Details for Patent: 6,002,008

Summary for Patent: 6,002,008

Title:	Substituted 3-cyano quinolines
Abstract:	This invention provides compounds having the formula: ##STR1## wherein: X is cycloalkyl which may be optionally substituted; or is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally substituted;n is 0-1;Y is --NH--, --O--, --S--, or --NR--;R is alkyl of 1-6 carbon atoms;R1, R2, R3, and R4 are each, independently, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, hydroxymethyl, halomethyl, alkanoyloxy, alkenoyloxy, alkynoyloxy, alkanoyloxymethyl, alkenoyloxymethyl, alkynoyloxymethyl, alkoxymethyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy, carboalkyl, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino, alkylamino, dialkylamino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, phenylamino, benzylamino, ##STR2## R5 is alkyl which may be optionally substituted, or phenyl which may be optionally substituted;R6 is hydrogen, alkyl, or alkenyl;R7 is chloro or bromoR8 is hydrogen, alkyl, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, N-cycloalkylaminoalkyl, N-cycloalkyl-N-alkylaminoalkyl, N,N-dicycloalkylaminoalkyl, morpholino-N-alkyl, piperidino-N-alkyl, N-alkyl-piperidino-N-alkyl, azacycloalkyl-N-alkyl, hydroxyalkyl, alkoxyalkyl, carboxy, carboalkoxy, phenyl, carboalkyl+, chloro, fluoro, or bromo;Z is amino, hydroxy, alkoxy, alkylamino, dialkylamino, morpholino, piperazino, N-alkylpiperazino, or pyrrolidino;m=1-4,q=1-3, and p=0-3;any of the substituents R1, R2, R3, or R4 that are located on contiguous carbon atoms can together be the divalent radical --O--C(R8)2 --O--;or a pharmaceutically acceptable salt thereof with the proviso that when Y is --NH--, R1, R2, R3, and R4 are hydrogen, and n is 0, X is not 2-methylphenyl, which are inhibitors of protein tyrosine kinase.
Inventor(s):	Allan Wissner, Bernard D. Johnson, Marvin F. Reich, Middleton B. Floyd, Jr., Douglas B. Kitchen, Hwei-Ru Tsou
Assignee:	Wyeth Holdings LLC
Application Number:	US09/049,718
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 6,002,008: What the Claims Cover, What They Exclude, and Where the Landscape Tightens

US Patent 6,002,008 is a broad genus patent for substituted quinoline-3-carbonitrile (and closely related) compounds, with downstream claim coverage that extends from the compounds themselves into methods of treating cancers tied to kinase deregulation and into polycystic kidney disease (PKD), plus standard pharmaceutical composition language. Claim 1 is the operative scope driver: it recites a large, functionally diverse chemical space through a layered formula definition and extensive substitution variables, then narrows with a small number of explicit provisos/limitations.

What is claimed in Claim 1 (core genus)

Claim 1 is a “compound of the formula” genus with variable substituents and linkages:

• Core scaffold variables

  • X:
  • cycloalkyl (C3 to C7), optionally substituted with alkyl (C1 to C6), or
  • pyridinyl / pyrimidinyl / phenyl, optionally di- or tri-substituted (within the allowed substituent set)
  • n: 0 to 1
  • Y: --NH--, --O--, --S--, or --NR--
  • R: alkyl C1 to C6
  • R1, R2, R3, R4: each independently selected from a long list of allowed substituents (hydrocarbons, heteroatom-rich groups, halo, cyano, nitro, carboxy, protected forms, amino derivatives, sulfonamide/sulfone-like groups, etc.)
  • R5: alkyl C1 to C6 (optionally halogenated), phenyl (optionally halogenated), or phenyl/alkoxy/cyano/trifluoromethyl/amino/nitro substituted phenyl-type options
  • R6: hydrogen, alkyl C1 to C6, or alkenyl C2 to C6
  • R7: chloro or bromo
  • R8: hydrogen or substituted amine substituents including multiple dialkylamino/piperazine/morpholine-like variants
  • Z: amino, hydroxy, alkoxy (C1 to C6), alkylamino (C1 to C6), dialkylamino (each C1 to C6), morpholino, piperazino, N-alkylpiperazino, or pyrrolidino
  • p, m, q:
  • m = 1 to 4
  • q = 1 to 3
  • p = 0 to 3 (as written in the claim set)
  • Contiguous carbon substitution option: “any two of R1, R2, R3, R4 located on contiguous carbon atoms can together be the divalent radical --O--C(R8)2--O--”
    This is a key structural “escape hatch” that allows an O-bridged motif rather than two independent substituents.

• Compound class closure

  • “or a pharmaceutically acceptable salt thereof”
  • The claim is framed as a genus, not a single molecule.

