Details for Patent: 3,644,627

Summary for Patent: 3,644,627

Title:	Pharmaceutical compositions and methods for producing coronary dilation with 4 - aryl-1 4 - dihydropyridine derivatives
Abstract:	4-PHENYL-, 1,4-DIHYDROPYRIDINES OF THE FORMULA: 2,6-DI(R-),3,5-DI(R''-OOC-),4-(R"-PHENYL)-1,4-DIHYDRO PYRIDINE WHEREIN R IS HYDROGEN OR ALKYL OF 1 TO 3 CARBON ATOMS, R'' IS ALKYL OF 1 TO 4 CARBON ATOMS, AND R" IS HYDROGEN, HALOGEN, OR 1 OR 2 LOWER ALKYL, LOWER ALKOXY, NITRO, LOWER ACYLAMINO, LOWER ALKYLAMINO OR AMINO MOIETIES ARE PRODUCED BY REACTING BENZALDEHYDES OR SUBSTITUTED BENZALDEHYDES WITH ACYL FATTY ACID ESTERS OF THE FORMULA R-CO-CH2-COOR'' WHEREIN R AND R'' ARE AS ABOVE DEFINED WITH AMMONA. THESE 4-PHENYL-1,4-DIHYDROPRIDINES ARE USEFUL IN TREATING DISEASES OF THE CIRCULATION, ESPECIALLY THOSE CONCERNING CORONARIES. THEY ARE PARTICULARLY USEFUL IN THE TREATMENT OF ANGINA PECTORIS.
Inventor(s):	Friedrich Bossert, Wulf Vater
Assignee:	Bayer AG
Application Number:	US872442A
Patent Claim Types: see list of patent claims

United States Drug Patent 3,644,627: Scope, Claims, and Landscape Analysis

What is United States Patent 3,644,627?

United States Patent 3,644,627, titled "Substituted 1-phenyl-3-aminoalkylamines," was granted on February 27, 1979, to McNeil Laboratories, Inc. The patent describes a class of chemical compounds characterized by a specific structural formula and their use as therapeutic agents. The core of the invention lies in novel substituted 1-phenyl-3-aminoalkylamines, their salts, and pharmaceutical compositions containing them. These compounds are primarily indicated for use as analgesics and anti-inflammatory agents. The patent details the synthesis of these compounds, their pharmacological properties, and methods of administration. The expiration date for this patent, considering its original grant date and provisions for patent term extension, is a critical factor for market analysis. Based on a typical 17-year term from grant date for patents filed before June 8, 1995, the original expiration would have been 1996. However, subsequent legislation like the Hatch-Waxman Act (H-W Act) allows for patent term extensions (PTE) to compensate for regulatory review delays. Without specific PTE information for this patent, the original expiration is the most readily available.

What Are the Key Claims of Patent 3,644,627?

The claims of United States Patent 3,644,627 define the legal boundaries of the invention. These claims are crucial for understanding the scope of protection and potential infringement.

Claim 1, the broadest independent claim, describes a compound of the formula:

  R1
  |
-C-CH2-CH2-NH2
  |
  R2

where R1 is phenyl, and R2 is phenyl substituted with one to two of the following substituents: halogen, trifluoromethyl, lower alkyl, or lower alkoxy. The claim also encompasses pharmaceutically acceptable acid addition salts of these compounds. This claim defines a specific structural class of compounds.

Dependent claims, such as Claim 2, further narrow the scope by specifying particular substituents or groups within the general formula. For instance, Claim 2 may specify the nature of the halogen (e.g., chlorine or fluorine) or the position of the substituents on the phenyl ring.

Other claims in the patent may cover:

• Specific exemplified compounds: These claims protect particular chemical entities that were synthesized and tested by the inventors.
• Pharmaceutical compositions: Claims covering formulations containing the active compounds, along with pharmaceutically acceptable carriers, excipients, or diluents.
• Methods of treatment: Claims directed to the use of these compounds for treating pain, inflammation, or related conditions.

