Details for Patent: 5,753,677

Summary for Patent: 5,753,677

Title:	Benzoheterocyclic compounds
Abstract:	Novel benzoheterocyclic compounds of the formula: ##STR1## which have excellent vasopressin antagonistic activities and are useful as vasodilator, hypotensive agent, water diuretics, platelet agglutination inhibitor, and a vasopressin antagonistic composition containing the compound as the active ingredient.
Inventor(s):	Hidenori Ogawa, Hisashi Miyamoto, Kazumi Kondo, Hiroshi Yamashita, Kenji Nakaya, Hajime Komatsu, Michinori Tanaka, Shinya Kora, Michiaki Tominaga, Yoichi Yabuuchi
Assignee:	Otsuka Pharmaceutical Co Ltd
Application Number:	US08/474,544
Patent Claim Types: see list of patent claims	Use;

US Patent 5,753,677: Scope, claim coverage, and US patent landscape for vasopressin antagonism benzoheterocyclic compounds

US Patent 5,753,677 is a US method claim family directed to antagonizing vasopressin by administering benzoheterocyclic compounds defined by extremely broad Markush-type structural variables (R1–R5, R6–R16, W, m, n, q, etc.) and including specific exemplified embodiments toward substituted tetrahydro-1H-benzazepines (eg, “5-dimethylamino-1-…-2,3,4,5-tetrahydro-1H-benzazepine”). Claim scope is functional on the pharmacological outcome (“antagonizing vasopressin”) while being structurally tethered to the defined benzoheterocyclic scaffold and a large set of substituent/graft options.

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What is US Patent 5,753,677 and what does it claim for vasopressin antagonists?

Short answer: US 5,753,677 claims a method of treatment: administering a therapeutically effective amount of a benzoheterocyclic compound of a defined general formula for vasopressin antagonism, including pharmaceutically acceptable salts.

Core claim structure: method-of-use over defined compounds

• Claim 1 is a method claim:
  • “A method for antagonizing vasopressin… comprising administering… a therapeutically effective amount of a benzoheterocyclic compound of the formula…”
  • Ends with “and a pharmaceutically acceptable salt thereof.”

Why this matters for enforcement

• Because the claim is method-of-use, enforcement typically targets:
  • commercial drug products whose labels/instructions correspond to the claimed use; and/or
  • clinical/marketing conduct that constitutes practicing the method (depending on jurisdiction and evidence standards).
• Structural Markush breadth makes compound-to-claim mapping the key technical step for any infringement or design-around.

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How broad are the compound definitions in claim 1 of US 5,753,677?

Short answer: Claim 1 uses multi-parameter Markush ranges for aromatic substitution, heteroatom-containing linkers, acyl/amido substituents, leaving-group-like substituent options, and variable tether lengths, producing very large theoretical coverage within the tetrahydro-benzazepine/related benzoheterocycle space.

Markush variables and functional intent

Claim 1 defines a benzoheterocyclic compound via a scaffold plus substitution variable groups:

• R1 and R2: large allowed sets (hydrogen, halogen, C1–C6 alkyl/alkoxy; amino optionally substituted; and benzoyloxy with optionally halogenated phenyl ring; plus phenyl(C1–C6) alkoxy; hydroxy; carbamoyl-substituted alkoxy).
• R3 and R4: defined as groups attached to the scaffold through formula fragments (R3 is defined via two alternative group formulae; R4 is hydrogen, benzoyl optionally halogenated on phenyl, or C1–C6 alkyl).
• R5: the most expansive “side-chain / substituent class” variable:
  • includes multiple substituent families like halogenated or hydroxy-substituted alkyls, phenyl rings, cycloalkyl, alkoxy/alkanoyloxy substituted alkoxy species, cyano/nitro/amino, carboxy-substituted alkoxy, phthalimido-substituted alkoxy, aminocarbonyl alkoxy with alkyl, and a further “group of the formula” (denoted in the claim) involving A and R6/R7 and m.
• R6 and R7: can be independently hydrogen/alkyl/alkanoyl/benzoyl; can optionally cyclize (bind together on a nitrogen atom) to yield 5- or 6-member saturated heterocycles selected from:
  • pyrrolidinyl, piperidinyl, piperazinyl, morpholino,
  • optionally substituted with piperidinyl or C1–C6 alkyl.
• m: integer 0–3, and additional allowed acyl/aryl acyl/cyclic carbonyl types (including tricyclo(3.3.1.1)decanylcarbonyl, thenoyl, naphthylcarbonyl, furoyl, quinolylsulfonyl-like blocks, etc.).
• W: substituent linker chosen from:
  • -(CH2)p- where p is 3–5, or
  • -CH=CH-(CH2)q- where q is 1–3, each optionally substituted with a long list of functional groups (alkyl with hydroxy, alkoxycarbonyl, carboxy, oxo, halogenated alkanoyloxy, aminoalkyl acyl-substituted, azido, sulfoxyimino-like groups, and multiple oxime/imino-like motifs including groups of formulae).
• n: integer 0 or 1 in another variable fragment (connected to a sulfonamide/sulfonyl-containing motif in the claim text).
• R8, R9, R10, R11, R12: additional substitution points and optional ring-forming options (including heterocycles and diverse substituent classes).

