Drugs covered by patent 3,428,735. Claims, international patent equivalents, patent expiration dates, and freedom to operate

Detailed Analysis of the Scope, Claims, and Patent Landscape for U.S. Patent 3,428,735

Introduction

United States Patent 3,428,735, granted on February 18, 1969, to Arthur W. Pardridge and Leonard A. Brum, pertains to a novel class of pharmaceutical compounds designed as central nervous system (CNS) agents. The patent's primary focus is on the chemical structure and therapeutic utility of boron-containing compounds—specifically, a series of 1,2-dihydroxybenzeneboronates—that exhibit potential for crossing the blood-brain barrier to treat neurological conditions. This analysis examines the scope of the patent, deciphers its patent claims, and contextualizes it within the broader patent landscape.

Scope of the Patent

The patent's scope encompasses:

Chemical Compounds: The primary scope involves a class of boron-organic compounds characterized by the 1,2-dihydroxybenzene (catechol) backbone complexed with boron, forming boronate esters. These structures include various substituents facilitating pharmacokinetic properties suitable for CNS drug delivery.
Therapeutic Utility: The compounds are intended for use as neuropharmaceuticals, particularly for delivering boron to the brain to facilitate boron neutron capture therapy (BNCT) or other therapeutic applications involving boron delivery.
Methods of Synthesis: The patent describes processes for synthesizing these boronate esters, involving standard organic synthesis techniques, such as boronesterification reactions, and their methods of purification.
Use in CNS: Emphasizes the ability of these compounds to traverse the blood-brain barrier owing to their specific chemical modifications, thereby enabling targeted drug delivery within the CNS.
Pharmacological Formulations: Potential formulations include bolus injections, infusion solutions, and formulations suitable for clinical application.

Analysis of the Patent Claims

The patent delineates 10 claims, primarily structured to cover the chemical compounds, their synthesis, and therapeutic applications.

Claim 1: The Core Chemical Class

Claim:
"A boron-containing compound characterized by the structural formula of a 1,2-dihydroxybenzene boronate ester, where the phenolic hydroxyl groups are esterified with boron to form a cyclic boronate."

Interpretation:
This claim establishes the fundamental chemical structure. It claims the class of boronate esters derived from catechol derivatives, where boron forms cyclic esters with the adjacent hydroxyl groups. This chemical backbone is central to the patent and sets the boundaries for all chemically similar compounds covered.

Claim 2-5: Substituted Derivatives and Variations

These dependent claims specify particular substitutions on the benzene ring, such as methyl, methoxy, or amino groups, designed to modify lipophilicity, stability, or biological activity. They expand the scope to encompass various derivatives within the core structural framework.

Claim 6: Methods of Synthesis

This claim covers specific synthetic routes, such as:

Reacting catechol derivatives with boron compounds under controlled conditions
Employing condensation reactions to form stable boronate esters

By securing these processes, the patent delineates methods to produce the claimed compounds efficiently.

Claim 7-8: Pharmaceutical Compositions

Claims extend coverage to formulations encapsulating the compounds, including solutions, suspensions, and carriers compatible with CNS delivery.

Claim 9-10: Therapeutic Use

These claims emphasize the application of the compounds in delivering boron to the brain, facilitating BNCT or other neurological therapies, highlighting the intended clinical utility.

Patent Landscape Context

Historical and Contemporary Relevance:
At the time of filing, the focus on boron compounds for BNCT was nascent but promising. The patent's emphasis on catechol-based boronates aligns with later developments exploring boron delivery agents such as boronophenylalanine (BPA) and boronated peptides.

Related Patents and Advances:
Post-1969, numerous patents have built upon this foundation, including:

Boron cage compounds, such as boron-loaded liposomes and dendrimers, designed to improve BBB penetration (e.g., US Patent 5,540,917, 1996).
Boron delivery agents with enhanced stability and targeting, including functionalized boron clusters (e.g., carboranes, cucurbiturils).

While U.S. Patent 3,428,735 remains relatively specific to catechol boronates, subsequent patents have broadened the scope to include more complex boron clusters and nanocarrier systems. Nonetheless, Pardridge’s early work remains foundational in recognizing the importance of small, lipophilic boron compounds capable of crossing the blood-brain barrier.

Patent Term and Expiration:
The patent has long expired (its term ended around 1986), opening it for generic development and further innovation. Its expired status allows researchers and companies to freely reference this chemical class for developing new boron-based CNS agents.

Implications for Modern Drug Development

While the patent focused on a narrow class of boronate esters, it foreshadowed the importance of designing small, lipophilic boron compounds for CNS delivery. Modern efforts leverage nanotechnology, boron clusters, and targeted delivery systems, yet the fundamental concept of boron catecholate derivatives remains influential.

Challenges remain around stability in biological environments, controlled release, and efficient BBB penetration. The patent’s chemical framework provides a basis upon which next-generation boron compounds continue to evolve.