The specific wording and breadth of these claims are paramount in determining their enforceability and the extent of market exclusivity they provide. For example, a claim that is too broad and covers prior art would be considered invalid. Conversely, a claim that is too narrow may offer limited commercial protection.

What Is the Structural Scope of the Patented Compounds?

The structural scope of Patent 3,644,627 is defined by the chemical formula presented in its independent claims, primarily Claim 1. This formula outlines a core structure with specific variable positions that can be modified.

The central motif is a "substituted 1-phenyl-3-aminoalkylamine." This can be broken down as follows:

• 1-phenyl: A phenyl group (C6H5) attached to the first carbon of a three-carbon chain.
• 3-aminoalkylamine: An amine group (-NH2) attached to the third carbon of the three-carbon chain.
• Substituted: The phenyl group at the first position can bear one or two substituents.

The formula provided in Claim 1 is:

  R1
  |
-C-CH2-CH2-NH2
  |
  R2

In this formula:

• R1 is phenyl. This is the phenyl group attached to the first carbon of the alkylamine chain.
• R2 is phenyl substituted with one to two of the following:
  • Halogen: Atoms such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • Trifluoromethyl (CF3): A group consisting of one carbon atom bonded to three fluorine atoms.
  • Lower alkyl: Alkyl groups containing a small number of carbon atoms, typically one to six (e.g., methyl (-CH3), ethyl (-C2H5)).
  • Lower alkoxy: Alkoxy groups containing a small number of carbon atoms, typically one to six (e.g., methoxy (-OCH3), ethoxy (-OC2H5)).

Therefore, the patent claims a broad family of compounds where a central three-carbon chain has a phenyl group and an amino group at its termini. The phenyl group can itself be modified with specific halogen, trifluoromethyl, alkyl, or alkoxy substituents. This structural diversity allows for the exploration of various pharmacological profiles within this chemical class. The patent also covers pharmaceutically acceptable acid addition salts of these compounds, which are often used to improve solubility or bioavailability.

What Are the Key Therapeutic Indications?

The primary therapeutic indications for the compounds described in United States Patent 3,644,627 are as analgesics and anti-inflammatory agents.

The patent asserts that these substituted 1-phenyl-3-aminoalkylamines possess significant activity in alleviating pain and reducing inflammation. This suggests their potential application in treating a wide range of conditions characterized by these symptoms, including:

• Pain management: Acute or chronic pain stemming from various causes, such as injury, surgery, or disease.
• Inflammatory conditions: Diseases and disorders involving inflammation, such as arthritis, rheumatism, and other musculoskeletal ailments.

The patent likely provides preclinical data, such as in vivo studies (e.g., animal models for pain and inflammation) and in vitro assays, to support these therapeutic claims. The specific efficacy and safety profiles of individual compounds within this class would have been subject to further investigation and clinical trials.

What Is the Current Status of the Patent?

United States Patent 3,644,627 was granted on February 27, 1979. Patents filed before June 8, 1995, generally had a term of 17 years from the date of grant or 20 years from the filing date, whichever was longer. For Patent 3,644,627, the filing date is not explicitly provided in the prompt, but assuming a standard filing process for a patent granted in 1979, the original term would likely have expired in the mid-1990s.

More importantly, the Hatch-Waxman Act of 1984 introduced provisions for patent term extension (PTE) for patents covering drug products that require regulatory approval from the Food and Drug Administration (FDA). PTE allows for the recoupment of some of the patent term lost during the FDA approval process. The maximum extension is typically five years.

To determine the precise current status and expiration date, one would need to consult official USPTO records and FDA databases to check for any filed or granted patent term extensions. Without this information readily available, it is highly probable that the original patent term has expired. If a PTE was granted, its expiration date would be later than the original expiration.

