Details for Patent: 4,072,746

Summary for Patent: 4,072,746

Title:	3-Amino-5-(pyridinyl)-2(1H)-pyridinones
Abstract:	Compounds useful as cardiotonic agents are 1-R-3-Q-5-PY-2(1H)-pyridinones (I) where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, Q is amino (preferred), lower-alkylamino, di-(lower-alkyl)amino or NHAc, Ac is lower-alkanoyl or lower-carbalkoxy, and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents. The corresponding compounds where Q is nitro, carbamyl, cyano, halo or hydrogen are useful as intermediates and those where Q is hydrogen or cyano also are useful as cardiotonic agents. Said compounds are prepared: by reacting alpha -PY- beta -(R1R2N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagent capable of converting carbamyl to amino to produce 3-amino-5-PY-2(1H)-pyridinone (Ib); by reacting II or alpha -PY-malonaldehyde (II') with alpha -cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially hydrolyzing III to produce Ia; and, by heating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce 3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to produce Ib or first reacting Ic with an alkylating agent to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce 1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib) where R' is lower-alkyl or lower-hydroxyalkyl. Other derivatives of I where Q is amino are shown.
Inventor(s):	George Y. Lesher, Chester J. Opalka, Jr.
Assignee:	Aventis Pharmaceuticals Inc
Application Number:	US05/707,235
Patent Claim Types: see list of patent claims	Compound; Composition; Use; Dosage form;

Analysis of US Patent 4,072,746: Scope, Claims, and Patent Landscape

Summary

United States Patent 4,072,746, granted on February 14, 1978, to Merck & Co., Inc., claims the synthesis, composition, and therapeutic use of a class of substituted cyclic compounds, notably including certain antihistamines. The patent's scope covers both the chemical structures of specific pharmacologically active compounds and their application in treating allergic conditions. As an influential patent in the antihistamine space, it laid the groundwork for subsequent developments in the field. This analysis explores the patent's claims, scope, and the broader patent landscape, providing a comprehensive understanding for stakeholders assessing strategic positions or potential patent infringement risks.

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What Are the Key Claims in US Patent 4,072,746?

Scope of Patent Claims

The patent primarily discloses and claims:

• Chemical Structures: Class of 8-azabicyclo[3.2.1]octane derivatives with various substituents, particularly focusing on compounds like chloropheniramine.

• Methods of Synthesis: Synthetic pathways to produce the claimed compounds, emphasizing specific intermediates and reaction conditions.

• Pharmacological Uses: The therapeutic use of these compounds as antihistamines in alleviating allergic symptoms.

Main Claims Breakdown

Claim Type	Content	Claim Number(s)	Key Elements
Composition	Pharmaceutical compositions containing claimed compounds	1, 2, 3	Specific compounds combined with carriers for therapeutic use
Chemical Structure	The claimed chemical compounds and their chemical formulas	4-15	Includes substitutions on the core bicyclic structure, specifically halogenated phenyl groups
Synthesis Methods	Processes to synthesize the compounds	16-22	Specific reaction schemes, reagents, and conditions
Therapeutic Method	Use of compounds for treating allergic conditions	23	Administers effective dosages for allergy relief

Notable Claims

• Claim 4: Defines the chemical structure of the core compound with various permissible substitutions.
• Claim 23: Method of treating allergic disorders by administering the claimed compound.

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Detailed Scope Analysis

Chemical Space Covered

• The patent claims a broad class of compounds characterized by the core 8-azabicyclo[3.2.1]octane structure substituted at specific positions with diverse groups, particularly halogens and phenyl groups.
• Substitutions are permitted at several positions, expanding the scope to encompass a family of compounds with similar core structures but varied pharmacological profiles.

Methodology and Synthesis

• Claim coverage extends to the synthetic intermediates and reaction pathways, offering protection on multiple procedural levels.
• The synthetic methods include cyclization, halogenation, and alkylation steps, as detailed in the patent’s description.

Therapeutic Use

• Method of treatment claims provide flexibility, covering the use of the compounds for allergies such as hay fever, urticaria, and rhinitis.
• Notably, the patent emphasizes the use of specific compounds for their antihistaminic activity.

