| Abstract: | Compounds suitable for NMR imaging having the formula: ##STR1## wherein a is 2 or 3; b is an integer from 0 to 4; Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ; E.sup.(b+) is an ion of an alkali metal, alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyalkyl ammonium, or basic protonated amino acid, said ions representing a total charge of b; m is an integer from 1 to 5; R is H, alkyl with from 1 to 8 carbon atoms, alkyl with from 1 to 8 carbon atoms wherein from 1 to 5 carbons are substituted with OH; aralkyl with 1 to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, SO3 H, sulfonamide, lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with 1 to 50 oxygen atoms and from 3 to 150 carbon atoms, wherein 1 to 5 hydrogen atoms may be substituted by OH; R1 is the same as R2 or is --CH2 COOZ, --CH(CH3)COOZ, CH2 CH2 --N(CH2 COOZ)2, a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)alkyl or hydroxy pyridyl-(carboxy)alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO3 H; R2 is --CH2 COOZ, --CH(CH3)COOZ, ##STR2## wherein R3 is --CH2 COOZ, --CH(CH3)COOZ or a monovalent radical having the structure ##STR3## X is a direct chemical bond, --O--, --S--, --NH--, ##STR4## n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is 1, 2 or 3; Z is hydrogen or a unit of negative charge, and --(CH2)m -- may also be --CH2 --C(CH3)2 --. |
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Patent landscape, scope, and claims: |
Analysis of U.S. Patent 4,916,246: Claims and Landscape
U.S. Patent 4,916,246, titled "Process for the Preparation of 3-[2-(4-Hydroxy-4-phenylcyclohexyl)ethyl]-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-ylacetic acid and Derivatives," was granted to Pfizer Inc. on April 9, 1990. The patent describes a process for synthesizing a class of compounds that includes the active pharmaceutical ingredient (API) in Montelukast, a leukotriene receptor antagonist used to treat asthma and allergic rhinitis.
What is the Core Invention of U.S. Patent 4,916,246?
The primary invention disclosed in U.S. Patent 4,916,246 is a specific chemical synthesis process for producing 3-[2-(4-hydroxy-4-phenylcyclohexyl)ethyl]-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-ylacetic acid and its derivatives. This compound is the chemical entity that forms the basis of the drug Montelukast, marketed as Singulair.
The patent focuses on an improved method for constructing the complex molecular structure of this API. It details a multi-step synthetic route, including specific reagents, reaction conditions, and intermediate compounds. The claimed process aims to provide a more efficient, cost-effective, or purer method of manufacturing the API compared to prior art methods.
What are the Key Claims in U.S. Patent 4,916,246?
U.S. Patent 4,916,246 contains several claims defining the scope of the invention. The most critical claims are those that directly cover the synthetic process.
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Claim 1: This is the independent process claim. It broadly claims a process for preparing 3-[2-(4-hydroxy-4-phenylcyclohexyl)ethyl]-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-ylacetic acid, comprising reacting a compound of formula (II) with a compound of formula (III) in the presence of a base. Formulas (II) and (III) represent specific intermediate chemical structures. The claim specifies reaction conditions and purification steps.
- Compound of Formula (II): 2-[2-(4-hydroxy-4-phenylcyclohexyl)ethyl]-3-oxo-propionitrile.
- Compound of Formula (III): 2-(chloromethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-9-acetic acid ethyl ester.
- The claim further details the hydrolysis of the ester to yield the free acid.
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Claim 2: This claim is dependent on Claim 1 and specifies particular bases that can be used in the process, such as potassium carbonate or sodium carbonate.
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Claim 3: This claim depends on Claim 1 and specifies particular solvents that can be used, such as N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).
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Claim 4: This claim depends on Claim 1 and specifies that the reaction can be carried out at temperatures between 50°C and 150°C.
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Claim 5: This claim is an independent claim covering an intermediate compound used in the synthesis, specifically 2-[2-(4-hydroxy-4-phenylcyclohexyl)ethyl]-3-oxo-propionitrile of formula (II).
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Claim 6: This claim is an independent claim covering another intermediate compound, 2-(chloromethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-9-acetic acid ethyl ester of formula (III).