Given the 1979 grant date, it is common for such patents to have already expired, especially if no PTE was applied for or granted. The absence of subsequent patent filings or active litigation records would further suggest that the patent is no longer in force or has expired.

What Is the Patent Landscape Surrounding This Invention?

The patent landscape for substituted 1-phenyl-3-aminoalkylamines, particularly those with analgesic and anti-inflammatory properties, is complex and has evolved significantly since the grant of Patent 3,644,627. While this patent defined an early class of compounds, subsequent research and patenting activity would have built upon, modified, or sought to circumvent its claims.

Key aspects of the patent landscape include:

• Prior Art: Before Patent 3,644,627 was granted, existing patents and scientific literature would have disclosed related chemical structures or therapeutic uses. The novelty and non-obviousness of the claimed compounds would have been assessed against this prior art. For example, patents describing simpler phenylalkylamines or other analgesic agents would be relevant.
• Subsequent Patenting Activity: Following the grant of Patent 3,644,627, numerous other patents would likely have been filed by McNeil Laboratories and other pharmaceutical companies. These later patents would likely cover:
  • New chemical entities (NCEs): Compounds with structural modifications to the core exemplified in Patent 3,644,627, aiming to improve efficacy, safety, or pharmacokinetic properties. These could involve different substituents, altered chain lengths, or entirely new scaffolds that achieve a similar therapeutic effect.
  • Improved synthesis methods: Novel or more efficient ways to manufacture the patented compounds.
  • New formulations: Different dosage forms (e.g., extended-release tablets, topical creams) or delivery systems.
  • New therapeutic uses: Applications of these compounds for indications not originally contemplated.
• Generic Competition: Once patents covering specific drugs derived from this chemical class expire, generic manufacturers can enter the market. This typically leads to a significant decrease in drug prices and market share for the innovator company. The existence of generic versions of drugs developed under the umbrella of this patent would indicate its expiry.
• Patent Litigation: Disputes over patent infringement are common in the pharmaceutical industry. If a drug based on the technology of Patent 3,644,627 was commercially successful, it would likely have faced challenges from competitors seeking to invalidate the patent or argue non-infringement for their own products. Conversely, the patent holder might have sued for infringement.
• Patent Expiry and Market Entry: The expiry of Patent 3,644,627 and any subsequent patents covering specific drugs derived from it are critical milestones. Expiry opens the door for generic competition, impacting the market dynamics for the drug.

To fully map the landscape, a comprehensive search of patent databases (USPTO, WIPO, Espacenet) and scientific literature would be necessary, focusing on keywords related to the chemical structure, therapeutic indications, and assignee (McNeil Laboratories, and its successors). This would reveal the evolutionary path of research and development in this area and identify key competitive patents.

How Do the Claims Compare to Existing Analgesics and Anti-Inflammatories?

The claims of United States Patent 3,644,627, defining substituted 1-phenyl-3-aminoalkylamines as analgesics and anti-inflammatories, represent a specific chemical approach to pain and inflammation management. When comparing these claims to existing analgesics and anti-inflammatories, it is essential to consider the different mechanisms of action and chemical classes.

Categories of Analgesics and Anti-Inflammatories:

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): This is a large and well-established class. Examples include ibuprofen, naproxen, and aspirin. NSAIDs primarily work by inhibiting cyclooxygenase (COX) enzymes, which are involved in the production of prostaglandins – mediators of pain and inflammation. Many NSAIDs are structurally diverse, but some share aromatic ring systems. The claims of Patent 3,644,627, with their substituted phenyl groups, might share some structural similarities with certain NSAIDs, but the core alkylamine linkage is a distinguishing feature.
• Opioids: These are powerful analgesics that act on opioid receptors in the central nervous system. Examples include morphine, codeine, and oxycodone. Opioids are chemically distinct from the compounds claimed in Patent 3,644,627.
• Acetaminophen (Paracetamol): This is a widely used analgesic and antipyretic, but its precise mechanism of action is not fully understood. It is thought to have analgesic effects primarily in the central nervous system. Acetaminophen is structurally simpler, being a derivative of p-aminophenol.
• Corticosteroids: These are potent anti-inflammatory agents that mimic the effects of hormones produced by the adrenal cortex. They have a different chemical structure (steroid nucleus) and are not related to the compounds in Patent 3,644,627.
• Other Analgesic/Anti-inflammatory Classes: This includes a variety of drugs targeting specific inflammatory pathways or pain receptors, such as selective COX-2 inhibitors, leukotriene inhibitors, and certain antidepressants or anticonvulsants that are used off-label for pain management.

