Details for Patent: 4,906,755

Summary for Patent: 4,906,755

Title:	Esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one and related compounds
Abstract:	The present invention is directed to a group of esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(3H)-ones and related compounds. The compounds are prepared from the appropriate carboxylic acids and alcohols by standard procedures or, where steric factors are significant, a new process which makes use of heavy metal salts of super acids can be used. The compounds involved are useful in the treatment of migraine and similar disorders and in cytotoxic drug-induced vomiting.
Inventor(s):	Maurice W. Gittos
Assignee:	Aventis Pharmaceuticals Inc
Application Number:	US07/376,172
Patent Claim Types: see list of patent claims	Compound;

Patent 4,906,755 Claim Scope and US Patent Landscape: compound-formula coverage, substituent boundaries, and enforceability risk

US Drug Patent 4,906,755 is a structural Markush composition-of-matter patent. Independent claim 1 (and dependent claims 2-5) covers a family of compounds defined by a shared core scaffold plus broad substituent sets (A and B unsaturation patterns; R1 as an aryl/heteroaryl carbonyl- or thio-/oxy-linked group via Z; and optional ring stereochemistry endo/exo at an oxygen substituent). Claims 6-8 and 10 lock to specific stereoisomer/functionalized embodiments, while claim 9 recites an additional specific embodiment.

At a business level, the patent estate is strongest against competitors that make or sell compounds that fall inside the exact scaffold plus substituent constraints, especially where the marketed compound matches the specific endo/exo and the particular acyl/heteroaryl carboxylate/“carbonyloxy” substituents recited in the dependent claims.

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What compounds are covered by US Patent 4,906,755 claim 1?

Featured snippet answer: Claim 1 covers pharmaceutically acceptable salts and quaternary ammonium salts of compounds that share a single bicyclic core (“hexahydro-2,6-methano-2H-quinolizin-3(4H)-one” family implied by dependent claims) with a variable R1 substituent and constrained unsaturation/functionalization at positions represented by A and B, plus defined allowed substituent ranges for R5-R8, R7, R9-R11, and Z.

Core claim architecture (why the claims are broad but not infinite)

Claim 1 is a compound claim framed as:

• A Markush formula with:
  • A and B parameters indicating either:
    • a double bond to a single group, or
    • two single bonds to two individual groups, in the precise ways spelled out,
  • R1 as a substituted group defined by Z and multiple substituent variables (R5-R11),
• A stereochemical qualifier: “the wavy line indicates that the configuration of the oxygen substitutent on the ring can be endo or exo.”
• Coverage extends to:
  • pharmaceutically acceptable acid addition salts
  • quaternary ammonium salts

This structure typically yields two enforceability levers:

1. Literal infringement can be easier where a competitor’s compound matches the scaffold and allowed substituent options.
2. Design-around is possible by moving outside any one of the enumerated boundaries (for example, selecting a substituent type not allowed by Z or by the allowed R7/R10/R11 ranges, or shifting stereochemistry if the marketed compound does not match the “endo/exo” placement requirement as construed with the core).

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Which Markush variables define the US 4,906,755 chemical universe (A, B, Z, R1)?

A: ring position substitution patterns

Claim 1 defines A as one of:

• (H)(H)
• ═O (a carbonyl-type unsaturation representation in the claim’s drawing)
• (H)(OH)
• ═N--OH

This means the claim allows at that position either hydrogenated forms, a oxo form, a hydroxylated form, or an N-hydroxy form. Substitution choices outside those four are out of scope.

B: second ring position substitution/unsaturation options

Claim 1 defines B as one of:

• (H)(H)
• (H)(CH3)
• (H)(CH2 NR3 R4)
• ═CH2

And ties to:

• R3 and R4 constraints:
  • C2-4 alkyl, or
  • combined to form tetramethylene, pentamethylene, or
  • a bridging ether chain: --CH2CH2–O–CH2CH2--

So B supports either:

• methyl substitution,
• a dialkylamino substituent with constrained alkyl chain length or a fused cyclic/ether variant,
• or an exocyclic/vinyl type group via “═CH2”.

Z: linker/heteroatom identity inside R1

Claim 1 defines R1 as:

• R1 is ##STR6## wherein Z is NR9, O or S

So the “atom” connecting the core to the aryl/aryl-like fragment within R1 can be:

• NR9 (an amino linkage where R9 is defined),
• O (an oxygen linkage, consistent with “carbonyloxy” dependent claims),
• S (a thio linkage, also within Z options).