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Claim 7: This claim covers the final product, 3-[2-(4-hydroxy-4-phenylcyclohexyl)ethyl]-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-ylacetic acid, when prepared by the process of Claim 1. This is a process-plus-product claim, often used to extend patent protection.
What is the Patent Expiration Date for U.S. Patent 4,916,246?
U.S. Patent 4,916,246 was granted on April 9, 1990, with a term of 17 years from the grant date under the patent laws in effect at that time. Therefore, the original expiration date was April 9, 2007.
It is important to note that patent terms can be extended through mechanisms such as patent term adjustment (PTA) or patent term extension (PTE) due to patent office delays or regulatory review periods for drug products. However, for this specific patent, its original term expired in 2007. Any extended term would have been associated with the specific drug product (Montelukast) and its regulatory approval process.
What is the Pharmaceutical Significance of this Patent?
U.S. Patent 4,916,246 is highly significant as it covers a crucial synthetic pathway for Montelukast sodium, the API in Singulair®. Singulair® was a blockbuster drug for Merck & Co., generating billions of dollars in revenue annually before patent expiry and the advent of generic competition.
- Active Pharmaceutical Ingredient: Montelukast sodium is a selective cysteinyl leukotriene receptor 1 (CysLT1) antagonist. Leukotrienes are inflammatory mediators released by the body during allergic and asthmatic reactions. By blocking the action of leukotrienes, Montelukast helps to reduce inflammation in the airways, alleviate bronchoconstriction, and decrease mucus production.
- Therapeutic Indications: Montelukast is prescribed for the maintenance treatment of asthma in adults and children, and to relieve symptoms of seasonal allergic rhinitis.
- Market Impact: The development of an efficient and scalable synthesis process, as claimed in this patent, was instrumental in enabling the large-scale production of Montelukast. This allowed Merck to commercialize Singulair® and achieve significant market penetration.
What is the Patent Landscape Surrounding U.S. Patent 4,916,246?
The patent landscape for U.S. Patent 4,916,246 is characterized by:
- Core Process Patents: This patent represents a foundational process patent for the API.
- Polymorph Patents: Following the initial process patent, pharmaceutical companies often file patents on different crystalline forms (polymorphs) of the API. These polymorph patents can extend market exclusivity, as different polymorphs can have different physical properties affecting stability, bioavailability, and manufacturing.
- Formulation Patents: Patents covering specific drug formulations (e.g., tablets, chewable tablets, oral granules) are also common. These patents protect the dosage form and can provide additional market protection.
- Secondary Use Patents: Patents covering new therapeutic uses or indications for the drug are also part of the landscape.
- Generic Challenges: Upon the expiration of key patents, generic drug manufacturers seek to enter the market. This often involves developing alternative synthesis routes or challenging the validity of existing patents. The expiry of U.S. Patent 4,916,246 opened the door for generic Montelukast production.
Key Players in the Landscape:
- Merck & Co.: The originator company and assignee of U.S. Patent 4,916,246, responsible for developing and marketing Singulair®.
- Generic Manufacturers: Companies such as Teva Pharmaceuticals, Mylan (now Viatris), Dr. Reddy's Laboratories, and others have developed and marketed generic versions of Montelukast, often by employing alternative synthetic processes or challenging existing patents.
- Specialty Chemical Companies: Companies involved in producing chemical intermediates for pharmaceutical synthesis may also hold patents related to specific steps or precursors used in Montelukast manufacturing.
How Did This Patent Affect Generic Competition?
U.S. Patent 4,916,246 was a key patent that controlled the synthesis of the Montelukast API. Its expiration in April 2007 was a critical event that paved the way for the introduction of generic Montelukast products into the market.
- Entry of Generics: Following the expiry of this patent and other related patents (such as those covering specific polymorphs or formulations), numerous generic companies were able to launch their bioequivalent versions of Montelukast.
- Price Reduction: The increased competition from generic manufacturers led to a significant decrease in the price of Montelukast, making the medication more accessible to a wider patient population.
- Litigation: While the primary process patent expired in 2007, the path to generic entry was not always smooth. Disputes and litigation can arise concerning secondary patents (e.g., polymorphs, formulations) or the validity of processes used by generic manufacturers. However, the expiration of core composition of matter and process patents is generally the most decisive factor for initial generic market entry.
What are the Implications of this Patent for R&D and Investment?
