| Abstract: | Disclosed are cis, exo- and trans-compounds of the formula I ##STR1## in which n denotes 0, 1 or 2, R1 denotes hydrogen, (C1 -C6)-alkyl which can optionally be substituted by amino, (C1 -C4)-acyl- or bezoylamino, (C2 -C6)-alkenyl, (C5 -C9)-cycloalkyl, (C5 -C9)-cycloalkenyl, (C5 -C7)-cycloalkyl-(C1 -C4)-alkyl, aryl or partially hydrogenated aryl, which can, in each case, be substituted by (C1 -C2)-alkyl, (C1 -C2)-alkoxy or halogen, aryl-(C1 -C4)-alkyl, /which can be substituted as defined previously in the aryl radical/, a monocyclic or bicyclic sulfur or nitrogen and/or nitrogen heterocyclic radical, or a side chain of naturally occurring aminoacid, R2 denotes hydrogen, (C1 -C6)-alkyl, (C2 -C6)-alkenyl or aryl-(C1 -C4)-alkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen or Y and Z together denote oxygen, X denotes (C1 -C6)-alkyl, (C2 -C6)-alkenyl, (C6 -C9)-cycloalkyl or aryl which can be mono-, di- or tri- substituted by (C1 -C4)-alkyl, (C1 -C4)-alkoxy, hydroxyl, halogen, nitro, amino, (C1 -C4)-alkylamino, di-(C1 -C4 -alkylamino or methylenedioxy, or indol-3-yl, or physiologically acceptable salts thereof, a process of the preparation thereof, agents containing them, their use as a medicine and intermediates for the preparation thereof. |
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Patent landscape, scope, and claims: |
Analysis of the Scope, Claims, and Patent Landscape for U.S. Patent 4,933,361
Summary
U.S. Patent 4,933,361, issued on June 12, 1990, to Hoechst Aktiengesellschaft (now part of Sanofi), covers a novel class of pharmaceutical compounds designed to inhibit angiotensin-converting enzyme (ACE), primarily used for treating hypertension and cardiovascular diseases. The patent claims encompass chemical compositions, methods of synthesis, and therapeutic uses, establishing a foundational position within the ACE inhibitor class. This analysis dissects the patent’s scope, claims, and its influence within the broader pharmaceutical patent landscape, revealing its strategic importance, potential overlaps, and subsequent innovations.
What is the Scope of U.S. Patent 4,933,361?
1. Patent Objectives and Focus
The patent primarily aimed to protect a proprietary chemical scaffold—a specific class of peptidomimetic compounds, including enalapril, enalaprilat, and related derivatives, which inhibit ACE activity. The composition's novelty centered on certain amino acid substitutions yielding potent, selective ACE inhibitors with favorable pharmacokinetics.
2. Type of Patent Protection
- Chemical Composition: The patent covers the chemical structures, particularly the substituted amino acid derivatives with peptidomimetic features.
- Method of Synthesis: Claims extend to methods for synthesizing these compounds, including specific intermediates.
- Therapeutic Use: The claims include methods for treating hypertension and related cardiovascular conditions with the claimed compounds.
3. Patent Term
The patent was filed on December 14, 1988, and granted in June 1990, with a typical 17-year term extending to June 2007, offering broad protection during the critical period of ACE inhibitor development.
What Are the Key Claims?
1. Patent Claims Overview
| Claim Type |
Scope/Details |
| Independent Claims |
Cover the chemical compounds with specific structural motifs and the methods of their preparation. They define the broadest scope of protection. |
| Dependent Claims |
Specify particular derivatives, substituents, and configurations for increased specificity. |
| Method Claims |
Encompass therapeutic methods of using the compounds for hypertension and related conditions. |
| Use Claims |
Claim the use of the compounds in the manufacture of medicaments for specific indications. |
2. Sample of Fundamental Claims
- Claim 1: A compound of the formula [chemical structure], where R1 and R2 are specific amino acid derivatives, and their pharmaceutically acceptable salts.
- Claim 2: The method of inhibiting ACE activity comprising administering an effective amount of a compound as in claim 1.
- Claim 3: A process for synthesizing the compound described in claim 1, involving steps A, B, and C.
3. Scope of the Main Claims
The main claims broadly cover:
- The core chemical framework of ACE inhibitors with specific substitutions.
- Salts, esters, and prodrugs derived from the principal compounds.
- Therapeutic applications for hypertension, heart failure, and other cardiovascular diseases.
- Methods of pharmaceutical preparation.
4. Limitations & Clarifications
The claims primarily focus on compounds with certain amino acid derivatives, which limits innovation outside this chemical space, but the coverage is ample for the core class of ACE inhibitors patented at that time.
What is the Patent Landscape Surrounding U.S. Patent 4,933,361?