This is often a key design-around vector: changing an oxygen linkage to a different linkage type or using a linkage not corresponding to O/S/NR9 can avoid literal coverage.

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What substituents are allowed on R1 in claim 1 (R5-R11)?

R5, R6, R8: terminal substituent sets on the aromatic/aryl system portion

Claim 1 provides:

• R5, R6, and R8 are each hydrogen, halogen, C1-3 alkyl, or C1-3 alkoxy.

This is moderately broad. It covers:

• haloaromatics,
• small alkyl and alkoxy patterns,
• and unsubstituted analogs.

Notably excluded by claim language are:

• larger alkyl groups beyond C1-3,
• substituents like CF3 unless treated as halogen (it is carbon + fluorine; typically not a single “halogen” substituent),
• and heteroatom substituents not captured in the explicit set.

R7: position that supports nitrogen-containing and nitro substituents

Claim 1 provides R7 as:

• hydrogen,
• amino,
• (C1-4 alkyl)amino,
• (C1-4 alkyl)2 amino,
• C1-3 alkoxy,
• nitro.

This is a second strong enforceability boundary. Competitors can design around by using different functional groups at that position (for example, cyano alone is covered elsewhere as R10, not R7).

R9: substituent on the NR9 branch

Claim 1 provides:

• R9 is hydrogen, C1-4 alkyl, or phenyl(C1-2 alkyl)

So if Z is NR9, the amine’s substituent set is limited to:

• unsubstituted amino,
• small alkyls up to C4,
• or benzyl-like phenyl(C1-2 alkyl) motifs.

R10 and R11: other aromatic positions

Claim 1 provides:

• R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano, or --CONH2
• R11 is hydrogen, halogen, C1-4 alkyl, or phenyl(C1-2 alkyl)

So R10 allows cyano and amide (--CONH2) explicitly; that matters because it captures certain aryl-heteroatom substitution patterns used in medicinal chemistry around receptor ligands and related cores.

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How do dependent claims 2-5 narrow the claim 1 scaffold?

Claims 2-5 recite additional embodiments with fewer variable freedoms. These dependent claims matter for infringement strategy because they can be easier to map to a competitor’s structure.

Claim 2: a specific intermediate breadth within the R1 structure

Claim 2 includes a formula with:

• B options still including (H)(CH3), (H)(CH2NR3R4), etc.
• A still drawn from the same A list,
• and R1 defined with the same Z options and aromatic substituent variable set, but with tighter ranges:
  • R5, R6, R8 limited to hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy
  • R10 allows the same set (hydroxy, cyano, CONH2)
  • R11 allows hydrogen, halogen, C1-3 alkyl or phenyl(C1-2 alkyl)

In practice, claim 2 functions as a narrower “family subset” within claim 1.

Claim 3: narrows to R1 and removes B’s presence

Claim 3 differs by specifying:

• A in the list,
• and R1 as defined, while B becomes implicitly resolved (the provided text shows A options and R1 definitions, without the B variable enumeration visible in the claim excerpt).

This is typical: dependent claims often “lock” one structural segment and leave the rest to the Markush set.

Claims 4 and 5: further narrowing of R1 and/or ring substitutions

Claims 4 and 5 each define R1 with:

• Z = NR9, O, or S
• R5, R6, R8 limited to H/halo/C1-3 alkyl/C1-3 alkoxy
• R7 from H/amino and alkylamino and alkoxy and nitro
• R9, R10, R11 restricted as in the claim language

Net effect: claims 4 and 5 primarily narrow the “what” of R1’s allowed substituent patterns into discrete sub-ranges of claim 1.

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Which specific stereoisomers and named embodiments are explicitly claimed (claims 6-10)?

These dependent claims are the most actionable for freedom-to-operate and infringement because they name concrete compounds.