Practical read-through

For diligence, the claim is best treated as covering:

• a family of vasopressin antagonists sharing a defined benzoheterocycle core (illustrated by repeated exemplified tetrahydro-1H-benzazepine derivatives); and
• wide latitude in substitutions that likely map to structure-activity optimization.

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Which specific compounds are exemplified in US 5,753,677?

Short answer: The specification of dependent claim 66–78 lists multiple concrete benzoheterocyclic embodiments. These are not the exclusive coverage if claim 1 is construed broadly, but they anchor likely commercial “hit” compounds.

Exemplified substituted tetrahydro-1H-benzazepines listed as dependent-claim embodiments

From the provided claim text:

1. Claim 66: 5-dimethylamino-1-(4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
2. Claim 67: 5-dimethylamino-1-(2-chloro-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
3. Claim 68: 5-methylamino-1-(2-chloro-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
4. Claim 69: 5-cyclopropylamino-1-(2-chloro-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
5. Claim 70: 5-cyclopropylamino-1-(2-chloro-4-(2-chlorobenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
6. Claim 71: 5-dimethylamino-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
7. Claim 72: 4-dimethylamino-1-(3-methoxy-4-(2-methylbenzoylamino)benzoyl?)-1,2,3,4-tetrahydroquinoline
8. Claim 73: 7-chloro-5-methylamino-1-(4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
9. Claim 74: 7-chloro-5-methylamino-1-(4-(2-chlorobenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
10. Claim 75: 7-chloro-5-hydroxy-1-(2-methoxy-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
11. Claim 76: 7-chloro-5-hydroxy-1-(2-methoxy-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
12. Claim 77: 7-fluoro-5-hydroxy-1-(2-chloro-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine
13. Claim 78: 7-fluoro-5-hydroxymethyl-5-hydroxy-1-(2-chloro-4-(2-methylbenzoylamino)benzoyl?)-2,3,4,5-tetrahydro-1H-benzazepine

Interpretation for landscape work: these exemplars show the “center of gravity” of the Markush variables:

• amine substitution at the benzoheterocycle nitrogen position (dimethylamino / methylamino / cyclopropylamino / hydroxy),
• aryl benzoylamino motifs on the benzoyl-linked portion,
• halogen patterning on the benzoyl ring (2-chloro, 7-chloro, 7-fluoro, 2-methyl, etc.),
• tetrahydro-1H-benzazepine as the key core.

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What is the scope of R1/R2 variations and how do they drive infringement risk?

Short answer: R1 and R2 variations substantially broaden claim 1 while still being limited to specific chemical classes. The practical infringement risk concentrates on whether an accused vasopressin antagonist fits the benzoheterocycle and substituted benzoyl-amide architecture, not on minor substituent changes at R1/R2.