What Claim 1 explicitly excludes (proviso stack)

Two provisos meaningfully narrow the broad genus:

1. When Y is --NH--, then
   • R1 = R2 = R3 = R4 = hydrogen
   • n = 0
   • X is not 2-methylphenyl
2. “R3 ≠ Cl”

These provisos operate like hard gating conditions. In practical scope terms:

• If the chemotype sets Y = amide-like (--NH--), the claim collapses many substituent degrees of freedom: it forces hydrogen at R1-R4 and sets n to 0, which sharply reduces the “covered space” for that Y-branch.
• Independently, across the whole claim, R3 cannot be chloro.

How the dependent claims scale the scope (Claim 2 to 20+)

Dependent claims add specific slices of the genus:

• Claim 2: fixes Y = --NH-- and n = 0 (or salt). This is consistent with the proviso requirement for Y = --NH-- in Claim 1.
• Claim 3 to 4: narrow X to optionally substituted phenyl and then set R1 and R4 to hydrogen (or salt).
• Claims 5 to 20: enumerate large sets of specific compounds (a dense “list” claim family). Each entry is a specific instantiation of the variables from Claim 1.

This structure signals two strategic goals:

1. Genus capture: Claim 1 can read on many unlisted analogs by formula construction.
2. Fallback to enumerated embodiments: the enumerated compounds provide definitional anchors that can support validity and enforcement narratives, particularly if novelty/enablement issues arise for the very broad genus.

What the claim set covers beyond chemistry (methods and compositions)

Methods: kinase deregulation and neoplasms

• Claim 21: method of inhibiting biological effects of a deregulated protein kinase in a mammal via administering an effective amount of a compound of the genus formula.
• Claims 22 to 27: treating/inhibiting/eradicating neoplasms with additional dependent specifiers:
  • Claim 23: neoplasm expresses EGFR
  • Claim 24: expresses MAPK
  • Claim 25: expresses ECK
  • Claim 26: expresses KDR
  • Claim 27: neoplasm site list: breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, lung.

These provide broad therapeutic coverage while tying it to a kinase target framework.

PKD

• Claim 28: method of treating/inhibiting progression/eradicating polycystic kidney disease with administration of the genus compounds.

Pharmaceutical composition

• Claim 29: a composition comprising:
  • the genus compound plus a pharmaceutically acceptable carrier.

The “real” scope leverage: what variables drive coverage density

The broadest enforcement risk and freedom to design around is driven by which parts of Claim 1 retain combinatorial freedom.

Highest degrees of freedom (most design space under the claim)

• Aryl/heteroaryl substitution on X

  • X is a cycloalkyl C3-C7 option, or pyridinyl/pyrimidinyl/phenyl.
  • The aryl substituent set is extensive and includes many medicinal chemistry knobs: halogen, alkyl, alkenyl/alkynyl, azido, hydroxyalkyl, alkoxymethyl, alkylthio, trifluoromethyl, cyano, nitro, carboxy/carboalkoxy, and large amino/protected-amino classes.

• R1-R4 independently

  • R1-R4 can be selected from an extremely broad substituent list.
  • This alone gives the claim an enormous analog space even with the R3 ≠ Cl rule and the Y = --NH-- collapse.

• R8-linked amine branch

  • R8 is defined to allow a wide range of amine substituents including aminoalkyl, N-alkylaminoalkyl, dialkylaminoalkyl, cycloalkylaminoalkyl, morpholino-N-alkyl, piperidino-N-alkyl, azacycloalkyl-N-alkyl, hydroxyalkyl, alkoxyalkyl, carboxy-like, chloro/fluoro/bromo substituted aryl.

• Z selection

  • Z gives additional heteroatom content: amino, hydroxy, alkoxy, dialkylamino, morpholino/piperazino/pyrrolidino.

Lowest degrees of freedom / hard constraints

• Y = --NH-- branch is constrained
  • It forces hydrogen at R1-R4, n = 0, and X cannot be 2-methylphenyl.
• R7 is only chloro or bromo
• R3 cannot be chloro
• m/q/p are bounded
  • m: 1-4
  • q: 1-3
  • p: 0-3

In enforcement terms, R3 ≠ Cl and the Y-branch proviso are the two clear “safe harbor” candidates for design-around hypotheses.

Claim coverage is reinforced by enumerated exemplars (Claims 5 to 20, and 15 to 18 in particular)

Claims 5 to 20 list a large set of specific compounds that satisfy Claim 1. Two patterns stand out:

1. Repeated quinoline-3-carbonitrile / substituted phenylamino linkage

   • Many entries are of the form “4-(aryl-amino)-...-quinolinecarbonitrile” with varied aryl halogenation and ring substituents like methoxy/ethoxy and nitro or halogens.

2. Common modulation at the “alkoxy” positions

   • Several entries include 6,7-dimethoxy, 6,7-diethoxy, 7-methoxy, and 6-methoxy-7-(alkoxyalkyl) motifs.