Claim 6

• endo-8-(3,5-dimethylbenzoyloxy) hexahydro-2,6-methano-2H-quinolizin-3(4H)-one

Key elements:

• endo stereochemistry specified
• “benzoyloxy” indicates an O-linked R1 consistent with Z = O in claim 1
• substitution pattern 3,5-dimethyl on the benzoyl phenyl ring

Claim 7

• endohexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one

Key elements:

• endo stereochemistry
• “indolylcarbonyloxy” indicates Z likely = O, and the aryl fragment is an indole substituent class, mapped against allowed R-substituent sets for the aryl portion (claim 1’s R9/R10/R11 allowances can capture indole substitution patterns depending on exact positions).

Claim 8

• endo-hexahydro-8-(1-methyl-3-indazolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one

Key elements:

• endo stereochemistry
• indazole-derived carbonyloxy substituent with 1-methyl and 3- linkage orientation.

Claim 9

• Endo-Hexahydro-8hydroxy-2,6-methano-2H-quinolizin-3(4H)-one

Key elements:

• endo stereochemistry
• direct 8-hydroxy form rather than a benzoyloxy/carbonyloxy acyloxy ester form. This can create a distinct infringement path because hydroxy substitution can fall inside the generic Markush for A/B or oxygen substituent logic, depending on how the formula drawing maps.

Claim 10

• exo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one

Key elements:

• exo stereochemistry specified
• same “3-indolylcarbonyloxy” pattern as claim 7 but opposite endo/exo configuration.

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What is the practical scope of literal infringement under 4,906,755?

Strongest literal coverage zones

1. Competitors selling compounds that are structurally identical to claims 6-8 and 10:

   • the named endo/exo indolyl/indazolyl/benzoyloxy embodiments
   • with the same core scaffold (“hexahydro-2,6-methano-2H-quinolizin-3(4H)-one” family)

2. Competitors selling compounds that fall within claim 1’s Markush:

   • Z limited to NR9, O, or S
   • R5/R6/R8 restricted to H/halo/C1-3 alkyl/C1-3 alkoxy
   • R7 restricted to H/amino/alkylamino/alkoxy/nitro
   • R9 limited to H/C1-4 alkyl/phenyl(C1-2 alkyl)
   • R10 restricted to include cyano and amide
   • R11 restricted to H/halo/C1-4 alkyl/phenyl(C1-2 alkyl)
   • stereochemistry at oxygen substituent is endo or exo

Weakest coverage zones

1. Compounds using:

   • different linkage atoms than Z ∈ {NR9, O, S}
   • substituents beyond the enumerated size ranges (C1-3 vs C1-4 matters)
   • aromatic substitution patterns outside R5/R6/R8/R7/R10/R11 sets.

2. Compounds with the “right” aryl acyloxy/heteroaryloxy group but with mismatched:

   • allowed A/B patterning at the ring positions as drawn in the Markush.

Design-around focus

A competitor can often avoid literal claim 1 by:

• changing the linkage type (Z) away from O/S/NR9,
• using substituent sizes outside the Markush ceilings,
• changing the functional group type at R7/R10.

Doctrine of equivalents is possible but typically less predictable against explicit enumerations; the tighter the Markush, the more courts treat the listed choices as limiting.

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How does the endo/exo language affect infringement for stereoisomer competitors?

The claim’s statement:

• “the wavy line indicates that the configuration of the oxygen substitutent on the ring can be endo or exo”

and the explicit dependent claims:

• claim 6, 7, 8, 9 use endo
• claim 10 uses exo

This structure supports the argument that both stereochemical configurations are within scope, but claim 10 provides explicit coverage for an exo variant in one concrete embodiment. If a competitor sells a stereoisomer not aligned with the oxygen substituent configuration as construed, it can fall outside literal coverage. The dependent claims also help map stereochemistry to specific substituents.

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What is the US “drug patent” landscape around 4,906,755 (how other patents usually layer)?

No Orange Book status or related U.S. application/patent numbers are provided in the prompt. Without the branded drug name, active ingredient, FDA application number, or Orange Book listing, an exhaustive landscape across continuations, divisionals, method patents, and formulation patents cannot be completed from claim text alone.

What can be concluded from the face of 4,906,755 claim structure:

• This is composition-of-matter focused on structural analog coverage (Markush).
• The patent likely sits at the top of a typical layering stack:
  • later patents may cover specific formulations, salt forms, process improvements, or additional analogs not captured by the specific R-group boundaries here.
  • earlier patents may disclose the scaffold class or synthesis intermediates, but 4,906,755 is itself directed to the compounds defined by the formula and salts.

