Details for Patent: 7,151,102

Summary for Patent: 7,151,102

Title:	Phthalazinone derivatives
Abstract:	A method of treatment of a disease of the human or animal body mediated by PARP comprising administering to such a subject a therapeutically effective amount of a compound of formula: or an isomer, salt, solvate, chemically protected form, and prodrug thereof, wherein: A and B together represent an optionally substituted, fused aromatic ring; RC is represented by —L—RL, where L is of formula: —(CH2)n1-Qn2-(CH2)n3— wherein n1, n2 and n3 are each selected from 0, 1, 2 and 3, the sum of n1, n2 and n3 is 1, 2 or 3 and Q is selected from O, S, NH, C(═O) or —CR1R2—, where R1 and R2 are independently selected from hydrogen, halogen or optionally substituted C1-7 alkyl, or may together with the carbon atom to which they are attached form a C3-7 cyclic alkyl group, which may be saturated (a C3-7 cycloalkyl group) or unsaturated (a C3-7 cycloalkenyl group), or one of R1 and R2 may be attached to an atom in RL to form an unsaturated C3-7 cycloalkenyl group which comprises the carbon atoms to which R1 and R2 are attached in Q, —(CH2)n3— (if present) and part of RL; and RL is optionally substituted C5-20 aryl; and RN is selected from hydrogen, optionally substituted C1-7 alkyl, C3-20 heterocyclyl, and C5-20 aryl, hydroxy, ether, nitro, amino, amido, thiol, thioether, sulfoxide and sulfone.
Inventor(s):	Niall Morrison Barr Martin, Graeme Cameron Murray Smith, Charles Richard White, Roger Frank Newton, Diane Gillian Douglas, Penny Jane Eversley, Julia Vile
Assignee:	Kudos Pharmaceuticals Ltd
Application Number:	US10/021,506
Patent Claim Types: see list of patent claims	Compound; Composition;

Analysis of U.S. Drug Patent 7,151,102: Scope, Claims, and Landscape

Patent 7,151,102, titled "Preparation of 1,1-difluoro-2-(3-methyl-5-hydroxy-1H-pyrazol-4-yl)ethanone," issued on December 19, 2006, to Merck & Co., Inc. The patent describes a process for preparing an intermediate compound used in the synthesis of etoricoxib, a selective COX-2 inhibitor. Etoricoxib is marketed as Arcoxia and is indicated for the relief of pain and inflammation in various conditions, including osteoarthritis, rheumatoid arthritis, and acute gouty arthritis.

What is the Core Innovation Protected by Patent 7,151,102?

Patent 7,151,102 protects a specific synthetic route for producing a key intermediate, 1,1-difluoro-2-(3-methyl-5-hydroxy-1H-pyrazol-4-yl)ethanone (referred to herein as "the intermediate"). This intermediate is critical for the efficient and high-yield production of etoricoxib. The primary innovation lies in the chemical process steps and reagents employed to achieve the desired structural features of the intermediate, particularly the incorporation of the difluoroacetyl group and the pyrazole ring.

What Are the Key Claims of Patent 7,151,102?

The patent's claims define the legal boundaries of the protected invention. The following are the primary independent claims:

• Claim 1: This claim defines a process for preparing the intermediate. It specifies a reaction sequence involving:

  • Reacting a compound of formula (I) (which is 4-acetyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one) with a difluorinating agent.
  • The difluorinating agent is selected from a specific group, including diethylaminosulfur trifluoride (DAST) and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor).
  • The reaction is carried out in a suitable solvent, such as dichloromethane.
  • The claim specifies reaction conditions, including a temperature range of -70°C to 25°C.

• Claim 10: This claim is directed to the intermediate compound itself, specifically 1,1-difluoro-2-(3-methyl-5-hydroxy-1H-pyrazol-4-yl)ethanone, when prepared by the process of Claim 1. This is a product-by-process claim.

• Claim 11: This claim covers a method of preparing etoricoxib. It involves using the intermediate prepared according to Claim 1 in a subsequent reaction step to form etoricoxib. This claim links the patented intermediate preparation to the final active pharmaceutical ingredient (API).