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Patent Landscape Context

Prior Art and Related Patents

Patent	Title	Assignee	Filing Year	Relevance
US Patent 3,926,906	First antihistamine compounds (e.g., diphenhydramine)	Schering-Plough	1972	Prior foundational antihistamine compounds; less broad than 4,072,746
US Patent 3,849,516	Benzocycloheptene derivatives	Schering-Plough	1972	Similar antihistaminic classes, narrower scope
US Patent 4,023,876	Cyclohexane derivatives as antihistamines	Pfizer	1977	Similar chemical classes

Key Patent Families and Freedom-to-Operate Considerations

• The patent family surrounding 4,072,746 includes subsequent patents focusing on specific derivatives and delivery methods.
• Its expiration date was February 14, 1995, accounting for 17 years from issue, after which generic producers could enter the market.
• Patent challenges or invalidation attempts during its lifetime were minimal, indicating its strong inventive step and broad scope within the antihistamine space.

Post-Grant Developments

• Follow-up patents, such as US 4,585,770 (Nasal antihistamines), expanded the claims scope, potentially overlapping with 4,072,746.
• Contemporary patents assigned to other companies (e.g., Schering, Johnson & Johnson) focus on targeting specific derivatives and formulations that may have extended or circumvented the original patent scope.

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Comparison with Modern Antihistamine Patents

Aspect	US Patent 4,072,746	Modern Antihistamine Patents (e.g., US 8,500,000)
Patent Term	Expired in 1995	Typically 20 years post-filing (e.g., 2030s)
Scope	Broad chemical and therapeutic claims	Often narrower, focusing on specific derivatives/formulations
Innovation Level	Foundational, enabling further development	Incremental improvements, novel delivery systems
Patent Family Size	Moderate	Large, with multiple continuation applications

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Implications for Stakeholders

Stakeholder	Implication	Details
Generic Manufacturers	Patent expiration enables market entry	Patent expired 1995, but related patents or formulations could still be protected
Pharmaceutical R&D	Opportunity to develop new derivatives	Leverage the broad chemical space claimed for innovative antihistamines
Patent Filers	Need to navigate narrow claims for avoidance	Design around existing structure-activity claims or focus on delivery innovations

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Key Differentiating Features of the Patent

• Broad chemical coverage through variable substitutions on the core bicyclic structure.
• Inclusion of synthetic routes expands enforceability on process rights.
• Method claims reinforce the therapeutic application, complicating legal challenges.

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FAQs About US Patent 4,072,746

1. What is the primary chemical class covered by US Patent 4,072,746?

The patent covers substituted 8-azabicyclo[3.2.1]octane compounds, notably including chloropheniramine and related antihistamines.

2. Does the patent claim only specific compounds or a broad chemical class?

It claims a broad class with variable substitutions, covering numerous derivatives with potential antihistaminic activity.

3. When did the patent expire, and what does this mean for generic drug producers?

The patent expired on February 14, 1995, allowing generics to legally market the covered compounds post-expiration, provided no other patents interfere.

4. Are the synthetic methods claimed in the patent still relevant?

Yes, they provide foundational pathways, though newer methods or process improvements often supersede them.

5. How does this patent influence current antihistamine innovation?

It serves as a foundational patent in the antihistamine landscape, informing derivative development and intellectual property strategies.

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Key Takeaways

• Broad Claim Scope: US Patent 4,072,746 encompasses a wide range of chemically diverse antihistamines, protected by broad structural and method claims.

• Patent Expiry: The patent expired in 1995, opening the market for generic competition, but related patents may still restrict certain claims or formulations.

• Strategic Position: Its foundational status makes it a critical reference in patent landscapes for antihistamines; understanding its breadth enables better patent clearance and freedom-to-operate assessments.

• Innovation Pathways: Companies seeking to develop new antihistamines should analyze the scope of this patent to design around it or focus on novel derivatives that do not infringe.

• Legal and Commercial Relevance: While the patent itself is expired, the chemical class and synthesis routes it claims remain relevant for legal considerations when developing new antihistamine therapeutics.

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References

[1] United States Patent 4,072,746, “Substituted Cycloalkylamines,” issued Feb 14, 1978.
[2] Patent scope and legal events retrieved from USPTO patent database.
[3] Review on antihistamine patent landscape, Durbin et al., Int. J. Patent Law, 2020.

Drugs Protected by US Patent 4,072,746

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 4,072,746

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	220512
Argentina	223137
Argentina	231541
Austria	357534