R1 options (claim 1 depends)

Dependent claims map specific R1 substitutions:

• Claim 2: R1 = hydrogen
• Claim 3: R1 = halogen
• Claim 4: R1 = C1–C6 alkyl, amino (optionally C1–C6 alkyl), or C1–C6 alkoxy

R2 options (claim 1 depends)

Dependent claims map:

• Claim 5: R2 = hydrogen
• Claim 6: R2 = halogen or C1–C6 alkoxy or C1–C6 alkyl
• Claim 7/10/13: R2 includes phenyl-(C1–C6) alkoxy, hydroxy, amino optionally substituted, carbamoyl-substituted alkoxy, amino-substituted alkoxy, benzoyloxy (with optional halogen on phenyl)

In practice: if an accused product changes only R1/R2 to another permitted member, it still likely falls within the structural class.

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What side-chain and linker classes are covered by R3/R5/W?

Short answer: The combination of R3, R4, R5, and W covers a wide set of:

• benzoyl/acyl substitution patterns,
• heterocycle-forming substituents (piperidine/pyrrolidine/piperazine/morpholine),
• varied linker lengths (p = 3–5; q = 1–3),
• multiple functional handles (alkoxycarbonyl, carboxy, azido, oxime/imino-like motifs, halogenated alkanoyloxy).

R4 options

Dependent claims show R4 can be:

• hydrogen (multiple dependent claims),
• benzoyl optionally halogen-substituted,
• C1–C6 alkyl (claim 24, 27, 30, 33, 36, 39, 42, 45, 48).

R3 options

Dependent claims alternate R3 between at least two defined group formulae (claims 14–21, 18–21, etc.), each tied to other variables (R4 and R5 or R11/R12).

W options

Dependent claims 53–54 and 56–64 set:

• W = -(CH2)p- (p = 3–5) and optionally substituted,
• W = -CH=CH-(CH2)q- (q = 1–3) and optionally substituted,
• explicit dependent claim instantiations:
  • claim 56: p = 3 and no substituent,
  • claim 58: p = 4 and no substituent,
  • claim 60: p = 5,
  • claim 61–63: q = 1, 2, 3.

Landscape relevance: accused designs that change linker length or swap a saturated -(CH2)p- to an alkenyl tether -CH=CH-(CH2)q- may still land inside claim 1 if the altered structure remains within the enumerated p/q ranges and permitted substitutions.

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How do claims 66–78 function: do they narrow or expand coverage?

Short answer: Claims 66–78 operate as narrower dependent embodiments. They are not strict limits on claim 1, but they:

• give concrete claim targets for compound-family mapping,
• reduce ambiguity when comparing an accused compound’s substitution pattern to the exemplified member set.

Examples most relevant for claim mapping

• amine at position corresponding to “5-” substitution (dimethylamino, methylamino, cyclopropylamino)
• halogen at “1-… benzoyl” ring and benzoheterocycle ring (2-chloro, 7-chloro, 7-fluoro)
• benzoylamino substituent where the benzoyl anilide has methyl or chloro substitution patterns (2-methylbenzoylamino, 2-chlorobenzoylamino)

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How many patent families could be needed to fully cover a vasopressin antagonist program built around this scaffold?

Short answer: Within the provided record, only US 5,753,677 is addressed. However, claim structure strongly implies a standard medicinal-chemistry patent portfolio pattern:

• a broad core scaffold claim set (like claim 1),
• dependent claim coverage for side-chain classes and specific substituent embodiments (like claims 14–64 and 66–78),
• likely additional related patents for:
  • specific substituted compounds,
  • salt forms,
  • formulations,
  • dosing regimens,
  • and potentially additional therapeutic indications beyond “vasopressin antagonism.”

Because only one patent number is in-scope here, any numeric count of “how many patents cover” cannot be made from the provided information without adding external sources.

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How strong is the patent estate for US 5,753,677’s claim 1 coverage against generics or design-arounds?

Short answer: The claim 1 breadth is structurally expansive, but the strength in litigation depends on:

• whether a target compound truly meets the benzoheterocyclic formula limitations,
• whether the “vasopressin antagonism” method-of-use element is satisfied (label, actual use),
• and claim construction outcomes for the Markush portions.

Strength drivers

• Very broad substituent allowance across R1–R5, R6–R16, W, m, n, q.
• Direct inclusion of pharmaceutically acceptable salts.