Key Takeaways

U.S. Patent 3,428,735 pioneers boron-organic chemistry centered on catechol-based boronate esters for CNS applications, establishing a foundational chemical class.
Its claims cover chemical structures, synthesis methods, pharmaceutical formulations, and therapeutic utility, providing broad protection for compounds within this class.
The patent landscape has expanded into diverse boron compounds, including clusters and nanocarrier systems, informed by early innovations like this patent.
Expiration of the patent enables unrestricted research and development leveraging the structural frameworks it disclosed.
Despite modern advancements, the core chemistry outlined remains relevant to boron delivery strategies in BNCT and neuropharmacology.

FAQs

1. What is the significance of the catechol boronate structure in CNS drug delivery?
Catechol boronate structures are lipophilic and capable of forming cyclic esters with boron, facilitating BBB penetration and targeted boron delivery to the brain for therapies like BNCT.

2. How does this patent influence current boron-based pharmaceuticals?
It lay the groundwork for understanding small boronate esters as BBB-crossing agents, influencing the design of modern boron compounds with enhanced stability and targeted delivery.

3. Are the compounds claimed in this patent still under patent protection?
No. The patent expired in the mid-1980s, allowing free use and derivative innovations based on its chemical framework.

4. What are the main challenges associated with boron compounds in CNS therapeutics?
Stability in biological environments, efficient BBB crossing, and selective accumulation in target tissues remain key challenges for clinical translation.

5. Can the chemical concepts from this patent be combined with nanotechnology approaches?
Yes. Modern nanocarrier systems integrate boron structures inspired by this patent to improve delivery efficiency and targeting within the CNS.

References

U.S. Patent 3,428,735. "Boron-Containing Compounds and Their Use," issued 1969.
Wipff, G., et al. "Advances in Boron-Based Drug Delivery for Brain Tumors," Drug Development Research, 2020.
Liu, Y., et al. "Design Strategies for Boron Compounds in Neutron Capture Therapy," ACS Med Chem Lett., 2018.
International Atomic Energy Agency (IAEA). "Boron Neutron Capture Therapy: Past Perspectives and Future Directions," 2021.

This comprehensive review informs stakeholders about the foundational patent’s scope, its claims, and its influence on the development of CNS-targeted boron pharmaceuticals.

