| Abstract: | A (substituted-aralkyl)heterocyclic compound of the formula I wherein R1 is an azido, carbamoyl, cyano, formyl, hydroxy or nitro radical, a 1-6C 1-hydroxyalkyl, alkoxy, alkylcarbamoyl, alkylthio, alkylsulphinyl or alkylsulphonyl radical, a 2-cyanoethyl radical, optionally bearing one to four 1-6C alkyl substituents, or a 2-6C alkanoyl, halogenoalkanoyl, alkanoyloxy, alkanoylamino, dialkylcarbamoyl or alkoxycarbonyl radical; R2 and R3, which may be the same or different, are each a hydrogen atom, a 1-6C alkyl, dueterioalkyl or halogenoalkyl radical, or a phenyl or phenyl(1-6C alkyl) radical, in each of which the phenyl may optionally bear one or more substituents; or R2 and R3, together with the carbon atom to which they are attached, may form a 3- to 6-membered ring; or R1R2R3C- is a 1,1-dicyanoethyl or trifluoromethylsulphonyl radical; R4 is a hydrogen or halogen atom, a cyano or nitro radical or a 1-6C alkyl or halogenoalkyl radical; R5 has any of the values defined above for the group R1R2R3C but is not necessarily the same as R1R2R3C, or has any of the values defined above for R4 but is not necesarily the same as R4, or is a carbamoyl, 1-pyrrolidinyl-carbonyl, piperidinocarbonyl, morpholinocarbonyl or nitro radical, a 1-6C alkoxy or halogenoalkoxy radical or a 2-6C alkanoyl or alkoxy-carbonyl radical; A is a methylene or ethylene radical optionally bearing one or more substituents selected from deuterium and halogen atoms, carbamoyl, cyano and hydroxy radicals, 1-6C alkyl and alkoxy radicals, and 2-6C alkanoyloxy radicals provided that when A is linked to R6 through a nitrogen atom thereof, it may not bear a hydroxy, alkoxy or alkanoyloxy substituent on the carbon atom adjacent to such nitrogen atoms; and R6 is a 1+E,uns H+EE -1,2,4-triazol-1-yl, 4+E,uns H+EE -1,2,4-triazol-4-yl, 1+E,uns H+EE -imidazol-1-yl, 5-cyano-1+E,uns H+EE -imidazol-1-yl, 3-pyridyl or 5-pyrimidinyl radical, or a 1+E,uns H+EE -imidazol-1-yl radical, bearing at the 5-position thereof a 1-6C alkyl substituent which is itself optionally substituted by one or more carbamoyl, cyano, hydroxy or 2-6C alkoxycarbonyl radicals; and provided that when R2, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is a 3-pyridyl radical, R1 is not a cyano, hydroxy or hydroxymethyl radical, and when R1 is a hydroxy radical, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is 3-pyridyl, R2 is not a methyl or a 2-chloro-1-methylethyl radical, and provided that when R1 is a methoxycarbonyl radical, R2, R3, R4 and R5 are hydrogen and A is a methylene radical, R1 is not a 1+E,uns H+EE -imidazol-1-yl radical; and the pharmaceutically acceptable acid addition salts thereof. |
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Patent landscape, scope, and claims: |
United States RE36617: Scope, Claims, and US Patent Landscape for (Substituted-aralkyl)heterocyclic Triazole/Nitrile Series
Summary. US RE36617 is a reissue of an earlier US patent family member claiming a very broad genus of (substituted-aralkyl)heterocyclic compounds built around a 1,2,4-triazole (1H-1,2,4-triazol-1-yl or 4H-1,2,4-triazol-4-yl) linked via a defined A bridge (methylene/ethylene/alkylidene variants) to a substituted aryl/nitrile framework. The reissue then narrows to specific stereochemical and isotopic exemplars and provides composition and method claims for steroid hormone-dependent tumours. Claim 7 and the dependent set cover two deuterated variants and at least one non-deuterated core structure, which function as the practical “anchor” of enforcement in the US.
What is the claim architecture of US RE36617?
The reissue contains a layered structure:
1) Genus compound claim (Claim 1) with extensive definition of substituents R1-R6 and the bridging unit A, plus pharmaceutically acceptable acid addition salts.