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Key claim-to-competitor mapping matrix (actionable claim coverage cues)

Competitor compound attribute	Does it map to 4,906,755 claim language?	Practical effect
Uses the hexahydro-2,6-methano-2H-quinolizin-3(4H)-one core family	Needed for literal coverage via the formula	Main infringement gate
Has oxygen substituent on the ring configured endo or exo	Explicitly included	Supports both stereoisomers if oxygen substituent matches
Has Z linkage in R1 as O (acyloxy/carbonyloxy/benzoyloxy)	Allowed in claim 1 (Z = O); supported by claims 6-8, 10	Strong coverage for acyloxy variants
Has Z linkage as NR9 (amine linkage) or S	Allowed in claim 1	Coverage extends beyond ester-like forms
Aromatic ring substituted with halogen / C1-3 alkyl / C1-3 alkoxy at R5/R6/R8	Allowed	Strong coverage for common medicinal chemistry patterns
Aromatic ring substituted with amino or alkylamino at R7	Allowed if amino types within C1-4 alkyl limits	Design-around via different group types at R7
Uses substituents larger than allowed carbon counts	Not allowed (based on explicit C1-3 or C1-4 ceilings)	Literal design-around lever
Uses cyano or CONH2 at R10	Allowed	Captures a subset of polar substituent variants
Uses different functional group at R7 (e.g., carboxyl, sulfonyl, CF3)	Not enumerated	Potential non-infringement if changes fall outside Markush

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Key Takeaways

• US 4,906,755 is a Markush composition-of-matter patent covering a compound family defined by:
  • A/B unsaturation and substituent patterns,
  • an R1 group built from Z = NR9, O, or S,
  • and tightly enumerated substituent sets for R5-R11.
• The patent explicitly claims both endo and exo stereochemical forms via the oxygen substituent logic, with dependent claims pinpointing:
  • endo-8-(3,5-dimethylbenzoyloxy) (claim 6),
  • endo indolylcarbonyloxy (claim 7),
  • endo indazolylcarbonyloxy with 1-methyl (claim 8),
  • endo hydroxy (claim 9),
  • and exo indolylcarbonyloxy (claim 10).
• The most reliable infringement pathway is literal mapping of a competitor’s structure to:
  1. the specific dependent embodiments, or
  2. claim 1’s enumerated Markush boundaries (especially Z, the C-chain limits, and the allowed R7/R10/R11 functional types).
• Without the branded product identity and Orange Book/FDA linkage, the broader US landscape (other patents, Paragraph IV, exclusivity expirations, and litigation timing) cannot be populated from claim text alone.

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FAQs

What does “Z is NR9, O or S” allow in practice for 4,906,755?

It allows the R1 connection to the core to be an amine-linked (NR9) group, an oxygen-linked (O) acyloxy/carbonyloxy-type group, or a sulfur-linked (S) analog, constrained by the defined substituents for R9.

Are both endo and exo stereoisomers covered under claim 1?

Yes. Claim 1 states the oxygen substituent configuration “can be endo or exo,” and dependent claims explicitly include both endo (claims 6-9) and exo (claim 10) embodiments.

Which claim is strongest for enforcement against a specific marketed analog?

The dependent claims 6-8 and 10 are typically strongest because they recite specific compound identities (e.g., “endo-8-(3,5-dimethylbenzoyloxy)…”, “endo…(3-indolylcarbonyloxy)…”, “exo…(3-indolylcarbonyloxy)…”).

What substitutions can most easily avoid the Markush in claim 1?

Changes that move any R-group outside the enumerated sets, particularly:

• switching Z away from NR9/O/S,
• using substituents larger than C1-3 or C1-4 allowances,
• or placing functional groups at R7/R10/R11 positions not listed in the claim.

Do claims 1-5 cover salts?

Yes. Claim 1 explicitly includes pharmaceutically acceptable acid addition salts and quaternary ammonium salts of the compounds.

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References (APA)

1. United States Patent No. 4,906,755.

Drugs Protected by US Patent 4,906,755

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 4,906,755

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0266730		SPC/GB97/005	United Kingdom
European Patent Office	0266730		98C0014	Belgium
European Patent Office	0266730		C970043	Netherlands
European Patent Office	0266730		73/1997	Austria
Argentina	246264