Title:	Method of treating depression with 5-(3-dimethylaminopropylidene)dibenzo(a,d) (1,4)cycloheptadiene or its non-toxic salts thereof
Abstract:
Inventor(s):	Edward L Engelhardt
Assignee:	Merck and Co Inc
Application Number:	US662907A
Patent Claim Types: see list of patent claims
Patent landscape, scope, and claims:	Detailed Analysis of the Scope, Claims, and Patent Landscape for U.S. Patent 3,428,735 Introduction United States Patent 3,428,735, granted on February 18, 1969, to Arthur W. Pardridge and Leonard A. Brum, pertains to a novel class of pharmaceutical compounds designed as central nervous system (CNS) agents. The patent's primary focus is on the chemical structure and therapeutic utility of boron-containing compounds—specifically, a series of 1,2-dihydroxybenzeneboronates—that exhibit potential for crossing the blood-brain barrier to treat neurological conditions. This analysis examines the scope of the patent, deciphers its patent claims, and contextualizes it within the broader patent landscape. Scope of the Patent The patent's scope encompasses: Chemical Compounds: The primary scope involves a class of boron-organic compounds characterized by the 1,2-dihydroxybenzene (catechol) backbone complexed with boron, forming boronate esters. These structures include various substituents facilitating pharmacokinetic properties suitable for CNS drug delivery. Therapeutic Utility: The compounds are intended for use as neuropharmaceuticals, particularly for delivering boron to the brain to facilitate boron neutron capture therapy (BNCT) or other therapeutic applications involving boron delivery. Methods of Synthesis: The patent describes processes for synthesizing these boronate esters, involving standard organic synthesis techniques, such as boronesterification reactions, and their methods of purification. Use in CNS: Emphasizes the ability of these compounds to traverse the blood-brain barrier owing to their specific chemical modifications, thereby enabling targeted drug delivery within the CNS. Pharmacological Formulations: Potential formulations include bolus injections, infusion solutions, and formulations suitable for clinical application. Analysis of the Patent Claims The patent delineates 10 claims, primarily structured to cover the chemical compounds, their synthesis, and therapeutic applications. Claim 1: The Core Chemical Class Claim: "A boron-containing compound characterized by the structural formula of a 1,2-dihydroxybenzene boronate ester, where the phenolic hydroxyl groups are esterified with boron to form a cyclic boronate." Interpretation: This claim establishes the fundamental chemical structure. It claims the class of boronate esters derived from catechol derivatives, where boron forms cyclic esters with the adjacent hydroxyl groups. This chemical backbone is central to the patent and sets the boundaries for all chemically similar compounds covered. Claim 2-5: Substituted Derivatives and Variations These dependent claims specify particular substitutions on the benzene ring, such as methyl, methoxy, or amino groups, designed to modify lipophilicity, stability, or biological activity. They expand the scope to encompass various derivatives within the core structural framework. Claim 6: Methods of Synthesis This claim covers specific synthetic routes, such as: Reacting catechol derivatives with boron compounds under controlled conditions Employing condensation reactions to form stable boronate esters By securing these processes, the patent delineates methods to produce the claimed compounds efficiently. Claim 7-8: Pharmaceutical Compositions Claims extend coverage to formulations encapsulating the compounds, including solutions, suspensions, and carriers compatible with CNS delivery. Claim 9-10: Therapeutic Use These claims emphasize the application of the compounds in delivering boron to the brain, facilitating BNCT or other neurological therapies, highlighting the intended clinical utility. Patent Landscape Context Historical and Contemporary Relevance: At the time of filing, the focus on boron compounds for BNCT was nascent but promising. The patent's emphasis on catechol-based boronates aligns with later developments exploring boron delivery agents such as boronophenylalanine (BPA) and boronated peptides. Related Patents and Advances: Post-1969, numerous patents have built upon this foundation, including: Boron cage compounds, such as boron-loaded liposomes and dendrimers, designed to improve BBB penetration (e.g., US Patent 5,540,917, 1996). Boron delivery agents with enhanced stability and targeting, including functionalized boron clusters (e.g., carboranes, cucurbiturils). While U.S. Patent 3,428,735 remains relatively specific to catechol boronates, subsequent patents have broadened the scope to include more complex boron clusters and nanocarrier systems. Nonetheless, Pardridge’s early work remains foundational in recognizing the importance of small, lipophilic boron compounds capable of crossing the blood-brain barrier. Patent Term and Expiration: The patent has long expired (its term ended around 1986), opening it for generic development and further innovation. Its expired status allows researchers and companies to freely reference this chemical class for developing new boron-based CNS agents. Implications for Modern Drug Development While the patent focused on a narrow class of boronate esters, it foreshadowed the importance of designing small, lipophilic boron compounds for CNS delivery. Modern efforts leverage nanotechnology, boron clusters, and targeted delivery systems, yet the fundamental concept of boron catecholate derivatives remains influential. Challenges remain around stability in biological environments, controlled release, and efficient BBB penetration. The patent’s chemical framework provides a basis upon which next-generation boron compounds continue to evolve. Key Takeaways U.S. Patent 3,428,735 pioneers boron-organic chemistry centered on catechol-based boronate esters for CNS applications, establishing a foundational chemical class. Its claims cover chemical structures, synthesis methods, pharmaceutical formulations, and therapeutic utility, providing broad protection for compounds within this class. The patent landscape has expanded into diverse boron compounds, including clusters and nanocarrier systems, informed by early innovations like this patent. Expiration of the patent enables unrestricted research and development leveraging the structural frameworks it disclosed. Despite modern advancements, the core chemistry outlined remains relevant to boron delivery strategies in BNCT and neuropharmacology. FAQs 1. What is the significance of the catechol boronate structure in CNS drug delivery? Catechol boronate structures are lipophilic and capable of forming cyclic esters with boron, facilitating BBB penetration and targeted boron delivery to the brain for therapies like BNCT. 2. How does this patent influence current boron-based pharmaceuticals? It lay the groundwork for understanding small boronate esters as BBB-crossing agents, influencing the design of modern boron compounds with enhanced stability and targeted delivery. 3. Are the compounds claimed in this patent still under patent protection? No. The patent expired in the mid-1980s, allowing free use and derivative innovations based on its chemical framework. 4. What are the main challenges associated with boron compounds in CNS therapeutics? Stability in biological environments, efficient BBB crossing, and selective accumulation in target tissues remain key challenges for clinical translation. 5. Can the chemical concepts from this patent be combined with nanotechnology approaches? Yes. Modern nanocarrier systems integrate boron structures inspired by this patent to improve delivery efficiency and targeting within the CNS. References U.S. Patent 3,428,735. "Boron-Containing Compounds and Their Use," issued 1969. Wipff, G., et al. "Advances in Boron-Based Drug Delivery for Brain Tumors," Drug Development Research, 2020. Liu, Y., et al. "Design Strategies for Boron Compounds in Neutron Capture Therapy," ACS Med Chem Lett., 2018. International Atomic Energy Agency (IAEA). "Boron Neutron Capture Therapy: Past Perspectives and Future Directions," 2021. This comprehensive review informs stakeholders about the foundational patent’s scope, its claims, and its influence on the development of CNS-targeted boron pharmaceuticals. More… ↓ ⤷ Get Started Free

Details for Patent: 3,428,735

Summary for Patent: 3,428,735