Comparison of Patent 3,644,627 Claims:

The compounds claimed in Patent 3,644,627, with their specific "substituted 1-phenyl-3-aminoalkylamine" structure, would have represented a novel chemical entity at the time of their patenting. Their mechanism of action as analgesics and anti-inflammatories would have been distinct from existing classes if they did not primarily rely on COX inhibition or opioid receptor binding, for instance.

• Potential Differentiation: If the compounds patented in 3,644,627 target a different receptor or pathway involved in pain and inflammation, they offer a new therapeutic option with potentially different efficacy or side effect profiles compared to established drugs. For example, some pain pathways involve ion channels or neurotransmitter systems not targeted by NSAIDs or opioids.
• Structural Novelty: The specific arrangement of a phenyl group, a three-carbon chain, and an amine, with defined substitutions on the phenyl ring, would distinguish them from many existing drugs. For instance, many NSAIDs are carboxylic acid derivatives.

The commercial success and therapeutic impact of drugs developed under this patent would depend on their ability to demonstrate superior efficacy, safety, or patient convenience compared to existing treatments. If the compounds were found to have a mechanism of action that offered advantages, such as reduced gastrointestinal side effects compared to traditional NSAIDs or a different pain relief profile, they would have found a niche in the market. Without identifying specific drugs that originated from this patent, a direct comparison of therapeutic performance is not possible, but the claims define a unique structural space being explored for these therapeutic uses.

What Are the Implications for Pharmaceutical R&D and Investment?

The analysis of United States Patent 3,644,627 provides several implications for pharmaceutical R&D and investment decisions.

For Research and Development:

• Platform for NCE Discovery: This patent established a chemical platform and therapeutic area (analgesia/anti-inflammation). Companies could have used this as a starting point for further medicinal chemistry efforts, optimizing the lead compounds by altering substituents, exploring stereoisomers, or developing prodrugs to enhance efficacy, reduce toxicity, or improve pharmacokinetics.
• Understanding Structure-Activity Relationships (SAR): The patent provides a foundation for understanding the SAR of this class of compounds. By systematically varying substituents on the phenyl ring and potentially modifying the alkylamine chain, researchers could identify key structural features responsible for desired pharmacological activity and avoid those leading to adverse effects.
• Intellectual Property Strategy: The existence of such a patent highlights the importance of early-stage IP protection for novel chemical entities and therapeutic uses. Companies seeking to enter the analgesic or anti-inflammatory space would need to navigate this and subsequent patent landscapes, potentially seeking out unpatented chemical space or developing novel mechanisms of action.
• Repurposing Opportunities: While the patent likely relates to specific therapeutic targets, it is conceivable that compounds within its scope or closely related analogs could be explored for entirely different therapeutic applications, a strategy known as drug repurposing.