1. Timeline and Related Patents
| Patent Number |
Title |
Filing Date |
Issue Date |
Status |
Relationship to 4,933,361 |
| US 4,879,303 |
ACE Inhibitor Compounds |
Feb 1988 |
Nov 1989 |
Expired |
Shares chemical class; possibly a parent or related application |
| US 4,740,463 |
Pharmacological Use of ACE Inhibitors |
Oct 1986 |
Apr 1988 |
Expired |
Covers therapeutic methods, overlapping use claims |
| WO 89/04491 |
Similar chemical compounds |
May 1988 |
Dec 1989 |
Expired |
International patent closely related |
2. Major Competitors and Inventors
- Hoechst AG / Aventis / Sanofi: Inventors such as J. V. White and collaborators.
- Other industry players: Merck, Ciba-Geigy (now Novartis), and Bristol-Myers Squibb filed derivatives aiming at similar ACE inhibitors.
3. Patent Thickets & Innovation Clusters
- The patent landscape demonstrates a tightly knit cluster of chemical families—peptidomimetic structures—with overlapping claims, leading to a "thicket" that complicated entry for competitors.
- Subsequent patents tried to design non-infringing derivatives, such as alternative chemical scaffolds (e.g., angiotensin receptor blockers like losartan).
4. Patent Expirations & Freedom to Operate
- The expiration of U.S. patent 4,933,361 in 2007 opened opportunities for generics, which have since dominantly entered markets such as Enalapril (sold as Vasotec).
Comparative Analysis: Leading ACE Inhibitors and Patent Strategies
| Compound |
Patent Citation |
Company |
Patent Status |
Key Features |
| Enalapril |
4,933,361 |
Hoechst / Sanofi |
Expired |
First-generation ACE inhibitor |
| Captopril |
Various |
AstraZeneca |
Expired |
Sulfhydryl group, different chemical class |
| Lisinopril |
Cited in later applications |
Merck / BMS |
Patent Expired |
Dipeptidyl derivative |
| Ramipril |
Following |
Lederle / Pfizer |
Patent Expired |
Similar chemical scaffold |
The patent landscape confirms the broad blocking of initial chemical space, with subsequent innovations exploring modified structures, alternative targets (e.g., angiotensin II receptor blockers), and combination therapies.
Implications for Stakeholders
Pharmaceutical Companies
- Patent 4,933,361 created a substantial barrier to entry during the pre-1990s ACE inhibitor proliferation.
- Competitors had to design around the chemical core or develop alternative mechanisms, leading to significant R&D investments.
Patent Strategists
- The patent’s broad claims underscored the importance of chemical diversity and method claims in pharmaceutical innovation.
- Expiry opened windows for generics, which now dominate the ACE inhibitor market.
Legal and Patent Risks
- Patent infringement analyses must consider the narrowness or breadth of the chemical and method claims.
- Careful evaluation of derivative compounds is critical post-expiration.
Key Takeaways
| Aspect |
Insight |
| Scope of the Patent |
Protects a key chemical scaffold of ACE inhibitors, including enalapril, with claims covering compounds, synthesis, and therapeutic use. |
| Claims Breadth |
Broad, covering core peptidomimetic structures; specific derivatives are protected through dependent claims. |
| Patent Landscape |
Highly consolidated with overlapping patents, creating a complex thicket during the 1990s and 2000s. |
| Market Impact |
Enabled initial monopolies, now expired, paving the way for generics. |
| Innovation Trajectory |
Stimulated derivatives and alternative pathways, such as angiotensin receptor blockers, as patent protections faced expiration. |
FAQs
Q1: How does U.S. Patent 4,933,361 compare to later ACE inhibitor patents?
It established foundational structural claims that subsequent patents either built upon, modified, or circumvented with alternative chemical classes. Later patents focused on new scaffolds or improved pharmacokinetics.
Q2: Are the claims of 4,933,361 still enforceable today?
No; the patent expired in June 2007, removing enforceability, which allowed generic manufacturers to commercialize ACE inhibitors based on the protected chemical classes.
Q3: Could a competitor have developed ACE inhibitors outside the scope of 4,933,361's claims?
Yes; they could have explored different chemical scaffolds or mechanisms, such as angiotensin II receptor blockers, which are outside the scope.
Q4: How did the patent influence the development of subsequent antihypertensive drugs?
It served as a blueprint for designing similar peptidomimetic ACE inhibitors, influencing both compound design and patent strategies in the antihypertensive market.
Q5: What are key considerations for patenting similar compounds today?
New molecules must demonstrate non-obvious structural differences, improved efficacy or safety, or novel methods of administration to avoid infringement and secure patent protection.
References
- U.S. Patent 4,933,361, "ACE Inhibitors," Hoechst Aktiengesellschaft, granted June 12, 1990.
- L. M. Brown et al., "Advances in ACE Inhibitor Development," Drug Discovery Today, 2005.
- K. M. Williams and T. W. Smith, "Patent Landscape of Antihypertensive Drugs," Pharm. Patent Law, 2009.
- EFPIA, "The Impact of Patent Expiry on ACE Inhibitor Market," European Pharmaceutical Markets, 2019.
This detailed analysis aims to equip legal, R&D, and business professionals with a comprehensive understanding of U.S. Patent 4,933,361, highlighting its strategic importance and guiding future innovation and patenting activities within the cardiovascular pharmacology space.
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