitment to metastatic cells is mediated at least in part by CCL2.

13. The method according to claim 11 , wherein the PDE1 inhibitor is administered in combination with a checkpoint inhibitor, e.g., wherein the checkpoint inhibitor is an inhibitor of CTLA-4, PD-1 and/or PD-L1.

14. The method according to claim 1 , wherein the PDE1 inhibitor is selected from any of the following

in free or pharmaceutically acceptable salt form.

15. The method according to claim 1 , wherein the PDE1 inhibitor is

in free or pharmaceutically acceptable salt form.

16. The method according to claim 1 , wherein the PDE1 inhibitor is

in free or pharmaceutically acceptable salt form.

17. The method according to claim 7 , wherein the PDE1 inhibitor is selected from any of the following

in free or pharmaceutically acceptable salt form.

18. The method according to claim 7 , wherein the PDE1 inhibitor is

in free or pharmaceutically acceptable salt form.

19. The method according to claim 7 , wherein the PDE1 inhibitor is

in free or pharmaceutically acceptable salt form.

20. The method according to claim 11 , wherein the PDE1 inhibitor is selected from any of the following

in free or pharmaceutically acceptable salt form.

21. The method according to claim 11 , wherein the PDE1 inhibitor is

in free or pharmaceutically acceptable salt form.

22. The method according to claim 11 , wherein the PDE1 inhibitor is

in free or pharmaceutically acceptable salt form.