3. Amide/acrylamide/butenamide and propenamide variants

   • A number of enumerated compounds are named as but-2-enoic acid amides and chloro- or bromo-substituted acrylamide/propenamide forms.
   • Claim 1 includes Y = --NH-- and --NR-- branches, and the enumerations demonstrate the builders intended to lock on to electrophilic/acrylamide-like warheads and Michael acceptor behavior via allowed variable combinations.

Practical “patent landscape” reading (without relying on external filings)

Even without external patent citations, the structure of Claim 1 and the dependent claim strategy supports a landscape conclusion:

• Breadth is high because Claim 1 is a genus with many independent substitution variables and a very large allowed substituent list.
• Breadth is not infinite because of:
  • two Y-branch collapse conditions (when Y = --NH--),
  • R3 ≠ Cl, and
  • discrete constraints on R7 (only chloro/bromo) and on the parameter ranges (m, q, p).
• Defensibility is supported by extensive embodiment lists in dependent claims (5, 6, 7, 8, 9, … up to 20) that give the patent a factual basis that the genus is not purely speculative.

Scope map: what a competitor must change to step outside Claim 1 (high-level)

Using only the claim language provided, the design-around levers are:

Lever A: break the “R3 is chloro” restriction

• Since Claim 1 states R3 ≠ Cl, any candidate that maps to a structure where the group occupying R3 equals Cl would fall outside the claim (subject to correct structural interpretation of what “R3” corresponds to in the formula depiction).

Lever B: avoid the Y = --NH-- collapse pattern

• If the candidate forces Y into the --NH-- category, then the claim requires:
  • n = 0,
  • X is not 2-methylphenyl,
  • R1-R4 must all be hydrogen,
  • and still R3 ≠ Cl.
• Any deviation from these conditions should reduce or eliminate coverage for the Y = --NH-- branch.

Lever C: alter R7 away from chloro/bromo

• Claim 1 hard-limits R7 to chloro or bromo.
• A candidate where R7 is not Cl or Br would not satisfy Claim 1.

Lever D: alter m/q/p or the contiguous O-bridged option

• If a candidate’s ring/linkage parameters do not fall within the bounded ranges (m = 1-4; q = 1-3; p = 0-3) or cannot realize the contiguous substitution mapping, it would fail the formula.

Enforcement posture: what claims are strongest for infringement arguments

• Claim 1 is strongest for read-across enforcement because it is a genus tied to the formula and substitution logic.
• Dependent claim slices (2-4) are strongest when the accused product uses the specific constrained sub-branch (notably Y = --NH--, n = 0).
• Enumerated compound claims (5-20) are strong fallback targets because they remove ambiguity for specific structures and offer multiple independent infringement hooks across different analogs.

Key Takeaways

• Claim 1 defines a large genus of substituted quinoline-3-carbonitrile-type compounds using many independent substitution variables (X, Y, R1-R4, R5-R8, m/q/p, Z).
• The claim has two major narrowing provisos: when Y = --NH--, it forces n = 0, R1-R4 = H, and X ≠ 2-methylphenyl; and it globally requires R3 ≠ Cl.
• Claim 1 also hard-limits R7 to chloro or bromo, and bounds m/q/p ranges.
• The patent escalates coverage from compounds (Claim 1 and enumerated dependents 5-20) into methods (kinase deregulation and neoplasms with EGFR/MAPK/ECK/KDR-specific dependents) and into PKD (Claim 28) and pharmaceutical compositions (Claim 29).
• The dependent “embodiment lists” create multiple enforcement-ready anchors that complement the broad genus definition.

FAQs

1) Is Claim 1 written to cover only the listed examples or a broader set?
It is written as a broader genus. The list in Claims 5-20 are specific embodiments that fall within Claim 1’s formula and substitution variables.

2) What is the single clearest absolute exclusion in Claim 1?
The claim states R3 ≠ Cl.

3) How does Claim 1 treat the Y = --NH-- scenario?
When Y = --NH--, it imposes multiple constraints simultaneously: R1-R4 are hydrogen, n = 0, and X is not 2-methylphenyl.

4) Does the patent include method-of-use coverage beyond cancer?
Yes. It includes polycystic kidney disease treatment/inhibition/eradication via administration of the genus compounds (Claim 28).

5) Which claim elements most affect design-around efforts based on the text alone?
The biggest levers are R7 (must be chloro/bromo), R3 (cannot be chloro), and the Y = --NH-- branch collapsing constraints that restrict n, R1-R4, and X.

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References

1. United States Patent 6,002,008, “Compounds and methods for inhibiting protein kinases and treating diseases,” claims 1-29 (text as provided in prompt).

Drugs Protected by US Patent 6,002,008

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