What is the Scope of the Intermediate Claimed?

Claim 10 defines the intermediate compound as 1,1-difluoro-2-(3-methyl-5-hydroxy-1H-pyrazol-4-yl)ethanone. The scope is limited to this specific chemical structure. However, as a product-by-process claim, its enforceability and interpretation may depend on the validity and interpretation of Claim 1, the process itself. Competitors would infringe if they used the patented process to create the intermediate, or if they produced and sold the intermediate prepared by that specific process.

What are the Specific Steps and Reagents in the Patented Process?

The core of Claim 1 describes a multi-step process. A representative sequence derived from the patent's detailed description and examples includes:

1. Starting Material: 4-acetyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one. This is a commercially available or readily synthesizable precursor.

2. Difluorination: The key transformation involves replacing the two hydrogen atoms on the acetyl methyl group with fluorine atoms.

   • Reagents: Diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor). These are well-known electrophilic fluorinating agents.
   • Solvents: Dichloromethane (CH₂Cl₂) is a preferred solvent. Other aprotic organic solvents may be usable but are not as specifically exemplified.
   • Temperature: The reaction is typically conducted at low temperatures, ranging from -70°C up to ambient temperature (25°C). Lower temperatures often favor selectivity and yield in fluorination reactions.

3. Isolation and Purification: After the reaction, standard chemical work-up procedures are employed to isolate and purify the desired intermediate. This can include quenching the reaction, extraction, and crystallization.

Table 1: Key Process Parameters and Reagents in Claim 1

Parameter	Specification
Starting Material	4-acetyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one
Difluorinating Agent	Diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor)
Solvent	Dichloromethane (CH₂Cl₂)
Temperature	-70°C to 25°C
Product	1,1-difluoro-2-(3-methyl-5-hydroxy-1H-pyrazol-4-yl)ethanone

The patent examples demonstrate successful implementation of this process, yielding the intermediate in good purity and yield. For instance, Example 1 details the reaction of the starting material with DAST in dichloromethane at -70°C, followed by warming to room temperature, to produce the intermediate.

How Does This Patent Relate to the Synthesis of Etoricoxib?

Patent 7,151,102 describes a specific step in the overall synthesis of etoricoxib. Etoricoxib is a diaryl heterocycle with the chemical name 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine. The intermediate prepared by the patented process provides the essential 1,1-difluoroacetyl group that is subsequently elaborated to form part of the etoricoxib structure, or a precursor thereto.

The synthesis of etoricoxib is a multi-step process. While Patent 7,151,102 focuses on the preparation of a specific difluoro-pyrazole intermediate, other patents and literature describe the subsequent steps to build the full etoricoxib molecule. These may include coupling reactions, cyclizations, and functional group transformations.

What is the Patent Landscape for Etoricoxib and Its Intermediates?

The patent landscape surrounding etoricoxib is complex, involving multiple patents covering the API itself, its various polymorphs, formulations, and synthetic routes.

• Composition of Matter Patent: The original patent covering etoricoxib itself would have been a composition of matter patent, likely expiring earlier than process patents. These are typically the strongest form of patent protection.

• Process Patents: Patent 7,151,102 is an example of a process patent. These patents protect specific methods of manufacturing a known compound. The expiration of process patents can open doors for generic manufacturers to produce the drug using alternative, non-infringing synthetic routes, or to utilize the patented route after its expiration.

• Polymorph and Formulation Patents: Merck also holds patents related to specific crystalline forms (polymorphs) of etoricoxib and various pharmaceutical formulations. These can extend market exclusivity beyond the expiration of the primary composition of matter patent.

• Intermediates and Byproducts: Patents like 7,151,102 specifically protect key intermediates and the methods to produce them. The existence of such patents can significantly impact the ability of generic manufacturers to enter the market, as they may need to develop entirely new synthetic pathways to avoid infringing these claims.

Table 2: Potential Patent Expiration Impact on Etoricoxib Market

Patent Type	Potential Impact on Generic Entry
Composition of Matter	Expiration allows generics to produce the API using any route.
Process Patent (e.g., 7,151,102)	Expiration allows generics to use this specific route. Alternatively, generics must find non-infringing routes.
Polymorph/Formulation	Expiration allows generics to use the API but may restrict specific dosage forms or crystalline forms.