Weakness drivers (within this record)

• Method-of-use claims are harder to trigger against products without corresponding use conduct.
• Wide Markush breadth can increase susceptibility to:
  • indefiniteness arguments in some contexts,
  • lack of enablement or written description challenges,
  • claim interpretation limits tied to the specification.

No litigation posture or prosecution history is provided in the prompt.

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What generic entry risks exist for vasopressin antagonists that might fall within this scaffold?

Short answer: For any generic entrant, the primary risk is whether their active ingredient and approved labeling/practice would fall within claim 1’s compound-defined structure and “vasopressin antagonism” method-of-use claim.

Risk categories tied to claim structure

1. Active ingredient match risk
   • If the generic’s API is within the benzoheterocyclic formula family, chemical infringement risk rises.
2. Salt/form risk
   • If the generic markets a pharmaceutically acceptable salt within the defined compound, the salt language supports capture.
3. Labeling/use risk
   • Method-of-use claims require evidence of practicing the vasopressin antagonism method.

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What formulations, delivery systems, or dosage forms are claimed?

Short answer: In the provided claim set, no formulation-specific claims or dosage-form limitations are stated. The claim is a method of treatment defined by compound and administration, not by formulation parameters.

• Claim 1: “administering… therapeutically effective amount”
• No excipient, tablet coating, injection vehicle, or specific release profile appears in claim 1 through the provided dependent-claim text.

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What is the Orange Book status of US 5,753,677?

Short answer: Not determinable from the provided information. Orange Book status requires linking the patent number to an FDA-approved NDA/BLA with Orange Book listings.

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What patent litigation affects US 5,753,677 or its claims?

Short answer: Not determinable from the provided information. Litigation requires external docket and settlement data.

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Which companies are challenging or would likely license around this patent estate?

Short answer: Not determinable from the provided information. Company mapping requires inventors/assignee and external enforcement or licensing records.

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Key Takeaways

• US 5,753,677 is a method-of-use patent for vasopressin antagonism by administering a benzoheterocyclic compound defined by a large Markush set.
• Claim 1 is structurally broad: R1/R2 substitution breadth plus major variability at R3/R4/R5 and W, including linker length ranges (p = 3–5; q = 1–3) and optional heterocycle-forming substituents (pyrrolidinyl/piperidinyl/piperazinyl/morpholino).
• Dependent claims 66–78 list multiple specific substituted embodiments centered on tetrahydro-1H-benzazepine frameworks with benzoylamino/aryl substitution patterns.
• Enforcement strength hinges on (i) whether an accused compound truly falls inside the defined formula and (ii) whether the method element (“antagonizing vasopressin”) is practiced in a way that matches the claim.

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FAQs

1) Does US 5,753,677 claim a specific vasopressin receptor antagonist molecule or a class?
It claims a class of benzoheterocyclic compounds defined by a general formula, used to antagonize vasopressin, with broad Markush substitution variables.

2) Can changing linker length avoid infringement of claim 1?
Avoidance would require the accused structure to fall outside the enumerated p (3–5) or q (1–3) ranges (and also any additional substitution constraints tied to W), because the claim expressly covers both saturated and unsaturated tether types within those ranges.

3) Are salts included in the protected subject matter?
Yes. Claim 1 concludes with “a pharmaceutically acceptable salt thereof.”

4) Are formulations or dosage forms limited in US 5,753,677?
No formulation/dosage-form limitations appear in the provided claim text; the claim is an administration-based method-of-use anchored to the defined compounds.

5) Do the exemplified benzazepine compounds narrow the scope of claim 1?
They appear as dependent-claim embodiments. They narrow those dependent claims but do not limit claim 1’s broader Markush coverage.

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References (APA)

1. US Patent 5,753,677. (claims text as provided in the prompt).

Drugs Protected by US Patent 5,753,677

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 5,753,677

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0450097		CA 2009 00031	Denmark
European Patent Office	0450097		SPC/GB09/037	United Kingdom
European Patent Office	0450097		300408	Netherlands
European Patent Office	0450097		09C0049	France
European Patent Office	0450097		C300408	Netherlands
Australia	630284
Australia	7291791