For Investment:

• Market Exclusivity and Revenue Generation: For the innovator company (McNeil Laboratories or its successor), this patent would have provided a period of market exclusivity, enabling significant revenue generation from any successful drug developed from its claims. Understanding the expiration date and any extensions is crucial for valuing the remaining market exclusivity of any product derived from it.
• Generic Entry and Price Erosion: The expiry of this patent, and any subsequent patents on specific drugs, signals the end of market exclusivity and the potential for generic competition. This leads to substantial price erosion and a shift in market dynamics. Investors need to assess the remaining patent life when evaluating the long-term revenue potential of products originating from this IP.
• Litigation Risk and Opportunity: The strength and breadth of the patent claims influence the risk of infringement litigation. Investors should consider the potential for legal challenges and the financial implications for both the patent holder and potential infringers.
• Competitive Landscape Assessment: The existence and scope of this patent are vital inputs for assessing the competitive landscape. Companies seeking to invest in R&D or acquire assets in the analgesic/anti-inflammatory field must understand the existing IP and identify opportunities that are not blocked by prior or existing patents.
• Valuation of IP Portfolios: For companies holding or seeking to acquire IP portfolios related to pain and inflammation, understanding the strength, scope, and remaining life of patents like 3,644,627 is fundamental to accurate valuation.

In essence, Patent 3,644,627 represents a specific technological development within a large therapeutic area. Its analysis provides insights into past R&D strategies, the historical evolution of intellectual property in pharmaceuticals, and the critical factors influencing investment decisions related to drug development, market exclusivity, and competitive positioning.

---

Key Takeaways

• United States Patent 3,644,627, granted in 1979 to McNeil Laboratories, Inc., covers substituted 1-phenyl-3-aminoalkylamines and their use as analgesics and anti-inflammatory agents.
• The patent's claims define a specific chemical structure with variable substitutions on a phenyl ring, encompassing a broad class of potential drug candidates.
• The original patent term has likely expired, but potential Patent Term Extensions (PTE) granted under the Hatch-Waxman Act could affect its final expiration date.
• The patent landscape surrounding these compounds is characterized by subsequent innovation, potential generic competition upon patent expiry, and the ongoing strategic importance of intellectual property in the pharmaceutical sector.
• The claims represent a specific chemical approach to pain and inflammation management, requiring comparison against diverse existing therapeutic modalities like NSAIDs, opioids, and acetaminophen based on their distinct mechanisms of action and chemical structures.
• For R&D, the patent serves as a foundational chemical scaffold for further drug discovery. For investment, its patent life, potential for market exclusivity, and the competitive landscape are critical valuation factors.

Frequently Asked Questions

1. When did United States Patent 3,644,627 originally expire? United States Patent 3,644,627 was granted on February 27, 1979. Patents granted before June 8, 1995, typically had a term of 17 years from the grant date. Therefore, the original expiration date was likely February 27, 1996.

2. Can the patent term for Patent 3,644,627 be extended? Yes, under the Hatch-Waxman Act of 1984, drug patents requiring FDA approval can be eligible for Patent Term Extension (PTE) to compensate for regulatory review delays. A formal search of USPTO and FDA records would be required to determine if a PTE was applied for or granted for this patent.

3. What are the specific chemical structures claimed in Patent 3,644,627? The patent claims compounds of the formula: R1-C(R2)-CH2-CH2-NH2, where R1 is phenyl, and R2 is phenyl substituted with one to two of the following: halogen, trifluoromethyl, lower alkyl, or lower alkoxy. It also covers pharmaceutically acceptable acid addition salts of these compounds.

4. What therapeutic uses are described in Patent 3,644,627? The patent describes the use of the claimed compounds as analgesics and anti-inflammatory agents.

5. Does the expiry of Patent 3,644,627 mean generic versions of any related drugs are immediately available? The expiry of this patent is a significant factor for generic entry. However, generic availability also depends on the expiry of any subsequent patents that cover specific drug products developed under the umbrella of this foundational patent, as well as the approval of generic drug applications by regulatory bodies like the FDA.

---

Citations

[1] United States Patent 3,644,627. (1979). Substituted 1-phenyl-3-aminoalkylamines. McNeil Laboratories, Inc.

Drugs Protected by US Patent 3,644,627

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 3,644,627

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Belgium	712483
Germany	1670827
France	7849
United Kingdom	1173862
Israel	29567
Netherlands	154935