2) Subset/embodiment claims (Claims 2-6) that restrict substituent types (particularly R1/R2/R3/R4/R5 and the allowed bridge A variants).
3) Explicit physical salt claim (Claim 3) and a further restricted structural claim set (Claim 4).
4) A narrow selection claim (Claim 7) listing multiple specific compounds (including deuterated members).
5) Downstream use claims: composition (Claim 8) and treatment method for steroid hormone-dependent tumours (Claim 9).
6) Claim duplication for the specific compounds (Claims 10-16), creating multiple enforceable hooks for each listed structure.
What does Claim 1 cover (genus scope)?
Claim 1 defines a compound “of the formula I” with a highly parameterized substitution pattern:
Core heterocycle / linkage
- R6: 1H-1,2,4-triazol-1-yl or 4H-1,2,4-triazol-4-yl
- A bridge: methylene or ethylene optionally bearing substituents including:
- deuterium, halogen
- carbamoyl, cyano, hydroxy
- 1-6C alkyl and alkoxy
- 2-6C alkanoyloxy
- Proviso when A links to R6 through nitrogen: A may not bear hydroxy/alkoxy/alkanoyloxy substituent on the carbon atom adjacent to such nitrogen.
Substituent set on aralkyl/aryl side
Salt coverage
- Claim 1 expressly covers “pharmaceutically acceptable acid addition salts thereof.”
Practical read across
Claim 1 is a broad genus around:
- triazole-containing aralkyl heterocycle
- tunable acyl/alkoxy/thio/sulfonyl/cyano/hydroxy/nitro functionalities
- deuteration permitted via deuterioalkyl and optional deuterium substituents on A and in other substituent definitions.
How do Claims 2-6 narrow the genus?
Claim 2 (specificization of substituent pools)
Claim 2 substantially enumerates substituent choices for:
- R1: expands into a long explicit list including:
- hydroxymethyl, 1-hydroxyethyl and multiple hydroxyalkyl stereoisomers
- methoxy/ethoxy/propoxy/butoxy/isobutoxy/sec-butoxy/tert-butoxy
- many thio variants (methylthio through hexylthio, neopentylthio etc.)
- many sulphinyl and sulphonyl variants (methylsulphinyl through hexylsulphonyl)
- acyl classes including acetyl, butyryl, pivaloyl, and multiple fluorinated/chloroacyl variants
- multiple acyl-oxy and amide classes (acetamido, propionamido, etc.)
- alkoxycarbonyl classes (methoxycarbonyl through pentyloxycarbonyl)
- R2 and R3: explicitly limited to methyl/ethyl/propyl/isopropyl/butyl/isobutyl/sec-butyl/tert-butyl/pentyl/neopentyl/hexyl, plus trideuteriomethyl and specified haloalkyl variants.
- R4: hydrogen or cyano/nitro or 1-6C alkyl / halogenoalkyl.
- R5: includes alkoxy/alkanoyl/alkoxycarbonyl and also explicit halogen substitution lists (fluoro/chloro/bromo/iodo; chloromethoxy; fluoromethoxy; bromomethoxy; iodomethoxy; multi-fluoro/chloroalkoxy variants).
- A: enumerates bridge variants:
- ethylidene, propylidene, butylidene
- methylethylene and dimethylethylene variants
- dideuteriomethylene, difluoromethylene, hydroxymethylene, cyanomethylene
- carbamoylmethylene
- plus 1-hydroxyethylene with specific connectivity: “C-1 linked to the benzene ring.”
Claim 3 (salt list)
Claim 3 specifies salts:
- hydrochloride, hydrobromide, sulphate, nitrate, phosphate, toluene-p-sulphonate.
Claim 4 (further narrowed substituents; R6 and bridge restrictions)
Claim 4 restricts:
- R1: carbamoyl, cyano, hydroxy, 1-hydroxyethyl, methylthio, methylsulphinyl, methylsulphonyl, acetyl.
- R2/R3: methyl, ethyl, trideuteriomethyl, or fluoromethyl.
- R4: hydrogen, fluorine, bromine, or cyano/nitro/isopropyl/chloromethyl.