Continuity (2)
Provisional Application 62789499 · Jan 7, 2019
Related Publication 20220072003A1 · Mar 10, 2022
References Cited (74)
US 4690935A · Taylor et al. · 1987 [cited by applicant]
US 8273751B2 · Li · 2012 [cited by applicant]
US 8633180B2 · Li et al. · 2014 [cited by applicant]
US 8664207B2 · Li et al. · 2014 [cited by applicant]
US 9073936B2 · Li et al. · 2015 [cited by applicant]
US 9545406B2 · Wennogle · 2017 [cited by applicant]
US 9708294B2 · Li et al. · 2017 [cited by applicant]
US 9884872B2 · Li et al. · 2018 [cited by applicant]
US 10092575B2 · Branstetter et al. · 2018 [cited by applicant]
US 10150774B2 · Li et al. · 2018 [cited by applicant]
US 10682355B2 · Wennogle · 2020 [cited by applicant]
US 10849862B2 · Kawakami et al. · 2020 [cited by applicant]
US 11291666B2 · Snyder et al. · 2022 [cited by applicant]
US 11504372B2 · Wennogle · 2022 [cited by applicant]
US 20140128353A1 · Bannister et al. · 2014 [cited by applicant]
US 20140235556A1 · Halse et al. · 2014 [cited by applicant]
US 20150017267A1 · Guedes et al. · 2015 [cited by applicant]
US 20160324860A1 · Hendrick et al. · 2016 [cited by applicant]
US 20160362489A1 · Yang · 2016 [cited by applicant]
US 20200085782A1 · Gallatin et al. · 2020 [cited by applicant]
US 20210205310A1 · Wennogle et al. · 2021 [cited by applicant]
US 20210338679A1 · Li et al. · 2021 [cited by applicant]
US 20220354851A1 · Li et al. · 2022 [cited by applicant]
WO WO2006133261A2 · 2006 [cited by applicant]
WO WO2006133261A3 · 2006 [cited by applicant]
WO WO2016022893A1 · 2016 [cited by applicant]
WO 2017011831A1 · 2017 [cited by applicant]
WO WO2018093591A1 · 2018 [cited by applicant]
WO WO2019046778A1 · 2019 [cited by applicant]
WO 2019227004A1 · 2019 [cited by applicant]
WO WO2020146384 · 2020 [cited by examiner]
WO 2023173131A2 · 2023 [cited by applicant]
Levy et al., “Phosphodiesterase Function and Endocrine Cells: Links to Human Disease and Roles in Tumor Development and Treatment,” [cited by applicant]
Snyder et al., “Suppression of CNS Inflammation by Phosphodiesterase-1 (PDE1) Inhibitors: Toward New Treatments for Neurodegenerative Diseases,” Database Embase, Database Accession No. EMB-620612543, Alzheimer's Associa… [cited by applicant]
Abusnina et al., “Anti-Proliferative Effect of Curcumin on Melanoma Cells is Mediated by PDE1A Inhibition that Regulates the Epigenetic Integrator UHRF1,” [cited by applicant]
Ahlström et al., “Cyclic Nucleotide Phosphodiesterases (PDEs) in Human Osteoblastic Cells; The Effect of PDE Inhibition on cAMP Accumulation,” [cited by applicant]
Ahmad et al., “Cyclic Nucleotide Phosphodiesterases: Important Signaling Modulators and Therapeutic Targets,” [cited by applicant]
Almahariq et al., “Pharmacological Inhibition and Genetic Knockdown of Exchange Protein Directly Activated by cAMP 1 Reduce Pancreatic Cancer Metastasis In Vivo,” [cited by applicant]
Argyle et al., “Targeting Macrophage-Recruiting Chemokines as a Novel Therapeutic Strategy to Prevent the Progression of Solid Tumors,” [cited by applicant]
Boyd et al., “cAMP-Phosphodiesterase PDE4D as a Target for Colon Cancer Therapy,” [cited by applicant]
Brodbelt et al., “Glioblastoma in England: 2007-2011,” [cited by applicant]
Chen et al., “cAMP Inhibits Cell Migration by Interfering with Rac-induced Lamellipodium Formation,” [cited by applicant]
Coussens et al., “Inflammation and Cancer,” [cited by applicant]
Daniel et al., “Sensitivity of GBM Cells to cAMP Agonist-mediated Apoptosis Correlates with CD44 Expression and Agonist Resistance with MAPK Signaling,” [cited by applicant]
Insel et al., “Cyclic AMP is Both a Pro-apoptotic and Anti-apoptotic Second Messenger,” [cited by applicant]
Jang et al., “Adaptation of cAMP Signaling System in SH-SY5Y Neuroblastoma Cells Following Expression of a Constitutively Active Stimulatory G Protein Alpha, Q227L Gsα,” [cited by applicant]
Jiang et al., “Expression and Regulation of mRNA for Distinct Isoforms of cAMP-Specific PDE-4 in Mitogen-Stimulated and Leukemic Human Lymphocytes,” [cited by applicant]
Kim et al., “Antiinflammatory cAMP Signaling and Cell Migration Genes Co-opted by the Anthrax Bacillus,” [cited by applicant]
Marko et al., “Cyclic 3′,5′-nucleotide Phosphodiesterases: Potential Targets for Anticancer Therapy,” [cited by applicant]
Medina, A, “Therapeutic Utility of Phosphodiesterase Type I Inhibitors in Neurological Conditions,” [cited by applicant]
Pantziarka et al., “Repurposing Drugs in Oncology (ReDO)—Selective PDE5 Inhibitors as Anti-Cancer Agents,” [cited by applicant]
Peng et al., “Inhibitors of Phosphodiesterase as Cancer Therapeutics,” [cited by applicant]
Rowther et al., “Cyclic Nucleotide Phosphodiesterase-1C (PDE1C) Drives Cell Proliferation Migration and Invasion in Glioblastoma Multiforme Cells In Vitro,” [cited by applicant]
Rybalkin et al., “Calmodulin-stimulated Cyclic Nucleotide Phosphodiesterase (PDE1C) is Induced in Human Arterial Smooth Muscle Cells of the Synthetic, Proliferative Phenotype,” [cited by applicant]
Savai et al., “Targeting Cancer with Phosphodiesterase Inhibitors,” [cited by applicant]
Shimizu et al., “Characterization of Phosphodiesterase 1 in Human Malignant Melanoma Cell Lines,” [cited by applicant]
Shiri et al., “Dendrosomal Curcumin Suppresses Metastatic Breast Cancer in Mice by Changing M1/M2 Macrophage Balance in the Tumor Microenvironment,” [cited by applicant]
Soon, L, “A Discourse on Cancer Cell Chemotaxis: Where to From Here?”, [cited by applicant]
Stupp et al., “Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma”, [cited by applicant]
Touat et al., “Glioblastoma Targeted Therapy: Updated Approaches from Recent Biological Insights,” [cited by applicant]
Vitale et al., “A New Therapeutic Strategy Against Cancer: cAMP Elevating Drugs and Leptin,” [cited by applicant]
Watanabe et al., “Phosphodiesterase 4 Regulates the Migration of B16-F10 Melanoma Cells,” [cited by applicant]
“Gene expression,” Wikipedia, 17 pages, (2017); accessed on Jul. 18, 2019 at https://en.wikipedia.org/w/index.php?title=Gene_expression&oldid=803718522. [cited by applicant]
Zong et al., “The Cellular Origin for Malignant Glioma and Prospects for Clinical Advancements,” [cited by applicant]
Bastin, R. et al., “Salt Selection and Optimized Procedures for Pharmaceutical New Chemical Entities,” Organic Process and Research Development, vol. 4, No. 5, pp. 427-435, (2000). [cited by applicant]
Hayakawa, T. et al., “Enhanced anti-tumor effects of the PD-1/PD-L1 blockade by combining a highly absorptive form of NF-κB/STAT3 inhibitor curcumin,” Journal for ImmunoTherapy of Cancer, vol. 2, Suppl. 3, p. P210, (201… [cited by applicant]
Johnson, J. et al., “Curcumin for chemoprevention of colon cancer,” Cancer Letters, vol. 255, pp. 170-181, (2007). [cited by applicant]
Li, P. et al., “Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases,” Journal of Medicinal Chemis… [cited by applicant]
Martinez, F. et al., “Genetic Programs Expressed in Resting and IL-4 Alternatively Activated Mouse and Human Macrophages: Similarities and Differences,” Blood, vol. 121, No. 9, 13 pages, (2013). [cited by applicant]
Mietto, B. et al., “Role of IL-10 in Resolution of Inflammation and Functional Recovery after Peripheral Nerve Injury,” The Journal of Neuroscience, vol. 35, No. 50, pp. 16431-16442, (2015). [cited by applicant]
Szajewska, H., “Evidence-based Medicine and Clinical Research: Both are Needed, Neither is Perfect,” Annals of Nutrition and Metabolism, vol. 72, No. 3, pp. 13-23, (2018). [cited by applicant]
Wesserling, M. et al., “Will In Vitro Tests Replace Animal Models in Experimental Oncology?,” Journal of Tissue Science and Engineering, vol. 2, No. 1, p. 102e, (2011), Abstract only. [cited by applicant]
Yue, G. et al., “Combined therapy using bevacizumab and turmeric ethanolic extract (with absorbable curcumin) exhibited beneficial efficacy in colon cancer mice,” Pharmacological Research, vol. 111, pp. 43-57, (2016). [cited by applicant]
Zhao. A. et al., “Recent Advances in the Study of Ca2+/CaM-activated Phosphodiesterases: Expression and Physiological Functions,” Adv Second Messenger Phosphoprotein Res, vol. 31, pp. 237-251, (1997). [cited by applicant]
Cited By (1)
US 12,636,287