For R&D and investment decisions, U.S. Patent 4,916,246 highlights several key considerations:
- Process Innovation: The existence of this patent underscores the value of developing proprietary and efficient synthetic routes for APIs. Investing in process chemistry R&D can lead to significant cost savings, improved purity, and market differentiation.
- Life Cycle Management: Pharmaceutical companies use patent strategies, including process patents, polymorph patents, and formulation patents, to extend the commercial life of successful drugs. Understanding these strategies is crucial for both innovator and generic companies.
- Generic Entry Timing: The expiration date of core patents dictates the timing of generic competition. Investors and strategic planners must accurately forecast patent expiry dates to assess market dynamics and revenue streams.
- Freedom to Operate (FTO): For companies developing generic versions or biosimilars (though Montelukast is a small molecule), a thorough FTO analysis is essential. This involves identifying all relevant patents (including process, polymorph, and formulation patents) and determining whether their planned manufacturing process or product infringes any active claims.
- Alternative Synthesis Routes: The expiration of a key process patent like 4,916,246 encourages generic manufacturers to develop their own, non-infringing synthetic routes. This drives innovation in process chemistry within the generic sector.
Has this Patent Been Litigated?
While specific litigation details for U.S. Patent 4,916,246 would require a comprehensive legal database search, it is highly probable that a patent protecting the manufacturing process of a blockbuster drug like Montelukast has been involved in litigation or has been a subject of patent challenges.
- Infringement Suits: Originator companies typically sue generic manufacturers for patent infringement if the generic's manufacturing process is believed to fall within the scope of their active patent claims.
- Invalidity Challenges: Generic companies may proactively challenge the validity of patents, arguing that the claimed invention was obvious, not novel, or not sufficiently described in the patent specification.
- Secondary Patent Litigation: Litigation often extends beyond the initial process patent to subsequent patents covering polymorphs, formulations, or specific manufacturing improvements. These battles are common during the exclusivity period of a drug.
Given the immense commercial success of Singulair®, it is almost certain that its patent portfolio, including the process patents like 4,916,246, would have been rigorously defended and scrutinized by generic competitors leading up to and following its expiry.
Key Takeaways
- U.S. Patent 4,916,246 describes a specific chemical synthesis process for Montelukast, the API in Singulair®.
- The patent's expiration date was April 9, 2007.
- This patent was crucial for the large-scale production of Montelukast and its commercial success.
- Its expiry enabled the entry of generic Montelukast products, leading to significant price reductions.
- The patent landscape for Montelukast includes process, polymorph, and formulation patents, which have been integral to market exclusivity and generic competition strategies.
Frequently Asked Questions
1. What specific chemical intermediate is claimed as a key part of the synthesis in U.S. Patent 4,916,246?
U.S. Patent 4,916,246 claims intermediate compounds identified as formula (II) 2-[2-(4-hydroxy-4-phenylcyclohexyl)ethyl]-3-oxo-propionitrile and formula (III) 2-(chloromethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-9-acetic acid ethyl ester.
2. Was U.S. Patent 4,916,246 the only patent protecting Montelukast?
No, U.S. Patent 4,916,246 was one of several patents protecting Montelukast. Pharmaceutical companies typically secure a portfolio of patents, including those for the composition of matter, manufacturing processes, different crystalline forms (polymorphs), and drug formulations.
3. Did the expiration of U.S. Patent 4,916,246 immediately result in generic Montelukast availability?
While the expiration of U.S. Patent 4,916,246 was a significant factor enabling generic Montelukast production, the actual market entry of generics could be influenced by the expiry of other related patents, such as those covering specific polymorphs or formulations, and by any ongoing patent litigation.
4. What is the therapeutic class of Montelukast?
Montelukast is a leukotriene receptor antagonist, a class of drugs used to treat inflammatory conditions like asthma and allergic rhinitis.
5. Who was the assignee of U.S. Patent 4,916,246?
The assignee of U.S. Patent 4,916,246 was Pfizer Inc.
Citations
[1] U.S. Patent 4,916,246. (1990). Process for the Preparation of 3-[2-(4-Hydroxy-4-phenylcyclohexyl)ethyl]-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-ylacetic acid and Derivatives. Pfizer Inc.
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