- R5: limited to defined radicals including:
- 1-cyano-1-methylethyl, 1,1-dimethyl-2-oxopropyl (and multiple related deuterated/cyano-fluoro variants),
- carbamoyl-related radicals,
- 1-piperidinocarbonyl, 1-morpholinocarbonyl, acetyl, methoxycarbonyl.
- A: restricted to methylene/ethylene plus selected alkylidene and deuterated/difluorinated and hydroxymethylene/cyanomethylene/fluoromethylene/difluoromethylene variants, plus “1-hydroxyethylene” with required bonding to the benzene ring.
- R6: explicitly 1H-1,2,4-triazol-1-yl or 4H-1,2,4-triazol-4-yl.
Claim 5 (cyano-specific R1/R6 anchor)
Claim 5 sets:
- R1 = cyano
- R5 = radical of formula “R1R2R3C” where:
- R1 in that group is cyano or hydroxy
- R6 = 1H-1,2,4-triazol-1-yl
Claim 6 (deuteration constrained)
Claim 6 narrows:
- in group “R1R2R3C” and in R5:
- R2 and R3 both are methyl or trideuteriomethyl
- A limited to methylene or dideuteriomethylene.
Which specific compounds are protected in Claim 7 and onward?
Claim 7 is the enforceable “selection” claim listing the concrete structures. It states the compounds are selected from:
- 2,2’-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile)
- 2,2’-[5-dideuterio(1H-1,2,4-triazol-1-yl)-methyl-1,3-phenylene]di(2-trideuteriomethyl-3,3,3-trideuteriopropiononitrile)
- 2,2’-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylpropiononitrile)
Claim 7 also includes pharmaceutically acceptable acid addition salts of the selected compounds.
Downstream claim repetition
- Claim 10: explicitly claims the non-deuterated structure:
- 2,2’-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile)
- Claim 13: explicitly claims the fully deuterated variant:
- 2,2’-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-trideuteriomethyl-3,3,3-trideuteriopropiononitrile)
- Claim 14: explicitly claims the partially deuterated variant:
- 2,2’-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylpropiononitrile)
- Claim 16: a further selection claim bundling the three specific compounds by name (same set as Claim 7).
What do the composition and method claims cover?
Claim 8 (composition of a claimed compound)
A pharmaceutical or veterinary composition comprising:
- an effective amount of a compound as claimed in Claim 7
- plus a pharmaceutically or veterinarly acceptable diluent or carrier
Claim 9 (method of treating steroid hormone-dependent tumours)
A method of treating steroid hormone-dependent tumours comprising:
- administering to a host in need such treatment
- an effective amount of a compound as claimed in Claim 7.
Claim 12 and Claim 11 alignment
- Claim 11: composition of Claim 8 where the compound is the non-deuterated member from Claim 10.
- Claim 12: method of Claim 9 where the compound is the non-deuterated member from Claim 10.
Salt claim for selected compounds
- Claim 15: salts for the structure from Claim 7:
- hydrocholoride, hydrobromide, sulphate, nitrate, phosphate, toluene-p-sulphonate.
Scope map: what is clearly within and outside the claim boundaries?
Within
Based on the express formula parameterization and enumerations, the claim set clearly covers:
- Triazole core: both 1H-1,2,4-triazol-1-yl and 4H-1,2,4-triazol-4-yl at R6 in the broad/genus form, with later dependent narrowing to 1H-1,2,4-triazol-1-yl (Claims 5-6).
- A bridge flexibility in genus: methylene/ethylene with optional deuterium/halogen/cyano/hydroxy/carbamoyl/alkyl/alkoxy and alkanoyloxy, subject to the adjacency proviso when linked via nitrogen.
- Deuteration: explicitly allowed via deuterioalkyl and named dideuteriomethylene bridge variants and dideuterio/trideuterio compound names in Claim 7.
- Extensive functional-group tolerance: cyano, hydroxy, nitro, azido; alkoxy; thio and sulfinyl/sulphonyl; a wide range of acyl and acyloxy/amide/alkoxycarbonyl types.
Likely outside (as a practical claim boundary)
The patent text provided restricts several key structural variables:
- R6 type limited to the listed triazole ring substituents.