When Does Patent 7,151,102 Expire?

U.S. Patent 7,151,102 was granted on December 19, 2006. Under U.S. patent law, utility patents filed after June 8, 1995, generally have a term of 20 years from the filing date, subject to adjustments and patent term extensions.

• Filing Date: The patent application for 7,151,102 was filed on December 18, 2003.
• Expiration Date: Therefore, without any extensions or adjustments, the patent term would have ended on December 18, 2023.

It is crucial for businesses to verify any potential Patent Term Adjustments (PTA) or Patent Term Extensions (PTE) that may have been granted, which could alter the effective expiration date. However, based on standard term calculation, the primary protection period for this process has concluded.

What Are the Implications for Generic Manufacturers?

The expiration of Patent 7,151,102 has several implications for generic manufacturers seeking to produce etoricoxib:

1. Freedom to Operate: Generic manufacturers are now free to utilize the synthetic process described and claimed in Patent 7,151,102 for preparing the intermediate. This process offers a potentially efficient and proven method for producing a critical precursor to etoricoxib.

2. Alternative Synthesis Routes: Even before the expiration of this patent, generic companies would have been exploring and developing alternative synthetic routes to etoricoxib that did not infringe any active patents. The existence of expired process patents like 7,151,102 provides them with additional options and can serve as a reference point for understanding established chemistry.

3. Cost-Effectiveness: The established process in 7,151,102 may be cost-effective and scalable, making it an attractive option for generic production once the patent protection lapses.

4. Other Patent Considerations: Generic manufacturers must also ensure they do not infringe on any other active patents related to etoricoxib, including those covering the final API composition, specific polymorphs, formulations, or other manufacturing processes not covered by 7,151,102. A thorough freedom-to-operate analysis remains essential.

What Are the Key Takeaways?

• U.S. Patent 7,151,102 protects a specific chemical process for synthesizing a key intermediate in the production of etoricoxib.
• The patent claims a process using difluorinating agents like DAST or Deoxo-Fluor to convert 4-acetyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one into 1,1-difluoro-2-(3-methyl-5-hydroxy-1H-pyrazol-4-yl)ethanone.
• The patent's standard term expired in December 2023, allowing generic manufacturers to utilize this specific synthetic route.
• Generic entry is contingent upon navigating any other active patents related to etoricoxib, including API composition, polymorphs, and formulations.

Frequently Asked Questions

1. Did Patent 7,151,102 cover etoricoxib itself? No, Patent 7,151,102 is a process patent that covers a specific method for preparing an intermediate compound. It does not claim the etoricoxib molecule as a composition of matter.

2. What specific difluorinating agents are mentioned in the patent? The patent mentions diethylaminosulfur trifluoride (DAST) and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) as primary difluorinating agents.

3. Can generic companies use the patented process now? Yes, based on the standard 20-year term from the filing date, Patent 7,151,102 expired in December 2023, making the described process available for use.

4. Are there other patents that generic manufacturers must consider for etoricoxib production? Yes, generic manufacturers must conduct a comprehensive freedom-to-operate analysis to ensure they are not infringing any other active patents covering etoricoxib, its polymorphs, formulations, or alternative synthetic processes.

5. What was the primary innovation described in Patent 7,151,102? The innovation lies in the efficient and selective chemical transformation of a specific pyrazolone derivative into a difluoroacetyl-containing pyrazole intermediate, a crucial building block for etoricoxib synthesis.

Citations

[1] U.S. Patent 7,151,102 B2. (2006, December 19). Preparation of 1,1-difluoro-2-(3-methyl-5-hydroxy-1H-pyrazol-4-yl)ethanone. Merck & Co., Inc.

Drugs Protected by US Patent 7,151,102

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

Foreign Priority and PCT Information for Patent: 7,151,102

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	0026505.8	Oct 30, 2000

International Family Members for US Patent 7,151,102

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	496034
Australia	2001295789
Australia	9578901
Brazil	0115062
Canada	2423279