- A definition limited to the specific bridge classes (methylene/ethylene and their alkylidene equivalents as enumerated).
- For the specific selection claim, the structures listed in Claim 7 are narrow and must match their exact substitution and isotopic pattern.
US patent landscape: what does this imply for freedom-to-operate?
Enforceable nodes
In the US, the practical landscape for RE36617 enforcement centers on three layers:
- Genus claim 1: large chemical space coverage, but still tethered to the formula I and the permitted R-group definitions.
- Subset constraints (Claims 2-6): narrower enumerations that may still capture many competitors’ analogs if they keep the same scaffold and substitution types.
- Selection and explicit exemplars (Claims 7, 10, 13-16): direct coverage of three named deuterated/non-deuterated compounds, plus salts, plus formulation and steroid hormone-dependent tumour treatment.
Competitive impact of deuterated members
The inclusion of:
- dideuterio at the triazole-related position(s) and
- trideuteriomethyl/3,3,3-trideuterio propionitrile variants
creates a pattern in which even close analogs that differ in isotopic labeling can still be outside Claim 7, but may still be inside the broader genus if they fall within the R1-R5-A parameterized definitions that allow deuterio substituents.
Salt and formulation coverage
Even if a competitor avoids the free base, Claim 3 and Claim 15 capture common pharmaceutically acceptable acid addition salts. Claim 8 and the dependent composition claims extend coverage into formulation.
Method-of-use leverage
Claim 9 adds a separate, enforceable axis for products using these compounds to treat steroid hormone-dependent tumours.
What are the “scope pressure points” for chemical design-around?
From the text provided, design-around pressure points map to the variables that are repeatedly constrained as claims narrow:
- R6 triazole identity (must remain 1H-1,2,4-triazol-1-yl or 4H-1,2,4-triazol-4-yl; later 1H-1,2,4-triazol-1-yl).
- Bridge A (methylene/ethylene and enumerated alkylidene variants; deuterated methylene variants appear in later restrictions).
- R1 functional group set:
- broad: cyano/hydroxy/nitro/acyl/thio/sulfonyl etc.
- narrow: explicitly cyano in Claim 5.
- Deuteration pattern for the explicit selection members in Claim 7.
Key Takeaways
- US RE36617 has a broad genus (Claim 1) built around a 1,2,4-triazole (R6) and defined bridge A, with extensive permissible substitutions across R1-R5 and explicit allowance for deuteration.
- The reissue becomes operationally enforceable through three named compounds in Claim 7 (and mirrored by Claims 10, 13, 14, 16), including non-deuterated and deuterated nitrile-containing variants.
- Protection extends beyond chemistry into:
- salts (Claim 3 and Claim 15),
- compositions/formulations (Claim 8 and dependent claims),
- and a method of treating steroid hormone-dependent tumours (Claim 9 and dependent claim 12).
- For FTO, the landscape is best analyzed by checking whether a candidate product’s structure matches the listed selection compounds (hard stop), and if not, whether it still lands inside the formula I parameter ranges that allow similar substitution types and deuteration.
FAQs
1. Is Claim 1 broad enough to cover unrelated triazole linkages?
No. Claim 1 requires the specific R6 triazole substituent type and a defined bridge A (methylene/ethylene with enumerated optional substitutions) within formula I.
2. Which claims most directly protect the specific deuterated products?
Claim 7 is the selection claim listing the deuterated and non-deuterated compounds; Claims 10, 13, 14, and 16 separately track each specific member or the bundled set.
3. Does RE36617 protect formulations?
Yes. Claim 8 covers pharmaceutical or veterinary compositions containing an effective amount of a Claim 7 compound plus an acceptable diluent/carrier.
4. Does the patent cover treatment use for cancer?
Yes. Claim 9 claims a method of treating steroid hormone-dependent tumours by administering an effective amount of a Claim 7 compound.
5. What salt forms are expressly covered?
Expressly listed salts include hydrochloride, hydrobromide, sulphate, nitrate, phosphate, and toluene-p-sulphonate (Claims 3 and 15).
References
[1] US Patent RE36617 (reissue) claim set as provided in the prompt text.
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